# Patent

## Title
Bioresorbable thermoset polyester/urethane elastomers

## Abstract

Bioresorbable thermoset elastomers and methods of making the same are disclosed. In certain embodiments, the thermoset elastomers include soft segments comprising branched polyesters, and hard segments including urethane and/or urea. The thermoset elastomers are made in certain embodiments by curing a branched prepolymer with a cross-linking agent. In certain embodiments, the mechanical properties of the thermoset elastomers are tailored by selecting the average molecular weight of the prepolymer, or by tuning the ratio of prepolymer to the cross-linking agent during curing, or by selecting a cross-linking agent with specific chemical characteristics.

## Background
This application is a continuation-in-part of, and claims the benefit of priority to, U.S. patent application Ser. No. 12/783,261, filed May 19, 2010, now U.S. Pat. No. 8,137,396 by inventors Lee Core et al., entitled “Medical Implant,” and further claims the benefit of priority to U.S. Patent Application 61/179,834, filed May 20, 2009, by inventors Lee Core et al., entitled “Medical Implant,” to U.S. Patent Application 61/227,308, filed Jul. 21, 2009, by inventors Lee Core et al., entitled “Medical Implant,” and to U.S. Patent Application 61/251,984, filed Oct. 15, 2009, by inventors Lee Core et al.


TECHNICAL FIELD
The present invention relates to bioresorbable thermoset polyester/urethane elastomers and methods of making and using the same.
BACKGROUND
Bioresorbable elastomers are synthetic polymers that are broken down in vivo and can be used, for example, as coatings for stents and catheters, as drug delivery systems, as vascular grafts, as scaffolds for tissue engineering, and as guides for nerve growth. Examples of medical devices coated with such polymers are disclosed in U.S. patent application Ser. No. 12/783,261, the entire content of which is disclosed herein by reference. To achieve their widest utility, elastomers should be able to mimic the resilience, flexibility, and tensile strength exhibited by natural materials and encountered in a wide range of potential medical applications. However, bioresorbable elastomers currently known in the art have not simultaneously achieved high tensile strength, flexibility and low permanent deformation under cyclic mechanical use that approach what is found in nature. Accordingly, there is a need for a bioresorbable elastomer that combines high tensile strength with a high degree of flexibility and low permanent deformation.
SUMMARY OF THE INVENTION
The present invention addresses the need described above by providing bioresorbable elastomers and methods of making the same. The bioresorbable elastomers of the present invention have a range of applications, including but not limited to vascular grafts, drug delivery systems, stent coatings to improve radial recovery, and as tissue engineering substrates including nerve guides, small blood vessels, bladders, cardiac tissues, cartilages, tendons, and ligaments.
In one aspect, the present invention relates to bioresorbable elastomers that include a branched prepolymer and an isocyanate crosslinker and that have high tensile strength and a high degree of flexibility along with low permanent deformation under cyclic mechanical use.
In another aspect, the present invention relates to a method of making such a bioresorbable elastomer by providing a branched prepolymer and crosslinking it with an isocyanate crosslinker.
In still another aspect, the present invention relates to a method of optimizing the mechanical characteristics of a bioresorbable elastomer by optimizing the crosslink density and/or the average molecular weight of branched subunits. In certain embodiments, the tensile strength, flexibility, and long-term deformation of a bioresorbable elastomer are optimized by providing a symmetrical isocyanate crosslinker having a plurality of isocyanate moieties of equal reactivity during the curing of the bioresorbable elastomer. In other embodiments, these characteristics are optimized by adjusting the average molecular weight of the prepolymer used during production of the bioresorbable elastomer. In yet other embodiments, these characteristics are optimized by adjusting the ratio of prepolymer to cross-linker during production of the bioresorbable elastomer.



DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic illustration of a thermoset elastomer of the present invention.
FIG. 2 is a representative 1H NMR spectrum of a 4-arm prepolymer of the present invention.
FIG. 3 is a representative plot of the relative tear strengths of two different thermoset elastomers of the present invention.
FIG. 4 is a comparative SEM micrograph showing stent coatings comprising thermoset elastomers of the present invention.
FIG. 5 is a representative plot of the degradation rates of polymers made with or without the polyurethane catalyst Zinc Octoate.



