AU657267B2 - Polyurethane or polyurethane-urea elastomeric compositions - Google Patents

Description

OPI DATE 23/01/92 AOJP DATE 27/02/92 APPLN. ID 80065 91 PCT NUMBER PCT/AU91/00270 INTERNATI. REATY(PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 92/00338 C08G 18/48, A61L 27/00, 29/00 Al A61L 31/00 (43) International Publication Date: 9 January 1992 (09.01.92) (21) International Application Number: PCT/AU91/00270 (74) Agents: CORBETT, Terence, G. et al.; Davies Collison, 1 Little Collins Street, Melbourne, VIC 3000 (AU).

(22) International Filing Date: 26 June 1991 (26.06.91) (81) Designated States: AT (European patent), AU, BE (Euro- Priority data: pean patent), CH (European patent), DE (European pa- PK 0817 26 June 1990 (26.06.90) AU tent), DK (European patent), ES (European patent), FR (European patent), GB (European patent), GR (European patent), IT (European patent), JP, LU (European (71) Applicants (for all designated States except US): COMMON- patent), NL (European patent), SE (European patent), WEALTH SCIENTIFIC AND INDUSTRIAL RE- US.

SEARCH ORGANISATION [AU/AU]; Limestone Avenue, Campbell, ACT 2601 UNISEARCH LI- MITED [AU/AU]; 221-227 Anzac Parade, Kensington, Published NSW 2033 With international search report.

(72) Inventors; and Inventors/Applicants (for US only) MEIJS, Gordon, Francis [AU/AU]; 3 Henty Street, Murrumbeena, VIC 3163 RIZZARDO, Ezio [AU/AU]; 26 Alex Avenue, Wheelers Hill, VIC 3150 BRANDWOOD, Arthur [GB/AU]; 91 Garden Street, Alexandra, NSW 2015 6 GUNATILLAKE, Pathiraja [LK/AU]; I Conrad Place, Mulgrave, VIC 3170 SCHINDHELM, Klaus, Henry [AU/AU]; 72 Francis Greenway Drive, Cherrybrook, NSW 2126 (AU).

(54)Title: POLYURETHANE OR POLYURETHANE-UREA ELASTOMERIC COMPOSITIONS (57) Abstract A polyurethane or polyurethane-urea elastomeric composition, characterized in that the composition is a reaction product of: a soft segment macrodiol which is either: a homopolymer represented by formula HO-[(CH2)nO]m-H, wherein n represents an integer greater than 5 and less than 13, m is a number such that the number average molecular weight of the compound of formula falls in the range from 218 to 5000 and optionally at least one hydrogen atom represented in formula is substituted by a CI to C 3 alkyl group or a halogen atom; (ii) a copolymer containing at least 25 by mass of repeating units -(CH2)nO- wherein n is as defined in formula above; or (iii) mixture of macrodiols comprising greater than of a macrodiol as defined in formula above; an aliphatic or aromatic diisocyanate known in the art of polyurethane manufacture; and optionally a chain extender. A biomaterial and a medical device which are composed wholly or partly of the polyurethane or polyurethane-urea elastomeric composition are also described.

WO 92/00338 PCr/AU91/00270 -1- POLYURETHANE OR POLYURETHANE-UREA ELASTOMERIC COMPOSITIONS The invention relates to polyurethane or polyurethane-urea elastomeric compositions which are particularly suitable for use in devices that contact living tissue or bodily fluids.

The applications of polyurethane elastomers are limited by their susceptibility to degradation, particularly hydrolysis and oxidation. For example, degradation problems have arisen with artificial leathers, shoe soles and cable sheathing. This problem has been partially overcome by the use of polyether macrodiols. The problem is particularly acute in biomedical applications where because of their good mechanical performance high tensile strength, good tear and abrasion resistance), inherent biocompatibility and nonthrombogenicity, polyurethanes are the materials of choice for many applications and have found use in pacemakers leads, various types of catheters, implantable prostheses, cardiac assist devices, heart valves, sutures, and vascular grafts, as well as in extra-corporeal blood contacting applications.

Polyurethane elastomers are usually prepared by reacting excess diisocyanate with a polyol "soft segment" to form a prepolymer having terminally reactive isocyanate groups, which is then reacted with a diol or diamine chain extender. Although the diisocyanate plays an important role, many of the properties associated with the polyurethane elastomer are derived from the soft segment portion of the chain. The soft segments of most commercial polyurethane elastomers are derived from polyether macrodiols, for example poly(ethylene oxide), poly(propylene oxide) and oo C.r o c' o\;S poly(tetramethylene oxide) and polyester.(poly(ethyene adipate) and polycaprolactone glycols. Polyurethanes that have polyether soft segments have better resistance to hydrolysis than those with polyester soft segments and are preferred as biomaterials. The most widely accepted commercial medical-grade "J WO 92/00338 PCT/AU91/00270 -2polyurethanes are Pellethane (Registered Trade Mark) and Biomer (Registered Trade Mark), although Tecoflex (Registered Trade Mark), Vialon (Registered Trade Mark) and Mitrathane (Registered Trade Mark) have found some acceptance. These materials all have in common the use of poly(tetramethylene oxide) as the macrodiol soft segment. S. Gogolewski in Colloid and Polymer Science, volume 267, pp 757-785 (1989) summarizes the prior art commercial and experimental biomedical polyurethanes which have been disclosed. There are no reports of biomedical polyurethanes having the composition described below.

The biostability of polyurethanes is reviewed by Michael Szycher, a recognized leader in the field, in Journal of Biomaterials Applications, volume 3, pp 297-402 (October, 1988). Degradation can be manifested in terms of surface or deep cracking, stiffening, erosion, or the deterioration of mechanical properties, such as flex life. The deterioration ultimately leads to failure of the device. Degradation can also cause the leaching of cytotoxic agents, resulting in tissue necrosis or in some cases, the formation of tumors. The inadequate biostability of polyurethanes is generally recognised as a severe limitation to the successful development of long term artificial hearts and synthetic polyurethane small bore vascular grafts.

