Biodegradable and/or bioabsorbable thermoplastic polyurethanes

Abstract

The thermoplastic polyurethane (TPU) compositions described herein have biodegradable and/or bioabsorbable hard and soft segments. The TPU hard segment can be formed from a polyisocyanate and a 2,5-substituted diketopiperazine.

Claims

1. A thermoplastic polyurethane, comprising the reaction product of: a. a polydiisocyanate component; b. a polyol component; and c. at least one chain extender component comprising a cyclic dimer of an amino acid having a side chain containing a functional group comprising —OH, —COOH, —NH, —NH.sub.2 or —SH.

2. The thermoplastic polyurethane of claim 1, wherein the polydiisocyanate component comprises an aliphatic or aromatic diisocyanate.

3. The thermoplastic polyurethane of claim 2, wherein the aliphatic diisocyanate is selected from the group consisting of dicyclohexylmethane-4,4′-diisocyanate, hexamethylene diisocyanate, 4,4′-diisocyanato dicyclohexylmethane, isophorone diisocyanate, lysine diisocyanate, 1,4-butane diisocyanate, PDI, 1,4-cyclohexyl diisocyanate, dicyclohexylmethane-4,4′-diisocyanate, and combinations thereof.

4. The thermoplastic polyurethane of claim 2, wherein the aromatic diisocyanate is selected from the group consisting of 4,4′-methylenebis(phenyl isocyanate), m-xylene diisocyanate, toluene diisocyanate, 3,3′-dimethyl-4,4′-biphenylene diisocyanate, naphthalene-1,5-diisocyanate, and combinations thereof.

5. The thermoplastic polyurethane of claim 1, wherein the polyol component is a polyester polyol selected from the group consisting of poly(L-lactide) (PLA), polglycolide (PGA), or polycaprolactone (PCL), and combinations thereof; or a polyether polyol selected from the group consisting of poly(propylene glycol), poly(ethylene glycol), poly(tetramethylene ether glycol), and combinations thereof.

6. The thermoplastic polyurethane of claim 2, wherein the chain extender component is selected from the group consisting of a cyclic dimer of glutamic acid, serine, lysine, glycine, aspartic acid, cysteine, arginine, histidine, glutamine, asparagine, threonine, hydroxyproline, tryptophan, tyrosine, and optical isomers thereof.

7. The thermoplastic polyurethane of claim 1, further comprising an additional chain extender.

8. The thermoplastic polyurethane of claim 7, wherein the additional chain extender comprises at least one diol chain extender of the general formula HO—(CH.sub.2).sub.x—OH wherein x is an integer from 2 to 6.

9. The thermoplastic polyurethane of claim 8, wherein the at least one diol chain extender comprises 1,4-butane diol.

10. A thermoplastic polyurethane, comprising the reaction product of: a. a polydiisocyanate; b. a substituted 2,5-diketopiperazine of the formula: ##STR00006## wherein: R and R′ are the side chain of an amino acid containing a functional group comprising —OH, —COOH, —NH, —NH.sub.2 or —SH, and R and R′ may be the same or different; and c. a polyol component.

11. The thermoplastic polyurethane of claim 10, wherein the substitution is a symmetrical or asymmetrical substitution.

12. The thermoplastic polyurethane of claim 10, wherein the substituted 2,5-diketopiperazine is present in an amount from 5 wt % to 45 wt % of the total weight of the thermoplastic polyurethane composition.

13. The thermoplastic polyurethane of claim 10, wherein the amino acid is selected from the group consisting of glutamic acid, serine, lysine, aspartic acid, cysteine, arginine, histidine, glutamine, asparagine, threonine, hydroxyproline, tryptophan, tyrosine, and optical isomers thereof.

