WO2018185650A1 - Polyurethane composite - Google Patents

Abstract

The present invention relates to a thermoplastic polyurethane composite comprising functionalised nanoparticles incorporated into a polyurethane matrix, and to the synthesis method thereof. The method comprises melting a diisocyanate in a reactor in an inert-gas atmosphere, adding a macrodiol until a pre-polymer is obtained, and adding a chain extender. The functionalised nanoparticles can be incorporated into the diisocyanate, the macrodiol or the chain extender.

Description

 POLYURETHANE COMPOSITE

FIELD OF THE INVENTION The invention pertains to the field of composite materials, particularly to synthetic polymer composites of the polyurethane type.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a composite comprising functionalized nanoparticles incorporated in a polyurethane matrix and their synthesis process. The process comprises melting a diisocyanate in a reactor in an inert gas atmosphere; add a macrodiol controlling temperature and constant stirring until a prepolymer is obtained; add a chain extender and cure the polymer obtained. At any stage of the process, functionalized nanoparticles are incorporated, which are made up of primary particles embedded in a protein matrix.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1 Particle size distribution of calcium carbonate nanoparticles functionalized with protein.

 FIG. 2 Scanning electron micrograph of 50% CaCC calcium carbonate nanoparticles, 50% Sodium caseinate.

 FIG. 3 Scanning electron micrograph of polyurethane-calcium carbonate nanoparticles (0.5% nanoparticles).

 FIG. 4 Scanning electron micrograph of polyurethane-calcium carbonate nanoparticles (2.0% nanoparticles).

BACKGROUND OF THE INVENTION

Among the most commonly used synthetic polymers for biomedical applications are polyurethanes, polycarbonates and polyesters, given their biocompatibility, biodegradation and adjustable mechanical properties. In the case of polyurethanes, it is It is possible to achieve a wide variation in the mechanical and adhesive properties of the materials obtained, due to the diversity in the chemical composition of the monomers involved in their synthesis (ie isocyanates, alcohols, amines and chain extenders). The thermoplastic properties of polyurethanes are associated with the presence of two microfases or microdomains, a hard one that gives it mechanical strength and a soft one that provides flexibility to the material and modular adhesive properties. These mechanical and adhesive properties of thermoplastic polyurethanes allow their application in the production of biomaterials for the total or partial replacement of tissues that are permanently subjected to compressive, shear or elongation forces. This is how thermoplastic polyurethanes have been used in the repair or replacement of heart muscles, nerves, blood vessels, bones and cartilage.

However, thermoplastic polyurethanes, like other pure synthetic or natural polymers, have imbalances in their mechanical, adhesive or functional properties. This is why in nature proteins or polysaccharides usually bind to inorganic materials (eg calcium carbonate or phosphate) to generate composite materials or composites, which develop the elasticity of the natural polymer and the biological properties of the inorganic material (eg stimulation of cell growth and adhesion between tissues).

Thermoplastic polyurethane composites have been developed for biomedical applications using calcium carbonate as filler material to promote cell growth, due to their better adhesive properties with respect to polyurethanes without added filler material (Ida Dulinska-Molaka, Malgorzata Lekka, Krzysztof J. Kurzydlowski Surface properties of polyurethane composites for biomedical applications Applied Surface Science 270 (2013) 553-560).

Similarly, hydroxyapatite nanoparticles have been disclosed as biocompatible support material (Laís P. Gabriel, Maria Elizabeth M. dos Santos, André L. Jardini, Gilmara NT Bastos, Carmen GBT Dias, Thomas J. Webster, Rubens Maciel Filho, Bio -based polyurethane for tissue engineering applications: How hydroxyapatite nanoparticles influence the structure, thermal and biological behavior of polyurethane composites Nanomedicine: Nanotechnology, Biology, and Medicine 13 (2017) 201-208), bone particles or bone substitute materials (eg calcium carbonate, calcium phosphate) for osteoimplants (US20050027033) and for orthopedic applications (US20100112032).