The biologically-induced degradation of polyurethanes has been attributed to several factors and some of these are summarized in the review by Michael Szycher cited above. Although there is still some controversy, it is widely held that the following mechanisms of degradation are important: a) environmental stress cracking; b) oxidation; c) hydrolysis; d) calcification; and e) other metal ion promoted degradation silver, cobalt).

Other agents fungi) have also been implicated by some workers. Of -3these degradative pathways, environmental stress cracking is arguably the most complex and depends on a combination of a chemical agent and either residual internal stress from processing), or externally applied stress from flexing of an implant during use). Calcification has been reviewed by R. J. Thoma and coworkers in Journal of Biomaterials Applications, volume 3, pp 180-206 (October, 1988) and is a problem in certain applications, such as in the artificial heart and in heart valve replacements. The soft segment has been implicated as a site of initial complexation with metal ions.

The present invention provides a polyurethane or polyurethane-urea elastomeric composition which has improved durability in hostile environments, particularly as a biomaterial. More specifically, the composition of tie invention displays a surprisingly enhanced resistance to in vivo degradation, oxidation and hydrolysis while maintaining good mechanical properties and blood and tissue compatability making the composition suitable for the construction of medical devices, implants and extra corporeal devices as discussed above. The biostability of the composition of the invention is greater than that of the commercially accepted polyurethanes Pellethane 2363-80A (Registered Trade SMark) and Biomer (Registered Trade Mark). Such improvements are a consequence of the actual polyurethane or polyurethane-urea elastomer composition itself, integral to which is the inclusion of a soft segment defined below.

t I The polyurethane or polyurethane-urea elastomeric composition of the invention may be used as a biomaterial. The te-m "biomaterial" as used herein refers to a material which is used in situations where it comes into intimate contact with the cells and body fluids of living animals or humans.

According to the present invention there is provided use of a polyurethane or polyurethane-urea elastomeric composition which comprises a reaction product of: a soft segment macrodiol which is either: 941222,popedab80065.s,3 94 1222,p:\opcdab80065.spc,3 -4a homopolymer represented by formula I, HO-[(CH2)nO]m-H

I

wherein n represents an integer greater than 5 and less than 13, m is a number such that the number average molecular weight of the compound of formula I falls in the range from 218 to 5000 and optionally at least one hydrogen atom represented in formula I is substituted by a C 1 to C 3 alkyl group or a halogen atom; (ii) a copolymer containing at least 25% by mass of repeating units -(CH2)nO- wherein n is as defined in formula I above; or (iii) mixture of macrodiols comprising greater than 10% of a macrodiol as defined in formula I above; an aliphatic or aromatic diisocyanate known in the art of polyurethane Smanufacture; and optionally a chain extender as a degradation resistant material.

Further according to the present invention there is provided a polyurethane or polyurethane-urea elastomeric composition as defined above.

Preferably, the aliphatic or aromatic diisocyanate is selected from 4,4'-diphenylmethane diisocyanate (MDI), methylene bis(cyclohexyl) diisocyanate (H 12

MDI),

p-phenylene diisocyanate (p-PDI), trans-cyclohexane-l,4-diisocyanate (CHDI), 1,6-diisocyanatohexane (DICH), 2,4-toluene diisocyanate (2,4-TDI), 941222,p:\operdab,80065.spe,4 WO 92/00338 PCT/AU91/00270 c Hz OCN cO 3

CH

3 C II CH NCO and para-tetramethylxylene diisocyanate (p-TMXDI) represented by the formula III, cF3 CH OC-N-CO III The chain extender is preferably selected from 1,4-butanediol (BDO), 1,6-hexanediol (HDO), 1,2-ethylenediamine (EDA), 1,6-hexanediamine (HDA) and 1,2-propanediamine (1,2-PDA).

The composition of the invention may be prepared by any suitable known technique, using either one-step or two-step procedures. Preferably a two-step solution polymerization method is used employing solvents such as dimethyl acetamide and dimethylformamide (DMF). It will be appreciated however that one step procedures and procedures that do not employ a reaction solvent which are well known in the art are also applicable. In addition, small amounts of cross-linking ag. ats, preferably may be WO 92/00338 PCr/AU9100270 -6incorporated in the composition. Other materials, such as polysiloxanecontaining polymers or oligomers may also be blended with the composition.

In addition, the composition of the invention may optionally contain reaction catalysts, antioxidants, stabilizers and processing aids.

The soft segments may be prepared by acid catalysed condensation of the appropriate low molecular weight diol or by acid catalysed ring opening reactions of cyclic ethers. The preparation of these materials may be accomplished by the method outlined by K. Yamamoto and H. Fujita in Polymer, volume 7, pp 557-562 (1966) or by the procedure given below, in which poly(hexamethylene oxide) was prepared by the acid catalysed condensation of the corresponding monomer diol, 1,6-hexamethylene diol.

In another aspect of the present invention there is provided a biomaterial which is wholly or partly composed of the polyurethane or polyurethane-urea elastomeric composition described above.

In a further aspect of the present invention there is provided a medical device, article or implant which composed wholly or partly of the polyurethane or polyurethane-urea elastomeric composition described above.

Preferably the biomaterial, medical device, article or implant is composed of a material comprising not less than 10% of the polyurethane or polyurethane-urea elastomeric composition described above.

The medical device, ar.icle or implant may be produced by any suitable known technique, such as extrusion, solvent casting and injection molding.

WO 92/00338 PCT~AU91/00270 -7- PROCEDURE 1 1,6-Hexamethylene diol (200 g) was placed in a 500 ml round bottom flask and heated under vacuum (0.1 torr) at 100 C for 1 hour. The flask was cooled to 50 C, and fitted with a nitrogen bleed, Dean-Stark tube and a condenser. Concentrated sulphuric acid (2.2 ml) was added dropwise with stirring, and the reaction mixture was heated at 170 C for three hours under a stream of dry nitrogen. The flask was then connected to a vacuum pump, and heating continued at the same temperature under a vacuum of 0.1 torr.