14. The thermoplastic polyurethane of claim 13, wherein R and R′ are the side chains of tyrosine.

15. The thermoplastic polyurethane of claim 13, wherein R and R′ are the side chains of lysine.

16. The thermoplastic polyurethane of claim 13, wherein R and R′ are the side chains of serine.

17. The thermoplastic polyurethane of claim 13, wherein R and R′ are the side chains of hydroxyproline.

18. The thermoplastic polyurethane of claim 13, wherein R and R′ are the side chains of glutamic acid.

19. The thermoplastic polyurethane of claim 13, wherein R and R′ are the side chains of aspartic acid.

20. The thermoplastic polyurethane of claim 13, wherein R and R′ are the side chains of cysteine.

21. The thermoplastic polyurethane of claim 13, wherein R and R′ are the side chains of arginine.

22. The thermoplastic polyurethane of claim 13, wherein R and R′ are the side chains of histidine.

23. The thermoplastic polyurethane of claim 13, wherein R and R′ are the side chains of glutamine.

24. The thermoplastic polyurethane of claim 13, wherein R and R′ are the side chains of threonine.

25. The thermoplastic polyurethane of claim 13, wherein R and R′ are the side chains of asparagine.

26. The thermoplastic polyurethane of claim 13, wherein R and R′ are the side chains of tryptophan.

27. A method of making a thermoplastic polyurethane, comprising the step of (I) reacting: a) a polydiisocyanate component; b) a polyol component; and c) at least one chain extender component comprising a cyclic dimer of an amino acid having a side chain containing a functional group comprising —OH, —COOH, —NH, —NH.sub.2 or —SH.

Description

EXAMPLES

(1) The technology described herein may be better understood with reference to the following non-limiting examples.

(2) Materials

(3) The materials are generally commercially available and were purchased from Sigma Aldrich, Fisher and Fluka and used as received unless stated otherwise, as indicated below.

(4) TABLE-US-00001 Cmmercial Name Identity source Amino acids Alfa Aeser HMDI ,4′-Methylenebis(cyclohexyl isocyanate) TCI LDI L-Lysine diisocyanate ethyl ester Carbosynth PCL2000 (dried under vacuum) Polycaprolactone diol M.sub.n~2000 The Lubrizol Corporation Amberlyst A21 (washed with Free base resin Sigma MeOH and dried before use) Aldrich BDO (distilled over CaH.sub.2) 1,4-butane diol Sigma Aldrich DBU (distilled over CaH.sub.2) 1,8-Diazabicyclo[5.4.0]undec-7-ene Sigma Aldrich DMSO (dried over activated 3Å dimethylsulfoxide Fisher molecular sieves for minimum 24 hrs)

(5) .sup.1H and .sup.13C NMR spectra were obtained on a Bruker DPX-400 spectrometer (400 MHz) at 293 K. All chemical shifts were reported as δ in parts per million (ppm) and referenced to the residual solvent signal. FT-IR spectra were recorded on a Perkin Elmer FT-IR spectrometer and were obtained from a thin film of the product expressing the absorption maxima are expressed in wavenumbers (cm.sup.−1). Gel permeation chromatography (GPC) was used to determine the number (M.sub.n) and weight average molecular weight (M.sub.w). GPC was conducted in dimethylformamide (DMF) using an Varian PL-GPC 50 system equipped with 2×PLgel 5 μL MIXED-D columns in series and either a differential refractive index (RI) detector or triple detection at a flow rate of 1.0 mL min at 50° C. The systems were calibrated against

(6) Varian Polymer Laboratories Easi-Vial linear poly(methyl methacrylate) (PMMA) or PMMA single standard M.sub.n=73200 and respectively and analyzed by the software package Cirrus v3.3. Thermal gravimetric analysis (TGA) was conducted using a Mettler Toledo DSC1 star and a TGA/DSC star system between 25 and 550° C. at a heating rate of 10° C. min.sup.−1 in a 40 μL aluminum crucible. Tensile data was obtained at ambient temperature by axially loading “dog-bones” (10 mm length) in a Tensiometric M100-1CT system with a load cell capacity of 1 kN and crosshead speed of 10 mm min.sup.−1 with a premeasured grip-to-grip separation. All values reported were obtained from an average of 5 repeat specimens and the results were recorded using winTest v4.3.2 software. Molten polymer samples were molded into “dog-bones” via compression moulding. The melting points were measured on a MPA100 OptiMelt. Percentage crystallinity was measured using wide angle X-ray diffraction measurements (WAXS) were carried out with a Panalytical X-Pert Pro MPD Diffractometer equipped with a focussing Johanson monochromator and using Cu K.sub.α1 radiation (40 kV; 40 mA). Contact angles of polymer films evaporated on glass slides were measured on the Krüss DSA 100 Drop Shape Analyser using DSA3 software.

