Chain extenders

Abstract

The present invention relates to chain extenders, processes for their preparation and their use in the preparation of biocompatible biodegradable polyurethanes and polyurethane ureas for biomedical applications such as stents, scaffolds for tissue engineering. The chain extenders comprise a compound of formula (I) ##STR00001##

Claims

1. A biocompatible biodegradable polyurethane comprising the reaction product of an aliphatic isocyanate, polyol, and a chain extender; wherein said polyurethane contains hard segments and soft segments; wherein said polyurethane comprises a hard segment formed from a chain extender, wherein the chain extender is a compound of formula (1) or formula (2): ##STR00016## wherein R.sub.1, R.sub.2 and R.sub.3 are independently selected from C.sub.1-20 alkylene and C.sub.2-20 alkenylene, and wherein R.sub.1, R.sub.2 and R.sub.3 are optionally substituted by one or more groups selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, halo, halo C.sub.1-6 alkyl, halo C.sub.2-6 alkenyl, halo C.sub.2-6 alkynyl, haloaryl, hydroxy, C.sub.1-6 alkoxy, C.sub.2-6 alkenyloxy, C.sub.1-6 aryloxy, benzyloxy, halo C.sub.1-6 alkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroC.sub.1-6 alkyl, nitroC.sub.2-6alkenyl, nitroC.sub.2-6alkynyl, nitroaryl, nitroheterocyclyl, amino, C.sub.1-6 alkylamino, C.sub.1-6dialkylamino, C.sub.2-6 alkenylamino, C.sub.2-6 alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, C.sub.1-6 alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocyclyloxy, heterocyclylamino, haloheterocyclyl, C.sub.1-6 alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy, mercapto, C.sub.1-6 alkylthio, benzylthio, acylthio and phosphorus-containing groups; wherein said polyurethane comprises a soft segment comprising the polyol of general formula: ##STR00017## wherein h and/or k are independently 0 or an integer, with the proviso that at least one of h or k is non-zero, j is a non-zero integer, Z is a linear or branched alkylene or arylene wherein each occurrence of Z independently within the segment j may be the same or different, and R is a linear or branched alkylene, alkenylene, aminoalkylene, alkoxyalkylene or arylene function wherein each occurrence of R independently within the segments h or k may be the same or different; and wherein the polyurethane degrades such that the reduction in the number average molecular weight (M.sub.n) of the polyurethane is increased by 15% or more, relative to a polyurethane having ethylene glycol as chain extender in said hard segment, after three months under the conditions of ASTM F1635, the polyurethane does not contain aromatic isocyanates or isothiocyanates, and the polyurethane does not contain urea functions.

2. A biocompatible, biodegradable polyurethane according to claim 1, wherein the hard segments and the soft segments degrade at comparable rates.

3. A biocompatible, biodegradable polyurethane according to claim 1, wherein said polyurethane has a glass transition temperature between 20 C. and 37 C.

4. A biocompatible, biodegradable polyurethane according to claim 1, in which R.sub.1 to R.sub.3 are independently selected from optionally substituted C.sub.1-6 alkylene and optionally substituted C.sub.2-6 alkenylene.

5. A biocompatible, biodegradable polyurethane according to claim 1, wherein the compound of formula (1) is as follows: ##STR00018##

6. A biocompatible, biodegradable polyurethane according to claim 1, wherein the compound of formula (2) is as follows: ##STR00019##

7. A biocompatible, biodegradable polyurethane according to claim 1, wherein the chain extender has a molecular weight of less than 400.

8. A biocompatible biodegradable polyurethane according to claim 1 wherein the chain extender of formula (1) of (2) is prepared by a process which comprises the step of transesterification of a compound of formula (3) or (4): ##STR00020## wherein n is an integer from 1 to 50; with a compound of formula HOR.sup.1OH.

9. A biocompatible biodegradable polyurethane according to claim 1 comprising the chain extender of formula (1) or formula (2) and another chain extender.