Polymers with different molecular weights were obtained by varying the interval of this heating process. The sulphuric acid catalyst was removed by treating the polymerized reaction mixture with a saturated solution of calcium hydroxide. The product was further purified by recrystallization with a 70/30 mixture of ethanol and water. The solid product isolated by filtration was dried in a vacuum oven at 45 C for 48 hours. The same experimental procedure was followed for the preparation of poly(octamethylene oxide) and poly(decamethylene oxide).

The invention is further illustrated by the following non-limiting examples.

EXAMPLE 1 Poly(octamethylene oxide) was placed in a 500 ml round bottom flask and heated at 100 C under vacuum (0.1 torr) for 15 hours to remove volatiles.

The dried poly(octamethylene oxide) (MW 870) (60.67 g, 0.069 mole) was placed in a 500 ml round bottom flask, fitted with a nitrogen bleed, magnetic stirrer, condenser, and drying tube. rrTMXDI (43.59 g, 0.178 mole), DMF I.o% (105.0 and dibutyltin dilaurate (1.72 ml of aP w/v solution in toluene) were also placed in the flask and the resulting mixture was stirred at 100 C under a slow stream of dry nitrogen for 4 hours. The isocyanate content of the prepolymer solution was 3.0% as determined by ASTM method D 1638-74.

The prepolymer (191.2 g) was then diluted to 25% w/v by adding anhycdrous WO 92/00338 PCr/AU91/00270 -8- DMF and was transferred to a 1.0 L round bottom flask fitted with a nitrogen bleed, mechanical stirrer, condenser and a drying tube.

Hexamethylenediamine (7.931 g) was added as a 10% w/v solution in DMF to the reaction mixture under dry nitrogen at room temperature over a period of 15 mins. The reaction mixture was stirred at room temperature for 1 hour followed by 3 hours at 100 C. The resulting polymer solution was then diluted to 7% w/v and precipitated into deionized water The precipitated polymer was stirred in fresh deionized water for 15 hours, filtered and dried in a vacuum oven at 55 C for 72 hours. The dried polymer was melt pressed at 120 C (8 tons) into 1 mm thick sheets and tested for mechanical properties.

The results are shown in Table 1.

This material showed enhanced biostability compared with Pellethane 2363-80A (Registered Trade Mark) and Biomer (Registered Trade Mark) on subcutaneous implantation in an unstressed configuration in sheep (see Example 10 for details of that method). It also displayed good tissue compatibility as shown by examining the tissue surrounding the specimen after explant (6 months). There was a less active interface with fewer macrophages, giant cells and granulation tissue than Biomer (Registered Trade Mark) and the material gave a response similar to Tecoflex EG80A (Registered Trade Mark).

WO 92/00338 PCT/AU91/00270 -9- EXAMPLE 2 The procedure described in Example 1 was followed, except that poly(hexamethylene oxide) with a number average molecular weight of 1190 was used. The prepolymer was produced by mixing: 45.17 g (0.038 mole) of poly(hexamethylene oxide), having a number average molecular weight of 1190, with: 67.78 g of DMF; with 22.61 g(0.093 mole) of m-TMXDI; in the presence of gQ% by weight, based on the weight of of dibutyltin dilaurate.

The isocyanate content of the prepolymer was 3.35%. The prepolymer solution (57.15 g) was diluted with DMF to 25%, and chain extended with 1,6hexamethylenediamine (2.648 using the procedure in Example 1. The dried polymer was melt pressed at 160 C into 1 mm thick sheets and its mechanical properties were evaluated. The results are shown in Table 1.

EXAMPLE 3 Poly(octamethylene oxide) was placed in a 500 mL round bottom flask and heated at 100 C under vacuum (0.1 torr) for 15 hours to remove volatiles.

The dried poly(octamethylene oxide) (MW 1172, 32.51g, 0.028mole) was placed in a 100 mL addition funnel along with DMF (25.0 A 500 mL round bottom flask was fitted with a nitrogen bleed, magnetic stirrer and a condenser, and a drying tube. nrTMXDI (16.94 g, 0.069 mole), DMF (48.84 g), and dibutyltin dilaurate (0.8 ml of a 0.5% w/v solution in toluene) were placed in the flask and heated to 100 C. Poly(octamethylene oxide) solution was added to the flask over a period of 30 mins under a slow stream of dry nitrogen. Upon completion of the addition, the resulting polymer was heated for 4 hours at 100 C. The isocyanate content of the prepolymer solution was VO 92/00338 PC/AU91/00270 3.15% as determined by ASTM method D 1638-74. The prepolymer (51.07 g) was diluted to 25% by adding DvMF and placed in a 500 mL round bottom flask fitted with a nitrogen bleed, mechanical stirrer, condenser and a drying tube. Hexamethyienediamine (2.222 g) was added as a 10% solution in DMF to the reaction mixture over a period of 15 mins. The reaction mixture was stirred at room temperature for 1 hour followed by 4 hours at 100 C. The resulting polymer solution was diluted to 10% and precipitated into deionized water(4L). The precipitated polymer was stirred in fresh deionized water for hours, filtered and dried in a vacuum oven at 55 C for 72 hours. Te dried polymer was melt pressed at 120 C into 1 mm thick sheets and its mechanicla properties were evaluated. The results are shown in Table 1.

