WO2005111110A1 - Non-toxic biodegradable polyurethanes which are intended for the controlled release of pharmaceuticals and for tissue engineering - Google Patents

Non-toxic biodegradable polyurethanes which are intended for the controlled release of pharmaceuticals and for tissue engineering Download PDF

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Publication number
WO2005111110A1
WO2005111110A1 PCT/ES2005/070063 ES2005070063W WO2005111110A1 WO 2005111110 A1 WO2005111110 A1 WO 2005111110A1 ES 2005070063 W ES2005070063 W ES 2005070063W WO 2005111110 A1 WO2005111110 A1 WO 2005111110A1
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amino acid
glycol
ethylene oxide
polyurethane material
lysine
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PCT/ES2005/070063
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Spanish (es)
French (fr)
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Ángel A. MARCOS FERNÁNDEZ
Julio SAN ROMÁN DEL BARRIO
Gustavo Abel Abraham
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Consejo Superior De Investigaciones Científicas
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Publication of WO2005111110A1 publication Critical patent/WO2005111110A1/en

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/83—Chemically modified polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/0804—Manufacture of polymers containing ionic or ionogenic groups
    • C08G18/0819—Manufacture of polymers containing ionic or ionogenic groups containing anionic or anionogenic groups
    • C08G18/0823—Manufacture of polymers containing ionic or ionogenic groups containing anionic or anionogenic groups containing carboxylate salt groups or groups forming them
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
    • C08G18/4269—Lactones
    • C08G18/4277—Caprolactone and/or substituted caprolactone
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/65—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen

Definitions

  • Biodegradable polymers are becoming increasingly important for various biomedical applications, such as tissue engineering, in which the current trend is to develop matrices that promote angiogenesis and support the cells of the tissue you are trying to replace, but of the Commercially available polymers there are very few that have elastomeric properties. Intentionally degraded polymers can avoid various problems and negative physiological responses: fibrous encapsulation, need for a second surgical intervention to remove the implant, etc.
  • Polyurethanes (broadly understood as polyurethanes, polyurethaneurea and polyureas) are a family of polymers widely used in medicine, but mainly as biostable materials, and in very few cases as biodegradable materials (Artelon TM, related to reference [Flodin, P. US Patent 6,220,441 B1 (Artimplant, Sweden), 2001] Although the percentage of publications dedicated to biostable polyurethanes is also overwhelming in scientific and technical literature, several publications and patents of biodegradable polyurethanes aimed at medical applications have appeared for a few years [ Flodin, P ..
  • biodegradable polyurethanes described are both rigid materials and elastomeric materials.
  • reagents commonly used in the manufacture of polyurethanes give rise to toxic products in their degradation, which excludes their use in the synthesis of these polyurethanes.
  • toluendiisocyanate and its derivatives methylene diisocyanate and its derivatives
  • isophorone diisocyanate and its derivatives the amines corresponding to all these isocyanates
  • MOCA or MBOCA 3,3'-dichloro-4,4'-diphenylamino methane
  • the degradation products to which the polymer gives rise are non-toxic [Chauvel-Lebret, DJ; Auroy, P .; Bonnaure-Mallet, M .. "Polymeric Biomaterials. Second Edition", S. Dumitriu Ed., Marcel Dekker, Inc .. Chapter 13. 2001; Woodhouse, KA; Skarje, GA. US Patent 6,221, 997 B1, 2001; Skarja, GA; Woodhouse, KA. J. Appl.
  • biodegradable polymers include the amino acids (or derivatives thereof), most of which form the proteins, and which are therefore not toxic.
  • Amino acids have long been used in the formation of a multitude of synthetic polymers [Kemnitzer, J .; Kohn, J .. "Handbook of biodegradable polymers", AJ Domb, J. Kost, DM Wiseman, Eds., Harwood Academic Publishers. Chapter 13, p.251-272. 1997; Domb, AJ. Biomaterials, 11, 686, 1990], including polyurethanes [Flodin, P ..
  • amino acid residues in the main chain has been primarily as diisocyanate, especially lysine [Fontaine, L .; M nard, 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.
  • the object of the present invention is therefore to 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.
  • an object of the present invention is a biodegradable polyurethane material with hydrophilicity / hydrophobicity adjustment, whose degradation products are substantially non-toxic, 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 or random copolymer consisting of antagonistic hydrophilic / hydrophobic monomers or mixing thereof with other peer copolymers. characteristics and with homopolymers.
  • a preferred embodiment of the present invention is a polyol formed by block copolymers, in particular of triblocks, resulting from the combination of polyethylene glycol-caprolactone, hereinafter PEG / CL, so that a CL-PEG-CL structure is obtained.
  • PEG / CL polyethylene glycol-caprolactone
  • the incorporation of the amino acid residue in the chain is done through the polyisocyanate or chain extender.
  • the process of obtaining provides a segmented linear polyurethane obtained from the reagents in a 1: 1 molar ratio between the isocyanate groups and the groups that react with the isocyanate group, being carried out by the prepolymer method or by the one- method. shot, in bulk or in solution, in a continuous or discontinuous reactor.
  • the mechanical properties of the resulting polyurethanes can be varied from soft elastomers to rigid plastics. Although there are numerous commercial examples of biodegradable rigid polymers, many of them turn out to be too rigid and sometimes fragile, while polyurethanes are often tenacious. On the other hand, there is the possibility of obtaining degradable elastomers with varying degrees of elasticity or hardness, of which there are few commercial examples, which makes the materials described in this invention can be commercially very attractive. It is industrially applicable as a material for controlled drug release and tissue engineering.
  • an object of the present invention is a polyurethane material, hereinafter polyurethane material of the present invention, biodegradable with hydrophilicity / hydrophobicity adjustment, whose degradation products are substantially non-toxic, characterized in that it is constituted by 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 consisting of a combination of monomers of antagonistic hydrophilic / hydrophobic character or mixture thereof with other copolymers of the same characteristics and with homopolymers.
  • the rest of the natural amino acid makes this polyurethane material recognizable by biological agents.
  • polyurethane as used in the present invention should be broadly understood as polyurethane, polyurethaneurea and polyurea.
  • substantially non-toxic as used in the present invention refers to materials that when present in the body, are physically tolerable, and more specifically, do not cause appreciable cell death (cytotoxicity) or a negative function impairment. normal cell (mutagenic response).
  • biological agent refers to molecules that bind and recognize amino acids, whether they are floating freely in the extracellular medium including enzymes, or proteins bound to cell surfaces such as receptors.
  • chain extender refers to a multifunctional molecule of relatively low molecular weight, less than 300 gr mol "1 , with a number of reactive groups against the isocyanate group equal to or greater than 2, preferably alcohol or amine groups, but also others such as phenol or thiol
  • amino acid residue as used in the present invention includes one or more amino acid residues of the naturally occurring configuration and which are substantially non-toxic.
  • a particular object of the invention is the polyurethane material of the present invention characterized in that the polyol results from the combination of the following monomers, by way of illustration and without limiting the scope of the invention, of the following group: a) ethylene and caprolactone, ethylene oxide and lactic acid, ethylene oxide and glycolic acid, ethylene oxide and alkyl carbonate, ethylene oxide and valerolactone, ethylene oxide and butyrolactone, ethylene oxide propylene oxide and caprolactone oxide ethylene-propylene oxide and lactic acid, ethylene oxide-propylene oxide and glycolic acid, ethylene oxide-propylene oxide and alkyl carbonate, ethylene oxide-propylene oxide and valerolactone, ethylene oxide-propylene oxide and butyrolactone, polyethylene glycol and caprolactone, a mixture thereof or a mixture with their homopolymers, or b) ethylene oxide oxide
  • the polyol has a molecular weight between 150 and 6000 gr-mol "1 preferably between 1000 and 3000 gr mol " 1 , and the chain structure must be, in the case of wanting to obtain elastomers, sufficiently flexible so it must be amorphous or, if it is crystalline, having a melting temperature or range preferably below 60 ° C.
  • the relative content of the monomers is variable being greater than 0 and less than 1.
  • the synthesis of block copolymers is very convenient because it allows very precise control of the amounts of monomer that is incorporate in the copolymer, the final molecular weight and the length of the blocks, which follow independently maintaining their hydrophilic / hydrophobic behavior.
  • a preferred embodiment of the present invention is a polyurethane material of the present invention characterized in that the polyol is formed of block copolymers, preferably of triblocks, resulting from the combination of polyethylene glycol-caprolactone, hereinafter PEG / CL (understood as PEG polyethylene glycols from triethylene glycol - polymerization degree 3- onwards), so that a CL-PEG-CL structure is obtained.