(7) Synthesis of Dipeptide-based Monomers

Example 1

Cyclic Dipeptide of L-Tyrosine

(8) The synthesis of the diketopiperazine of L-tyrosine is prepared as adapted from U.S. Pat. No. 7,709,639B2 to use as follows. L-Tyrosine (10 g, 5.52×10.sup.−2 mol) and phosphorus pentoxide (0.71 g, 5.28×10.sup.−3 mol) in m-cresol (20 mL) is stirred at 180-200° C. for 8 hours. After cooling to ambient temperature, the reaction is quenched with a mixture of deionized H.sub.2O (10 mL) and MeOH (40 mL). The crude product precipitates from solution and the suspension is stirred for 1 hour. Additional MeOH (40 mL) is added, the precipitate is collected by filtration, washed with MeOH, deionized H.sub.2O and MeOH. The product is recrystallized from glacial acetic acid (3 mL per g crude product) and then suspended in a 1:1 mixture of deionized H.sub.2O and MeOH. The product is dried under vacuum to produce an off-white solid with a yield of 65%.

Example 2

Cyclic Dipeptide of L-serine

(9) The diketopiperazine of L-serine is prepared in a two-step synthesis. Initially, the amino acid is converted into the methyl ester hydrochloride according to literature (J. Org. Chem. (1997), 62, 372-376). Acetyl chloride (20,41 g, 2.59×10.sup.−1 mol) is added dropwise to ice-cold MeOH (343 mL) under stirring. After ten minutes, L-serine (10 g, 9.63×10.sup.−2 mol) is added in one portion and the reaction mixture is allowed to reflux for 2.5 hours. The solvent is removed under vacuum and the raw product is recrystallized from MeOH (white solid, yield 100%). The synthesis of the diketopiperazine is then is conducted according to U.S. Pat. No. 4,871,736 (referred to J. Heterocycl. Chem. (1975), 12, 147-149). L-Serine methyl ester hydrochloride (10 g, 6.43×10.sup.−2 mol) is dissolved in MeOH (100 mL) and flushed through a column of Amberlyst A21 free base resin (pre-treated with 100 ML of a saturated aqueous solution of NaHCO.sub.3). Additional MeOH (50 mL) is flushed through the column. After removal of the solvent under vacuum, an oily liquid is obtained. The resulting free base dimerized over night at room temperature forming a crystalline solid. The crude product is recrystallized from deionized H.sub.2O and the product dried under vacuum to produce a white solid with a yield of 54%.

Example 3

Cyclic Dipeptide of L-glutamic acid

(10) The diketopiperazine of L-glutamic acid is prepared in a two-step synthesis according to literature (J. Org. Chem. (2002), 67, 6, 1820-1826). First, pyroglutamic diketopiperazine is prepared by adding L-pyroglutamic acid (10 g, 7.75×10.sup.−2 mol) to a 110° C. preheated stirred solution of acetic anhydride (45 mL) and pyridine (8 mL). After approximately 5 minutes the product starts to precipitate from the solution and heating is continued for a further 15 minutes. After cooling to room temperature, the product is collected by filtration and washed with cold MeOH. The product is purified by stirring in MeOH and deionized H.sub.2O and dried under vacuum (white solid, yield 82%). Second, the pyroglutamic diketopiperazine (5 g, 2.28×10.sup.−2 mol) is added to ice-cold H.sub.2SO.sub.4 under stirring until complete dissolution. The solution iss cooled in an ice-bath and deionized water is slowly added under vigorous stirring. The product precipitates from the solution and is collected by filtration. The product is washed with hot MeOH and dried under vacuum to produce a white solid with a yield of 72%.