Table 1 Example 1 Example 2 Example 3 Hardness, Shore A 86 Stress at 50% elongation, MPa 4.8 4.7 Stress at 100% elongation, MPa 12.5 6.3 5.6 Stress at 300% elongation, MPa 9.1 8.3 Tensile strength, MPa 23 26 23 Elongation at break, 920 980 920 Tensile set, 40 20 Number Average MW (daltons) 68,500 94,000 47,700 Dispersity (Mw/Mn) 1.49 2.04 1.71 WO 92/00338 PCF/AU9100270 11 EXAMPLE 4 Poly(hexamethylene oxide) (number average molecular weight of 650) was placed in a 500 mL round bottom flask and heated at 100 C under vacuum (0.1 torr) for 15 hours to remove volatiles. The dried poly(hexamethylene oxide) 4 7.54g, 0.073 mole) was placed in a 250 mL addition funnel along with anhydrous N,N-dimethylformamide [DMF] (50.0 A 500 mL round bottom flask was fitted with a nitrogen bleed, magnetic stirrer, condenser, and a drying tube. 4,4'-Diphenylmethane diisocyanate (45.48 g, 0.182 mole) and DMF (45.7 g were placed in the flask and heated to 80 C. The poly(hexamethylene oxide) solution was added to the flask over a period of 30 mins under a slow stream of dry nitrogen. Upon completion of the addition, the resulting mixture was heated for 2 hours at 80 C. The isocyanate content of the prepolymer solution was 4.15% as determined by ASTM method D 1638-74. The prepolymer solution (91.75 g) was diluted to 25% w/v by adding anhydrous DMF and then placed in a 500 mL round bottom flask fitted with a nitrogen bleed, mechanical stirrer, condenser and a drying tube. The catalyst, stannous octoate (0.015% w/w of total solids in the prepolymer), was added to the prepolymer solution. Chain extension of the prepolymer was carried out by adding a 10% w/v solution of 1,4-butanediol (4.037 g) in anhydrous DMF over a period of 30 mins to the prepolymer solution under dry nitrogen at room temperature. The reaction mixture was then heated for 2 hours at 80 C. The resulting polymer solution was cooled and diluted to 7% w/v and precipitated in deionized water The precipitated polymer was stirred in fresh deionized water for 15 hours, filtered, and dried in a vacuum oven at 55 C for 72 hours. The dried polymer was melt pressed at 140 C (8 tons) into 1 mm thick sheets and its mechanical properties were evaluated. The results obtained are shown in Table 2. The polymer exhibited characteristics expected of a degradation resistant material. For example, the material exhibited good hydrolytic and oxidative stability when tested by boiling weighted dumbells for 24 hours in 2M hydrochloric acid, in 2M sodium hydroxide and in hydrogen peroxide. After washing with water and drying, the dumbells showed WO 92/00338 Pa/AU9/00270 -12a 16%,9% and 19% decrease in ultimate stress respectively, whereas the corresponding decreases for Pellethane 2363-80A (Registered Trade Mark) were 47%, 23% and 62%.

The material, when implanted subcutaneously in sheep in both strained (3 month implant) and unstrained configurations (6 month implant), displayed a greater biostablility than either Pellethane 2363-80A (Registered Trade Mark) or Biomer (Registered Trade Mark) (see Examples 10 and 11 for details of the test method). Microscopic examination of the tissue surrounding the implanted material showed a similar tissue response to that of Pellethane 2363-80A (Registered Trade Mark). The material was, however, significantly more histocompatible than Biomer (Registered Trade Mark). There was low to moderate capsule cellularity and fewer dilated capillaries. Giant cell activity was not observed and there was a smooth interface with some scattered macrophages. The material had similar haemocompatibility to Biomer (Registered Trade Mark) or Pellethane 2363-80A (Registered Trade Mark) as assayed by whole blood clotting time and platelet adhesion tests. The material was judged to be a suitable biomaterial.

WO 92/'0338 PCT/AU91/00270 -13- Table 2 Example 4 Example 5 Example 6 Hardness, Shore A 90 93 Stress at 50% elongation,MPa 9.1 8.3 Stress at 100% elongation,MPa 13.1 8.4 5.6 Stress at 300% elongation,MPa 18.3 10.8 10.5 Tensile strength, MPa 19 13 17 Elongation at break, 390 560 460 Tensile set, 30 260 32 Mn (Number Average MW) (daltons) 47,250 25,200 Dispersity (Mw/Mn) 2.13 1.88 EXAMPLE Poly(octamethylene oxide) was placed in a 500 mL round bottom flask and heated at 100 C under vacuum (0.1 torr) for 15 hours to remove volatiles.

The dried poly(octamethylene oxide) (MW 1685) (40.02 g, 0.024 mole) was placed in a 500 ml round bottom flask fitted with a nitrogen bleed, magnetic stirrer, condenser, and a drying tube. A solution of MDI (14.87 g, 0.059 mole) in anhydrous DMF (58.0 g) was added to the flask which was then heated at C under a slow stream of dry nitrogen for 2 hours. The isocyanate content of the prepolymer solution was 2.14% as determined by ASTM method D1638-74. The prepolymer (63.1 g) was then diluted to 25% w/v by adding anhydrous DMF and placed in a 500 ml round bottom flask fitted with a nitrogen bleed, mechanical stirrer, condenser and a drying tube. The chain extension 'was carried out with 1,4-butanediol in the presence of stannous octoate (0.015% by weight of total solids in prepolymer) by heating at 90 C for PC/AU 9 1 0 2 -14- RECEIVED- 2 AUG 12 -14- 2 hours. The resulting polymer solution was diluted to 8% w/v and precipitated in deionized water The precipitated polymer was stirred in fresh deionized water for 15 hours, filtered and dried in a vacuum oven at C for 72 hours. The dried polymer was melt pressed at 120 C (8 tons) into 1 mm thick sheets and its tensile properties were measured. The results appear in Table 2. In in vitro testing the polymer exhibited stability characteristics expected of a material for long term implantation and showed good haemocompatibility as assayed by whole blood clotting time and platelet adhesion tests. The material exhibited good hydrolytic and oxidative stability when tested by boiling for 24 hours in 2M hydrochloric acid, in 2M sodium hydroxide and in 25% sodium hypochlorite. The material showed a 21%, 4% and 22% decrease in ultimate tensile stress respectively, whereas the corresponding decreases for Pellethane 2363-80A (Registered Trade Mark) were 47%, 23% and 31%, after treatment.