The compound developed by Duliska-Molaka et al. (2013) used calcium carbonate microparticles with sizes between 3.1 and 84.4 micrometers at a concentration of 10%, and incorporated into the macrodiol (ie polycaprolactone diol) during the synthesis process, with the sole purpose of generating adequate adhesion of human cells derived from bone.

The composition developed by Gabriel et al. (2017) used agglomerates of hydroxyapatite nanoparticles (150 nm) obtained by the sol-gel method at a concentration of 20% and incorporated into the polyurethane pre-polymer (obtained from the reaction between a polyol of the fruits of Acai and hexamethylene diisocyanate). The composite material was developed for the purpose of improving the adhesive properties of fibroblasts, inhibiting inflammatory reactions in cells and promoting tissue formation functions in cells. When using reinforcement material with a particle size in the micrometer range, it is necessary to add between 10% (m / m) and 50% (m / m) of reinforcement material to achieve the necessary requirements, which implies consumption of large amounts of reinforcement material, as well as the loss of other material properties such as hardness, ductility and appearance of the material obtained as the color. This effect is commonly called compensation property. Additionally, the material reinforcement-polymer matrix interaction tends to be ineffective due to the low area-volume ratio of the reinforcement material.

Composite type systems of the state of the art do not incorporate nanoparticles of minerals or metal oxides type multinuclear functionalized with proteins, which allow a strong interaction with the hard and soft segments of the polyurethane, thus improving the mechanical and adhesive properties of the material obtained and Its application for tissue restoration or replacement. DETAILED DESCRIPTION

The present invention relates to a composite or composite material comprising functionalized nanoparticles incorporated in a polymeric polyurethane matrix. Composite is understood as a material composed of two or more materials with significantly different physical or chemical properties.

The functionalized nanoparticles referred to in the present invention are primary particles of inorganic or organic nature embedded in a protein matrix (as shown in patent application WO2012 / 140626 and explained again herein), which form a nanoparticle of multicore type, where the protein matrix in turn acts as a functionalizing agent of the nanoparticle. The functionalized nanoparticles are suspended non-aggregated in the aqueous phase and are smaller than 10Onm. In one embodiment of the invention, the functionalized nanoparticles have a particle size between 5 nm and 1000 nm, preferably between 10 nm and 500 nm. In another embodiment of the invention, the functionalized nanoparticles have a particle size between 50nm and 400nm, preferably between 150nm and 300nm. Increasing the particle size above these sizes can reduce the mechanical properties of the material.

Functionalized nanoparticles are formed by primary particles embedded in a protein matrix. The primary particles have particle sizes less than 20nm. In one embodiment, the primary particles have a particle size between 3nm and 18nm. In another embodiment, the primary particles have a particle size between 5nm and lOnm. The content of the primary particles in the functionalized nanoparticles is between 5% and 70%. In one embodiment, the content of the primary particles in the functionalized nanoparticles is between 20% and 50% or between 30% and 45%, where the remaining percentage corresponds to the protein matrix.

The primary particles may be inorganic compounds, minerals, metal oxides, non-metal oxides, iron oxides, zinc oxides, carbonates, phosphates, aluminosilicates. The primary particles may be, among others, CaCC, CaMg (C03) 2, MgC0 ₃ , FeC0 ₃ , CaFe (C0 ₃ ) ₂ , MnC0 ₃ , FeC0 ₃ , MgC0 ₃ , CaMn (C0 ₃ ) ₂ , CaFe (C0 ₃ ) ₂ , CaMg (C0 ₃ ) ₂ , Ca ₃ (P0 ₄ ) ₂ , ZnO, Cu ₂ 0, CuO, CoO, Au ₂ 0 ₃ , Ti0 ₂ , Ni ₂ 0 ₃ , Ag ₂ 0, HgO, CrO, BaO, Cr ₂ 0 ₃ , PbO, FeO, Fe ₂ 0 ₃ , CaO, Li ₂ 0, SnO, Sn0 ₂ , BaS0 ₄ , The protein matrix has dispersant and stabilizing activity, which allows the formation of multicore type nanoparticles and gives them stability over time, since proteins in the protein matrix can act as dispersing agents , stabilizers and functionalizers of nanoparticles. The protein matrix is selected from dairy, meat and vegetable proteins. In one embodiment of the invention, the proteins can be whey protein, caseins, caseinate, beta lactalbumine, egg protein such as ovalbumin, sarcoplasmic and myofibrillar meat proteins, vegetable proteins such as soy protein, corn, rice, barley, He sang it, oatmeal, among others, and its combinations. In one embodiment of the invention, the protein matrix is selected from: calcium caseinate, sodium caseinate and whey protein.