Example 4

Cyclic Dipeptide of L-lysine

(11) The diketopiperazine of L-serine is prepared in a three-step synthesis. First, L-lysine is selectively EN-protected by a copper complex according to literature (Biomacromolecules (2010), 11, 11, 2949-2959). A solution of CuSO.sub.4×5H.sub.2O (6.92 g, 2.76×10.sup.−2 mol) in deionised H.sub.2O (20 mL) is added to a solution of L-lysine hydrochloride (10 g, 5.54×10.sup.−2 mol) and NaOH (4.34 g, 1.09×10.sup.−1 mol) in deionized H.sub.2O (50 mL). NaHCO.sub.3 (5.48 g, 7.14×10.sup.−2 mol) is added after cooling the solution to 0° C. Thereafter, benzyl chloroformate (9 mL, 6,30×10.sup.−2 mol) is added dropwise under nitrogen over a period of 20 minutes. The reaction mixture is allowed to stir for 1 hour at 0° C. and continued stirring for 17 hours at room temperature. The blue precipitate is collected by filtration and washed with deionized H.sub.2O (200 mL), acetone (100 mL) and CHCl.sub.3 (50 mL) and then air dried. The blue copper complex is refluxed for 1.5 h in a suspension of EDTA (16.78 g, 5.74×10.sup.−2 mol) in deionized H.sub.2O (120 mL). After cooling to room temperature, aqueous NaOH solution (2 M) is added to obtain a final pH of 7. The white solid is collected by filtration and washed successively with deionized H.sub.2O. The product is recrystallized from deionized H.sub.2O (off-white solid, yield 85%). Second, the synthesis of the diketopiperazine was conducted according to U.S. Pat. No. 7,709,639B2. εN-Cbz-L-Lysine (5 g, 1.78×10.sup.−2 mol) and phosphorus pentoxide (0.36 g, 2.64×10.sup.−3 mol) in m-cresol (10 mL) is stirred at 165° C. for 1.5 hours. After cooling to ambient temperature, the reaction is quenched with a mixture of deionized H.sub.2O (5 mL) and MeOH (20 mL). The crude product precipitates from solution and the suspension is stirred for 1 hour. Additional MeOH (20 mL) is added, the precipitate is collected by filtration, washed with MeOH, deionized H.sub.2O and MeOH. The product is recrystallized from glacial acetic acid (3 mL per g crude product) and afterwards suspended in a 1:1 mixture of deionized H.sub.2O and MeOH. The product is dried under vacuum (yield 42%). Finally, the diketopiperazine hydrobromide is obtained by deprotection. εN-Cbz-Protected diketopiperazine (2 g, 3.81×10.sup.−3 mol) is suspended in formic acid (2 mL) and hydrobromic acid solution (33% in acetic acid) (2 mL) is added dropwise. The starting material dissolves almost completely and with rapid evolution of gas (carbon dioxide) the product starts to precipitate from the solution. After 30 min, additional hydrobromic acid solution (2 mL) is added to complete the reaction. After a total reaction time of 2 hours, anhydrous ethyl ether (12 mL) is added to the reaction mixture to complete the precipitation. The product is successively washed with ethyl ether and dried under vacuum to produce a white solid with a yield of 54%.

Example 5

Cyclic dipeptide of 4-hydroxy-L-proline

(12) The diketopiperazine of 4-hydroxy-L-proline is prepared in a two-step synthesis. First, the amino acid is converted into the methyl ester hydrochloride according to literature (Tetrahedron (1995), 51, 9, 2719-2728). Thionyl chloride (8.5 g, 7.60×10.sup.−2 mol) is added dropwise to an ice-cooled suspension of 4-hydroxy-L-proline (10 g, 7.60×10.sup.−2 mol) in MeOH (250 mL). The reaction solution is allowed to stir for 4 hours at room temperature. The solvent is removed under vacuum and traces of thionyl chloride are removed by co-evaporation with dichloromethane (white solid, yield 100%). Second, the synthesis of the diketopiperazine is adapted from the synthesis of the diketopiperazine of L-proline (or J. Heterocycl. Chem. (1975), 12, 147-149) to use as follows: Hydrazine monohydrate (2.75 g, 5.50×10.sup.−2 mol) is added to a solution of 4-hydroxy-L-proline methyl ester hydrochloride (5 g, 2.75×10.sup.−2 mol) in MeOH (13.75 mL). The mixture is allowed to stir for 16 hours at room temperature. The precipitate is collected by filtration and washed with MeOH.

(13) The product is dried under vacuum to produce a white solid with a yield of 60%.

