ES2243142B1 - NON-TOXIC BIODEGRADABLE POLYURETHANS FOR CONTROLLED RELEASE OF PHARMACES AND FABRIC ENGINEERING. - Google Patents

Abstract

Non-toxic biodegradable polyurethanes for controlled drug release and tissue engineering. The object of the invention is a biodegradable polyurethane material with adjustment of the hydrophilic / hydrophobic character whose degradation products are non-toxic, and which contains at least one amino acid residue in the main chain, which makes it recognizable by biological agents. The polymers are synthesized from a long chain monomer, such as a polyol consisting of a copolymer with units or segments of different hydrophilic / hydrophobic character, a di- or polyisocyanate and a chain extender, so that the degradation products of these three basic components do not give rise to toxic products, and that at least one amino acid residue is included in the structure of the main chain. The main applications are based on its use as a material for the production of products for the pharmaceutical and biotechnology sector, specifically its main application is for the transport and controlled release of drugs and for tissue engineering.

Description

Biodegradable Polyurethanes non-toxic for controlled drug release and for tissue engineering.

Technical sector

Materials for application in the sector Medical-Pharmacist Polyurethane material non-toxic biodegradable for controlled release of drugs and tissue engineering it contains in its chain Main at least one amino acid residue.

State of the art

Biodegradable polymers are becoming increasingly important for several biomedical applications, such as tissue engineering, in which the current trend is develop matrices that promote angiogenesis and support tissue cells that you try to replace, but of the polymers commercially available there are very few that have properties elastomeric

Polymers that degrade in a way intentionally can avoid various problems and answers negative physiological: fibrous encapsulation, need for a second surgical intervention for implant removal, etc. Therefore, a lot of research has been done on them, but most of those commercially available are essentially material rigid, such as polyglycol, the first polymer absorbable synthetic that appeared in the early 70s, what which makes it desirable, at least in regards to the engineering of fabrics, the existence of materials with a wide variety of physical properties that allow its integration with the various tissues found in the body.

These degradable polymers, with a design and a choice of suitable monomers in the synthesis, may have a hydrophilicity / hydrophobicity, and consequently a degradability, controlled or adjusted [Yen, M.-S .; Kuo, S.-C .. J. Appl. Polym Sci., 65, 883-892, 1997; Cohn, D .; Stern, T .; González, M.F .; Epstein, J. J. Biomed. Mater. Beef., 59 (2), 273-281, 2002; Li, S .; Garreau, H .; Vert, M .; Petrova, T .; Manolova, N .; Rashkov, I .. J. Appl. Polym Sci., 68, 989-998, 1998; Petrova, Ts .; Manolova, N .; Rashkov, I .; Li, S .; Vert, M .. Polym. Int., 45, 419-426, 1998; Li, S.M .; Chen, X.H .; Gross, R.A .; McCarthy, S.P .. J. Mater. Sci .: Mater. Med., 11, 227-233, 2000; Gorna, K .; Gogolewski, S .. Polym. Degrad Stab., 79, 465-474, 2003; Bohlmann, G.M .; Yoshida, Y .. CEH Marketing Research Report, CEH-SRI International, 2000; Saad, B .; Neuenschwander, P .; Uhlschmid, G.K .; Suter, U.W .. Int. J. Biol. Macromol., 25, 293-301, 1999], the polyoxide pair being very common ethylene / polycaprolactone [Yen, M.-S .; Kuo, S.-C .. J. Appl. Polym Sci., 65, 883-892, 1997; Cohn, D .; Stern, T .; González, M.F .; Epstein, J. J. Biomed. Mater. Res., 59 (2), 273-281, 2002; Li, S .; Garreau, H .; See, M .; Petrova, T .; Manolova, N .; Rashkov, I .. J. Appl. Polym Sci., 68, 989-998, 1998; Petrova, Ts .; Manolova, N .; Rashkov, I .; Li, S .; See, M .. Polym. Int., 45, 419-426, 1998; Li, S.M .; Chen, X.H .; Gross, R.A .; McCarthy, S.P .. J. Mater. Sci .: Mater. Med., 11, 227-233, 2000; Gorna, K .; Gogolewski, S .. Polym. Degrad Stab., 79, 465-474, 2003].

