NON-ISOCYANATE POLYURETHANE THERMOREVERSIBLE HYDROGEL AND METHOD FOR ITS PREPARATION

Abstract

The present invention relates to non-isocyanate polyurethane thermoreversible hydrogel comprising poloxamers, aliphatic di-urethanes, aliphatic di-esters and polyethylene glycol and to a method for their preparation.

Claims

1. Thermoreversible hydrogel of general formula I:
HO-{M-Y}.sub.n-A-H  Formula I wherein: HO— represents a hydroxyl group; M represents a moiety which is represented by a moiety X or moiety Z, such that at least one X moiety and at least one Z moiety are present in the formula I, wherein: each moiety X represents one of the poloxamers with the formula:
—(CH.sub.2—CH.sub.2—O).sub.a—(CH.sub.2—CH(CH.sub.3)—O).sub.b—(CH.sub.2—CH.sub.2—O).sub.a—  wherein a is an integer from 20 to 100 and b is an integer from 70 to 85; each moiety Z represents one of the aliphatic di-urethanes with the formula:
—R.sub.1—OOCNH—R.sub.2—NHCOO—R.sub.1—,  wherein R.sub.1 represents an aliphatic radical with 2 to 3 carbon atoms and R.sub.2 represents an aliphatic moiety with 2 to 8 carbon atoms; each Y represents one of the aliphatic diester moieties with the formula:
—OOC—(CH.sub.2).sub.y—COO—,  wherein y represents an integer between 2 and 10; A represents a PEG (polyethylene glycol) moiety having the formula:
—(CH.sub.2—CH.sub.2—O).sub.w— with a molecular mass of 400 to 3000 g/mole wherein w is an integer representing the number of ethylene glycol moieties in the PEG; n represents the degree of polymerization and is an integer from 2 to 12.

2. Thermoreversible hydrogel according to claim 1, which is free from isocyanate.

3. Thermoreversible hydrogel according to claim 1, wherein each moiety X may be any of: Pluronic P-123, which is a poloxamer having a molecular mass of 5800 g/mole and wherein a=20 and b=70, Pluronic F-127, which is a poloxamer having a molecular mass of 12600 g/mole and wherein a=100 and b=83.

4. Thermoreversible hydrogel according to claim 3, wherein each moiety X may be further be polyethylene glycol.

5. Thermoreversible hydrogel according to claim 1, wherein each moiety Y may be represented by any of the aliphatic diesters of succinic acid, glutaric acid or sebacic acid.

6. Thermoreversible hydrogel according to claim 1, wherein each moiety Z may represented by a di-urethane wherein radical R.sub.2 having 4 or 5 carbon atoms.

7. Method for the preparation of a thermoreversible hydrogel of formula I, comprising the following steps: i) ethylene carbonate and/or propylene carbonate is dissolved in pure water without CO.sub.2 in a suitable reactor; ii) an aqueous solution of an aliphatic diamine with 2 to 8 carbon atoms is added at a temperature of 1° C. to 30° C. and under inert atmosphere; iii) a poloxamer X as defined above is added and the composition is stirred until the pH drops under 8; iv) the water is eliminated from the reactor at low temperature (−100° C. to −80° C.) and low pressure (0.1-0.2 mmHg); v) the temperature of the anhydrous paste obtained after step iv) is slowly raised to about 20° C. to 100° C.; vi) an aliphatic diester Y as defined above is added under energetic stirring and the resulting gases are eliminated, for example with a vacuum pump; vii) PEG is added and the system is homogenized, and the resulting gases are eliminated, for example with a vacuum pump.

8. Method according to claim 7, wherein no isocyanates and no catalysts are used.

9. Thermoreversible hydrogel according to claim 1, wherein the R.sub.2 represents an aliphatic moiety with 2 to 6 carbon atoms.

10. Thermoreversible hydrogel according to claim 1, wherein the y represents an integer between 2 and 8.

11. Thermoreversible hydrogel according to claim 1, wherein the A has a molecular mass of 400 to 3000 g/mole

12. Thermoreversible hydrogel according to claim 1, wherein the A has a molecular mass of about 2000 g/mole.

13. Thermoreversible hydrogel according to claim 1, wherein the n is an integer from 2 to 6.

14. Method according to claim 7, wherein the aqueous solution of aliphatic diamine has 2 to 6 carbon atoms.

15. Method according to claim 7, wherein the aqueous solution is added at a temperature of 1° C. to 10° C.

16. Method according to claim 7, wherein the aqueous solution is added at a temperature of 2° C. to 4° C.

17. Method according to claim 7, wherein the temperature of the anhydrous past obtained after step iv) is slowly raised to 30° C. to 60° C.

18. Method according to claim 7, wherein the temperature of the anhydrous past obtained after step iv) is slowly raised to about 53° C.

Description

FIGURES

[0063] FIG. 1—Illustrates the characteristic vibrations FTIR for a hydrogel according to example 1 of the invention measured at 25° C.

[0064] FIG. 2—illustrates, for example 1 of the invention, the evolution with temperature of viscoelastic parameters (G′, G″, tan δ) at a heating rate of 0.5° C./min (1 Pa, 1 rad/s)

[0065] FIG. 3—illustrates, for Example 1 of the invention, the evolution of complex viscosity (η*) as a function of time (t) at 37° C., during gelation.

