POLYURETHANES BASED ON SIDE CHAIN DIOL- AND DIAMINOPOLYPHOSPHAZENES AND THEIR HYDROGELS

Abstract

The present invention relates to polyphosphazenes, polyurethanes based on these polyphosphazenes, methods for their manufacture and hydrogels based on the polyurethanes. The invention further relates to the use of the hydrogels in medical, veterinary and agricultural applications. The terminal ends of the polyphosphazenes bear NCO-reactive hydrogen atoms for reaction with polyisocyanates.

Claims

1. A polyphosphazene comprising the structural unit according to general formula (I): ##STR00004## where: each radical ZH is, independent of other radicals ZH, a group comprising an NCO-reactive hydrogen atom; each radical X is, independent of other radicals X, an organic rest; each radical R.sub.1 is, independent of other radicals R.sub.1, hydrogen or an organic radical; each radical R is, independent of other radicals R, halogen, an organic radical or the radical group NR.sub.1—X—ZH, n is a positive integer and wherein at least one radical X comprises one of the following groups: —B—CH.sub.2—CH.sub.2—, —Si—CH.sub.2—CH.sub.2—or —S—CH.sub.2—CH.sub.2—, wherein the —CH.sub.2—CH.sub.2— groups are located between the B, Si or S atoms and an N atom to which radicals R.sub.1 are bond.

2. The polyphosphazene according to claim 1, wherein at least one radical ZH is a hydroxyl group, a primary amino group or a secondary amino group.

3. The polyphosphazene according to claim 1 or 2, wherein at least one radical X comprises one of the following groups: —(CH.sub.2).sub.m—B—, —(CH.sub.2).sub.m—Si—or —(CH.sub.2).sub.m—S— with m being an integer from 1 to 16, wherein the —(CH.sub.2).sub.m, — groups are located between the B, Si or S atoms and a radical ZH.

4. The polyphosphazene according to one of claims 1 to 3, wherein at least one radical X—ZH comprises the group —(CH.sub.2).sub.m—C(═O)—O—(CH.sub.2).sub.o—S—(CH.sub.2).sub.p—OH or —(CH.sub.2).sub.m—C(=O)—O—(CH.sub.2).sub.o—S—(CH.sub.2).sub.p—NH.sub.2 with m, o and p independently being an integer from 1 to 16.

5. The polyphosphazene according to one of claims 1 to 4, wherein the radical group NR.sub.1—X comprises an ester of an α-amino acid as a structural unit.

6. A method of manufacturing a polyphosphazene comprising the structural unit according to general formula (II), the method comprising reacting a C═C double bond-carrying compound comprising the structural unit of general formula (III) with an element-hydrogen bond-carrying compound according to general formula H—E—L—ZH: ##STR00005## where: each radical E is, independent of other radicals E, B, Si or S; each radical L is, independent of other radicals L, an organic radical; each radical ZH is, independent of other radicals ZH, a group comprising an NCO-reactive hydrogen atom; each radical R.sub.1 is, independent of other radicals R.sub.1, hydrogen or an organic radical; each radical R.sub.2 is, independent of other radicals R.sub.2, halogen, an organic radical or the radical group NR.sub.1—Y—; each radical Y is, independent of other radicals Y, an organic rest and n is a positive integer.

7. A polyurethane polymer obtained by reacting a polyphosphazene (I) according to one of claims 1 to 5 with a polyisocyanate.

8. A method of manufacturing a polyurethane polymer comprising the step of reacting a polyphosphazene (I) according to one of claims 1 to 5 with a polyisocyanate.

9. The polymer of claim 7 or the method of claim 8, wherein the polyisocyanate is an NCO-terminated prepolymer obtained by the reaction of a monomeric polyisocyanate and a polyether polyol.

10. The polymer of claim 9 or the method of claim 9, wherein the polyether polyol is a random copolymer of an alkylene oxide and a comonomer selected from: lactides, glycolides, cyclical dicarboxylic acid anhydrides and mixtures of at least two of the aforementioned compounds.

11. A hydrogel obtained by contacting a polyphosphazene (I) according to one of claims 1 to 5 and/or a polyurethane according to claim 7 with water.

12. The hydrogel of claim 11, further comprising, distributed within the hydrogel, a pharmaceutical compound, a pesticide, a herbicide, a pheromone or a combination of at least two of the aforementioned compounds.

13. A hydrogel according to claim 11 for use as a post-operative separator between internal organs of a human or an animal.

14. A hydrogel according to claim 12 for use as a delayed-release formulation for the pharmaceutical compound, pesticide, herbicide, pheromone or combination of at least two of the aforementioned compounds distributed within the hydrogel.

Description

EXAMPLES

[0067] The present invention will be further described with reference to the following figures and examples without wishing to be bound by them.

[0068] Desmodur LP DSB 3227 (“DSB 3227”) designates a trifunctional NCO-terminated prepolymer with an NCO content of 2.6% (DIN EN ISO 11909) obtained from hexamethylene diisocyanate and a trifunctional poly(oxyethylene) polyol having an ethylene oxide content of 70 to 75 weight % and a number-average molecular weight of 4500 g/mol.