Polyurethanes (broadly understood as polyurethanes, polyurethaneureas and polyureas) are a family of polymers widely used in medicine, but mainly as biostable materials, and in very few cases as materials biodegradable (Artelon ™, related to reference [Flodin, P. US Patent 6,220,441 B1 (Artimplant, Sweden), 2001]. Although in the scientific-technical literature also be overwhelming the percentage of publications dedicated to polyurethanes biostable, for a few years they have appeared different publications and patents of biodegradable polyurethanes aimed at medical applications [Flodin, P .. US Patent 6,220,441 B1 (Artimplant, Sweden), 2001; Ganta, S.R .; Piesco, N.P .; Lomg, P .; Gassner, R .; Motta, L.F .; Papworth, G.D .; Stolz, D.B .; Watkins, S.C .; Agarwal, S .. J. Biomed. Mater. Res., 64A, 242-248, 2003; Gorna, K .; Gogolewski, S .. "Synthetic bioabsorbable polymers for implants, ASTM STP 1396", C.M. Agrawal, J.E. Parr, and S.T. Lin Eds., ASTM, West Conshohocken, PA. Pages 39-57, 2000; Skarja, G.A .; Woodhouse, K.A .. J. Biomater. Sci. Polymer Edn., 9 (3), 271-295, 1998; Gorna, K .; Gogolewski, S .. Polym. Degrad Stab., 79, 465-474, 2003; Müller, M .; Henschler, D .; Sabbioni, G .. Helv. Chim. Minutes, 81, 1254-1263, 1998; Fontaine, L .; Mènard, L .; Cayuela, OR.; Brosse, J.-C .; Sennyey, G .; Senet, J.-P .. Macromol. Symp., 122, 287-290, 1997; Chen, H .; Jiang, X .; He, L .; Zhang, T .; Xu, M .; Yu, X .. J. Appl. Polym Sci., 84, 2474-2480, 2002; Kartvelishvili, T .; Kvintradze, TO.; Katsarava, R .. Macromol. Chem. Phys., 197, 249-257, 1996; Kartvelishvili, T .; Tsitlanadze, G .; Edilashvili, L .; Japaridze, N .; Katsarava, R .. Macromol. Chem Phys., 198, 1921-1932, 1997; Shi, F.Y .; Wang, L.F .; Tashev, E .; Leong, K.W .. "Polymeric Drugs and Drug Delivery Systems ", R.L. Dunn and R.M. Ottenbrite Eds., ACS Symposium Series 469, ACS Washington DC. Chapter 14. 1991; Chauvel-Lebret, D.J .; Auroy, P .; Bonnaure-Mallet, M .. "Polymeric Biomaterials. Second Edition ", S. Dumitriu Ed., Marcel Dekker, Inc. Chapter 13. 2001]. Among the biodegradable polyurethanes described are They find both rigid materials and elastomeric materials. Several of the reagents commonly used in the preparation of polyurethanes give rise to toxic products in their degradation, which  excludes its use in the synthesis of these polyurethanes. Between these mention may be made of toluendiisocyanate and its derivatives, the methylene diisocyanate and its derivatives, isophorone diisocyanate and their derivatives, the amines corresponding to all these isocyanates, and the 3,3'-dichloro-4,4'-diphenylamino-methane (MOCA or MBOCA). If an appropriate choice is made of the reagents, the degradation products to which the polymer are non-toxic [Chauvel-Lebret, D.J .; Auroy, P .; Bonnaure-Mallet, M .. "Polymeric Biomaterials. Second Edition ", S. Dumitriu Ed., Marcel Dekker, Inc .. Chapter 13. 2001; Woodhouse, K.A .; Skarje, G.A .. US Patent 6,221,997 B1, 2001; Skarja, G.A .; Woodhouse, K.A .. J. Appl. Polym Sci., 75, 1522-1534, 2000; Zhang, J.-Y., Beckman, E.J., Hu, J., Yang, G.-G., Agarwal, S., Hollinger, J.O. Tissue Engineering, 8 (5), 771-785, 2002; Storey, R.F., Wiggins, J.S., Puckett, A.D. J. Polym. Sci., Polym. Chem., 32, 2345-2363, 1994; Bruin, P., Veenstra, G.J., Nijenhuis, A.J., Pennings, A.J. Makromol Chem., Rapid Commun., 9, 589-594, 1988; de Groot, J.H .. Dissertation, U. Groningen, Netherlands. nineteen ninety five; Zhang, J.Y .; Beckman, E.J., Piesco, N.P., Agarwal, S. Biomaterials, 21, 1247-1258, 2000; Kiyotsukuri, T .; Nagata, M .; Kitazawa, T .; Tsutsumi, N. Eur. Polym. J., 28 (2), 183-186, 1992; Hettrich, W., Becker, R. Polymer, 38 (10), 2437-2445, 1997; Yamanaka, C., Hashimoto, K. J. Polym. Sci., Polym. Chem., 40, 4158-4166, 2002; Storey, R.F., Wiggins, J.S., Mauritz, K.A., Puckett, A.D. Polym Compos. 14, 17, 1993].