  • PEG / CL understood as PEG polyethylene glycols from triethylene glycol - polymerization degree 3- onwards
  • tin 2-ethyl hexanoate usually called tin octoate
  • tin octoate is because its use as a catalyst is approved by the US FDA [FDA (Food and Drugs Administration), USA, 2002. Title 21 , Chapter I, 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 main chain through the polyisocyanate or through the chain extender.
  • the polyisocyanates used in polyurethane formation are diisocyanates and triisocyanates, preferably butanediisocyanate and hexamethylene diisocyanate.
  • the polyisocyanates used in the formation of the polyurethane are a diisocyanate or triisocyanate derived from the ester of a monoalcohol, preferably methyl or ethyl, of the L-lysine or of L-omitin.
  • the chain extenders used are difunctional glycols such as ethylene glycol, propylene glycol, butanediol and hexanodiol, polyfunctional glycols such as glycerin, trimethylolpropane, glucose, fructose, ribose and deoxyrilendiamine, diamines, diamines Butylenediamine, hexamethylenediamine, piperazine, diaminodiphenylsulfone and Polacure 740M (diamine of the Air Products company, product of the reaction of 1, 3- propylene glycol with p-aminobenzoic acid) or molecules with alcohol and amine groups such as ethanolamine and p-aminophenol .
  • difunctional glycols such as ethylene glycol, propylene glycol, butanediol and hexanodiol
  • polyfunctional glycols such as glycerin, trimethylolpropane, glucose, fructose,
  • an 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, is used as an extender or L-omitin, with two amine groups, L-serine or L-threonine, with an 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.
  • the amino acid When apart from the acid group, the amino acid only carries a group capable of reacting with the isocyanate group, as a chain extender a compound resulting from the reaction of an amino acid with a substantially non-toxic molecule that provides the functional groups necessary to convert is used. the resulting polyfunctional molecule with respect to the isocyanate group.
  • an amino acid is reacted, including frequent protein amino acids 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, rare proteins such as 4-hydroxyproline, 5-hydroxylysine, desmosin, isodesmosine, epsilon-N-methyl-lysine, epsilon-N-trimethyl-lysine and 3-methyl-histidine, non-proteins such as omitin, beta-alanine, 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 can be reacted 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 outlined in the Figure 2.
  • the amino acid-derived extenders can be isolated as salts, in which case each acid group is accompanied by an acid moiety (HCI or p-toluenesulfonic acid, for example), or by treating the salt with a base molar excess. in aqueous solution [Skarja, GA; Woodhouse, KA. J. Biomater. Sci. Polymer Edn., 9 (3), 271-295, 1998 .; Woodhouse, KA; Skarje, GA.
  • the amino acid may occasionally be desirable for the amino acid to be present in a lower content or at random locations in the chain, for which two different polyisocyanates, one containing at least one amino acid residue, can be combined in varying molar proportion and another 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, in each case being the polyisocyanate or the chain extender that does not contain at least an amino acid residue, of a nature such that when degrading its degradation products they are substantially non-toxic.
  • the process for obtaining the polyurethane material of the invention preferably provides a segmented linear polyurethane, for which it starts from difunctional reagents in a 1: 1 molar ratio between the isocyanate groups and the groups that react with the isocyanate group.
  • the polymer could be previously synthesized by a method such as that of the prepolymer or the one-shot method, in a discontinuous reactor or in a continuous reactor, in bulk or in solution, and subsequently transformed into its final form, which means an advantage over crosslinked materials, in which some of the reagents have functionality greater than two, and must be polymerized directly in their final or pre-finished form.
  • the molar ratio between the isocyanate groups and the groups that react with the isocyanate group does not necessarily have to be 1: 1, and excess groups of any of the two types can be used, for example of isocyanate groups to give rise to crosslinking by formation of allophanate bonds with urethane groups or biuret bonds with urea groups.
  • excess groups of any of the two types can be used, for example of isocyanate groups to give rise to crosslinking by formation of allophanate bonds with urethane groups or biuret bonds with urea groups.
  • the chain extender is added in the polyurethane formulation during synthesis, it is possible to generate it in situ in the reaction medium.
  • a formulation with polyol, LDI and water can be prepared, in which 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.
  • a salt chain extender such as lysine ethyl ester dihydrochloride
  • a base that sequesters the acid groups from the reaction medium should be added to the reaction mixture, and that does not react with isocyanate groups.
  • Tertiary amines such as triethylamine
  • solvents classified as Class 3 are preferably used in the pharmaceutical industry ["Handbook of solvents", G. Wypych Ed., ChemTec Publishing, Toronto. Chapter 16, p.1143-1145.
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • MEK methyl ethyl ketone
  • MIBK methyl isobutyl ketone
  • Class 2 such as N, N-dimethylacetamide (DMAc), N, N-dimethylformamide (DMF ) and N-methyl-2-pyrrolidone (NMP)
  • Class 1 solvents such as 1,2-dichloroethane (DCE).
  • the catalyst preferably used is tin 2-ethyl hexanoate, usually called tin octoate. Any other substantially non-toxic amine or organometallic type catalyst is also valid.
  • 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 high enough molecular weight of the final polymer is always reached so that it hardly influences, depends on the reagents chosen that constitute the polymer chain, and on the resulting morphology.
  • the polymer will have a plastic behavior, in which after a certain elongation the polymer will permanently deform, while if at the temperature of use the polyol remains amorphous, material may have, depending on another series of factors, an elastomeric behavior.
  • Figure 3 shows polymers derived from several dihydroxy triblocks, some very soft with low mechanical properties, and others with better properties that behave like tough plastics, in which the stress increases greatly at the beginning, with a creep point at low deformation from which the deformation is permanent and the effort increases slowly with the increase in deformation until breakage.
  • the hard segments derived from LDI and amino acid ethyl ester are amorphous.
  • the polyol does not crystallize, the absence of phase separation in the system was verified, or what is the same, the hard segments are mixed with the soft segments formed by the polyol and form a single phase. If the polyol crystallizes, a practically pure polyol phase is formed, while it is expected that the amorphous part of the polyol and the hard segments form a mixed phase.
  • phase separation prevents the crystallization of the hard segments, which would promote phase separation, and therefore, when the hard segments do not contain aromatic rings or other rigid structural units, it is expected that phase separation does not take place.
  • the hard segments contain aromatic rings or other rigid structural elements, for example using p-aminophenol as an extender, although crystallization remains highly unlikely, the thermodynamic incompatibility with the soft segments of the polyol is greater, and the separation of a Hard amorphous segment phase.
  • phase separation could be advantageous, since it generally improves the mechanical properties of the material, achieving in the best possible scenario an elastomeric material with an amorphous soft segment and a hard segment separated into phases with very good mechanical properties.
  • the biodegradable polyurethane material can be formulated with additives, including fillers and plasticizers, to adjust the properties of the material or its behavior under specific conditions, being biodegradable or removable additives and they and their non-toxic degradation products.
  • 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 pharmacological or biotechnological products and for tissue engineering.
  • Example 1 Synthesis of polyethylene glycol and caprolactone triblocks Materials: Triethylene glycol (molecular weight 150), polyethylene glycols (PEG) 400, 900 and 2000, tin 2-ethyl-hexanoate and epsilon-caprolactone (CL) were obtained from Aldrich. The glycols were dried under vacuum and 75 ° C overnight, and kept in desiccator until use. The other reagents were used directly. The molecular weight (Mn) of the polyethylene glycols was determined by proton nuclear magnetic resonance (NMR) in deuterated chloroform and adding a few drops of trifluoroacetic anhydride to displace the signal from the terminal groups.
  • NMR proton nuclear magnetic resonance
  • Example 2. Synthesis of the LDI polymer and ethyl ester of L-lysine, L-omitin, L-serine and L-tyrosine.
  • L-lysine, L-omitin, L-serine, and L-tyrosine were obtained from Fluka, L-lysine methyl ester diisocyanate (LDI) from Kyowa Hakko, 2-ethyl-hexanoate from Aldrich tin, triethylamine, thionyl chloride, ethanol and Scharlau dimethyl
  • the resulting esters were characterized by proton NMR and elemental analysis, coinciding with the corresponding crystallized ethyl esters, for L-lysine and L-ornithine with two HCI molecules, and for L-serine and L-tyrosine with one HCI molecule.
  • the triethylamine was dried by distillation on potash, collected in a topaz bottle with molecular sieves.
  • the dimethylacetamide was purified by distillation under reduced pressure on isocyanates. The isocyanates react with the remains of water and amines present in the solvent, which would unbalance the stoichiometric balance in the polymerization reaction.
  • Example 3 Synthesis of polyurethane from tribes of PEG / CL, LDI and ethyl ester of L-lysine.
  • Materials The 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.