Example 1: Polyphosphazene Polyol Via Thiol-Ene Addition—FIG. 1

[0069] 1 g allylglycine polyphosphazene (prepared according to WO 2015/192158) was weighed into a UV-transparent vessel and dissolved in 10 mL MeOH. Then, 0.51 mL (7.28 mmol) mercaptoethanol was added to the solution. As photoinitiator, 0.01 g (0.04 mmol) 2,2-dimethoxy-2-phenylacetophenone (DMPA) was added and the solution purged with N.sub.2 for 30 minutes. The solution was then irradiated for 3 hrs at 5° C. in a UV-reactor (254 nm). The volatiles were removed under vacuum at 40° C. and 337 mbar, followed by further drying under vacuum. .sup.1H-NMR DMSO-d.sub.6: 1.83 (s 2H) 2.5 (s 4H) 3.52 (m 2H) 3.63 (m 2H) 4.09 (s 1H) 4.78 (s 1H) 7.63 (m 0.3H) ppm. .sup.31P-NMR: 0.89 and 10.71 and .sup.13C-NMR: 28.20; 28.83; 34.23; 42.95; 61.27; 63.50; 129-133; 172.76 ppm.

Example 2: Polyurethane Synthesis from Polyphosphazene Polyols and Hydrogel—FIG. 2

[0070] A 10% w/w solution of the polyphosphazene polyol of example 1 in DMSO was prepared. 0.57 mL of the solution was added to 0.5 g Desmodur LP DSB 3227 and stirred vigorously. Subsequently, the mixture was poured into a glass form with a thickness of 1 mm and dimensions of 10*10 cm. After evacuation of air, the reaction was allowed to proceed for 72 h at room temperature for gelation to occur. The reaction was quenched upon the addition of 5 mL MeOH. FTIR: 1667 C═O; 2269 N═C═O; 2865 C—H; 3505 N—H. Solid state .sup.31P-NMR: 0.51 ppm. Soaking in 37° C. phosphate buffer (pH=7.4) produced a hydrogel.

Example 3: Degradation Studies—FIG. 3

[0071] For degradation studies, samples of hydrogels obtained according to example 2 were placed in a mechanical shaker in phosphate buffer pH 7.4 at 37° C. and dried and weighed at regular time intervals. The results are depicted in FIG. 3.

Example 4: Cytotoxicity Studies—FIGS. 4a to 4d

[0072] Cytotoxicity studies of the following selection of materials were carried out. “Ppz-OH” designates the polyphosphazene polyol of example 1.

TABLE-US-00001 Sample no. Ratio (weight:weight) Components Blank 1:1 DSB 3227:glycerol Sample I 1:1 DSB 3227:Ppz-OH Sample II 1:2 DSB 3227:Ppz-OH Sample III   1:0.5 DSB 3227:Ppz-OH

[0073] The hydrogels were tested against three cell lines: human embryonic kidney (HEK), normal dermal fibroblasts and normal vascular fibroblasts and were shown to have excellent biocompatibility. The results are depicted in FIGS. 4a to 4d. Studies of the supernatant for buffer immersed hydrogels showed no inhibition of cell proliferation after 24 h for all three tested cell lines (FIGS. 4a to 4c). After 48 and 72 hours, for all of the hydrogels (including the blank specimen) only very slight inhibition in proliferation is observed (FIGS. 4a to 4c). Contact assays showed good cell growth in contact with the hydrogels and hence the absence of toxicity. Direct growth was not possible on all of the hydrogels due to lack of binding, although even in these cases the cells continued to grow around the gels, suggesting a lack of any cytotoxicity (FIG. 4d).

Example 5: Release Studies—FIGS. 5a to 5f

[0074] In this series of experiments three exemplary active pharmaceutical ingredients (APIs) having the international nonproprietary names (INNs) of ibuprofen, nimodipine and nifedipine were incorporated into hydrogels and their release was monitored.

[0075] Drug loading was conducted by in-situ gelation. To the gelation mixture of DSB 3227 (1.2877 g) and a solution of the polyphosphazene polyol of example 1 (0.185 g in 3.1 mL DMSO), API (ca. 200 mg) was added before mixing. After pouring the mixture in a culture dish, the gel was cured under vacuum for 48 h. The gels were then soaked in DMSO:H.sub.2O mixture (10 mL, 1:1 ratio). At certain time intervals samples (1 mL) were taken from the stirred solution and new buffer was added. These samples were measured by UV-Vis spectroscopy with the concentration of APIs released measured from calibrations curves for the free compounds. Where necessary, the samples were further diluted to achieve a value below 1 for this calculation.

[0076] FIGS. 5a and 5b show cumulative release profiles and exemplary UV-Vis spectra, respectively, for the hydrogel containing ibuprofen. FIGS. 5c and 5d show cumulative release profiles and exemplary UV-Vis spectra, respectively, for the hydrogel containing nifedipine. FIGS. 5e and 5f show cumulative release profiles and exemplary UV-Vis spectra, respectively, for the hydrogel containing nimodipine. In FIG. 5d the apparent inconsistency in the order of the release curves—the absorption curve for 0 minutes has higher absorption values than the curves for 1 minute and for 5 minutes—is attributed to unavoidable experimental uncertainties when measuring UV-Vis spectra at low concentrations of the analyte.