Among the possible reagents to select for the constitution of biodegradable polymers are amino acids (or derivatives thereof), most of which form the proteins, and that are not therefore toxic. Amino acids have long used in the formation of a multitude of polymers synthetics [Kemnitzer, J .; Kohn, J .. "Handbook of biodegradable polymers ", A.J. Domb, J. Kost, D.M. Wiseman, Eds., Harwood Academic Publishers Chapter 1 3, p.251-272. 1997; Domb, A.J .. Biomaterials, 11, 686, 1990], including polyurethanes [Flodin, P .. US Patent 6,220,441 B1 (Artimplant, Sweden), 2001; Skarja, G.A .; Woodhouse, K.A .. J. Biomater. Sci. Polymer Edn., 9 (3), 271-295, 1998; Gorna, K .; Gogolewski, S .. Polym. Degrad Stab., 79, 465-474, 2003; Fontaine, L .; Mènard, L .; Cayuela, O .; Brosse, J.-C .; Sennyey, G .; Senet, J.-P .. Macromol. Symp., 122, 287-290, 1997; Chen, H .; Jiang, X .; He, L .; Zhang, T .; Xu, M .; Yu, X .. J. Appl. Polym Sci., 84, 2474-2480, 2002; Kartvelishvili, T .; Kvintradze, A .; Katsarava, R .. Macromol. Chem. Phys., 197, 249-257, 1996; Kartvelishvili, T .; Tsitlanadze, G .; Edilashvili, L .; Japaridze, N .; Katsarava, R .. Macromol. Chem Phys., 198, 1921-1932, 1997; Shi, F.Y .; Wang, L.F .; Tashev, E .; Leong, K.W .. "Polymeric Drugs and Drug Delivery Systems ", R.L. Dunn and R.M. Ottenbrite Eds., ACS Symposium Series 469, ACS Washington DC. Chapter 14. 1991; Chauvel-Lebret, D.J .; Auroy, P .; Bonnaure-Mallet, M .. "Polymeric Biomaterials. Second Edition ", S. Dumitriu Ed., Marcel Dekker, Inc .. Chapter 13. 2001; Woodhouse, K.A .; Skarje, G.A .. US Patent 6,221,997 B1, 2001; Skarja, G.A .; Woodhouse, K.A .. J. Appl. Polym Sci., 75, 1522-1534, 2000; Zhang, J.-Y .; Beckman, E.J .; Hu, J .; Yang, G.-G .; Agarwal, S .; Hollinger, J.O .. Tissue Engineering, 8 (5), 771-785, 2002; Storey, R.F .; Wiggins, J.S .; Puckett, A.D .. J. Polym. Sci., Polym. Chem., 32, 2345-2363, 1994; Bruin, P .; Veenstra, G.J .; Nijenhuis, A.J .; Pennings, A.J .. Makromol. Chem., Rapid Commun., 9, 589-594, 1988; de Groot, J.H .. Dissertation, U. Groningen, Netherlands. nineteen ninety five; Zhang, J.Y .; Beckman, E.J .; Feet, N.P .; Agarwal, S .. Biomaterials, 21, 1247-1258, 2000; Kiyotsukuri, T .; Nagata, M .; Kitazawa, T .; Tsutsumi, N .. Eur. Polym J., 28 (2), 183-186, 1992; Hettrich, W .; Becker, R .. Polymer, 38 (10), 2437-2445, 1997; Storey, R.F .; Wiggins, J.S .; Mauritz, K.A .; Puckett, A.D .. Polym Compos., 14, 17, 1993]. The entrance of the remains of amino acid in the main chain has been mostly as diisocyanate, especially lysine [Fontaine, L .; Mènard, L .; Cayuela, O .; Brosse, J.-C .; Sennyey, G .; Senet, J.-P .. Macromol. Symp., 122, 287-290, 1997; Kartvelishvili, T .; Kvintradze, A .; Katsarava, R .. Macromol. Chem. Phys., 197, 249-257, 1996; Kartvelishvili, T .; Tsitlanadze, G .; Edilashvili, L .; Japaridze, N .; Katsarava, R .. Macromol. Chem Phys., 198, 1921-1932, 1997; Chauvel-Lebret, D.J .; Auroy, P .; Bonnaure-Mallet, M .. "Polymeric Biomaterials. Second Edition ", S. Dumitriu Ed., Marcel Dekker, Inc .. Chapter 13. 2001; Woodhouse, K.A .; Skarje, G.A .. US Patent 6,221,997 61, 2001; Skarja, G.A .; Woodhouse, K.A .. J. Appl. Polym Sci., 75, 1522-1534, 2000; Zhang, J.-Y .; Beckman, E.J .; Hu, J .; Yang, G.-G .; Agarwal, S .; Hollinger, J.O .. Tissue Engineering, 8 (5), 771-785, 2002; Storey, R.F .; Wiggins, J.S .; Puckett, A.D .. J. Polym. Sci., Polym. Chem., 32, 2345-2363, 1994; Bruin, P .; Veenstra, G.J .; Nijenhuis, A.J .; Pennings, A.J .. Makromol. Chem., Rapid Commun., 9, 589-594, 1988; de Groot, J.H .. Dissertation, U. Groningen, Netherlands. nineteen ninety five; Zhang, J.Y .; Beckman, E.J .; Feet, N.P .; Agarwal, S .. Biomaterials, 21, 1247-1258, 2000; Storey, R.F .; Wiggins, J.S .; Mauritz, K.A .; Puckett, A.D .. Polym Compos., 14, 17, 1993], called LDI, whose patent for Synthesis dates back to 1968 [Merck & Co., Inc .. GB Patent 1,118,916, 1968] and currently commercially available at through the Japanese company Kyowa Hakko, although there are also examples with diisocyanates derived from other amino acids [Hettrich, W .; Becker, R .. Polymer, 38 (10), 2437-2445, 1997] or with lysine triisocyanate [Kiyotsukuri, T .; Nagata, M .; Kitazawa, T .; Tsutsumi, N .. Eur. Polym J., 28 (2), 183-186, 1992]. But references are also found in which the rest of the amino acid enter as chain extender [Skarja, G.A .; Woodhouse, K.A .. J. Biomater Sci. Polymer Edn., 9 (3), 271-295, 1998; Fontaine, L .; Mènard, L .; Cayuela, O .; Brosse, J.-C .; Sennyey, G .; Senet, J.-P .. Macromol. Symp., 122, 287-290, 1997; Chen, H .; Jiang, X .; He, L .; Zhang, T .; Xu, M .; Yu, X .. J. Appl. Polym Sci., 84, 2474-2480, 2002; Kartvelishvili, T .; Kvintradze, TO.; Katsarava, R .. Macromol. Chem. Phys., 197, 249-257, 1996; Kartvelishvili, T .; Tsitlanadze, G .; Edilashvili, L .; Japaridze, N .; Katsarava, R .. Macromol. Chem Phys., 198, 1921-1932, 1997; Shi, F.Y .; Wang, L.F .; Tashev, E .; Leong, K.W. "Polymeric Drugs and Drug Delivery Systems ", R.L. Dunn and R.M. Ottenbrite Eds., ACS Symposium Series 469, ACS Washington DC. Chapter 14. 1991; Woodhouse, K.A .; Skarje, G.A .. US Patent 6,221,997 B1, 2001; Skarja, G.A .; Woodhouse, K.A .. J. Appl. Polym Sci., 75, 1522-1534, 2000]. Of all these polyurethanes with amino acid residues in the chain, only a few exhibit elastomeric properties [Storey, R.F .; Wiggins, J.S .; Puckett, A.D .. J. Polym. Sci., Polym. Chem., 32, 2345-2363, 1994; Bruin, P .; Veenstra, G.J .; Nijenhuis, A.J .; Pennings, A.J .. Makromol Chem., Rapid Commun., 9, 589-594, 1988; de Groot, J.H .. Dissertation, U. Groningen, Netherlands. 1995] and in some poor case [Storey, R.F .; Wiggins, J.S .; Puckett, A.D .. J. Polym Sci., Polym. Chem., 32, 2345-2363, 1994].

Description of the invention Brief Description of the Invention

The object of the present invention is therefore both provide new biodegradable polyurethane materials with several potential biomedical applications, which exhibit from elastomeric properties with varying degrees of elasticity and hardness to plastic properties.