  • the mixture is heated to 80 ° C with stirring and low nitrogen stream for 3 hours to carry out the pre-polymerization. After this time, it is known from previous tests that it is sufficient for the alcohol groups to react completely, it is allowed to cool, 1.5 moles of lysine ethyl ester and 4.5 moles of triethylamine are added, and the mixture is reheated reaction at 80 ° C for 2.5 hours. After that time, it is verified by IR that the reaction has come to an end and the resulting dispersion is cooled (the triethylamine hydrochloride formed during the reaction is kept precipitated) and poured onto a mixture of ice / distilled water.
  • the resulting precipitate is decanted, washed with distilled water and filtered with the help of a Büchner funnel. It is washed again with water in the funnel and the remaining white polymer is dried under vacuum.
  • Polymer samples for characterization tests were prepared by casting from 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 too rapid evaporation of the solvent. After 48 hours of evaporation at room temperature inside a showcase, the polymer film was peeled off and dried under vacuum for another 24 hours at room temperature.
  • Table 3 shows the name and composition of the synthesized polymers and their thermal and mechanical properties.
  • the name of the polymers consists of the letters PU, which indicate poly (urethane-urea), followed by the reference to the triblock as found in Table 1.

Abstract

The invention relates to a biodegradable polyurethane material having adjustable hydrophilic/hydrophobic properties and non-toxic degradation products, the main chain thereof containing at least one amino acid group, thereby rendering same recognisable by biological agents. The polymers are synthesised form a long-chain monomer, such as a polyol formed by a copolymer comprising units or segments with different hydrophilic/hydrophobic properties, a di- or polyisocyanate and a chain extender, such that: the degradation products of said three basic components do not produce toxic products, and the structure of the main chain contains at least one amino acid group. The principal applications of the invention are based on the use thereof as a material for the production of products that are intended for the pharmaceutical and biotechnological industries. More specifically, the invention is intended primarily for the transport and the controlled release of pharmaceuticals and for tissue engineering.

Description

TÍTULOTITLE
POLIURETANOS BIODEGRADABLES NO-TÓXICOS PARA LIBERACIÓNNON-TOXIC BIODEGRADABLE POLYURETHANS FOR RELEASE
CONTROLADA DE FÁRMACOS Y PARA INGENIERÍA DE TEJIDOSCONTROLLED DRUGS AND FABRIC ENGINEERING
SECTOR DE LA TÉCNICA Materiales para su aplicación en el sector Médico-farmacéutico. Material de poliuretano biodegradable no-tóxico para liberación controlada de fármacos y para ingeniería de tejidos que contiene en su cadena principal al menos un resto de aminoácido.SECTOR OF THE TECHNIQUE Materials for its application in the medical-pharmaceutical sector. Non-toxic biodegradable polyurethane material for controlled drug release and for tissue engineering that contains at least one amino acid residue in its main chain.
ESTADO DE LA TÉCNICA Los polímeros biodegradables se están volviendo cada vez más importantes para varias aplicaciones biomédicas, como la ingeniería de tejidos, en la cual la tendencia actual es desarrollar matrices que promuevan angiogénesis y soportar las células del tejido que intenta reemplazar, pero de los polímeros disponibles comercialmente hay muy pocos que tengan propiedades elastoméricas. Los polímeros que se degradan de forma intencionada pueden evitar diversos problemas y respuestas fisiológicas negativas: encapsulación fibrosa, necesidad de una segunda intervención quirúrgica para la extracción del implante, etc.. Por ello se ha investigado mucho sobre ellos, pero la mayoría de los disponibles comercialmente son esencialmente materiales rígidos, como por ejemplo el poliglicólico, primer polímero sintético absorbible que apareció a principio de los años 70, lo que hace deseable, al menos en lo que respecta a la ingeniería de tejidos, la existencia de materiales con una amplia variedad de propiedades físicas que permitan su integración con los varios tejidos encontrados en el cuerpo. Estos polímeros degradables, con un diseño y una elección de monómeros convenientes en la síntesis, pueden tener una hidrofilicidad/hidrofobicidad, y consecuentemente una degradabilidad, controlada o ajustada [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.; Vert, M.; Petrova, T.; Manolova, N.; Rashkov, I.. J. Appl. Polym. Sci., 68, 989-998, 1998; Petrova, Ts.; Manolova, N.; Rashkov, I.; L¡, S.; Vert, M.. Polym. Int., 45, 419-426, 1998; L¡, S.M.; Chen, X.H.; Gross, R.A.; McCarthy, S.P.. J. Mater. Sci.: Mater. Med., 11 , 227-233, 2000; Goma, 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], siendo muy común el par polióxido de etileno/policaprolactona [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.; 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; Goma, K.; Gogolewski, S.. Polym. Degrad. Stab., 79, 465-474, 2003]. Los poliuretanos (entendido de forma amplia como poliuretanos, poliuretanoureas y poliureas) son una familia de polímeros ampliamente usados en medicina, pero principalmente como materiales bioestables, y en muy pocos casos como materiales biodegradables (Artelon™, relacionado con referencia [Flodin, P. Patente US 6,220,441 B1 (Artimplant, Suecia), 2001]. Aunque en la literatura científico-técnica también sea abrumador el porcentaje de publicaciones dedicadas a poliuretanos bioestables, desde hace unos años han aparecido distintas publicaciones y patentes de poliuretanos biodegradables dirigidos a aplicaciones médicas [Flodin, P.. Patente US 6,220,441 B1 (Artimplant, Suecia), 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; Goma, 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. Páginas 39-57, 2000; Skarja, G.A.; Woodhouse, K.A.. J. Biomater. Sci. Polymer Edn., 9(3), 271 -295, 1998; Goma, K.; Gogolewski, S.. Polym. Degrad. Stab., 79, 465-474, 2003; Müller, M.; Henschler, D.; Sabbioni, G.. Helv. Chim. Acta, 81 , 1254-1263, 1998; Fontaine, L; M nard, 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. Capítulo 14. 1991 ; Chauvel-Lebret, D.J.; Auroy, P.; Bonnaure-Mallet, M.. "Polymeric Biomaterials. Second Edition", S. Dumitriu Ed., Marcel Dekker, Inc. Capítulo 13. 2001]. Entre los poliuretanos biodegradables descritos se encuentran tanto materiales rígidos como materiales elastoméricos. Varios de los reactivos comúnmente usados en la elaboración de poliuretanos dan lugar a productos tóxicos en su degradación, lo que excluye su empleo en la síntesis de estos poliuretanos. Entre estos se puede citar al toluendiisocianato y sus derivados, el metilendiisocianato y sus derivados, el diisocianato de isoforona y sus derivados, las aminas correspondientes a todos estos isocianatos, y la 3,3'-dicloro-4,4'-difenilamino- metano (MOCA o MBOCA). Si se efectúa una adecuada elección de los reactivos, los productos de degradación a los que da lugar el polímero son no- tóxicos [Chauvel-Lebret, D.J.; Auroy, P.; Bonnaure-Mallet, M.. "Polymeric Biomaterials. Second Edition", S. Dumitriu Ed., Marcel Dekker, Inc.. Capítulo 13. 2001 ; Woodhouse, K.A.; Skarje, G.A.. Patente US 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. 1995; 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]. Entre los posibles reactivos a seleccionar para la constitución de polímeros biodegradables están los aminoácidos (o derivados de éstos), la mayoría de los cuales forman las proteínas, y que no son por tanto tóxicos. Los aminoácidos se han empleado desde hace tiempo en la formación de multitud de polímeros sintéticos [Kemnitzer, J.; Kohn, J.. "Handbook of biodegradable polymers", A.J. Domb, J. Kost, D.M. Wiseman, Eds., Harwood Academic Publishers. Capítulo 13, p.251-272. 