The material showed enhanced biostability when compared with Pellethane 2363-80A (Registered Trade Mark) and Biomer (Registered Trade Mark), using the ovine implantation procedures described in Example 4 and in more detail in Examples 10 and 11.

EXAMPLE 6 A similar procedure to that described in Example 5 was used.

However, in this example poly(decamethylene oxide) of number average molecular weight of 1270 was used as the macrodiol. The prepolymer was made by mixing: 36.24 g (0.029 mole) of poly(decamethylene oxide), having a number average molecular weight of 1270; with 54.3 g of DMF and with S(c) 17.88 g (0.071 mole) of MDI SU13SIM -)TE- SU BSTIT'lJTE S WO 92/40339 PCr/AU91/00270 15 and then heating for 2 hours at 90 C. The NCO content of the prepolymer was 2.35%. The prepolymer solution (18.2 g) was diluted with DMF to w/v, and chain extended with 1,4-butanediol (0.458 g) in the presence of stannous octoate (0.015% by weight of total solids in prepoiymer) catalyst, using the procedure in Example 5, except the reaction was carried out for 1 hour at 90 C. The dried polymer was melt pressed at 160 C (8 tons) into 1 mm thick sheets and tested for mechanical properties. The results are summarised in Table 2. The material was also shown to be readily extrudable.

The polymer exhibited good stability. For example, the material exhibited good hydrolytic and oxidative stability when tested by refluxing for 24 hours in 2M hydrochloric acid, in 2M sodium hydroxide and in 25% sodium hypochlorite, respectively. The material showed a 15% and 7% decrease in ultimate stress respectively, whereas the corresponding decreases for Pellethane 2363-80A (Registered Trade Mark) were 47%, 23% and 31%. The material was more biostable than Pellethane 2363-80A (Registered Trade Mark) and Biomer (Registered Trade Mark), as evidenced by strained and unstrained ovine implantation tests as described in Examples 10 and 11. Whole blood clotting time and platelet adhesion tests also indicated that the material had good compatibility with blood.

EXAMPLE 7 A similar procedure to that described in Example 1 was used.

However, in this example poly(decamethylene oxide) of number average molecular weight of 1270 was used as the macrodiol. The prepolymer was made by mixing: 43.9 g (0.035 mole) of poly(decamethylene oxide), having a number average molecular weight of 1270 with: 71.4 g of DMF 21.15 g (0.087 mole) of m-TMXDI and 0.015% by weight, based on the weight of of dibutyltin dilaurate and heating at 90 C for 4 hours.

WO 92/00338 PC/AU1/00270 16..

The NCO content of the prepolymer was 3.14%. The prepolymer solution (112.2 g) was diluted with DMF to 25% w/v, and chain extended with 1,6-hexanediamine (4.864 g) using the procedure in Example 1, except the reaction was carried out for 3 hours at 90 C. The dried.polymer was melt pressed at 140 C (8 tons) into 1 mm thick sheets and tested for mechanical properties. The results obtained are shown in Table 3.

The material had similar stability to Pellethane 2363-80A (Registered Trade Mark), but enhanced stability over Biomer (Registered Trade Mark), as measured by a test involving 6 month subcutaneous ovine implantation described in Example 10. The material displayed satisfactory tissue compatibility on histopathological examination, being similar to Biomer (Registered Trade Mark).

EXAMPLE 8 A similar procedure to that described in Example 4 was followed.

However, 2,4-toluene diisocyanate [TDI] was used instead of MDI, and the reaction was carried out for 3 hours at 90 C instead of 2 hours at 80 C. The prepolymer was made by mixing: 50.1 g (0.038 mole) of poly(hexamethylene oxide), having a number average molecular weight of 1320; with 102.4 g of DMF and 16.58 g (0.095 mole) of 2,4-TDI The NCO content of the prepolymer was 2.76%. The prepolymer solution (138.1 g) was diluted with DMF to 12% w/v, and chain extended with 1,2-ethylenediamine (2.725 g) in the presence of stannous octanoate (0.015% by weight of total solids in prepolymer) catalyst, using the procedure in Example 4, except that the reaction was carried out for 3 hours at 80 C. The dried polymer was melt pressed at 160 C into 1 mm thick sheets and tested for mechanical properties. The results are shown in Table 3.

WO 92/00338 PCT/AU91/00270 17- Table 3 Example 7 Example 8 Example 9 Hardness, Shore A Stress at 100% elongation, MPa 14.5 14.8 5.8 Stress at 300% elongation, MPa 18.8 17.3 Tensile strength, MPa 19.7 20.4 10.6 Elongation at break, 320 420 490 Tensile set, 85 48 Mn (daltons) 41,400 23,000 Dispersity (Mw/Mn) 1.66 1.86 The material showed improved biostability over Pellethane 2363-80A (Registered Trade Mark) or Biomer (Registered Trade Mark) when examined after subcutaneous implantation in sheep for 3 months in a stressed configuration (see Example 11). Examination of the surrounding tissue showed that the material displayed good histocompatability with a capsule thickness of 100-200 microns which was smaller than that from Biomer (Registered Trade Mark) and comparable with that from Pellethane 2363-80A (Registered Trade Mark).

EXAMPLE 9 A similar procedure to that described in Example 4 was followed.

However, methylene bis(cyclohexyl) diisocyanate (H 2 MDI) was used instead of MDI and the reaction was carried out for 4 hours at 90 C. The prepolymer was made by mixing: 35.75 g (0.055 mole) of poly(hexamethylene oxide), having a WO~ 92/00338 PCF/AU91/00270 18number average molecular weight of 650; with 68.8 g of anhydrous DMF; with 31.55 g (0.120 mole) of H 1 MDI; in the presence of 0.015% of the combined weight of of dibutyltin dilaurate.