This biodegradable polyurethane material consists of three basic elements such as a long chain monomer, called polyol or polyamine, a di- or polyisocyanate, and a relatively short chain monomer, called a chain extender. The resulting polymer of segmented structure, separated or not in phases, contains in its main chain at least one amino acid residue, incorporated in polyisocyanate and / or in the chain extender, to facilitate its recognition by biological agents. In addition, it is novel because of its design since the incorporation of hydrophilic and hydrophobic molecules allows the hydrophilic / hydrophobic character of the resulting material to be graded, the reagents being selected so that the degradation products are
non-toxic

Thus, an object of the present invention is It constitutes a biodegradable polyurethane material with adjustment of hydrophilicity / hydrophobicity, whose degradation products they are substantially non-toxic, characterized because it consists of the product resulting from the reaction between a polyol, a polyisocyanate and a chain extender, and because its structure includes at least one amino acid residue natural, where the polyol is a block or random copolymer consisting of hydrophilic / hydrophobic monomers antagonistic or mixture thereof with other copolymers of the same characteristics and with homopolymers.

A preferred embodiment of the present invention constitutes a polyol formed by copolymers of block, specifically of tribloques, resulting from the combination of polyethylene glycol-caprolactone, hereinafter PEG / CL, so that you get a structure CL-PEG-CL.

The incorporation of the remaining amino acid in the chain is made through the polyisocyanate or extender of chain.

The procurement procedure provides a segmented linear polyurethane obtained from the reagents in a 1: 1 molar ratio between isocyanate groups and groups that react with the isocyanate group, being carried out by prepolymer method or by the one-shot method, in mass or in solution, in a continuous or discontinuous reactor.

The mechanical properties of polyurethanes resulting can be varied from soft elastomers to plastics rigid. Although there are numerous commercial examples of polymers rigid biodegradable, many of them turn out to be too much rigid and sometimes fragile, while polyurethanes They are usually tenacious. On the other hand, there is the possibility of obtain degradable elastomers with varying degrees of elasticity or hardness, of which there are few commercial examples, what it does that the materials described in this invention may be Commercially very attractive.

It is industrially applicable as material for controlled release of drugs and tissue engineering.

Detailed description

Thus, an object of the present invention is constitutes a polyurethane material, hereinafter material of polyurethane of the present invention, biodegradable with adjustment of hydrophilicity / hydrophobicity, whose degradation products are substantially non-toxic, characterized in that it consists of the product resulting from the reaction between a polyol, a polyisocyanate and a chain extender, because its structure includes at least one natural amino acid residue, and because the polyol is a block or random copolymer constituted by a combination of character monomers antagonistic hydrophilic / hydrophobic or mixture thereof with others copolymers of the same characteristics and with homopolymers.

The rest of the natural amino acid makes this polyurethane material recognizable by biological agents.

A feature of this material of polyurethane is the adjustment of the hydrophilicity / hydrophobicity that is determined by the choice of the polyol, a relatively long chain molecule with two or more groups capable of reacting with the isocyanate group.

The term "polyurethane" as it uses in the present invention it should be broadly understood as polyurethane, polyurethaneurea and polyurea.

The term "substantially non-toxic "as used herein invention refers to materials that when present in the body, are physically tolerable, and more specifically, not cause appreciable cell death (cytotoxicity) or an alteration negative of normal cellular function (mutagenic response).

The term "biological agent" such as used in the present invention refers to molecules that bind and recognize amino acids, they are already floating freely in the middle extracellular including enzymes, or proteins bound to cell surfaces such as receptors.

The term "chain extender" as used in the present invention refers to a multifunctional molecule of relatively low molecular weight, less than 300 gr • -1, with a number of reactive groups against the same isocyanate group or greater than 2, preferably alcohol or amine groups, but also others such as phenol or
thiol

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The term "amino acid residue" such as used in the present invention includes one or more residues of amino acid of the configuration occurring in nature and that be substantially non-toxic. These remains of amino acid are incorporated into the main chain either via the polyisocyanate or via chain extender or both.

A particular object of the invention is constitutes the polyurethane material of the present invention characterized in that the polyol results from the combination of following monomers, by way of illustration and without limiting the Scope of the invention, of the following group:

to)

oxide of ethylene and caprolactone, ethylene oxide and lactic acid, oxide of ethylene and glycolic acid, ethylene oxide and carbonate of alkyl, ethylene oxide and valerolactone, ethylene oxide and butyrolactone, ethylene oxide-propylene oxide and caprolactone, ethylene oxide-propylene oxide and lactic acid, oxide ethylene-propylene oxide and glycolic acid, oxide ethylene-propylene oxide and alkyl carbonate, oxide ethylene-propylene oxide and valerolactone, ethylene oxide of propylene and butyrolactone, polyethylene glycol and caprolactone, a mixture of them or a mixture with their homopolymers,

or

b)

oxide of ethylene (or ethylene oxide-propylene oxide) / diacid or anhydride / glycol being the diacid or anhydride the malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic, sebacic, maleic, fumaric, and in general any that gives rise to degradation products substantially non-toxic, and glycol being ethylene glycol, Propylene Glycol, Butylene Glycol, Hexamethylene Glycol, Diethylene Glycol, triethylene glycol, glycerin, trimethylolpropane, and in general any glycol that leads to degradation products substantially non-toxic, or a mixture of them or with the polyols in section a) and / or with their homopolymers

The polyol has a molecular weight between 150 and 6000 gr • -1, preferably between 1000 and 3000 gr • -1, and the structure of the chain must be, in the if you want to get elastomers, flexible enough so which must be amorphous or, if it is crystalline, have a temperature or melting range preferably below 60 ° C. He relative content of monomers is variable being greater than 0 and less than 1.

The synthesis of block copolymers results very convenient because it allows very precise control of amounts of monomer that are incorporated into the copolymer, by weight final molecular and block length, which follow from independently maintaining its behavior hydrophilic / hydrophobic.