1997; Domb, A.J.. Biomaterials, 11 , 686, 1990], entre ellos poliuretanos [Flodin, P.. Patente US 6,220,441 B1 (Artimplant, Suecia), 2001 ; Skarja, G.A.; Woodhouse, K.A.. J. Biomater. Sci. Polymer Edn., 9(3), 271-295, 1998; Goma, K.; Gogolewski, S.. Polym. Degrad. Stab., 79, 465-474, 2003; Fontaine, L; M nard, 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. Capítulo 14. 1991 ; Chauvel-Lebret, D.J.; Auroy, P.; Bonnaure-Mallet, M.. "Polymeric Biomaterials. Second Edition", S. Dumitriu Ed., Marcel Dekker, Inc.. Capítulo 13. 2001 ; Woodhouse, K.A.; Skarje, G.A.. Patente US 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. 1995; 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; Storey, R.F.; Wiggins, J.S.; Mauritz, K.A.; Puckett, A.D.. Polym. Compos., 14, 17, 1993]. La entrada de los restos de aminoácido en la cadena principal ha sido sobre todo como diisocianato, especialmente de lisina [Fontaine, L.; M nard, 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.. Capítulo 13. 2001 ; Woodhouse, K.A.; Skarje, G.A.. Patente US 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. 1995; Zhang, J.Y.; Beckman, E.J.; Piesco, 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], denominado LDI, cuya patente de síntesis se remonta al año 1968 [Merck & Co., Inc.. Patente GB 1 ,118,916, 1968] y disponible comercialmente en la actualidad a través de la compañía japonesa Kyowa Hakko, aunque también hay ejemplos con diisocianatos derivados de otros aminoácidos [Hettrich, W.; Becker, R.. Polymer, 38(10), 2437-2445, 1997] o con triisocianato de lisina [Kiyotsukuri, T.; Nagata, M.; Kitazawa, T.; Tsutsumi, N.. Eur. Polym. J., 28(2), 183-186, 1992]. Pero también se encuentran referencias en las que el resto de aminoácido entra como extendedor de cadena [Skarja, G.A. Woodhouse, K.A.. J. Biomater. Sci. Polymer Edn., 9(3), 271-295, 1998 Fontaine, L.; M nard, 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. Capítulo 14. 1991 ; Woodhouse, K.A.; Skarje, G.A.. Patente US 6,221 ,997 B1 , 2001 ; Skarja, G.A.; Woodhouse, K.A.. J. Appl. Polym. Sci., 75, 1522-1534, 2000]. De todos estos poliuretanos con restos de aminoácido en la cadena, sólo unos pocos exhiben propiedades elastoméricas [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] y en algún caso pobres [Storey, R.F.; Wiggins, J.S.; Puckett, A.D.. J. Polym. Sci., Polym. Chem., 32, 2345-2363, 1994].STATE OF THE TECHNIQUE Biodegradable polymers are becoming increasingly important for various biomedical applications, such as tissue engineering, in which the current trend is to develop matrices that promote angiogenesis and support the cells of the tissue you are trying to replace, but of the Commercially available polymers there are very few that have elastomeric properties. Intentionally degraded polymers can avoid various problems and negative physiological responses: fibrous encapsulation, need for a second surgical intervention to remove the implant, etc. Therefore, much research has been done on them, but most of them are available commercially they are essentially rigid materials, such as polyglycol, the first absorbable synthetic polymer that appeared in the early 1970s, which makes it desirable, at least in regard to tissue engineering, 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 choice of monomers suitable in the synthesis, can 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, MF; Epstein, JJ Biomed. Mater. Res., 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 .; L¡, S .; Vert, M .. Polym. Int., 45, 419-426, 1998; L¡, SM; Chen, XH; Gross, RA; McCarthy, SP. J. Mater. Sci .: Mater. Med., 11, 227-233, 2000; Goma, K .; Gogolewski, S .. Polym. Degrad Stab., 79, 465-474, 2003; Bohlmann, GM; Yoshida, Y .. CEH Marketing Research Report, CEH-SRI International, 2000; Saad, B .; Neuenschwander, P .; Uhlschmid, GK; Suter, UW. Int. J. Biol. Macromol., 25, 293-301, 1999], the ethylene / polycaprolactone polyoxide pair being very common [Yen, M.-S .; Kuo, S.-CJ Appl. Polym Sci., 65, 883-892, 1997; Cohn, D .; Stern, T .; González, MF; Epstein, JJ Biomed. Mater. Res., 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, SM; Chen, XH; Gross, RA; McCarthy, SP. J. Mater. Sci .: Mater. Med., 11, 227-233, 2000; Goma, K .; Gogolewski, S .. Polym. Degrad Stab., 79, 465-474, 2003]. Polyurethanes (broadly understood as polyurethanes, polyurethaneurea and polyureas) are a family of polymers widely used in medicine, but mainly as biostable materials, and in very few cases as biodegradable materials (Artelon ™, related to reference [Flodin, P. US Patent 6,220,441 B1 (Artimplant, Sweden), 2001] Although the percentage of publications dedicated to biostable polyurethanes is also overwhelming in scientific and technical literature, several publications and patents of biodegradable polyurethanes aimed at medical applications have appeared for a few years [ Flodin, P .. US Patent 6,220,441 B1 (Artimplant, Sweden), 2001; Ganta, SR; Piesco, NP; Lomg, P .; Gassner, R .; Motta, LF; Papworth, GD; Stolz, DB; Watkins, SC ; Agarwal, S .. J. Biomed. Mater. Res., 64A, 242-248, 2003; Goma, K .; Gogolewski, S .. "Synthetic bioabsorbable polymers for implants, ASTM STP 1396", CM Agrawal, JE Parr , and ST Lin Eds., ASTM, West Conshohoc Ken, PA Pages 39-57, 2000; Skarja, GA; Woodhouse, KA. J. Biomater. Sci. Polymer Edn., 9 (3), 271-295, 1998; Goma, K .; Gogolewski, S .. Polym. Degrad Stab., 79, 465-474, 2003; Müller, M .; Henschler, D .; Sabbioni, G .. Helv. Chim. Acta, 81, 1254-1263, 1998; Fontaine, L; M nard, 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, FY; Wang, LF; Tashev, E .; Leong, KW. "Polymeric Drugs and Drug Delivery Systems", RL Dunn and RM Ottenbrite Eds., ACS Symposium Series 469, ACS Washington DC. Chapter 14. 1991; Chauvel-Lebret, DJ; Auroy, P .; Bonnaure-Mallet, M .. "Polymeric Biomaterials. Second Edition", S. Dumitriu Ed., Marcel Dekker, Inc. Chapter 13. 2001]. Among the biodegradable polyurethanes described are both rigid materials and elastomeric materials. Several of the reagents commonly used in the manufacture of polyurethanes give rise to toxic products in their degradation, which excludes their use in the synthesis of these polyurethanes. Among these, toluendiisocyanate and its derivatives, methylene diisocyanate and its derivatives, isophorone diisocyanate and its derivatives, the amines corresponding to all these isocyanates, and 3,3'-dichloro-4,4'-diphenylamino methane (MOCA or MBOCA). If a suitable choice of reagents is made, the degradation products to which the polymer gives rise are non-toxic [Chauvel-Lebret, DJ; Auroy, P .; Bonnaure-Mallet, M .. "Polymeric Biomaterials. Second Edition", S. Dumitriu Ed., Marcel Dekker, Inc .. Chapter 13. 2001; Woodhouse, KA; Skarje, GA. US Patent 6,221, 997 B1, 2001; Skarja, GA; Woodhouse, KA. J. Appl. Polym Sci., 75, 1522-1534, 2000; Zhang, J.-Y., Beckman, EJ, Hu, J., Yang, G.-G., Agarwal, S., Hollinger, JO Tissue Engineering, 8 (5), 771-785, 2002; Storey, RF, Wiggins, JS, Puckett, ADJ Polym. Sci., Polym. Chem., 32, 2345-2363, 1994; Bruin, P., Veenstra, GJ, Nijenhuis, AJ, Pennings, AJ Makromol. Chem., Rapid Commun., 9, 589-594, 1988; from Groot, JH. Dissertation, U. Groningen, Netherlands. nineteen ninety five; Zhang, JY; Beckman, EJ, Piesco, NP, 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, KJ Polym. Sci., Polym. Chem., 40, 4158- 4166, 2002; Storey, RF, Wiggins, JS, Mauritz, KA, Puckett, AD Polym. Compos. 14, 17, 1993]. Among the possible reagents to be selected for the constitution of biodegradable polymers are the amino acids (or derivatives thereof), most of which form the proteins, and which are therefore not toxic. Amino acids have long been used in the formation of a multitude of synthetic polymers [Kemnitzer, J .; Kohn, J .. "Handbook of biodegradable polymers", AJ Domb, J. Kost, DM Wiseman, Eds., Harwood Academic Publishers. Chapter 13, p.251-272. 1997; Domb, AJ. Biomaterials, 11, 686, 1990], including polyurethanes [Flodin, P .. US Patent 6,220,441 B1 (Artimplant, Sweden), 2001; Skarja, GA; Woodhouse, KA. J. Biomater. Sci. Polymer Edn., 9 (3), 271-295, 1998; Goma, K .; Gogolewski, S .. Polym. Degrad Stab., 79, 465-474, 2003; Fontaine, L; M nard, 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, FY; Wang, LF; Tashev, E .; Leong, KW. "Polymeric Drugs and Drug Delivery Systems", RL Dunn and RM Ottenbrite Eds., ACS Symposium Series 469, ACS Washington DC. Chapter 14. 