The NCO content of the prepolymer was The prepolymer solution (113.0 g) was diluted with DMF to 10% w/v, and chain extended with 1,4-butanediol (3.264 using the procedure in Example 4, except the reaction was carried out for 3 hours at 100 C. The dried polymer was melt pressed at 140 C (8 tons) into 1 mm thick sheets and its tensile properties were evaluated. The results are shown in Table 3. When implanted for 6 months subcutaneously in sheep in an unstressed configuration, the material degraded to a similar extent as Biomer (Registered Trade Mark). Examination of the tissue surrounding the explanted material indicated a capsule of 100-200 microns thick, compared with that from Biomer (Registered Trade Mark) of 210-300 microns. The material also caused a less active interface with fewer macrophages and giant cells and a smaller amount of granulation tissue indicating improved histocompatibility.

EXAMPLE Details of the six month ovine in vivo biostability test are given in this example.

Each of the novel materials in Table 4 was formed by melt pressing into sheets of 1 mm thickness. Similarly, sheets of similar thickness were prepared from Pellethane 2363-80A (Registered Trade Mark) and from Tecoflex EG-80A (Registered Trade Mark). Sheets of Biomer (Registered Trade Mark) of 1 mm thickness were prepared by solvent casting from a 30% w/v solution in N,N-dimethylacetamide in a nitrogen atmosphere.

WO 92/00338 PCT/AU91/00270 -19- Table 4 Polyurethanes assessed for biostability by using the unstressed ovine implant test polyurethane diisocyanate macrodiol macrodiol chain mol wt extender Example 1 m-TMXDI POMO 850 HDA Example 4 MDI PHMO 650 BDO Example 5 MDI POMO 1685 BDO Example 6 MDI PDMO 1270 BDO Example 7 m-TMXDI PDMO 1270 HDA Example 8 2,4-TDI PHMO 1320 EDA Example 9 H 12 MDI PHMO 650 BDO Pellethane (Registered Trade Mark) 2363-80A MDI PTMO a 1000 BDO Tecoflex (Registered Trade Mark)

H

1 2 MDI PTMOa Biomer (Registered Trade Mark) MDI PTMO a 1000 Primarily EDA apoiy(tetramethylene oxide) Specimens of size 35 mm by 10 mm were cut from these sheets.

Materials were identified by means of a binary code punched into one end of each specimen. The specimens were sterilized with ethylene oxide and implanted into the subcutaneous adipose tissue in the dorsal thoraco-lumbar region of adult crossbred wether sheep.

WO 92/00338 PCr/U91/00270 After a period of six months, the specimens were retrieved. Attached tissue was carefully dissected away and the specimens were washed by soaking in 0.1 M sodium hydroxide at ambient temperature for 2 days followed by rinsing in deionized water. The specimens were then dried in air and examined by scanning electron microscopy (SEM).

The specimens were ranked according to their surface structure as determined by SEM as follows: Rank Criteria 1 The specimen surface was smooth.

2 Cracking or pitting was present around the coding holes only. The remainder of the surface was smooth.

3 Fine cracks or pits were present both at coding holes and elsewhere over the specimen surface.

4 Coarse cracking or pitting was present around the holes only. Fine cracking or pitting was present elsewhere.

Coarse cracking or pitting was present over the entire surface of the specimen.

6 The surface showed extensive deep cracking or pitting associated with loss of material from the surface.

The rankings obtained by the materials listed in the examples of this ;'ntion were as follows.

WO 92/00338 PCr/AU91/00A'70 -21 Table Rank Polyurethane 1 Example 1 Example 6 2 Example 4 2 Example 1 3 Pellethane 2363-OA (Registered Trade Mark) 3 Tecoflex EG-80A (Registered Trade Mark) 3 Example 7 4 Biomer (Registered Trade Mark) 4 Example 8 Example 9 Control specimens that were not implanted in sheep, but cleaned with sodium hydroxide in an identical manner to those which had been implanted and control specimens that were neither implanted nor cleaned were also examined by SEM. Both of these control groups showed no changes in surface structure and were ranked 1 in all cases.

These results show that the novel polyurethanes produced according to the present invention had good biostability. In particular, the polyurethanes prepared in Examples 1, 4, 5 and 6 showed a much greater stability than that of the commercially accepted polyurethanes Pellethane 2363-80A (Registered Trade Mark), Biomer (Registered Trade Mark), and Tecoflex WO 92/00338 P(JT/AU91/00270 -22- (Registered Trade Mark).

Histopathological assessment was carried out by examining the surrounding tissue capsules preserved from separate implanted samples with reference particularly to capsule cellularity, capsule thickness, vascularity, presence or absence of polymorphonucleated cells and multinucleated giant cells, and the amount of granulation tissue at the interface (macrophages, fibroblasts, and giant cels). The assessment of tissue response was judged by considering these factors as a whole using Biomer (Registered Trade Mark) and Pellethane 2363-80A (Registered Trade Mark) as reference materials.

EXAMPLE 11 Each of the materials listed in Table 6 (with the exception of Biomer (Registered Trade Mark)) was formed, by melt pressing, into sheets of 0.5 mm thickness. Sheets of Biomer (Registered Trade Mark) of 0.5 mm thickness were prepared by solvent casting under nitrogen. The polyurethanes tested are listed in Table WO 92100338 PCT/AU91/00270 -23 Table 6 polyurethane diisocyanate macrodiol macrodiol chain mol wt extender 3-- Example 4 Example 5 Example 6 Example 8

MDI

MDI

MDI

2,4-TDI

PHMO

POMO

PDMO

PHMO

650 1685 1270 1320

BDO

BDO

BDO

EDA

Pellethane 2363-80A (Registered Trade Mark) Tecoflex (Registered Trade Mark) Biomer (Registered Trade Mark)

MDI

H

12

MDI

PTMOa pTMOa 1000 BDO MDI 1000 Primarily EDA apoly(tetramethylene oxide) Specimens shaped as dumbells were cut from the sheets and stretched over poly(methyl methacrylate) holders. This caused the central section to be strained to 250% of its original length. A polypropylene sutureAwas firmly tied around the centre of each specimen. This caused a localised increase in stress in the specimen. This test method provides a means for assessing the resistance to stress-induced biodegradation; the effect of stress on the acceleration of biodegradation is well established and is discussed in Szycher's \a c«iA\ vs review cited at page 2, linesA~l6tdi 4 6 of the present application.