DETAILED DESCRIPTION
Bioresorbable thermoset elastomers (hereinafter, “elastomers”) of the present invention simultaneously exhibit high elongation at break, low permanent deformation, and high tear resistance; by contrast, other bioresorbable elastomers currently known in the art do not simultaneously exhibit all of these characteristics. Elastomers of the present invention achieve this balance of properties by tuning the balance between chemical crosslinking via covalent bonding with physical crosslinking via non-covalent interactions. Elastomers of the invention comprise “soft” segments including branched polyesters, and “hard” segments including urethane or urea, as depicted in FIG. 1. These elastomers are formed by cross-linking branched prepolymers with cross-linking elements. In preferred embodiments, the prepolymers are branched polyesters, and the cross-linking elements are multifunctional isocyanates. Additionally, while the exemplary embodiments disclosed herein focus on “four arm” polyester prepolymers it will be understood by those skilled in the art that any branched prepolymer (n=3 or greater) with an appropriate glass transition temperature can be used to make elastomers of the present invention. It is expected that elastomers sharing some or all of the beneficial characteristics described above could be made comprising linear polymers cross-linked with branched multi-functional cross-linking elements.
Elastomers of the present invention exhibit good strength, high elasticity and a high degree of elastic recovery under cyclic mechanical strain. These properties are due to the optimized crosslinked nature—the degree of crosslinking—of these branched prepolymers crosslinked with isocyanates in combination with the phase separation of the “soft” (polyester) and “hard” (urethane/urea) segments. The soft segments of the elastomer permit elongation of the material while the hard segments impart strength. The combination of the hard and soft segments impart elasticity. The tensile strength and elongation to break of these elastomers can be adjusted by varying the crosslink density. If the crosslink density is high the resultant elastomer is strong with low permanent deformation but has a low elongation to break. Alternatively if the crosslink density is too low the elastomer has a high elongation to break but is weak, tacky and has high permanent deformation. Additional strength may also be obtained from secondary bonds that form between adjacent polymer chains; these are primarily hydrogen bonds between the hard (urethane/urea) segments of these elastomers. Phase separation of the hard and soft segments will also add to the high elasticity and low permanent deformation associated with these elastomers.
Elasticity and tensile strength of the elastomers can be optimized by adjusting the molecular weight and structure of the prepolymer, the structure of the isocyanate crosslinker, and the ratio of prepolymer to crosslinker used in the curing process. In a preferred embodiment, the average molecular weight (Mn) of the 4-arm prepolymer is at least 20,000 g/mol (i.e., 20 kDa), and more preferably at least 30,000 g/mol (i.e., 30 kDa). At the beginning of the curing process, the isocyanate cross-linker can be provided in a ratio of between 5 to 1 and 120 to 1 (mol/mol) relative to the prepolymer.
In certain preferred embodiments, the prepolymer is a 4 arm polymer such as poly (glycolide-co-ε-caprolactone) (50:50) (PGCL) or poly (lactide-co-ε-caprolactone) (50:50) (PLCL). Other multi-arm polymers, such as the block or random copolymers of glycolide and/or lactide with poly(ε-caprolactone), poly(butylene succinate) (PBS), poly(p-dioxanone) (PDO), and Poly(trimethylene carbonate) (PTMC), may also be used as the prepolymers. The ratio of the individual monomers is not limited to 50:50 and any other ratios are valid unless the glass transition temperature of the resultant copolymers is above room temperature.
The crosslinker used in the present invention is any suitable symmetrical isocyanate. In certain preferred embodiments, hexamethylene diisocyanate (HDI) is used as the cross-linker, and the polyester prepolymer is provided in a ratio of between 3 to 1 and 20 to 1 (wt/wt) relative to HDI.
Table 1 relates the mechanical properties of elastomers of the present invention made with PGCL and HDI including young's modulus, ultimate tensile strength and elongation to break measured on INSTRON according to standard procedures (Dey, J. et al. (2008), Biomaterials 29: 4638-4649). Mechanical tests were carried out at room temperature in air or at 37° C. in water. The table shows the impact of varying the average molecular weight of the PGCL prepolymer from 20,000 g/mol to 100,000 g/mol, and varying the quantity of HDI provided relative to the PGCL. It is noted that the mechanical properties are determined by both the molecular weight of the prepolymer and also by the ratio of prepolymer:HDI used. Increasing molecular weight of the prepolymer results in more elastic materials. For a given molecular weight increasing the wt:wt ratio of HDI:polymer results in a stronger elastomer.