1991; Chauvel-Lebret, DJ; Auroy, P .; Bonnaure-Mallet, M .. "Polymeric Biomaterials. Second Edition", S. Dumitriu Ed., Marcel Dekker, Inc .. Chapter 13. 2001; Woodhouse, KA; Skarje, GA. US Patent 6,221, 997 B1, 2001; Skarja, GA; Woodhouse, KA. J. Appl. Polym Sci., 75, 1522-1534, 2000; Zhang, J.-Y .; Beckman, EJ; Hu, J .; Yang, G.-G .; Agarwal, S .; Hollinger, JO. Tissue Engineering, 8 (5), 771-785, 2002; Storey, RF; Wiggins, JS; Puckett, AD. J. Polym. Sci., Polym. Chem., 32, 2345-2363, 1994; Bruin, P .; Veenstra, GJ; Nijenhuis, AJ; Pennings, AJ. Makromol Chem., Rapid Commun., 9, 589-594, 1988; from Groot, JH. Dissertation, U. Groningen, Netherlands. nineteen ninety five; Zhang, JY; Beckman, EJ; Piesco, NP; 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, RF; Wiggins, JS; Mauritz, KA; Puckett, AD. Polym Compos., 14, 17, 1993]. The entry of amino acid residues in the main chain has been primarily as diisocyanate, especially lysine [Fontaine, L .; M nard, 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, DJ; Auroy, P .; Bonnaure-Mallet, M .. "Polymeric Biomaterials. Second Edition", S. Dumitriu Ed., Marcel Dekker, Inc .. Chapter 13. 2001; Woodhouse, KA; Skarje, GA. US Patent 6,221, 997 B1, 2001; Skarja, GA; Woodhouse, KA. J. Appl. Polym Sci., 75, 1522-1534, 2000; Zhang, J.-Y .; Beckman, EJ; Hu, J .; Yang, G.-G .; Agarwal, S .; Hollinger, JO. Tissue Engineering, 8 (5), 771-785, 2002; Storey, RF; Wiggins, JS; Puckett, AD. J. Polym. Sci., Polym. Chem., 32, 2345-2363, 1994; Bruin, P .; Veenstra, GJ; Nijenhuis, AJ; Pennings, AJ. Makromol Chem., Rapid Commun., 9, 589-594, 1988; from Groot, JH. Dissertation, U. Groningen, Netherlands. nineteen ninety five; Zhang, JY; Beckman, EJ; Piesco, NP; Agarwal, S .. Biomaterials, 21, 1247-1258, 2000; Storey, RF; Wiggins, JS; Mauritz, KA; Puckett, AD. Polym Compos., 14, 17, 1993], called LDI, whose synthesis patent dates back to 1968 [Merck & Co., Inc .. Patent GB 1, 118,916, 1968] and currently commercially available through the company Japanese 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 there are also references in which the rest of the amino acid enters as a chain extender [Skarja, GA Woodhouse, KA. J. Biomater. Sci. Polymer Edn., 9 (3), 271-295, 1998 Fontaine, L .; M nard, 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, FY; Wang, LF; Tashev AND.; Leong, KW "Polymeric Drugs and Drug Delivery Systems", RL Dunn and RM Ottenbrite Eds., ACS Symposium Series 469, ACS Washington DC. Chapter 14. 1991; Woodhouse, KA; Skarje, GA. US Patent 6,221, 997 B1, 2001; Skarja, GA; Woodhouse, KA. 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, RF; Wiggins, JS; Puckett, AD. J. Polym. Sci., Polym. Chem., 32, 2345-2363, 1994; Bruin, P .; Veenstra, GJ; Nijenhuis, AJ; Pennings, AJ. Makromol Chem., Rapid Commun., 9, 589-594, 1988; from Groot, JH. Dissertation, U. Groningen, Netherlands. 1995] and in some cases poor [Storey, RF; Wiggins, JS; Puckett, AD. J. Polym. Sci., Polym. Chem., 32, 2345-2363, 1994].
DESCRIPCIÓN DE LA INVENCIÓN Breve descripción de la invención El objeto de la presente invención es por lo tanto proporcionar nuevos materiales biodegradables de poliuretano con varias potenciales aplicaciones biomédicas, que exhiban desde propiedades elastoméricas con diversos grados de elasticidad y dureza a propiedades plásticas. Este material biodegradable de poliuretano está constituido por tres elementos básicos como son un monómero de cadena larga, denominado poliol o poliamina, un di- o poliisocianato, y un monómero de cadena relativamente corta, denominado extendedor de cadena. El polímero resultante de estructura segmentada, separada o no en fases, contiene en su cadena principal al menos un resto de aminoácido, incorporado en poliisocianato y/o en el extendedor de cadena, para facilitar su reconocimiento por agentes biológicos. Además, resulta novedoso por su diseño ya que la incorporación de moléculas de carácter hidrófilo e hidrófobo permite graduar el carácter hidrofílico/hidrofóbico del material resultante, estando los reactivos seleccionados para que los productos de degradación sean no-tóxicos. Así, un objeto de la presente invención lo constituye un material de poliuretano biodegradable con ajuste de la hidrofilicidad/hidrofobicidad, cuyos productos de degradación son sustancialmente no-tóxicos, caracterizado porque está constituido por el producto resultante de la reacción entre un poliol, un poliisocianato y un extendedor de cadena, y porque su estructura incluye al menos un resto de aminoácido natural, donde el poliol es un copolímero de bloque o al azar constituido por monómeros de carácter hidrofílico/hidrofóbico antagónicos o mezcla de éste con otros copolímeros de iguales características y con homopolímeros.DESCRIPTION OF THE INVENTION Brief description of the invention The object of the present invention is therefore to 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 a biodegradable polyurethane material with hydrophilicity / hydrophobicity adjustment, whose degradation products are substantially non-toxic, 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 or random copolymer consisting of antagonistic hydrophilic / hydrophobic monomers or mixing thereof with other peer copolymers. characteristics and with homopolymers.
Una realización preferente de la presente invención lo constituye un poliol formado por copolímeros de bloque, en concreto de tribloques, resultante de la combinación de polietilenglicol-caprolactona, en adelante PEG/CL, de manera que se obtiene una estructura CL-PEG-CL. La incorporación del resto de aminoácido en la cadena se hace a través del poliisocianato o del extendedor de cadena. El procedimiento de obtención proporciona un poliuretano lineal segmentado obtenido a partir de los reactivos en una relación molar 1 :1 entre los grupos isocianato y los grupos que reaccionan con el grupo isocianato, llevándose a cabo mediante el método del prepolímero o por el método one- shot, en masa o en disolución, en un reactor continuo o discontinuo. Las propiedades mecánicas de los poliuretanos resultantes pueden variarse desde elastómeros blandos a plásticos rígidos. Aunque existen numerosos ejemplos comerciales de polímeros rígidos biodegradables, muchos de ellos resultan ser demasiado rígidos y en ocasiones frágiles, mientras que los poliuretanos suelen ser tenaces. Por otra parte, existe la posibilidad de obtener elastómeros degradables con diversos grados de elasticidad o dureza, de los cuales hay pocos ejemplos comerciales, lo que hace que los materiales descritos en esta invención puedan ser comercialmente muy atractivos. Es aplicable industrialmente como material para liberación controlada de fármacos y para ingeniería de tejidos.A preferred embodiment of the present invention is a polyol formed by block copolymers, in particular of triblocks, resulting from the combination of polyethylene glycol-caprolactone, hereinafter PEG / CL, so that a CL-PEG-CL structure is obtained. The incorporation of the amino acid residue in the chain is done through the polyisocyanate or chain extender. The process of obtaining provides a segmented linear polyurethane obtained from the reagents in a 1: 1 molar ratio between the isocyanate groups and the groups that react with the isocyanate group, being carried out by the prepolymer method or by the one- method. shot, in bulk or in solution, in a continuous or discontinuous reactor. The mechanical properties of the resulting polyurethanes can be varied from soft elastomers to rigid plastics. Although there are numerous commercial examples of biodegradable rigid polymers, many of them turn out to be too rigid and sometimes fragile, while polyurethanes are often tenacious. On the other hand, there is the possibility of obtaining degradable elastomers with varying degrees of elasticity or hardness, of which there are few commercial examples, which makes the materials described in this invention can be commercially very attractive. It is industrially applicable as a material for controlled drug release and tissue engineering.