(14) Polymer Synthesis

(15) Polyurethanes are synthesized in either a 2-step or 1-pot reaction. In general, the first step of the 2-step reaction is the formation of the prepolymer by the reaction of PCL diol in DMSO (100% (v/v)) with an excess amount of diisocyanate. The reaction is conducted under a nitrogen flow at 60° C. using DBU (5 mol % of macrodiol) as catalyst. After 30 min the temperature is raised to 100° C. and the cyclic dipeptide extender (dissolved/suspended in hot DMSO (50% (w/v)) and tetrabutylammonium bromide (200% (w/w))) is added. The reaction is followed upon completion by FT-IR (1-3 h) indicated by the disappearance of the NCO signal. The viscous crude product mixture is poured into MeOH/H.sub.2O (1:1) and after decanting the solvent the remaining DMSO in the polymer is removed under vacuum for 2 days at 50° C.

(16) The 1-pot reaction is conducted at 100° C. by adding the diisocyanate to a mixture of PCL, cyclic dipeptide extender and DBU in DMSO using the same calculated equivalents amounts as in the 2-step reaction. The hard segment of the polyurethanes is calculated according to the following formula:

(17) $\%\mathrm{HS}=\frac{100\left(R-1\right)\left(M_{\mathrm{di}}+M_{\mathrm{da}}\right)}{\left[M_{\mathrm{.Math.}}+R\left(M_{\mathrm{di}}\right)+\left(R-1\right)\left(M_{\mathrm{da}}\right)\right]}$
where, R=ratio of diisocyanates divided by polyols; M=molecular weight; di=diisocyanate; da=diol; and ε=polydiol.

(18) The following Table 1 summarizes the formulation of the Samples, where Inventive Examples 1-8 are thermoplastic polyurethanes made with a cyclic dipeptide chain extender, and Inventive Examples 9-11 are thermoplastic polyurethanes which are co-extended with a 1,4-butane diol chain extender in addition to the cyclic dipeptide chain extender.

(19) TABLE-US-00002 TABLE 1 Formulations of Examples Cyclic Dipeptide based amino % Diiso- % Hard M.sub.n M.sub.w Sample acid BDO cyanate Segment (g/mol) (g/mol) Inv. L-tyrosine H12MDI 15 52366 154711 Ex 1  Inv. L-tyrosine H12MDI 30 49472 80312 Ex 2  Inv. L-tyrosine H12MDI 45 26522 48475 Ex 3  Inv. DL- H12MDI 30 28093 48815 Ex 4  tyrosine Inv. L-serine 30 32438 102962 Ex 5  Inv. 4-hydroxy- H12MDI 30 54521 95909 Ex 6  L-proline Inv. L-glutamic H12MDI 30 48273 83762 Ex 7  acid Inv. L-lysine H12MDI 30 13824 21626 Ex 8  Comp 100 H12MDI 30 15324 26484 Ex 1 Inv. L-tyrosine 10 H12MDI 30 34433 62029 Ex 9  Inv. L-tyrosine 5 H12MDI 30 33211 60166 Ex 10 Inv. L-tyrosine 1.25 H12MDI 30 34117 61280 Ex 11

(20) Each sample in Table 1 is tested to verify its mechanical properties (strength, modulus and elongation as measured by ASTM D412) and degradation onset and peak, as measured by thermogravimetric analysis (TGA).

(21) TABLE-US-00003 TABLE 2 Physical Properties Results from Formulations of Table 1 4 Physical properties Degradation Degradation Tensile Young′s Ultimate onset peak strength Modulus elongation Sample (° C.) (° C.) (MPa) (MPa) (%) Inv. Ex 1 385.56 442.27 11.74 31.20 655.19 Inv. Ex 2 386.64 450.22 13.18 6.55 611.64 Inv. Ex 3 376.84 437.70 10.93 64.91 212.26 Inv. Ex 4 386.64 450.22 7.42 6.36 661.22 Inv. Ex 5 207.68 327.79 10.89 4.81 484.18 339.38 385.39 Inv. Ex 6 216.86 220.34 1.19 4.92 289.40 327.97 246.95 Inv. Ex 7 189.26 251.97 9.99 7.58 619.42 340.61 389.11 Inv. Ex 179.25 244.75 — — — 8* 326.17 359.78 Comp. Ex 347.21 409.64 7.28 68.26 23.40 1 Inv. Ex 9 226.41 252.51 8.45 11.35 706.95 351.58 390.87 Inv. Ex 225.08 436.11 9.40 11.06 788.71 10 343.11 Inv. Ex 229.88 252.35 9.90 15.90 816.88 11 348.80 384.33 * = glass-like material
In Vitro Degradation