A preferred embodiment of the present invention constitutes a polyurethane material of the present invention characterized in that the polyol is formed by block copolymers, preferably triblocks, resulting from the combination of polyethylene glycol-caprolactone, in forward PEG / CL (understood as PEG polyethylene glycol chains from triethylene glycol - polymerization degree 3- onwards), of way you get a structure CL-PEG-CL. In this case, in which Both blocks can crystallize, you can control the length of the blocks and therefore their crystallization, which influences the degradation rate In the case of random copolymers, the hydrophilicity / hydrophobicity is less predictable and controllable, depending on the sequences of the monomers disappearing the crystallization capacity that homopolymers have.

The synthesis of block copolymers d e P EG / CL, specifically of the tribloques, can be done by opening ε-caprolactone ring using PEG as initiator, without the presence of catalysts, following the Cerrai method (Cerrai, P .; Tricoli, M .; Andruzzi, F .; Paci, M .; Paci, M .. Polymer, 30, 338-343, 1989), or with catalysts (Cohn, D .; Stern, T .; González, M.F .; Epstein, J. J. Biomed Mater. Res., 59 (2), 273-281, 2002) in whose case is preferably used Tin 2-ethyl hexanoate, whose presence in later stages in the synthesis of polyurethanes not It is problematic, to be used in a very small amount, 0.1% in moles with respect to glycol or PEG, and because it acts, if not has deactivated, as catalyst of the reaction of the group Isocyanate with alcohol groups. The preference for Tin 2-ethyl hexanoate, Usually called tin octoate, it is because its use as a catalyst it is approved by the US FDA [FDA (Food and Drugs Administration), USA, 2002. Title 21, Chapter 1, Part 175, Subpart C, Sec. 175,300. Resinous and polymeric coatings] in coatings in contact with food at temperatures below 80 ° C and at a level not exceeding 1% by weight of the resin.

The amino acid residue is incorporated into the chain main through the polyisocyanate or through the extender of chain. Particularly when the amino acid residue is incorporates through the extender, the polyisocyanates that are used in the formation of polyurethane are diisocyanates and triisocyanates, preferably butanediisocyanate and hexamethylene diisocyanate. On the other hand, when the rest of amino acid is incorporated through polyisocyanate, the Polyisocyanates used in polyurethane formation are a diisocyanate or triisocyanate derived from the ester of a monoalcohol, preferably methyl or ethyl, of the L-lysine or L-ornithine.

When the amino acid is incorporated through the polyisocyanate, the chain extenders used are difunctional glycols such as ethylene glycol, propylene glycol, butanediol and hexanediol, polyfunctional glycols such as glycerin, trimethylolpropane, glucose, fructose, ribose and deoxyribose, diamines such as ethylenediamine, propylenediamine, butylenediamine, hexamethylenediamine, piperazine, diaminodiphenylsulfone and Polacure 740M (Air Products company diamine, reaction product of 1,3-propylene glycol with the acid p-aminobenzoic acid) or molecules with alcohol groups and amine such as ethanolamine and p-aminophenol.

When the chain extender is the one incorporates the amino acid residue, an ester is used as an extender of a monoalcohol, preferably ethyl or ethyl m, of a carrier amino acid of two or more groups capable of reacting with the isocyanate group, such as L-lysine or L-Ornithine, with two amine groups, the L-serine or L-threonine, with a alcohol group and an amine group, L-tyrosine with a phenol group and an amine group, or L-cysteine, with a thiol group and an amine group.

When apart from the acid group, the amino acid only carries a group capable of reacting with the group isocyanate, a compound used as a chain extender resulting from the reaction of an amino acid with a molecule substantially non-toxic that the groups contribute functional requirements to convert the resulting molecule into polyfunctional with respect to the isocyanate group. This is done for react an amino acid, including amino acids frequent proteins such as lysine, tyrosine, serine, threonine, cysteine, glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, asparagine, glutamine, tryptophan, methionine, aspartic acid, glutamic acid, arginine and histidine, little protein frequent as 4-hydroxyproline, the 5-hydroxylysine, desmosin, isodesmosin, epsilon-N-methyl-lysine, the epsilon-N-trimethyl-lysine  and 3-methyl-histidine, non-proteins such as ornithine, the beta-alanine acid gamma-aminobutyric acid, homocysteine, homoserine and citrulline, with a large molar excess of a diol, such as ethylene glycol or propylene glycol, to obtain chain extenders amino acid derivatives with an alcohol group and an amine group, as outlined in Figure 1. Or you can react the amino acid with half a mole of a diol, such as ethylene glycol or propylene glycol, to give rise to a derivative with two amino groups and two amino acid residues, as schematized in Figure 2.

The amino acid derived extenders, they can be isolated as salts, in which case each amino group accompanies an acid residue (HCl or acid p-toluenesulfonic, for example), or by treatment of the salt with a molar excess of base in aqueous solution [Skarja, G.A .; Woodhouse, K.A .. J. Biomater. Sci. Polymer Edn., 9 (3), 271-295, 1998 .; Woodhouse, K.A .; Skarje, G.A .. US Patent 6,221,997 B1, 2001; Huang, S.L .; Bansleben, D.A .; Knox, J.R .. J. Appl. Polym Sci., 23, 429-437, 1979], the Amine groups remain in their free form.

The amino acid residue is incorporated preferably for each isocyanate or extender molecule that Become part of the polyurethane chain. But nevertheless, occasionally it may be desirable for the amino acid to be present in a smaller content or in random locations in the chain, for which you can combine, in variable molar ratio, two different polyisocyanates, one that contains at least one remainder of amino acid and another that does not contain amino acid residues, or two different chain extenders, one that contains at least one amino acid residue and one that does not contain amino acid residues, being in each case the polyisocyanate or chain extender that does not contain at least one amino acid residue, of a nature such that when degrading their degradation products be substantially non-toxic

The procedure to obtain the material polyurethane of the invention preferably provides a segmented linear polyurethane, for which it is based on reagents difunctional in a 1: 1 molar ratio between isocyanate groups and the groups that react with the isocyanate group. Being linear, The polymer could be previously synthesized by a method such as of the prepolymer or the one-shot method, in a reactor discontinuous or in a continuous reactor, in bulk or in solution, and later transform into its final form, which implies a advantage over crosslinked materials, in which some of the reagents have functionality greater than two, and must polymerize directly in its final form or pre-finished When the polyurethane material resulting is not linear, the molar relationship between the groups isocyanate and the groups that react with the isocyanate group do not it must necessarily be 1: 1, being able to use an excess of groups of any of the two types, for example of groups isocyanate to give rise to crosslinking by formation of allophanate bonds with urethane or biuret bond groups with urea groups.