EXAMPLE 1

[0066] 1.0566 g (0.0012 moles) of etylene carbonate 99% (Sigma-Aldrich) were placed in a 250 cm.sup.3 cylindric glass reactor equipped with stirring means, vacuum pump and a nitrogen supply. 2 ml pure water without CO.sub.2 were then added and gently stirred for 20 minutes at 35° C. The temperature was then lowered to 2-4° C. and then, under pure N.sub.2 blanket and energetic stirring, a solution of 0.6 ml (0.006 moles) of 1,4-butanediamine (putrescene) 99% (Sigma Aldrich) in 2 ml pure water without CO.sub.2 was added drop by drop over 60 minutes. Thereafter, the components were lightly stirred together for another 4 hours, and then 116 g of Pluronic P-123 (Sigma-Aldrich) were added and the light stirring is continued for another 20 hours. The reactor was then coupled to the vacuum pump provided with a trap for retaining water at −100 to −80° C. and low pressure (0.1 to 0.2 mmHg), and the water was eliminated from the system for 8 hours, resulting an anhydrous paste having pH 7.4 to 7.6 at 25° C. The temperature of the system was slowly raised to 53° C., under dry nitrogen blanket, and then 8.3 g of dimethyl sebacate 99% (Sigma-Aldrich) were added under energetic stirring, after which the vacuum pump was turned on for 4 hours. Then, 40 g polyethylene glycol (PEG BioUltra 2000 (Sigma-Aldrich)) were added and the system was homogenized and the resulting gases were pumped out until eliminated. At the end of this process, it is obtained a thermoreversible polyurethane hydrogels soluble in water or normal saline with the general formula:

HO—(CH.sub.2—CH.sub.2—O).sub.20—(CH.sub.2—CH(CH.sub.3)—O).sub.70—(CH.sub.2—CH.sub.2—O).sub.20—OOC—(CH.sub.2).sub.8—COO—(CH.sub.2).sub.2—OOCNH—(CH.sub.2).sub.4—NHCOO—(CH.sub.2).sub.2—OOC—(CH.sub.2).sub.8—COO— . . . —(CH.sub.2—CH.sub.2—O).sub.w—H

[0067] The properties of the hydrogel thus obtained are depicted in FIGS. 1 to 3.

[0068] In FIG. 1, are illustrated the characteristic vibrations FTIR for the hydrogel of example 1, measured at 25° C. by Fourier-transform infrared spectroscopy (FTIR) with a Bruker Vertex 70 spectrometer equipped with an ATR diamond device (Golden Gate, Bruker) and with software for spectral processing.

[0069] The asymmetric vibrations ν(C—H).sub.asym from the CH.sub.3 and CH.sub.2 groups are those at 2966 and 2921 cm.sup.−1, and the symmetrical vibrations of the same groups are those at 2902 and 1866 cm.sup.−1. At the 1732 cm.sup.−1 appear the vibration of the urethane carbonyl group and the ester ν (C═O). Carbonyl vibration occurs so far because their concentration in the polymer matrix is small and they can no longer form urethane-urethane hydrogen or urethane ester bonds. At 1642 cm.sup.−1 vibrates the δ (H—O) linkage in water and at 1566 and 1552 cm.sup.−1 we have the specific vibrations from amide II (ν (C—N)+δ (N—H)). At 1454 cm.sup.−1 there is the asymmetrical deformation vibration δ (C—H).sub.asym from the CH.sub.3 group, and symmetrical vibration δ (C—H).sub.sym is at 1346 cm.sup.−1. The vibrations of amide III (ν (C—N)+δ (N—H)) are found at 1250 cm.sup.−1 and at 1115 cm.sup.−1 there are νC—O.sub.sym of CH.sub.2—O—CH.sub.2 and CH.sub.2—O—HC(CH.sub.3).

[0070] In FIG. 2 is illustrated the evolution with temperature of viscoelastic parameters (G′, G″, tan δ) of the hydrogel of example 1 at a heating rate of 0.5° C./min (1 Pa, 1 rad/s), and in FIG. 3 is illustrated the evolution of complex viscosity (η*) of the hydrogel of example 1 as a function of time (t) at 37° C., during gelation.

EXAMPLE 2

[0071] The process was carried out as in example 1, with the difference that, instead of 1,4-butanediamine was used 1,5-pentanediamine (cadaverine) in a concentration of at least 97% (Sigma Aldrich), and instead of ethylene carbonate 99% (Sigma-Aldrich) was used propylene carbonate 99.7% (Sigma-Aldrich).

EXAMPLE 3

[0072] The process was carried out as in example 1, with the difference that, instead of Pluronic P-123100% was used a mixture of 12.6 g Pluronic F-127 (Sigma Aldrich), 100 g Pluronic P-123 and 40.2 g PEG.

EXAMPLE 4

[0073] The process was carried out as in example 1, with the difference that, instead of dimethyl sebacate it is used a mixture of 6 g dimethyl sebacate, 0.8 g dimethyl glutarate at least 98% (Sigma Aldrich) and 0.73 g dimethyl succinate 98% (Sigma Aldrich).

[0074] The properties of the hydrogels of Examples 1-4 above are depicted in the following Table 1, wherein: [0075] HC=Hydrogel concentration [0076] Mn=number average molar mass; [0077] Mw=mass average molar mass; [0078] Mw/Mn—molar mass distribution; [0079] Tg—glass transition temperature; [0080] GT—gelling time at 37° C. deduced from complex viscosity (η*).

TABLE-US-00001 Example, HC, Mn, Mw, Tg, GT No % Da Da Mw/Mn ° C. second 1 12.5 16800 25704 1.53 −57.52  44 2 12.5 17900 39380 2.20 −62.70 150 3 12.5 17850 40341 2.26 −56.72 108 4 12.5 16920 27241 1.61 −55.82 143