Descripción detallada Así, un objeto de la presente invención lo constituye un material de poliuretano, en adelante material de poliuretano de la presente invención, biodegradable con ajuste de la hidrofilicidad/hidrofobicidad, cuyos productos de degradación son sustancialmente no-tóxicos, caracterizado porque está constituido por el producto resultante de la reacción entre un poliol, un poliisocianato y un extendedor de cadena, porque su estructura incluye al menos un resto de aminoácido natural, y porque el poliol es un copolímero de bloque o al azar constituido por una combinación de monómeros de carácter hidrofílico/hidrofóbico antagónicos o mezcla de éste con otros copolímeros de iguales características y con homopolímeros. El resto de aminoácido natural hace a este material de poliuretano reconocible por agentes biológicos. Una característica de este material de poliuretano lo constituye el ajuste de la hidrofilicidad/hidrofobicidad que viene determinado por la elección del poliol, molécula de cadena relativamente larga con dos o más grupos susceptibles de reaccionar con el grupo isocianato. El término "poliuretano" tal como utiliza en la presente invención debe entenderse de forma amplia como poliuretano, poliuretanourea y poliurea. El término "sustancialmente no-tóxico" tal como utiliza en la presente invención se refiere a materiales que cuando están presentes en el cuerpo, son físicamente tolerables, y más específicamente, no causan muerte celular apreciable (citotoxicidad) o una alteración negativa de la función celular normal (respuesta mutagénica). El término "agente biológico" tal como utiliza en la presente invención se refiere a moléculas que se unen y reconocen aminoácidos, ya estén flotando libremente en el medio extracelular incluyendo enzimas, o sean proteínas unidas a superficies celulares tales como receptores. El término "extendedor de cadena" tal como utiliza en la presente invención hace referencia a una molécula multifuncional de peso molecular relativamente bajo, inferior a 300 gr mol"1, con un número de grupos reactivos frente al grupo isocianato igual o mayor de 2, preferiblemente grupos alcohol o amina, pero también otros como fenol o tiol. El término "resto de aminoácido" tal como utiliza en la presente invención incluye uno o más residuos de aminoácido de la configuración ocurrente en la naturaleza y que sean sustancialmente no-tóxicos. Éstos restos de aminoácido se incorporan en la cadena principal ya sea vía el poliisocianato o vía el extendedor de cadena o ambos. Un objeto particular de la invención lo constituye el material de poliuretano de la presente invención caracterizado porque el poliol resulta de la combinación de los siguientes monómeros, a título ilustrativo y sin que limite el alcance de la invención, del siguiente grupo: a) óxido de etileno y caprolactona, óxido de etileno y ácido láctico, óxido de etileno y ácido glicólico, óxido de etileno y carbonato de alquilo, óxido de etileno y valerolactona, óxido de etileno y butirolactona, óxido de etileno-óxido de propileno y caprolactona, óxido de etileno- óxido de propileno y ácido láctico, óxido de etileno-óxido de propileno y ácido glicólico, óxido de etileno-óxido de propileno y carbonato de alquilo, óxido de etileno-óxido de propileno y valerolactona, óxido de etileno-óxido de propileno y butirolactona, polietilenglicol y caprolactona, una mezcla de ellos o una mezcla con sus homopolímeros, o b) óxido de etileno (u óxido de etileno-óxido de propileno)/diácido o anhídrido/glicol siendo el diácido o anhídrido el malónico, succínico, glutárico, adípico, pimélico, subérico, azelaico, sebácico, maleico, fumárico, y en general cualquiera que de lugar a productos de degradación sustancialmente no-tóxicos, y siendo el glicol el etilenglicol, propilenglicol, butilenglicol, hexametilenglicol, dietilenglicol, trietilenglicol, glicerina, trimetilolpropano, y en general cualquier glicol que de lugar a productos de degradación sustancialmente no-tóxicos, o una mezcla de ellos o con los polioles del apartado a) y/o con sus homopolímeros. El poliol tiene un peso molecular entre 150 y 6000 gr-mol"1 preferentemente entre 1000 y 3000 gr mol"1, y la estructura de la cadena debe ser, en el caso de querer obtener elastómeros, suficientemente flexible por lo que debe ser amorfo o, si es cristalino, tener una temperatura o intervalo de fusión preferiblemente por debajo de 60°C. El contenido relativo de los monómeros es variable siendo mayor que 0 y menor que 1. La síntesis de los copolímeros en bloque resulta muy conveniente porque permite un control muy preciso de las cantidades de monómero que se incorporan en el copolímero, del peso molecular final y de la longitud de los bloques, que siguen de forma independiente manteniendo su comportamiento hidrófilo/hidrófobo. Una realización preferente de la presente invención lo constituye un material de poliuretano de la presente invención caracterizado porque el poliol está formado por copolímeros de bloque, preferentemente de tribloques, resultante de la combinación de polietilenglicol-caprolactona, en adelante PEG/CL (entendiéndose como PEG cadenas de polietilenglicos desde trietilenglicol -grado de polimerización 3- en adelante), de manera que se obtiene una estructura CL-PEG-CL. En este caso, en el que ambos bloques pueden cristalizar, se puede controlar la longitud de los bloques y por tanto su cristalización, que influye en la velocidad de degradación. En el caso de copolímeros al azar, la hidrofilicidad/hidrofobicidad es menos predecible y controlable, dependiendo de las secuencias de los monómeros desapareciendo la capacidad de cristalización que tienen los homopolímeros. La síntesis de copolímeros de bloque de PEG/CL, en concreto de los tribloques, puede hacerse por apertura de anillo de la ε-caprolactona usando PEG como iniciador, sin la presencia de catalizadores, siguiendo el método de Cerrai (Cerrai, P.; Tricoli, M.; Andruzzi, F.; Paci, M.; Paci, M.. Polymer, 30, 338- 343, 1989), o con catalizadores (Cohn, D.; Stern, T.; González, M.F.; Epstein, J. J. Biomed. Mater. Res., 59(2), 273-281 , 2002) en cuyo caso se usa preferentemente 2-etil-hexanoato de estaño, cuya presencia en etapas posteriores en la síntesis de poliuretanos no es problemática, por emplearse en muy pequeña cantidad, 0,1% en moles respecto al glicol o PEG, y porque a su vez actúa, si no se ha desactivado, como catalizador de la reacción del grupo isocianato con los grupos alcohol. La preferencia por el 2-etil-hexanoato de estaño, habitualmente denominado octoato de estaño, se debe a que su empleo como catalizador está aprobado por la FDA norteamericana [FDA (Food and Drugs Administration), EE.UU., 2002. Title 21 , Chapter I, Part 175, Subpart C, Sec.175,300. Resinous and polymeric coatings] en recubrimientos en contacto con alimentos a temperaturas por debajo de 80°C y a un nivel que no supere el 1% en peso de la resina. El resto de aminoácido se incorpora a la cadena principal a través del poliisociananto o a través del extendedor de cadena. De forma particular cuando el resto de aminoácido se incorpora a través del extendedor, los poliisocianatos que se emplean en la formación del poliuretano son diisocianatos y triisocianatos, preferentemente butanodiisocianato y hexametilendiisocianato. Por otro lado, cuando el resto de aminoácido se incorpora a través del poliisocianato, los poliisocianatos que se emplean en la formación del poliuretano son un diisocianato o triisocianato derivado del éster de un monoalcohol, preferentemente metílico o etílico, de la L-lisina o de la L- omitina. Cuando el aminoácido se incorpora a través del poliisocianato, los extendedores de cadena que se emplean son glicoles difuncionales como etilenglicol, propilenglicol, butanodiol y hexanodiol, glicoles polifuncionales como glicerina, trimetilolpropano, glucosa, fructosa, ribosa y desoxirribosa, diaminas como etilendiamina, propilendiamina, butilendiamina, hexametilendiamina, piperacina, diaminodifenilsulfona y Polacure 740M (diamina de la compañía Air Products, producto de la reacción de 1 ,3- propilenglicol con el ácido p-aminobenzóico) o moléculas con grupos alcohol y amina como la etanolamina y el p-aminofenol. Cuando el extendedor de cadena es el que incorpora el resto aminoácido, se emplea como extendedor un éster de un monoalcohol, preferentemente metílico o etílico, de un aminoácido portador de dos o más grupos susceptibles de reaccionar con el grupo isocianato, como la L-lisina o la L-omitina, con dos grupos amina, la L-serina o la L-treonina, con un grupo alcohol y un grupo amina, la L-tirosina con un grupo fenol y un grupo amina, o la L-cisteina, con un grupo tiol y un grupo amina. Cuando aparte del grupo ácido, el aminoácido solamente porta un grupo susceptible de reaccionar con el grupo isocianato, como extendedor de cadena se emplea un compuesto resultante de la reacción de un aminoácido con una molécula sustancialmente no-tóxica que aporte los grupos funcionales necesarios para convertirse la molécula resultante en polifuncional respecto al grupo isocianato. Para ello se hace reaccionar un aminoácido, entre los que se incluyen los aminoácidos proteicos frecuentes como la lisina, la tirosina, la serina, la treonina, la cisteina, la glicina, la alanina, la valina, la leucina, la isoleucina, la fenilalanina, la prolina, la asparagina, la glutamina, el triptófano, la metionina, el ácido aspártico, el ácido glutámico, la arginina y la histidina, proteicos poco frecuentes como la 4-hidroxiprolina, la 