Although preferably the chain extender is added in the polyurethane formulation during synthesis, it is possible to generate it in situ in the reaction medium. For example, a formulation with polyol, LDI and water can be prepared, in which the water, which is added in the molar amount necessary to generate the amine groups required for the fixed stoichiometry, reacts with the isocyanate groups of the LDI to generate the group corresponding amine and a molecule of carbon dioxide. The carbon dioxide generated in some applications may be useful for the formation of a foamed material.

In the synthesis of polyurethanes, when part of a salt-shaped chain extender, such as the lysine ethyl ester dihydrochloride, should be added to the reaction mixture a base that sequesters the acid groups of the reaction medium, and that does not react with isocyanate groups. base dome tertiary amines, such as triethylamine, can be used. If acid groups are not sequestered, they greatly retard the polymerization reaction of the isocyanate group with the groups chain extender reagents, while it can lead to a higher proportion of side reactions and therefore a insufficient growth of the final polymer.

When the synthesis is carried out in solution, and in anticipation that solvent residues may remain in the final polymer, classified solvents are preferably used as a Class 3 in the pharmaceutical industry ["Handbook of solvents ", G. Wypych Ed., ChemTec Publishing, Toronto. Chapter 16, p.1143-1145. 2001], including dimethylsulfoxide (DMSO), tetrahydrofuran (THF), methyl ethyl ketone (MEK) and methyl isobutyl ketone (MIBK), or failing that, Class 2 as N, N-dimethylacetamide (DMAc), N, N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone (NMP), avoiding, whenever possible, the solvents of Class 1 as 1,2-dichloroethane (DCE).

In the synthesis of polyurethanes, especially for the reaction between the alcohol groups and the isocyanate group, if the reaction is too slow the addition of catalysts The catalyst will preferably be used as Tin 2-ethyl hexanoate, usually called tin octoate. It is also valid any other amine or organometallic type catalyst substantially non-toxic.

The mechanical tensile properties of polyurethanes prepared according to the present invention may vary between rigid plastics and soft elastomers. The properties, assuming that a molecular weight of the polymer is always reached final high enough so that it hardly influences, depend on the reagents chosen that constitute the chain of polymer, and the resulting morphology. For example, if the polyol crystallizes at the temperature of use, the polymer will have a plastic behavior, in which from a certain elongation the polymer will permanently deform while if at the temperature of use the polyol remains amorphous, the material may have, depending on another series of factors, a elastomeric behavior. In Figure 3 you can see the polymers derived from various dihydroxy triblocks, some very soft with low mechanical properties, and others with properties better that it behaves like tenacious plastics, in which the effort increases greatly at the beginning, with a low creep point deformation from which the deformation is permanent and the effort increases slowly with the increase in deformation until the break.

It was also verified, with models, that hard segments derived from LDI and amino acid ethyl ester are amorphous When they are part of a polyurethane, if the polyol does not crystallize, the absence of separation of phases in the system, or what is the same, the hard segments are mix with the soft segments formed by the polyol and form single phase If the polyol crystallizes, a polyol phase is formed practically pure, while hopefully the amorphous part of the polyol and the hard segments form a mixed phase. The structural irregularity introduced by amino acid residues in the polymer chain they prevent the crystallization of hard segments, which would promote phase separation, and therefore, when the hard segments do not contain aromatic or other rings rigid structural units, hopefully the phase separation If the hard segments contain rings aromatic or other rigid structural elements, for example using p-aminophenol as an extender, although still crystallization is very unlikely, incompatibility thermodynamics with soft polyol segments is greater, and the separation of a hard segment phase could take place amorphous. Depending on the application, phase separation could be advantageous, since it generally improves the mechanical properties of the material, getting in the best possible scenario a elastomeric material with a soft amorphous segment and a segment hard separated into phases with very good mechanical properties.

The biodegradable polyurethane material can formulated with additives, including fillers and plasticizers, to adjust the properties of the material or its behavior under specific conditions, being additive biodegradable or disposable and they and their degradation products non-toxic

The main applications are based on their use as material for the production of products for the sector pharmaceutical and biotechnology, specifically its main application It is for the transport and controlled release of products Pharmacological or biotechnological and for tissue engineering.

Brief description of the content of the figures

Figure 1. Scheme of the reaction of a amino acid with a molar excess of a diol to form a compound difunctional with an alcohol group and an amine group.

Figure 2. Scheme of the reaction of a amino acid with a 2: 1 molar ratio to form a difunctional compound with two amine groups.

Figure 3. Curves of strain-strain for a series of polymers of PCL / PEG / PCL-LDI-lysine ethyl ester. The Nomenclature of polymers as in Table 3.

Example of embodiment of the invention Example 1 Synthesis of polyethylene glycol and caprolactone triblocks

Materials: Triethylene Glycol (molecular weight 150), polyethylene glycols (PEG) 400, 900 and 2000, the Tin 2-ethyl hexanoate and the epsilon-caprolactone (CL) were obtained from Aldrich. The glycols were dried under vacuum and 75 ° C overnight, and were kept in desiccator until use. The other reagents are They employed directly. The molecular weight (Mn) of the polyethylene glycols was determined by nuclear magnetic resonance (NMR) of proton in deuterated chloroform and adding a few drops of trifluoroacetic anhydride to displace the signal of the groups terminals The results obtained were 474, 912 and 2466 g / mol for PEG 400, 900 and 2000 respectively.