10. A biocompatible biodegradable polyurethane according to claim 1, in which the other chain extender is a diol, dithiol, or dicarboxylic acid.

11. A biocompatible polyurethane according to claim 1 in which the polyurethane is thermoplastic and of the general formula: ##STR00021## in which R.sub.x is from the isocyanate, R.sub.y is from the chain extender and R.sub.z is from the soft segment polyol; q is the average number of repeat units in the hard segment; r is the average number of repeat units in the soft segment; and s is proportional to the molecular weight of the polymer and includes both the hard segments repeat units and the soft segment; and in which q is an integer between 1 and 100, r is an integer between 0 and 100, and s is an integer between 1 and 500.

12. A biocompatible polyurethane according to claim 1, in which the aliphatic isocyanate is an aliphatic diisocyanate.

13. A biocompatible polyurethane according to claim 1, wherein one or both of R and Z optionally comprises a bioactive moiety.

14. A biocompatible polyurethane according to claim 1, in which the polyol has a molecular weight of 200-5000.

Description

DETAILED DESCRIPTION OF THE DRAWINGS

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

(2) FIG. 1 is an IR Spectrum of GA-1,3-PD, NaCl plate;

(3) FIG. 2 is a .sup.1HNMR Spectrum of GA-1,3-PD in deuterated DMSO;

(4) FIG. 3 is a .sup.13CNMR Spectrum of GA-1,3-PD in deuterated DMSO;

(5) FIG. 4 is a .sup.1HNMR Spectrum of CL-EG Dimer; and

(6) FIG. 5 is a .sup.1HNMR Spectrum of CL-BDO Dimer.

EXAMPLES

Example IPreparation of Glycolic acid-1,3-propanediol Ester Diol (GA-1,3-PD)

(7) Step OnePolycondensation or Dehydration

(8) 56.7 g of glycolic acid was heated at 220 C. to remove water for 5 hours under nitrogen out gassing in a large round-bottomed flask equipped with a magnetic stirrer bead, a still-head sidearm and condenser to collect the water runoff. The resulting product was polyglycolic acid (PGA), a white solid polymer.

(9) Step TwoTransesterification

(10) To approximately 43 g of white solid PGA was added 283.6 g of 1,3-propane diol (five to one mole ratio) and the temperature set at 200 C. for a period of 17 hours and 30 minutes of transesterification. The glycolic acid ester diol was purified by fractional distillation as outlined below.

(11) Step ThreePurification by Fractional Distillation

(12) The dimer-containing liquid was then heated on the Kugelrohr at 50 C. under vacuum (0.01-0.001 torr) to remove unreacted 1,3-propane dial and then the temperature was increased to 70 C. to distil the dimer. The dimer fraction was collected and then distilled a second time to remove any 1,3-propane diol present. The GA-1,3-PD was a white somewhat slurry-like solid. In total there was 53 g GA-1,3-PD dimer (53% yield).

(13) The chemical structure and properties of the ester dial prepared are summarised in Table 1 below:

(14) TABLE-US-00003 TABLE 1 Properties of GA-1,3-PD Character- Abbreviation Chemical Structure isation GA-1,3-PD IR, .sup.1HNMR. .sup.13CNMR (Figures 1 to 3)

Example 2Preparation of Dicarboxylic Ester Diol Chain Extenders

(15) Step OneCondensation

(16) 23.6 g of succinic acid (a diacid) was heated with 248 g of ethylene glycol (1:10 mole ratio) to 170 C. for 20 hours under nitrogen out gassing in a round-bottomed flask equipped with a magnetic stirrer bead, a still-head sidearm and condenser to collect the water runoff.

(17) Step TwoPurification by Fractional Distillation

(18) The product from step one was then heated under vacuum (0.01 torr) on the Kugelrohr to remove ethylene glycol at 40-50 C. and then increased to 120 C. to distil the EG-Suc-EG trimer which came over as a colourless liquid. Yield was 22.7 g, (55.1% yield).