The protein matrix of the functionalized nanoparticles can be in a concentration between 10% and 70% of the functionalized nanoparticle. In one embodiment of the invention, the protein matrix is in a concentration between 10% and 30% of the functionalized nanoparticle. In another embodiment of the invention, the protein matrix is in a concentration between 40% and 60% of the functionalized nanoparticle. In another embodiment, the protein matrix is in a concentration between 45% and 55% of the functionalized nanoparticle. Additionally, the functionalized nanoparticles can encapsulate water soluble active ingredients, which can be chemical or biological compounds susceptible to being encapsulated or associated with the nanoparticle and are selected from the group consisting of drugs, cells and biotechnological products. The functionalized nanoparticles referred to in the present invention are incorporated into a polymeric polyurethane matrix, functioning as a reinforcing material. In one embodiment of the invention, the polyurethane is a thermoplastic polyurethane. Incorporating functionalized nanoparticles as reinforcement material to the polymeric material, it gives the material a better performance with respect to the material without reinforcement, because the constituents of a composite material have different chemical structures and compositions, and therefore, different physical properties. The result is a synergy of the properties of the initial materials.

Because of their high area-volume ratio, the nanometric particles (in this case the functionalized nanoparticles) tend to interact more easily with the polymer matrix, so the amount needed to improve the properties of the material is lower. Thus, the percentage of functionalized nanoparticles in the composition may be in the range of 0.1% m / m to 20.0% m / m. In one embodiment of the invention, the amount of functionalized nanoparticles in the composition is in a range of 0.5% m / m to 5.0% m / m. In another embodiment of the invention, the amount of functionalized nanoparticles in the composition is in the range of 0.5% m / m to 2.0% m / m. In another embodiment of the invention, the amount of functionalized nanoparticles in the composition is in the range of 0.6% m / m to 1.0% m / m.

In order to exploit this maximization of the area-volume relationship that nanoparticles have, it is necessary to meet certain requirements so that the interaction between the nanoparticles and the reinforcement material is effective and the desired mechanical properties can be achieved. The first requirement is to avoid aggregation of the nanoparticles; precisely because of the high area-volume ratio they have, the particles tend to aggregation avoiding the optimal interaction between reinforcement and polymer. The control of nanoparticle aggregation is achieved by stabilizing the particles electrostatically or sterically during the production process.

The second requirement is to generate a good dispersion of the nanoparticulate material in the polymer matrix since this leads to an increase in interfacial area, favoring the interaction between the inorganic reinforcing molecules and the organic molecules of the polymer matrix. In this aspect lies one of the great challenges of materials science, since generating composite materials with nanoparticles well dispersed in the polymer matrix will depend on chemical factors such as the type of polymer and the type of nanoparticulate reinforcement material, as well as factors physical as the method of inclusion of nanoparticles. In the synthesis process of the composite material of the invention, three parameters are kept constant, the ratio in percentage by mass of the soft segment, the ratio between the chemical amount of isocyanate groups with respect to the moles of hydroxyl groups, and the percentage of nanoparticles added. The mass percentage ratio of the soft segment between 40 and 60% and that of the rigid segment between 60 and 40%. In addition, the ratio between the chemical amount of isocyanate groups with respect to the moles of hydroxyl groups is between 0.9 and 1.2, in one embodiment the ratio is between 0.95 and 1.1; in another mode the ratio is between 1.0 and 1.05. On the other hand, the percentage of nanoparticles incorporated into the polymer matrix is between 0.1% m / m and 20.0% m / m.