Synthesis of the polyethylene glycol 400 triblock and epsilon-caprolactone with a molecular weight Approximately 2000 g / mol: In a round 250 ml dry flask, add 0.0241 moles of polyethylene glycol 400, 0.3377 moles of epsilon-caprolactone and 0.0000241 moles of Tin 2-ethyl hexanoate. Be heat the mixture at 130 ° C with stirring for 8 hours under nitrogen atmosphere. After that time the dough is allowed to cool reaction and a white solid of pasty consistency is obtained which It is characterized by proton NMR, differential calorimetry of scanning (DSC), and high angle X-ray diffraction (WAXD).

Following the same procedure they were synthesized a series of tribloques listed in table 1. The relationship CL / PEG molar was varied, and the tin catalyst was added always in a molar ratio of 0.1% with respect to the moles of glycol. By proton NMR, and following the procedure used to the PEG, the Mn was calculated for the tribloques, whose result is included in table 1. The denomination of the tribloque makes reference to the Mn of the starting glycol and the CL / PEG molar ratio of food. All the obtained tribloques were white solids at room temperature, more or less consistency pasty for those of Mn less or about 2000 g / mol.

Example 2 Synthesis of the LDI polymer and ethyl ester of L-Lysine, L-Ornithine, L-serine and L-tyrosine

Materials: L-lysine, the L-Ornithine, L-Serine, and L-tyrosine were obtained from Fluka, diisocyanate of Kyowa L-lysine methyl ester (LDI) Hakko, tin 2-ethyl hexanoate of Aldrich, triethylamine, thionyl chloride, ethanol and Scharlau dimethylacetamide. From the L-lysine, L-ornithine, L-serine and L-tyrosine, by reaction with ethanol and thionyl chloride, the corresponding ethyl esters following the procedure found in the bibliography [Shi, F.Y .; Wang, L.F .; Tashev, E .; Leong, K.W .. "Polymeric Drugs and Drug Delivery Systems", R.L. Dunn and R.M. Ottenbrite Eds., A CS Symposium Series 4 69, A CS Washington D. C. Chapter 14. 1991; Huang, S.L .; Bansleben, D.A .; Knox, J.R .. J. Appl. Polym Sci., 23, 429-437, 1979]. The resulting esters were characterized by proton NMR and elemental analysis, coinciding with the ethyl esters corresponding crystallized, for L-lysine and L-Ornithine with two HCl molecules, and for the L-serine and L-tyrosine with a HCI molecule. The triethylamine was dried by distillation on potash, collected in a topaz jar with molecular sieves. The dimethylacetamide was purified by distillation under reduced pressure on isocyanates. Isocyanates react with the remains of water and mines present in the solvent, which would unbalance the stoichiometric balance in the polymerization reaction. The distillation temperature was always kept below 60 ° C temperature, and the distilled solvent, stored under nitrogen in a sealed flask, was always used within seven days after distillation. The remaining reagents are They employed directly.

Synthesis of the LDI polymer and ethyl ester of L-lysine: In a dry 25 ml round flask it add 0.004 moles of the L-lysine ethyl ester,  0.004 moles of LDI and 15 ml of dimethylacetamide. It heats up mix at 80 ° C with stirring under nitrogen atmosphere until the L-lysine ethyl ester is dissolved, let cool to room temperature and add 0.008 moles of triethylamine A precipitate of triethylamine.HCl appears, and after A few minutes of reaction is checked by I R that the diisocyanate It has been consumed, and the mixture is poured onto ice / water. Separates a viscous solid in gel form, the solution is decanted, Wash the solid with water a couple of times, and dry in vacuo. He The resulting solid is characterized by proton NMR and DSC.

Following the same procedure, the LDI polymer + ornithine ethyl ester. For polymers LDI + ethyl ester of L-serine and LDI + ethyl ester of L-tyrosine, the procedure simply varied in the addition of 0.00004 moles of Tin 2-ethyl hexanoate and the Half moles of triethylamine.

These polymers were prepared to estimate the thermal properties of hard segments composed of LDI + ester ethyl of the aforementioned amino acids, in compound polyurethanes of these hard segments + a polyol.

Table 2 shows the models of prepared hard segments and their glass transition temperature (all turned out to be amorphous) obtained by DSC.

Example 3 Synthesis of polyurethane from tribes of PEG / CL, LDI and L-lysine ethyl ester

Materials: Dihydroxy triblocks obtained according to example 1 were dried by the same procedure used in example 1 for PEG.

The remaining reagents as in example 1 and example 2.

150-16 polymer synthesis, LDI, and lysine ethyl ester with 1: 2.5: 1.5 molar ratio (PU 150-16): In a flask the tribloque is added 150-16 and the LDI in 1: 2.5 molar ratio, dimethylacetamide to give a solution of approximately 1M of tribloque concentration, and 0.01 moles of Tin 2-ethyl hexanoate. The mixture is heated at 80 ° C with stirring and under a stream of nitrogen for 3 hours to effect the pre-polymerization After that time, that by previous tests it is known is enough for them to react completely alcohol groups, allowed to cool, 1.5 are added moles of lysine ethyl ester and 4.5 moles of triethylamine, and reheat the reaction mixture at 80 ° C for 2.5 hours. After that time, it is checked by IR that the reaction has completed and the resulting dispersion is cooled (the triethylamine hydrochloride formed during the reaction is keeps precipitated) and poured over an ice / water mixture distilled The resulting precipitate is decanted, washed with water distilled and filtered with the help of a Büchner funnel. Turns to wash with water in the funnel and the remaining white polymer dries empty

Polymer samples for the realization of characterization tests were prepared by casting from of a 10% weight / volume solution of the polymer in chloroform. The film was spread on a level glass and covered with a funnel to prevent contamination with dust and evaporation too fast solvent. After 48 hours of evaporation at room temperature inside a showcase the film took off of polymer and dried under vacuum another 24 hours at room temperature.  Samples were cut from the dried film for characterization of thermal properties by DSC (temperature of glass transition-Tg, in the second sweep -y melting temperature -Tf, in the first scan-) and mechanical traction according to ISO 37.