5-hidroxilisina, la desmosina, la isodesmosina, la epsilon-N-metil-lisina, la epsilon-N-trimetil-lisina y la 3-metil-histidina, no-proteicos como la omitina, la beta-alanina, el ácido gamma-aminobutírico, la homocisteína, la homoserina y la citrulina, con un gran exceso molar de un diol, como el etilenglicol o propilenglicol, para obtener extendedores de cadena derivados de aminoácidos con un grupo alcohol y un grupo amina, como se esquematiza en la Figura 1. O se puede hacer reaccionar el aminoácido con la mitad en moles de un diol, como el etilenglicol o propilenglicol, para dar lugar a un derivado con dos grupos amino y dos restos de aminoácido, como se esquematiza en la Figura 2. Los extendedores derivados de aminoácidos, pueden aislarse como sales, en cuyo caso a cada grupo amino le acompaña un resto ácido (HCI o ácido p-toluensulfónico, por ejemplo), o por tratamiento de la sal con un exceso molar de base en solución acuosa [Skarja, G.A.; Woodhouse, K.A.. J. Biomater. Sci. Polymer Edn., 9(3), 271-295, 1998.; Woodhouse, K.A.; Skarje, G.A.. Patente US 6,221 ,997 B1 , 2001 ; Huang, S.L.; Bansleben, D.A.; Knox, J.R.. J. Appl. Polym. Sci., 23, 429-437, 1979], los grupos amina quedan en su forma libre. El resto de aminoácido se incorpora preferentemente por cada molécula de isocianato o de extendedor que entre a formar parte de la cadena de poliuretano. Sin embargo, ocasionalmente puede ser deseable que el aminoácido esté presente en un contenido menor o en localizaciones al azar en la cadena, para lo cual se puede combinar, en proporción molar variable, dos poliisocianatos distintos, uno que contenga al menos un resto de aminoácido y otro que no contenga restos de aminoácido, o dos extendedores de cadena distintos, uno que contenga al menos un resto de aminoácido y otro que no contenga restos de aminoácido, siendo en cada caso el poliisocianato o el extendedor de cadena que no contenga al menos un resto de aminoácido, de naturaleza tal que al degradar sus productos de degradación sean sustancialmente no-tóxicos. El procedimiento de obtención del material poliuretano de la invención proporciona preferiblemente un poliuretano lineal segmentado, para lo cual se parte de reactivos difuncionales en una relación molar 1 :1 entre los grupos isocianato y los grupos que reaccionan con el grupo isocianato. Al ser lineal, el polímero podría sintetizarse previamente por un método como el del prepolímero o el método one-shot, en un reactor discontinuo o en un reactor continuo, en masa o en disolución, y transformarse posteriormente en su forma final, lo cual supone una ventaja frente a los materiales entrecruzados, en los cuales alguno de los reactivos tiene funcionalidad superior a dos, y deben polimerizarse directamente en su forma final o pre-acabada. Cuando el material de poliuretano resultante no es lineal, la relación molar entre los grupos isocianato y los grupos que reaccionan con el grupo isocianato no tiene necesariamente que ser 1 :1 , pudiéndose usar un exceso de grupos de cualquiera de los dos tipos, por ejemplo de grupos isocianato para dar lugar a entrecruzamiento por formación de enlaces alofanato con los grupos uretano o de enlaces biuret con los grupos urea. Aunque preferiblemente el extendedor de cadena se añade en la formulación del poliuretano durante la síntesis, es posible generarlo in situ en el medio de reacción. Por ejemplo se puede preparar una formulación con poliol, LDI y agua, en la cual el agua, que se añade en la cantidad molar necesaria para generar los grupos amina requeridos para la estequiometría fijada, reacciona con los grupos isocianato del LDI para generar el grupo amina correspondiente y una molécula de dióxido de carbono. El dióxido de carbono generado, en algunas aplicaciones puede resultar útil para la formación de un material espumado. En la síntesis de los poliuretanos, cuando se parte de un extendedor de cadena en forma de sal, como el dihidrocloruro del éster etílico de la lisina, debe añadirse a la mezcla de reacción una base que secuestre los grupos ácido del medio de reacción, y que no reaccione con los grupos isocianato. Como base se pueden emplear aminas terciarias, como la trietilamina. Si no se secuestran los grupos ácido, éstos retardan mucho la reacción de polimerización del grupo isocianato con los grupos reactivos del extendedor de cadena, al tiempo que puede llevar a una mayor proporción de reacciones secundarias y por tanto un crecimiento insuficiente del polímero final. Cuando la síntesis se realiza en disolución, y en previsión de que puedan quedar restos de disolvente en el polímero final, se emplean preferentemente disolventes clasificados como de Clase 3 en la industria farmacéutica ["Handbook of solvents", G. Wypych Ed., ChemTec Publishing, Toronto. Capítulo 16, p.1143-1145. 2001], entre ellos dimetilsulfóxido (DMSO), tetrahidrofurano (THF), metiletilcetona (MEK) y metilisobutilcetona (MIBK), o en su defecto, de Clase 2 como N,N-dimetilacetamida (DMAc), N,N- dimetilformamida (DMF) y N-metil-2-pirrolidona (NMP), evitándose, siempre que sea posible, los disolventes de Clase 1 como el 1 ,2-dicloroetano (DCE). En la síntesis de los poliuretanos, sobre todo para la reacción entre los grupos alcohol y el grupo isocianato, si la reacción es demasiado lenta se hace necesario la adición de catalizadores. Como catalizador se empleará preferentemente el 2-etil-hexanoato de estaño, habitualmente denominado octoato de estaño. También es válido cualquier otro catalizador de tipo amínico u organometálico sustancialmente no-tóxico. Las propiedades mecánicas a tracción de los poliuretanos preparados según la presente invención pueden variar entre plásticos rígidos y elastómeros blandos. Las propiedades, suponiendo que se alcanza siempre un peso molecular del polímero final lo suficientemente elevado como para que no influya apenas, dependen de los reactivos elegidos que constituyen la cadena del polímero, y de la morfología resultante. Por ejemplo, si el poliol cristaliza a la temperatura de uso, el polímero tendrá un comportamiento plástico, en el que a partir de un cierto alargamiento el polímero se deformará permanentemente, mientras que si a la temperatura de uso el poliol se mantiene amorfo, el material puede tener, dependiendo de otra serie de factores, un comportamiento elastomérico. En la Figura 3 se puede observar los polímeros derivados de varios tribloques dihidroxílicos, unos muy blandos con bajas propiedades mecánicas, y otros con propiedades mejores que se comporta como plásticos tenaces, en el que el esfuerzo aumenta mucho al inicio, con un punto de fluencia a baja deformación a partir del cual la deformación es permanente y el esfuerzo aumenta despacio con el aumento en la deformación hasta la rotura. Así mismo se comprobó, con modelos, que los segmentos duros derivados de LDI y éster etílico de aminoácido son amorfos. Cuando están formando parte de un poliuretano, si el poliol no cristaliza, se comprobó la ausencia de separación de fases en el sistema, o lo que es lo mismo, los segmentos duros se mezclan con los segmentos blandos formados por el poliol y forman una sola fase. Si el poliol cristaliza, se forma una fase de poliol prácticamente pura, mientras que es de esperar que la parte amorfa del poliol y los segmentos duros formen una fase mezclada. La irregularidad estructural que introducen los restos de aminoácido en la cadena del polímero impiden la cristalización de los segmentos duros, que promovería la separación de fases, y por ello, cuando los segmentos duros no contengan anillos aromáticos u otras unidades estructurales rígidas, es de esperar que no tenga lugar la separación de fases. Si los segmentos duros contienen anillos aromáticos u otros elementos estructurales rígidos, por ejemplo usando p-aminofenol como extendedor, aunque siga siendo muy improbable la cristalización, la incompatibilidad termodinámica con los segmentos blandos del poliol es mayor, y podría tener lugar la separación de una fase de segmento duro amorfo. Dependiendo de la aplicación, la separación de fases podría ser ventajosa, ya que en general mejora las propiedades mecánicas del material, consiguiendo en el mejor escenario posible un material elastomérico con un segmento blando amorfo y un segmento duro separados en fases con muy buenas propiedades mecánicas. El material de poliuretano biodegradable puede formularse con aditivos, entre los que se incluyen cargas y plastificantes, para ajustar las propiedades del material o su comportamiento bajo condiciones específicas, siendo aditivos biodegradables o eliminables y ellos y sus productos de degradación no tóxicos. Las principales aplicaciones se basan en su uso como material para la elaboración de productos destinados al sector farmacéutico y biotecnológico, en concreto su principal aplicación es para el transporte y liberación controlada de productos farmacológicos o biotecnológicos y para ingeniería de tejidos. BREVE DESCRIPCIÓN DEL CONTENIDO DE LAS FIGURAS Figura 1. Esquema de la reacción de un aminoácido con un exceso molar de un diol para formar un compuesto difuncional con un grupo alcohol y un grupo amina. Figura 2. Esquema de la reacción de un aminoácido con un diol en relación molar 2:1 para formar un compuesto difuncional con dos grupos amina. Figura 3. Curvas de tensión-deformación para una serie de polímeros de PCL/PEG/PCL-LDI-éster etílico de lisina. La nomenclatura de los polímeros como la de la Tabla 3.DETAILED DESCRIPTION Thus, an object of the present invention is a polyurethane