The synthesis process of the composition of the invention can be carried out by the pre-polymer method, where the addition of the nanoparticles is carried out by mixing them with each of the monomers. The synthesis process of the composition of the present invention includes steps a) b) and c).

In this way three different composite materials can be generated: a first material where the functionalized nanoparticles are added in a diisocyanate, which can be methylene diphenyl diisocyanate (MDI), dicyclohexylmethane diisocyanate (HMDI), hexamethylene diisocyanate (HDI), toluene diisocyanate ( TDI), butane diisocyanate (BDI) or mixtures thereof. A second material where the functionalized nanoparticles are mixed with a macrodiol, which can be polytetramethylene oxide (PTMO), polycaprolactone diol (PCL), hydroxyl polyacrylate polyol; and a third material where the functionalized nanoparticles are added with the chain extender, which can be a low molecular weight diol selected from: ethylene glycol, butane diol (BDO), hexanediol, cyclohexane dimetanol, isosorbide diol. a) melting a diisocyanate in an atmosphere with inert gas

In the synthesis of the composite material of the present invention, a diisocyte is initially melted at a temperature between 50 ° C and 80 ° C or at a temperature between 60 ° C and 70 ° C in an atmosphere with inert gas maintaining constant agitation between 150 and 500 rpm In one embodiment of the process of the invention, the inert gas is selected from: nitrogen, helium, neon, argon, krypton, xenon, among others. b) add a macrodiol continuously controlling temperature and stirring until a pre-polymer is obtained, increase the temperature again and stir;

The temperature is increased to a value between 70 ° C and 100 ° C and a macrodiol is added under mechanical stirring at between 100 rpm and 500 rpm or between 200 rpm and 400 rpm until a pre-polymer is obtained. To verify that a prepolymer is obtained, an infrared spectroscopy analysis can be performed. In one embodiment of the process of the invention, the temperature is increased to a value between 50 ° C and 80 ° C or to a value between 65 ° C and 70 ° C. After completing the addition of the macrodiol, the reaction is brought to a temperature between 80 ° C and 100 ° C for 60 to 120 minutes with stirring between 200 rpm and 700 rpm or between 400 rpm and 500 rpm. In one embodiment of the process of the invention, once the macrodiol addition is complete, the reaction is brought to a temperature between 100 ° C and 130 ° C. In another embodiment of the process of the invention, the reaction is maintained for 80 to 110 minutes. c) add a chain extender

Finally, a chain extender is added to the pre-polymer in a single step and stirred for 3 to 20 minutes or between 5 and 10 minutes. d) cure the compound

The curing stage of the composite can be carried out by any method known in the art. In one embodiment of the process of the invention, the composition is placed on a Teflon sheet, where it is cured at a temperature between 100 ° C and 150 ° C or between 110 ° C and 130 ° C under an inert gas atmosphere. The composition of the present invention is characterized as a biocompatible and biostable material. The composition of the present invention is characterized in that it has the following properties (Table 1):

Table 1

The incorporation of nanoparticles of minerals or metallic oxides type multinucleus functionalized with proteins, allows a strong interaction with the hard and soft segments of the polyurethane, which improves the mechanical and adhesive properties of the composition of the invention, extending its application to the restoration and / or tissue replacement.

Thus, for example, natural articular cartilage has a Young's modulus value of 18 MPa, while the present invention achieves values between 40 and 65 MPa. On the other hand, the Surface Free Energy values of the natural cartilage are around 60 mN / m compared to 52 mN / m of the compound of the present invention, indicating a great similarity with the natural cartilage. That compared to the case of ultra high molecular weight polyethylene (used for prostheses) has a Surface Free Energy of 31 mN / m, which represents a value far removed from that measured for natural cartilage.