TABLE 1







Mechanical properties of PGCL-HDI films with different


PGCL prepolymer molecular weights













E/




Sample ID
Materials
MPa
Smax/MPa
γb/%














101-034-01
PGCL (20k)/HDI (12:1 wt/wt)
5.7
5.4
350


101-034-02
PGCL (20k)/HDI (12:2 wt/wt)
4.5
3.0
310


101-034-03
PGCL (20k)/HDI (12:3 wt/wt)
37
5.4
280


101-034-04
PGCL (20k)/HDI (12:4 wt/wt)
43
7.5
320


089-090-01
PGCL (100k)/HDI (20:1 wt/wt)
4.2
7.3
820


089-090-02
PGCL (100k)/HDI (20:2 wt/wt)
3.9
9.0
860


089-090-03
PGCL (100k)/HDI (20:3 wt/wt)
6.0
6.7
700


089-090-04
PGCL (100k)/HDI (20:4 wt/wt)
10
9.6
810





Where E = Young's Modulus, S = Tensile strength and γb = elongation at break


All measurements were made at room temperature in air.






Table 2 relates mechanical properties of elastomers of the present invention made with PLCL and HDI. The PLCL/HDI elastomers behave similarly to the PGCL/HDI elastomers in that as molecular weight is increased from 8 k to 100 k the elongation to break increases. Additionally, for the lower molecular weight prepolymers, regardless of the ratio of prepolymer to isocyanate, the materials are stiff and have low elongation to break. Generally, PGCL based elastomers are stronger than PLCL based elastomers of similar molecular weight, and PGCL based elastomers have different degradation rates than PLCL based elastomers.







TABLE 2







Mechanical properties of PLCL-HDI films with different


PLCL molecular weights













E/




Sample ID
Materials
MPa
Smax/MPa
γb/%














089-087-02
PLCL (8k)/HDI (5:1 wt/wt)
7.1
3.7
220


089-087-03
PLCL (8k)/HDI (5:2 wt/wt)
36.3
6.2
190


101-018-01
PLCL (20k)/HDI (4:1 wt/wt)
18.7
6.0
420


101-005-03
PLCL (40k)/HDI (8:1 wt/wt)
3.9
3.9
700


089-085-01
PLCL (100k)/HDI (20:1 wt/wt)
2.0
2.6
940


089-085-02
PLCL (100k)/HDI (10:1 wt/wt)
4.6
3.7
670





Where E = Young's Modulus, S = Tensile strength and γb = elongation at break


All measurements were made at room temperature in air.






Table 3 sets forth the mechanical properties of polyester/urethane thermoset elastomers disclosed in the literature and measured on INSTRON according to standard procedures as discussed above. The thermoset elastomers listed in this table were prepared from a polyester prepolymer—poly(1,8-octanediol-co-citrate) (POC)—and then crosslinked with HDI. Although the elastomers of Table 3 are quite stiff, their elongation to break is far inferior to the elastomers of the present invention.







TABLE 3







Mechanical properties of POC-HDI films












Materials
E (MPa)
S (MPa)
γb (%)
















POC:HDI (1:0.6 mol:mol)
2.99
16.0
252



POC:HDI (1:0.9 mol:mol)
5.84
32.1
278



POC:HDI (1:1.2 mol:mol)
29.8
33.4
261







Where CUPE = crosslinked urethane doped polyesters






In addition to the molecular weight of the polyester prepolymer and ratio of prepolymer:isocyanate used, the choice of isocyanate cross-linker is also important in determining the final mechanical properties of the final elastomer. In a preferred embodiment, a symmetrical cross-linker is used, which has a plurality of isocyanate moieties of equal reactivity.
In certain embodiments, a catalyst may be used to catalyze the formation of the elastomer or a reaction involved therein, such as a gelling reaction. Any suitable catalyst may be used, including Zinc Octoate, Tin Octoate, Aluminum tris(acetylacetonate), etc. The type of catalyst used, or the absence of a catalyst, may influence the time and temperature required to fully cure the elastomer as shown in Table 4:







TABLE 4







Elastomer curing conditions using various catalysts or no catalyst








Catalyst
Curing condition





No catalyst
100° C., 16 hrs 


0.1% Zinc Octoate (Zn(Oct)2)
60° C., 16 hrs


0.2% Tin Octoate (Sn(Oct)2)
70° C., 16 hrs


0.5% Aluminum tris(acetylacetonate) (Al(acac)3)
70° C., 40 hrs









Surprisingly, the rate of degradation of elastomers of the invention (as measured by elastomer mass loss rate) is also affected by the presence or absence of a catalyst as shown in FIG. 5. Mass loss profiles of various PGCL and PLCL elastomers were established under degradation conditions in pH 12 buffer at 37° C., the elastomers were cured in the absence and presence of the catalyst Zn(Oct)2.
The following examples illustrate aspects of the current invention in preferred embodiments without limitation of the spirit or scope of the claimed invention.
Example 1
Synthesis of 4-Arm PGCL Prepolymer
A 250 mL round-bottom flask was dried in oven at 110° C. and then cooled down to room temperature under a nitrogen atmosphere. Then, the flask was charged successively with Sn(Oct)2 (90 mg), pentaerythritol (400 mg), glycolide (60.0 g), and ε-caprolactone (60.0 g). Subsequently, the flask was equipped with a magnetic stirrer bar and a three-way valve connected to a nitrogen balloon. The flask was thoroughly degassed under reduced pressure and flushed with nitrogen. This process took 2-3 h. The flask was then placed into an oil bath (with 1000 mL silica oil) which was preheated to 185° C. The temperature of the oil bath quickly dropped to 155 ̃160° C. Meanwhile, the solid in the flask started to melt. Under vigorous stirring, the liquid in the flask became clear after 1 ̃2 min. Generally, the stirrer bar stopped within 5 min due to an increase in the viscosity of the liquid. The reaction was continued at 170° C. for another 22 h under a nitrogen atmosphere. After cooling to room temperature, the solid obtained was dissolved in ca. 300 ̃400 mL dichloromethane. The solution was filtered through a sintered glass funnel (pore size 70 ̃100 μm) to remove the insoluble particulate (e.g. polyglycolide) and then precipitated from 1000 ̃1200 mL anhydrous diethyl ether in a 1500 mL glass beaker. The solution was decanted and the residual sticky solid was washed with diethyl ether (150 mL×3). Subsequently, the beaker containing the materials was transferred to a vacuum oven operating at 55 ̃60° C. After 3 d, the fully dried polymer material was taken out and transferred to a polypropylene bottle for storage. Typically, around 110 g polymer could be recovered. A 1H NMR spectrum of the purified polymer in CDCl3 is shown in FIG. 2. GPC characterization with polystyrenes as standards gives an average molecular weight (Mn) of 40,000 g/mol and a polydispersity index (PDI) of 1.23. The molecular weight of the prepolymer can be varied by adjusting the molar ratio of monomer:initiator.
Example 2
Fabrication of Thermoset PEU Elastomeric Films
A 4-arm PGCL (50:50) Mn 40000 g/mol (1.0 g) and hexamethylene diisocyanate (HDI) 125 μL were dissolved in 10 mL dichloromethane. The solution was placed in a aluminum pan with diameter of 9 cm. The solvent was evaporated at room temperature (ca. 20° C.) for 3 h. The residual film was cured in a 100° C. oven for 16 h.
Example 3
Varying Mechanical Properties Depending Choice of Cross-Linker and Ratio of Cross-Linker to Prepolymer
Films were prepared in a similar manner to that outlined in Example 2 using a prepolymer PLCL (50:50) Mn of 56000 g/mol and either an asymmetric isocyanate, lysine diisocyanate (LDI), or a symmetrical one, (HDI, as crosslinking agent. The films were cured in the presence of 0.1% zinc octoate at 60° C. for 20 hrs. Table 4 shows resulting mechanical properties of films prepared from PLCL 50:50 prepolymer using several varying ratios of LDI and HDI. The ratio of isocyanate to prepolymer (NCO:OH) was optimized to maximize the mechanical properties.







TABLE 4







Mechanical properties of PLCL-LDI & PLCL-HDI films with different


mol:mol ratio NCO:OH














Iso-
NCO:OH
E
Smax
γb
T


Sample ID
cyanate
(mol:mol)
(MPa)
(MPa)
(%)
(kN m−1)