(19) TABLE-US-00004 TABLE 2 Properties of dicarboxylic acid ester diols Chemical Structure Characterisation EG-Suc-EG IR, .sup.1HNMR, .sup.13CNMR EG-Fum-EG IR, .sup.1HNMR, .sup.13CNMR

Example 3Preparation of Polyurethanes Using Chain Extenders of Examples 1 and 2

(20) Materials: Poly(-caprolactone), (PCL), soft segments (molecular weight 426) were dried at 90 C. for 4 hours under vacuum (0.1 torr). HDI (Aldrich) was used as received (colourless). Stannous octoate (Aldrich) was kept moisture free and used as received. The chain extender was synthesised and distilled then kept sealed, refrigerated and dry until use.

(21) Method: A mixture of PCL soft segment diol (35.000 g), chain extender (21.311 g) and stannous octoate (0.050 g) were weighed into a 100 ml predried polypropylene beaker, covered with aluminium foil and heated to 70 C. under nitrogen in a laboratory oven. HDI (43.689 g) was weighed in a separate wet-tared predried polypropylene beaker and also heated to 70 C. The HDI was then added to the diol/EG/stannous octoate beaker and stirred manually until gelation occurred, at which time the hot viscous mixture was poured onto a Teflon coated metal tray to cure at 100 C. for a period of about 18 hours. The resulting polymer was clear and colourless.

(22) TABLE-US-00005 TABLE 3 Composition of polyurethanes containing degradable chain extenders Hard Chain Stannous segment extender, PCL-426 Octoate Polyurethane % (g) HDI (g) (g) (g) 1 65 GA-1,3PD, 42.306 35.000 0.050 22.694 2 65 EG-Suc-EG, 15.782 15.000 0.043 12.075 3 65 EG-Fum-EG, 15.835 15.000 0.043 12.022 4* 65 EG, 36.732 25.000 0.071 9.696 5* 35 EG, 10.121 20.000 0.031 0.648 *Comparative polyurethanes formed using the non-degradable chain extender EG
Degradation was Conducted on 1 mm Thick Melt-Pressed Specimens in PBS Buffer pH7.4 for 3 Months at 37 C.

(23) The method for degradation was as per ASTM International standard F 1635: Standard Test Method for in vitro Degradation Testing of Poly (L-lactic Acid) Resin and Fabricated Form for Surgical Implants. In short, the conditions were: Polymers were meltpressed to 100-200 m thick and strips were cut 5 mm45 mm, buffer was 0.1M PBS pH 7.4, temperature was 37 C., solution:specimen ratio was between 100:1 and 300:1, 0.1% sodium azide was added as antimicrobial, samples were all placed in a 50 rpm agitated incubator, 6 specimens per material and only one specimen per jar.

(24) TABLE-US-00006 TABLE 4 Mass loss and GPC molecular weights before and after degradation of the polyurethanes of Table 3 % Mass Pre Degradation Post Degradation % PU Loss Mn Mw PD Mn Mw PD Mn 1 0.88 0.1 28,096 46,838 1.67 18,596 31,122 1.67 66.2 2 2.82 0.2 15,802 26,973 1.71 13,071 20,673 1.58 82.7 3 0.51 0.2 34,123 91,026 2.67 19,281 38,163 1.98 56.5 4* 0.42 0.2 121,842 443,397 3.64 118,803 531,502 4.47 2.5 5* 1.91 0.2 16,953 29,660 1.75 16,920 29,013 1.71 0.2

Example 4Preparation of CL-EG-Dimer

(25) -caprolactone (114.14 g) and ethylene glycol (310.35 g) were added to a round-bottomed flask and heated to 190 C. overnight with a vertical condenser to avoid loss of reagents.

(26) The ethylene glycol was removed on the Kugelrohr (0.01-0.001 torr) at 40-50 C. and then the CL-EG dimer was distilled at 100 C. CL-EG dimer was collected and this was redistilled to remove ethylene glycol, giving 120 g of CL-EG dimer. The dimer was a colourless low-viscosity liquid. Characterisation was by .sup.1HNMR (FIG. 4).