The composition of the present invention can be used in the repair or replacement of cardiac muscles, nerves, blood vessels, bones, cartilage, fibrocartilage, meniscus, iliac crest, among others. The present invention will be presented in detail through the following examples, which are provided for illustrative purposes only and not for the purpose of limiting its scope. EXAMPLES

Example 1. Obtaining functionalized calcium carbonate nanoparticles in the form of dry powder of sodium carbonate and sodium caseinate A solution of 0.1 M sodium carbonate and 2.0% sodium caseinate was prepared. Similarly, a solution of calcium chloride was prepared at a concentration of 0.3 M. The solutions were quickly mixed using a high pressure homogenizer that allows the two solutions to enter the equipment separately to obtain carbonate nanoparticles. of functionalized calcium. The homogenizer working pressure was 28 MPa.

The multicore-type calcium carbonate nanoparticles and functionalized with protein obtained had an average size in intensity of 180 nm (FIG. 1), with primary particles between 10 and 30 nm (FIG. 2), according to the dynamic light scattering technique and transmission electron microscopy, respectively, with a 50% calcium carbonate and 50% protein content. The nanoparticle suspension was subsequently filtered and washed with water twice, then dried at 60 ° C and obtained calcium carbonate nanoparticles as a dry powder. Example 2. Obtaining functionalized calcium carbonate nanoparticles in the form of dry powder of calcium carbonate and sodium caseinate

Following the procedure of Example 1, 0.3M calcium carbonate functionalized nanoparticles stabilized with 1% sodium caseinate were obtained, which had an average intensity size of 170 nm, according to the dynamic light scattering technique, and did not settle up to three months when measured in an automatic tensiometer equipped with an accessory to determine sedimentation. Example 3. Obtaining functionalized calcium carbonate nanoparticles in the form of dry powder of calcium carbonate and sodium caseinate

Following the procedure of Example 1, functionalized 0.2M calcium carbonate nanoparticles stabilized with 1% sodium caseinate were obtained, which had an average size in intensity of 150 nm, according to the dynamic light scattering technique, and did not settle up to two months when measured in an automatic tensiometer equipped with an accessory to determine sedimentation. Example 4. Obtaining calcium carbonate nanoparticles in the form of dry powder of calcium carbonate, sodium caseinate and quercetin

Following the procedure of Example 1, functionalized 0.1M calcium carbonate nanoparticles stabilized with 1% sodium caseinate and 0.1% quercetin were obtained, had an average intensity size of 190nm, according to the dynamic light scattering technique , and did not settle for up to three months when measured in an automatic tensiometer equipped with an accessory to determine sedimentation. The encapsulation efficiency of quercetin was 60% measured by the UV-Vis spectrophotometry technique.

Example 5. Synthesis of a polyurethane compound

For the synthesis of the polyurethane, 43.3g of methyl bis (p-phenyl isocyanate) (MDI) was melted in a 70 ° C reactor by applying continuous stirring of 400 rpm and under a nitrogen atmosphere to avoid reactions of oxidation. Subsequently, 82 g of the poly (tetramethylene oxide) diol (PTMO) with a molecular weight of 2000 g / mol for 30 minutes and with 200 rpm of stirring were added. Once the addition of the PTMO was completed, the reactor temperature was raised to 85 ° C and maintained for 90 minutes.

Then the quick addition of 11.4g of 1,4-butanediol (BDO) and 0.69g of functionalized calcium functionalized calcium carbonate nanoparticles (obtained according to Example 1) and initially dispersed in the BDO. All The system was maintained at 85 ° C for 5 minutes. It was subsequently emptied into a Teflon dish and cured at 110 ° C for 4 hours in an oven with nitrogen recirculation.

The microstructure of the composite obtained was observed by scanning electron microscopy (FIG. 3).