Following the same reaction procedure in Two steps synthesized the rest of polymers. Molar relationship tribloque: LDI: lysine ethyl ester was always maintained 1: 2.5: 1.5, the concentration of dimethylacetamide 1 M with respect to the polyol, moles of tin 2-ethyl hexanoate 0.01, and moles of triethylamine 4.5. To obtain the polymer films chloroform was always employed as solvent

Table 3 shows the name and composition of synthesized polymers and their properties Thermal and mechanical The name of the polymers consists of the letters PU, which indicate poly (urethane-urea), followed by reference to the tribloque as found in table 1.

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TABLE 1 Synthesized triblocks of the combination of PEG-CL

one

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TABLE 2 Models of prepared hard segments and their glass transition temperature obtained by DSC

2

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TABLE 3 Denomination and composition of polyurethanes synthesized and its thermal and mechanical properties

3

Claims (11)

1. Biodegradable polyurethane material characterized in that it is constituted by the product resulting from the reaction between a polyol, a polyisocyanate and a chain extender, and because its structure includes at least one natural amino acid residue, where the polyol is a block copolymer or Randomly constituted by the combination of antagonistic hydrophilic and hydrophobic monomers such as:

to)

oxide of ethylene and caprolactone, ethylene oxide and lactic acid, oxide of ethylene and glycolic acid, ethylene oxide and carbonate of alkyl, ethylene oxide and valerolactone, ethylene oxide and butyrolactone, ethylene oxide-propylene oxide and caprolactone, ethylene oxide-propylene oxide and lactic acid, oxide ethylene-propylene oxide and glycolic acid, ethylene oxide of propylene and alkyl carbonate, ethylene oxide-oxide propylene and valerolactone, ethylene oxide-propylene oxide and butyrolactone, polyethylene glycol and caprolactone, a mixture of them or a mixture with homopolymers,

or

b)

oxide of ethylene (or ethylene oxide-propylene oxide) / diacid or anhydride / glycol, the diacid or anhydride being the malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic, sebacic, maleic, fumaric, and glycol being ethylene glycol, Propylene Glycol, Butylene Glycol, Hexamethylene Glycol, Diethylene Glycol, triethylene glycol, glycerin, trimethylolpropane, or a mixture of them or with the polyols of section a) and / or with the homopolymers

2. Biodegradable polyurethane material according to claim 1, characterized in that the polyol has a molecular weight between 150 and 6000 gr · mol-1, preferably between 1000 and 3000 gr · mol-1. 3. Biodegradable polyurethane material according to claim 1 to 2 characterized in that the relative content of the monomers in the polyol is greater than 0 and less than 1. 4. Biodegradable polyurethane material according to claim 1 to 3, characterized in that the polyol is preferably a triblock copolymer resulting from the combination of polyethylene glycol and caprolactone such that a caprolactone-polyethylene glycol-caprolactone structure is obtained. 5. Biodegradable polyurethane material according to claim 1 characterized in that the polyisocyanate is:

to)

a diisocyanate or triisocyanate, preferably butanediisocyanate and hexamethylene diisocyanate

or

b)

a diisocyanate or triisocyanate derived from the ester of a monoalcohol, preferably methyl or ethyl, of an amino acid such as L-lysine or L-ornithine.

6. Biodegradable polyurethane material according to claim 1 characterized in that the chain extender is:

to)

a difunctional glycol such as ethylene glycol, propylene glycol, butanediol and hexanediol, a polyfunctional glycol such as glycerin, trimethylolpropane, glucose, fructose, ribose and deoxyribose, a diamine such as ethylenediamine, propylenediamine, butylenediamine, hexamethylenediamine, piperazine, diaminodiphenylsulfone and Polacure 740M or a molecule with alcohol and amine groups such as ethanolamine and p-aminophenol,

or

b)

a ester of a monoalcohol, preferably methyl or ethyl, of a carrier amino acid of two or more groups capable of reacting with the isocyanate group, such as L-lysine or L-Ornithine, with two amine groups, the L-serine or L-threonine, with a alcohol group and a group to mine, L-tyrosine with a phenol group and an amine group, or L-cysteine, with a thiol group and an amine group,

or

C)

a compound resulting from the reaction between an amino acid, between that frequent protein amino acids such as lysine are included, tyrosine, serine, threonine, cysteine, glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, asparagine, glutamine, tryptophan, methionine, aspartic acid, glutamic acid, arginine and histidine, rare proteins such as 4-hydroxyproline, 5-hydroxylysine, desmosin, isodesmosin, the epsilon-N-methyl-lysine, the epsilon-N-trimethyl-lysine and 3-methyl-histidine, non-proteins such as ornithine, the beta-alanine acid gamma-aminobutyric acid, homocysteine, homoserine and citrulline, and a large molar excess of a diol, such as ethylene glycol or propylene glycol to obtain chain extender amino acid derivative with an alcohol group and an amine group, or the half moles of said diol to obtain chain extender amino acid derivative with two amino groups.

7. Biodegradable polyurethane material according to claims 1 to 6, characterized in that the amino acid residue is preferably incorporated by each molecule of polyisocyanate or chain extender being occasionally desirable for incorporation into a smaller content or at random locations in the polyurethane chain for which combines two different polyisocyanates, one that contains at least one amino acid residue and one that does not contain amino acid residues, or two different chain extenders, one that contains at least one amino acid residue and another that does not contain amino acid residues. . 8. Biodegradable polyurethane material according to claims 1 to 7, characterized in that it can be formulated with biodegradable additives, including fillers and plasticizers, to adjust the properties of the material or its behavior under specific conditions. 9. Use of biodegradable polyurethane material according to claims 1 to 8 for the production of products applied in the pharmaceutical and biotechnology sector. 10. Use of the biodegradable polyurethane material according to claim 9 characterized in that the product is a biomaterial for the transport and release of pharmacological or biotechnological products. 11. Use according to claim according to claim 9 characterized in that the product is a biomaterial usable in tissue engineering.