The specimens attached to their holders were sterilised with ethylene oxide and implanted into the subcutaneous adipose tissue in the dorsal WO 92/00338 PCT/AU91 /00270 24thoraco-lumbar region of adult crossbred wether sheep.

After a period of three months the polyurethanes were retrieved.

Attached tissue was carefully dissected away and the specimens were washed by soaking in 0.1M sodium hydroxide for 2 days at ambient temperature followed by rinsing in deionized water. The specimens weir then driel in air and examined by SEM.

The specimens were ranked according to surface structure in the central straight region as determined by SEM a follows: Rank Criteria 1 The specimen was smooth on all surfaces.

2 Small amounts of cracking or pitting were present adjacent to the ligature site.

3 Large amounts of cracking or pitting were present adjacent to the ligature site but no cracking or pitting was present elsewhere.

4 Large amounts of cracking or pitting were present adjacent to the ligature site and patches of stress cracks were present on the straight, central portion of the sample, remote from the ligature site.

5 Generalised stress cracking covered most or all of the central straight section of the sample.

cT/ 91 00 2 RECEIVED 2 AUG 1991 The rankings obtained were as follows.

Table 7 Rank Polyurethane 1 Example 4 1 Example 1 Example 6 1 Example 8 4 Tecoflex EG-80A (Registered Trade Mark) Pellethane 2363-80A (Registered Trade Mark) Biomer (Registered Trade Mark) Example 1 Control specimens, which were not implanted, but were cleaned with sodium hydroxide in an identical manner to those which had been explanted from sheep and control specimens which neither were implanted in sheep nor cleaned with sodium hydroxide were also examined by SEM. Both of these control groups showed no change in surface structure and were ranked 1 in all cases.

These results of these experiments show that the novel polyurethanes produced according to the present invention were of improved biostability when subjected to applied stress in vivo and would thus be suitable for use in implantable devices.

P i' U s" WO 92/00338 PC/AU9]/00270 26 EXAMPLE 12 This example illustrates the use of bulk polymerization to prepare a polyurethane. The polymerization was carried out in a glass reaction vessel fitted with a mechanical stirrer, nitrogen bleed,, and a condenser. Freshly distilled MDI (43.96g, 0.176 mol) and poly(hexamethylene oxide)(Mn 690), (60.6g, 0.087 nmol) were placed in the vessel and heated to 80 C for one hour under dry nitrogen. The prepolymer was allowed to cool to about 40 C and then degassed under vacuum. 1,4-Butanediol (7.837 g) was added from a syringe and the mixture was stirred at high speed for 1 minute. Stannous octoate 0.01%, added as a 2.5% solution in toluene) was then added and stirring was continued for 30 seconds. The mixture was then poured onto a dish lined with teflon-coated cloth and cured in an oven at 100 C for 15 hours under a flow of dry nitrogen. The cured polymer was melt pressed at 180 C into 1 mm thick sheets and tested for mechanical properties. The results obtained are given in Table 8.

Table 8 Example 12 Hardness, Shore A 89 Stress at 100% elongation, MPa 11 Stress at 300% elongation, MPa 15.6 Tensile strength, MPa 15.9 Elongation at break, 320 Tensile set, 57 Mn (daltons) 59,200 Dispersity (Mw/Mn) 1.48 26a Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

1.

t ~i

~F

94 222,p'.opcr\dib,80065.spc,26

Claims (4)

1. Use of a polyurethane or polyurethane-urea elastomeric composition which comprises a reaction product of: a soft segment macrodiol which is either: a homopolymer represented by formula I, HO-[(CH 2 )nO]m-H I wherein n represents an integer greater than 5 and less than 13, m is a number such that the number average molecular weight of the compound of formula I falls in the range from 218 to 5000 and optionally at least one hydrogen atom represented in formula I is substituted by a C 1 to C 3 alkyl group or a halogen atom; (ii) a copolymer containing at least 25% by mass of repeating units -(CH 2 )nO- wherein n is as defined in formula I above; or (iii) mixture of macrodiols comprising greater than 10% of a macrodiol as defined in formula I above; an aliphatic or aromatic diisocyanate known in the art of polyurethane manufacture; and optionally a chain extender as a degradation resistant material.

2. Use according to Claim 1, wherein the homopolymer comprises a range of molecular weights such that the number average molecular weight falls between 218 and

5000.

3. Use according to Claim 1 or Claim 2, wherein at least one hydrogen atom is substituted by fluorine atom in the homopolymer

4. Use according to any one of the preceding claims, wherein the aliphatic or aromatic diisocyanate is selected from 4,4'-diphenylmethane diisocyanate (MDI), methylene bis(cyclohexyl) diisocyanate (H 12 MDI), 941222,p:\operklab,80065.spe,27 -28 p-phenylene diisocyanate (p-PDI), trans-cyclohexane-1,4-diisocyanate (CHDI), 1,6-diisocyanatohexane (DICH), 2.4-toluene diisocyanate (2,4-TDI), meta-tetramethylxylene (x-TMXDI) and para-tetramethylxylene diisocyanate (p-TMXDI). Use according to any one of the preceding claims, wherein the chain extender (C) is selected from 1,4-butanediol (BDO), 1,6-hexanediol (HDO), 1,2-ethylene diamine (EDA), 1,6-hexanediamine (HDA) and 1,2-propanediamine (1,2-PDA). 6. Use according to any one of the preceding claims, wherein the composition further comprises one or more of a cross-linking agent, a catalyst, an antioxidant, a stabilizer and a processing aid. 7. Use of a polyurethane or polyurethane-urea elastomeric composition as defined in any one of Claims 1 to 6 as a material having inproved durability in hostile environments. 8. Use of a polyurethane or polyurethane-urea elastomeric composition as defined in any one of Claims 1 to 6 as an in vivo degradation resistant material. 9. Use of a polyurethane or polyurethane-urea elastomeric composition as defined in any one of Claims 1 to 6 as a biomaterial. 10. Use of a polyurethane or polyurethane-urea elastomeric composition as defined in any one of Claims 1 to 6 as a device or article.