Example 6. Synthesis of a polyurethane compound

For the synthesis of the polyurethane, 43.3g of methyl bis (p-phenyl isocyanate) (MDI) was melted in a 70 ° C reactor by applying continuous stirring of 400 rpm and under a nitrogen atmosphere to avoid reactions of oxidation. Subsequently, 82 g of the poly (tetramethylene oxide) diol (PTMO) with a molecular weight of 2000 g / mol for 30 min and with 200 rpm of stirring were added to the reactor. Once the addition of the PTMO was completed, the reactor temperature was raised to 85 ° C and maintained for 90 minutes.

Then, the rapid addition of ll, 4g of 1,4-butanediol (BDO) and 2.8 g of calcium carbonate nanoparticles (obtained according to Example 1) functionalized with protein and initially dispersed was performed in the BDO. The entire system was maintained at the temperature of 85 ° C for 5 minutes. Subsequently, the compound was emptied into a Teflon dish and cured at 110 ° C for 4 hours in an oven with nitrogen recirculation.

The microstructure of the composite was observed by scanning electron microscopy (FIG. 4).

Example 7. Mechanical properties of the composite obtained by Example 5 and Example 6 The mechanical properties of composites obtained according to Example 5 and Example 6 were determined in an Instron 4202 universal machine using a load of 5 kN and a velocity of 10 mm / min at 25 ° C, using type IV specimens obtained by injection molding. Shore A hardness was measured using a PCT hardness tester at 25 ° C. Finally, the adhesion work was calculated from the surface-free energies obtained by van Oss theory by measuring the contact angles with diiodometry and water in a K12 tensiometer from Krüss. The results are illustrated in Table 2.

Table 2

Claims

1. A composite comprising functionalized nanoparticles incorporated in a polyurethane matrix. 2. The composition according to Claim 1, characterized in that the functionalized nanoparticles are in a concentration between 0.1% m / m and 20.0% m / m of the compound. 3. The composition according to Claim 2, wherein the functionalized nanoparticles are formed by primary particles embedded in a protein matrix. 4. The compound according to Claim 3, wherein the primary particles are selected from the group of: metal oxides, minerals, carbonates, phosphates and aluminosilicates. 5. The composition according to Claim 3, wherein the protein matrix of the functionalized nanoparticle is at a concentration between 5% and 70%. 6. The composition according to Claim 1, wherein the functionalized nanoparticles have a particle size between 10 nm and 1000 nm. 7. The composition according to Claim 1, characterized in that it has the following properties:

8. The composition according to Claim 1, characterized in that it is a biocompatible and biostable material. 9. A process for the synthesis of the compound according to Claim 1, comprising the following steps:  a) melting a diisocyanate in a reactor in an atmosphere with inert gas; b) add a macrodiol by controlling temperature and stirring until a prepolymer is obtained, increase the temperature again and stir;  c) add a chain extender; where functionalized nanoparticles are incorporated either in the diisocyanate, in the macrodiol or in the chain extender. 10. The process according to Claim 9, which additionally comprises a curing step of the composite. 11. The process according to Claim 9, wherein step (a) is carried out at a temperature between 50 ° C and 80 ° C while maintaining constant agitation. 12. The process according to Claim 9, wherein in step (a) the diisocyanate is methylene diphenyl diisocyanate, dicyclohexylmethane diisocyanate, hexamethylene diisocyanate, toluene diisocyanate, butane diisocyanate or mixtures thereof. 13. The process according to Claim 9, wherein in step (b) the temperature is initially increased to a value between 50 ° C and 80 ° C with constant stirring until a pre-polymer is obtained. 14. The process according to Claim 9, wherein in step (b), once the pre-polymer is obtained, the temperature is increased to a value between 80 ° C and 100 ° C for 60 to 120 minutes while maintaining constant stirring and it increases again the temperature up to between 80 and 100 ° C for between 60 and 120 minutes with stirring between 200 and 700 rpm. 15. The process according to Claim 9, wherein in step (c) the chain extender is ethylene glycol, butane diol, hexanediol, cyclohexane dimethanol, isosorbide diol. 16. The process according to Claim 10 is carried out at a temperature between 100 ° C and 150 ° C for 2 to 6 hours in an atmosphere with inert gas.