113-021-04
LDI
1:1
Film too tacky to measure





mechanical properties













113-026-01
LDI
3:1
2.4
1.7
350
1.1


113-026-02
LDI
4:1
2.3
1.3
200
1.3


113-026-03
LDI
5:1
2.4
1.6
390
1.2










113-026-04
LDI
6:1
Film too tacky to measure





mechanical properties













101-155-01
HDI
15:1 
7.2
4.5
360
4.4


101-155-02
HDI
30:1 
10.7
5.5
320
11.0





Where E = Young's Modulus,


S = Tensile strength,


γb = elongation to break, and


T = tear strength


All measurements were made at 37° C. in water






FIG. 3 depicts tear strengths of films prepared from a PLCL (50:50) prepolymer Mn 56000 g/mol and crosslinked with either HDI or LDI. The HDI cured films have higher tear strengths compared to the LDI cured films.
Example 4
Effect of Elastomer Tear Strength on Performance of Coated Stents
To illustrate how differences in tear strength affects elastomer performance in coatings, solutions of polyester PLCL prepolymer and an optimized ratio of crosslinker (HDI or LDI) were prepared in dichloromethane, spray coated onto a braided PLGA 75:25 stent structure and cured to form a conformal elastomeric coating. The PLGA stent structure has dimensions of 7 mm outer diameter and a length of 20 mm pre coating. Coated stents were then crimped to a diameter of 1.85 mm using a MSI radial force tester and then allowed to recover their original diameter. SEM images of the stent structure are then taken. FIG. 4 shows a braided device coated with LDI-cured elastomer (A) which displays cracks on its surface (arrows) post crimping. Note that the coating integrity remains intact in the case of a braided device coated with an HDI-cured elastomer (B).
The superior mechanical properties obtained from the HDI cured elastomer are due at least in part to the symmetrical nature of the crosslinker which symmetry allows it to crosslink in a homogenous manner when compared to LDI.
While various aspects and embodiments of the present invention have been described above, it should be understood that they have been presented by way of illustration rather than limitation. The breadth and scope of the present invention is intended to cover all modifications and variations that come within the scope of the following claims and their equivalents.

## Claims

1. A polymer prepared by the process comprising the steps of:
providing a branched polyester having at least three branches and having a glass transition temperature less than about 25° Centigrade, wherein the polyester has an average molecular weight (Mn) of at least 20,000 g/mol; and
at least partially crosslinking said polyester with a symmetrical isocyanate cross linker,
wherein said polymer is an elastomer.

2. The polymer of claim 1, wherein the polyester is Poly(lactide-co-ε-caprolactone).

3. The polymer of claim 2, wherein the isocyanate crosslinker is hexamethylene diisocyanate.

4. The polymer of claim 1, wherein the polyester is Poly(glycolide-co-ε-caprolactone).

5. The polymer of claim 4, wherein the isocyanate crosslinker is hexamethylene diisocyanate.

6. The polymer of claim 1, wherein the polyester is provided in a ratio of between 8:1 and 20:1 wt/wt relative to the isocyanate crosslinker during the crosslinking step.

7. The polymer of claim 1, wherein the isocyanate crosslinker is present in a ratio of between approximately 1:1 and 120:1 mol/mol relative to the polyester during the cross-linking step.

8. The polymer of claim 1, wherein the polyester has four branches.

9. The polymer of claim 1, wherein the isocyanate crosslinker comprises two or more isocyanate groups of equal reactivity.

10. The polymer of claim 1, wherein the isocyanate crosslinker is chosen for its lack of steric hindrance.

11. A polymer prepared by the process comprising the steps of:
providing a branched prepolymer with an average molecular weight of between 33 kDa and 65 kDa, the prepolymer having at least three branches and having a glass transition temperature less than about 25° Centigrade; and
curing said polymer with an isocyanate crosslinker.

12. The polymer of claim 11, wherein the prepolymer is a polyester.

13. The polymer of claim 11, wherein the isocyanate crosslinker is symmetrical.

14. The polymer of claim 11, wherein the prepolymer is Poly(lactide-co-ε-caprolactone.

15. The polymer of claim 14, wherein the isocyanate crosslinker is hexamethylene diisocyanate.

16. The polymer of claim 11, wherein the prepolymer is Poly(glycolide-co-ε-caprolactone.

17. The polymer of claim 16, wherein the isocyanate crosslinker is hexamethylene diisocyanate.

18. The polymer of claim 11, wherein the prepolymer is provided in a ratio of between 8:1 and 20:1 wt/wt relative to the isocyanate crosslinker during the curing step.

19. The polymer of claim 11, wherein the curing step takes place at 100° C.

20. The polymer of claim 11, wherein the curing step is performed over 16 hours.

21. The polymer of claim 11, wherein the method further comprises the steps of:
dissolving the prepolymer and the isocyanate crosslinker in a solvent; and
removing the solvent by evaporation.

22. The polymer of claim 1, wherein said polymer is a thermoset elastomer.

23. The polymer of claim 22, wherein said polymer is a bioresorbable thermoset elastomer.

24. The polymer of claim 1, wherein the polymer exhibits an elongation at break that ranges from 280% to 940%.

25. The polymer of claim 24, wherein the polyester has an average molecular weight (Mn) of at least 30,000 g/mol.

26. The polymer of claim 1, wherein the polyester has an average molecular weight (Mn) of at least 30,000 g/mol.

27. The polymer of claim 1, wherein the polyester has an average molecular weight (Mn) ranging from 30,000 g/mol to 100,000 g/mol.

28. The polymer of claim 26, wherein the polyester is Poly(lactide-co-ε-caprolactone) or Poly(glycolide-co-ε-caprolactone).