941222.p:operdab,80065,spe,28 -29- 11. Use according to Claim 10, wherein the device or article is artificial leather, shoe soles or cable sheathing. 12. Use of a polyurethane or polyurethane-urea elastomeric composition as defined in any one of Claims 1 to 6 as a medical device, article or implant. 13. Use according to Claim 12, wherein the medical device, article or implant is a pacemaker lead, a catheter, an implantable prosthesis, a cardiac assist device, a heart valve, a suture, a vascular graft, an extra-corporeal device or an artificial heart. 14. Use according to any one of Claim 12 or Claim 13, wherein the medical device, article or implant is a pacemaker lead or a defibrillator lead. A polyurethane or polyurethane-urea elastomeric composition as defined in any one of Claims 1 to 6. 16. Polyurethane or polyurethane-urea elastomeric compositions or uses involving them, substantially as hereinbefore described with reference to the Examples. DATED this 23rd day of December, 1994 Commonwealth Scientific and Industrial Research Organisation AND Unisearch Limited By Its Patent Attorneys DAVIES COLLISON CAVE 941222,p\opcr\dab,8005.spc,29 Internatonal Application No. PCTIAU 91100270 INTERNATIONAL SEARCH REPORT I. CLASSIFICATION OF SUBJECT MATTER (if several clasificaton symbols apply, Indicate all)e According to International Patent classification (IPC) or to both National Classification and IPC Int. CI." C08G 18/48, A61L 27/00, 29/00, 31/00 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols IPC C08G 18/48 SDgocumentation Searched other than Minimum Docmentation. to th Extent that such ocumente are ncluded in the Fieds Searched AU: IPC C08G 18/48, A61L 27/00, 29/00, 31/00 III. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of Document, with indication, where appropriate of the relevant passages 12 Relevant to Claim No 13 A Patents Abstracts of Japan, C 345, page 104, JP,A, 60-252617 (1-12) (DAICEL KAGAKU KOGYO K K) 28 May 1984 (28.05.84) A EP,A, 0136396 (GOLDSCHMIDTTH AG) 10 April 1985 (10.04.85) (1-6) (See page 1, lines 1 to 16) P,X Derwent Abstract Accession No 91-019202/03, Class P23, (1-6) JP,A, 0-2292318 (KURARAY K K) 3 December 1990 (03.12.90) A FR,A, 2008761 (FARBENFABRIKEN BAYER AG) 23 January 1970 (1-6) (23.01.70) (See page 1, line 35 to page 2, line (continued) Special categories of cited documents 1 Later document published after the international filing date or priority date and not in conflict Document defining the general state of the art which is with the application but cited to understand the not considered to be of particular relevance principle or theory underlying the invention earlier document but published on or after the document of particular relevance; the claimed international filing date Invention cannot be considered novel or cannot be document which may throw doubts on priority claim(s) considered to involve an inventive step or which is cited to establish the publication date of document of particular relevance; the claimed another citation or other special reason (as specified) invention cannot be considered to involve an document referring to an oral disclosure, use, inventive step when the document is combined exhibition or other means with one or more other such documents, such document published prior t the international filing date combination being obvious to a person skilled in but later than the priority date claimed the art document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report 12 October 1991 (12.10.91) 17 Oc-o 91 International Searching Authority Signature of Authorize. Officer AUSTRALIAN PATENT OFFICE R.A. MELVIN 1 Fwm OCTAPS121O1 1mcond Wwat) Utwxwy 196) Intaruklional Application No. PCT/AU 91/00270 FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET Patents Abstracts of Japan, C 832, page 104, JP,A, 3-50225 (NIPPON SHOKUBAi KAGAKU KOGYO CO. LTD) 4 March 1991 (04.03.91) (1-6) V. OBSERVATIONS WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE 1 This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. Claim numbers because they relate to subject matter not required to be searched by this Authority, namely: 2. O Claim numbers begause they relate to parts of the intarnationel application that dp not comply with the prescribed Srequirements to such an extent that no meaningful international sarch can be carned out, specifically: 3. E] Claim numbers .bcause they are dependent claims and are not drafted in accordance with the second and third sentences of PTgRule .4a t VI. O OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING 2 This International Searching Authority found multiple inventions in this international application as follows: s all required caditional seorch fees wre ti ely paid by the applicant, this international search report covers all searchable claims of the Internationa application. 2. As only some of the required additional search fes were timely paid by the applicant, this international search report covers only those claims of the international application or whnlcn tees were paid, specifically claims: 3. No No rcuired additional eearch fees wre timely paid by the.applicant, Cospquently, this international search report Is rstricted to the invention first mentioned in the claims; it is covered y caim numbers: 4. i As all searchable claims could be searched without effort justifying an additional fee, the International Searching Authority 0 did not invite payment of any additional fee. Remark on Protest l The additional search fees were accompanied by applicant's protest. O No protest accompanied the payment of additional search fees. Foon PCTAPS12101 Wupplarnwu Wvb tZI Uwvry '1851) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL APPLICATION NO. PCT/AU 91/00270 This Annex lists the known publication level patent family members relating to the patent documents cited in the above-mentioned international search report. The Australian Patent Office is in no way liable for these particulars which are merely give.a for the purpose of information. Patent Document Cited in Search Patent Family Member Report US 3534000 JP 112554 US 4853054 JP 252017 JP 252617 EP 136396 FR 2008761 FR 1434802 END OF ANNEX