Example 5Preparation of CL-BDO Dimer

(27) -caprolactone (79.83 g) and 1,4-butane diol (450.60 g) were added to a round-bottomed flask and heated to 180 C. over the weekend (66 hours) with a vertical condenser to avoid loss of reagents.

(28) The 1,4-butane diol was removed on the Kugelrohr (0.01-0.001 torr) at 80 C. and then the CL-BDO dimer was distilled at 110 C. CL-BDO dimer was collected and redistilled to remove BDO, giving 63.75 g of CL-BDO dimer. The dimer was a colourless low-viscosity liquid. Characterisation was by .sup.1HNMR (FIG. 5).

Example 6Comparative Hydrolysis at 100 C.

(29) Two polymers from Table 3 can be compared for hydrolytic degradation at 100 C. and measured by change in concentration of amine in solution (due to urethane hydrolysis). Approximately 5 g of polymer is weighed out and placed in a round-bottomed flask. Distilled water is then added to the flask containing the sample such that the sample to water ratio Is approximately 1:50 (to obtain concentrated degradation products). The round-bottomed flask is then placed in an oil bath set to 130 C. and refluxed for 24 hours with a vertical condenser. The degradation products are collected and subjected to the Ninhydrin Assay. Ninhydrin Assay: Ninhydrin Reagent Solution is obtained from Sigma, product code number N 7285. The protocol on the product information sheet is followed with regard to the assay as well as the preparation of the standard curve.

Example 7Preparation of Cross Linked Polymers Incorporating Degradable Chain Extenders

(30) A prepolymer of pentaerythritol (PE) with ELDI (2.0 g) is weighed into a glass vial. Degassed and dried dimer from Table 3 0.461 g (MW 120) is added to the prepolymer. The mixture is manually stirred using a spatula for 3 minutes with stannous 2-ethyl hexanoate catalyst (0.002 g, 0.1% based on based on total weight of prepolymer) and is degassed under a vacuum for 5 min. The viscous mixture is taken into a 2.5 ml syringe and dispensed 0.33 g into each cylindrical cavity (6 mm D12 mm L) in a multi-cavity Teflon mould and cured overnight at 38 C. to give cylindrical polymer test specimens. A second polymer is prepared by incorporating 5 wt-% of -tricalcium phosphate (TCP, 5 micron particle size). TCP is added to the reactant mixture and stirred using a high speed mechanical stirrer for uniform distribution.

(31) The cured polymer samples is tested using Instron (Model 5568) for compressive strength and modulus according to ASTM method F451-756.

Example 8

(32) Materials: Poly(ethylene glycol (PEG) (molecular weight 1000) is dried at 90 C. for 4 hours under vacuum (0.1 torr). HDI (Aldrich) is used as received. Stannous octoate (Aldrich) is kept moisture free and used as received. The chain extender is synthesised using the procedure described in Example 1. The distilled product is kept sealed under refrigerated and dry conditions until use.

(33) Method: The polymer Is prepared using the method described in Example 3. A mixture of polyethylene glycol (10.000 g), chain extender (1.713 g), EG (1.330 g) and stannous octoate (0.010 g) are weighed into a 100 ml predried polypropylene beaker, covered with aluminium foil and heated to 70 C. under nitrogen in a laboratory oven. HDI (7.862 g) is weighed in a separate wet-tared predried polypropylene beaker and heated to 70 C. HDI is then added to the polyol/chain extender mixture in a beaker and stirred manually for 3 min. The viscous mixture is then poured onto a Teflon coated metal tray and cured at 100 C. for a period of about 18 hours in a nitrogen circulating oven.

(34) It will be apparent to the person skilled in the art that while the invention has been described in some detail for the purposes of clarity and understanding, various modifications and alterations to the embodiments and methods described herein may be made without departing from the scope of the inventive concept disclosed in this specification.