(22) The raw TPU material is melted into small discs (Ø 1 cm, ˜1 mm thickness) and all degradation studies are conducted in an incubator at 37° C. and 100 rpm. Sodium hydroxide (5 M NaOH) is used to accelerate the hydrolysis reaction. Phosphate buffered saline (PBS) at pH 7.4 is used to simulate in vivo conditions. The samples are removed at predetermined time points, rinsed with deionized water and left for minimum 1 hour drying at 100° C. before weighting. The mass loss is evaluated in triplicates determining the difference in mass between the final mass at specific time points and the initial mass expressed in percentage. PCL degradation in Biomed. Mater. (2008), 3, 1-15 was used as reference. Enzymes from animal sources (Sigma Aldrich) are used at an activity of 40 U/mL to simulate enzymatic degradation. The samples are removed at predetermined time points, rinsed with deionized water and the surface is wiped with tissue before weighting.

(23) The accelerated degradation of cyclic dipeptide-based thermoplastic polyurethanes using different amino acids under basic conditions is shown in Table 3 below.

(24) TABLE-US-00004 TABLE 3 Accelerated Degradation under basic conditions (5M NaOH) Inv Inv Inv Inv Inv Inv Inv Time Ex1 Ex2 Ex3 Ex5 Ex6 Ex7 Ex8 (h) Remaining weight (%) 0 100 100 100 100 100 100 100 1 100.50 100.53 99.07 100.25 75.04 96.98 80.62 3 99.11 98.68 43.90 93.51 44.07 90.27 72.48 5 96.50 93.19 37.55 92.99 16.95 84.70 55.88 8 96.35 89.42 16.54 72.08 2.36 72.30 15.98 12 91.53 77.37 4.22 55.81 — 63.60 7.21 24 79.08 65.21 4 42.12 — 42.38 — 48 65.74 53.87 — 28.66 — 27.53 — 72 60.67 46.29 — 21.95 — 16.00 — 96 41.42 37.26 — 13.51 — 8.01 — 144 28.77 30.85 — — — — — 192 11.24 13.42 — — — — —

(25) Each of the documents referred to above is incorporated herein by reference, including any prior applications, whether or not specifically listed above, from which priority is claimed. The mention of any document is not an admission that such document qualifies as prior art or constitutes the general knowledge of the skilled person in any jurisdiction. Except in the Examples, or where otherwise explicitly indicated, all numerical quantities in this description specifying amounts of materials, reaction conditions, molecular weights, number of carbon atoms, and the like, are to be understood as modified by the word “about.” It is to be understood that the upper and lower amount, range, and ratio limits set forth herein may be independently combined. Similarly, the ranges and amounts for each element of the technology described herein can be used together with ranges or amounts for any of the other elements.

(26) As described hereinafter the molecular weight of the materials described above have been determined using known methods, such as GPC analysis using polystyrene standards. Methods for determining molecular weights of polymers are well known. The methods are described for instance: (i) P. J. Flory, “Principles of star polymer Chemistry”, Cornell University Press 91953), Chapter VII, pp 266-315; or (ii) “Macromolecules, an Introduction to star polymer Science”, F. A. Bovey and F. H. Winslow, Editors, Academic Press (1979), pp 296-312. As used herein the weight average and number weight average molecular weights of the materials described are obtained by integrating the area under the peak corresponding to the material of interest, excluding peaks associated with diluents, impurities, uncoupled star polymer chains and other additives.

(27) As used herein, the transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, un-recited elements or method steps. However, in each recitation of “comprising” herein, it is intended that the term also encompass, as alternative embodiments, the phrases “consisting essentially of” and “consisting of,” where “consisting of” excludes any element or step not specified and “consisting essentially of” permits the inclusion of additional un-recited elements or steps that do not materially affect the basic and novel characteristics of the composition or method under consideration. That is “consisting essentially of” permits the inclusion of substances that do not materially affect the basic and novel characteristics of the composition under consideration.

(28) While certain representative embodiments and details have been shown for the purpose of illustrating the subject technology described herein, it will be apparent to those skilled in this art that various changes and modifications can be made therein without departing from the scope of the subject invention. In this regard, the scope of the technology described herein is to be limited only by the following claims.