material, hereinafter polyurethane material of the present invention, biodegradable with hydrophilicity / hydrophobicity adjustment, whose degradation products are substantially non-toxic, characterized in that it is constituted by 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 consisting of a combination of monomers of antagonistic hydrophilic / hydrophobic character or mixture thereof with other copolymers of the same characteristics and with homopolymers. The rest of the natural amino acid makes this polyurethane material recognizable by biological agents. A characteristic of this polyurethane material is the adjustment of 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 used in the present invention should be broadly understood as polyurethane, polyurethaneurea and polyurea. The term "substantially non-toxic" as used in the present invention refers to materials that when present in the body, are physically tolerable, and more specifically, do not cause appreciable cell death (cytotoxicity) or a negative function impairment. normal cell (mutagenic response). The term "biological agent" as used in the present invention refers to molecules that bind and recognize amino acids, whether they are floating freely in the extracellular medium 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 mol "1 , with a number of reactive groups against the isocyanate group equal to or greater than 2, preferably alcohol or amine groups, but also others such as phenol or thiol The term "amino acid residue" as used in the present invention includes one or more amino acid residues of the naturally occurring configuration and which are substantially non-toxic. These amino acid residues are incorporated into the main chain either via the polyisocyanate or via the chain extender or both. A particular object of the invention is the polyurethane material of the present invention characterized in that the polyol results from the combination of the following monomers, by way of illustration and without limiting the scope of the invention, of the following group: a) ethylene and caprolactone, ethylene oxide and lactic acid, ethylene oxide and glycolic acid, ethylene oxide and alkyl carbonate, ethylene oxide and valerolactone, ethylene oxide and butyrolactone, ethylene oxide propylene oxide and caprolactone oxide ethylene-propylene oxide and lactic acid, ethylene oxide-propylene oxide and glycolic acid, ethylene oxide-propylene oxide and alkyl carbonate, ethylene oxide-propylene oxide and valerolactone, ethylene oxide-propylene oxide and butyrolactone, polyethylene glycol and caprolactone, a mixture thereof or a mixture with their homopolymers, or b) ethylene oxide (or ethylene oxide-propylene oxide no) / 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 results in substantially non-toxic degradation products, and glycol being ethylene glycol, propylene glycol, butylene glycol, hexamethylene glycol, diethylene glycol, triethylene glycol, glycerin, trimethylolpropane, and in general any glycol that results in substantially non-toxic degradation products, or a mixture thereof or with the polyols of section a ) and / or with their homopolymers. The polyol has a molecular weight between 150 and 6000 gr-mol "1 preferably between 1000 and 3000 gr mol " 1 , and the chain structure must be, in the case of wanting to obtain elastomers, sufficiently flexible so it must be amorphous or, if it is crystalline, having a melting temperature or range preferably below 60 ° C. The relative content of the monomers is variable being greater than 0 and less than 1. The synthesis of block copolymers is very convenient because it allows very precise control of the amounts of monomer that is incorporate in the copolymer, the final molecular weight and the length of the blocks, which follow independently maintaining their hydrophilic / hydrophobic behavior. A preferred embodiment of the present invention is a polyurethane material of the present invention characterized in that the polyol is formed of block copolymers, preferably of triblocks, resulting from the combination of polyethylene glycol-caprolactone, hereinafter PEG / CL (understood as PEG polyethylene glycols from triethylene glycol - polymerization degree 3- onwards), so that a CL-PEG-CL structure is obtained. In this case, in which both blocks can crystallize, the length of the blocks and therefore their crystallization can be controlled, which influences the rate of degradation. In the case of random copolymers, hydrophilicity / hydrophobicity is less predictable and controllable, depending on the sequences of the monomers, the crystallization capacity of the homopolymers disappears. The synthesis of PEG / CL block copolymers, specifically of the triblocks, can be done by ring opening of the ε-caprolactone using PEG as an 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, MF; Epstein , JJ Biomed. Mater. Res., 59 (2), 273-281, 2002) in which case tin 2-ethyl hexanoate is preferably used, whose presence in later stages in the synthesis of polyurethanes is not problematic, to be used in a very small amount, 0.1 mol% with respect to glycol or PEG, and because it acts, if not deactivated, as a catalyst for the reaction of the isocyanate group with the alcohol groups. The preference for tin 2-ethyl hexanoate, usually called tin octoate, is because its use as a catalyst is approved by the US FDA [FDA (Food and Drugs Administration), USA, 2002. Title 21 , Chapter I, 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 main chain through the polyisocyanate or through the chain extender. Particularly when the amino acid residue is incorporated through the extender, the polyisocyanates used in polyurethane formation are diisocyanates and triisocyanates, preferably butanediisocyanate and hexamethylene diisocyanate. On the other hand, when the amino acid residue is incorporated through the polyisocyanate, the polyisocyanates used in the formation of the polyurethane are a diisocyanate or triisocyanate derived from the ester of a monoalcohol, preferably methyl or ethyl, of the L-lysine or of L-omitin. When the amino acid is incorporated through polyisocyanate, the chain extenders used are difunctional glycols such as ethylene glycol, propylene glycol, butanediol and hexanodiol, polyfunctional glycols such as glycerin, trimethylolpropane, glucose, fructose, ribose and deoxyrilendiamine, diamines, diamines Butylenediamine, hexamethylenediamine, piperazine, diaminodiphenylsulfone and Polacure 740M (diamine of the Air Products company, product of the reaction of 1, 3- propylene glycol with p-aminobenzoic acid) or molecules with alcohol and amine groups such as ethanolamine and p-aminophenol . When the chain extender is the one that incorporates the amino acid residue, an 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, is used as an extender or L-omitin, with two amine groups, L-serine or L-threonine, with an 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 isocyanate group, as a chain extender a compound resulting from the reaction of an amino acid with a substantially non-toxic molecule that provides the functional groups necessary to convert is used. the resulting polyfunctional molecule with respect to the isocyanate group. To do this, an amino acid is reacted, including frequent protein amino acids 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, rare proteins such as 4-hydroxyproline, 5-hydroxylysine, desmosin, isodesmosine, epsilon-N-methyl-lysine, epsilon-N-trimethyl-lysine and 3-methyl-histidine, non-proteins such as omitin, beta-alanine, 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 derived from amino acids with an alcohol group and an amine group, as outlined in Figure 1. Or the amino acid can be reacted 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 outlined in the Figure 2. The amino acid-derived extenders can be isolated as salts, in which case each acid group is accompanied by an acid moiety (HCI or p-toluenesulfonic acid, for example), or by treating the salt with a base molar excess. in aqueous solution [Skarja, GA; Woodhouse, KA. J. Biomater. Sci. Polymer Edn., 9 (3), 271-295, 1998 .; Woodhouse, KA; Skarje, GA. US Patent 6,221, 997 B1, 2001; Huang, SL; Bansleben, DA; Knox, JR. J. Appl. Polym Sci., 23, 429-437, 1979], the amine groups remain in their free form. The amino acid residue is preferably incorporated by each isocyanate or extender molecule that becomes part of the polyurethane chain. However, it may occasionally be desirable for the amino acid to be present in a lower content or at random locations in the chain, for which two different polyisocyanates, one containing at least one amino acid residue, can be combined in varying molar proportion and another 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, in each case being the polyisocyanate or the chain extender that does not contain at least an amino acid residue, of a nature such that when degrading its degradation products they are substantially non-toxic. The process for obtaining the polyurethane material of the invention preferably provides a segmented linear polyurethane, for which it starts from difunctional reagents in a 1: 1 molar ratio between the isocyanate groups and the groups that react with the isocyanate group. Being linear, the polymer could be previously synthesized by a method such as that of the prepolymer or the one-shot method, in a discontinuous reactor or in a continuous reactor, in bulk or in solution, and subsequently transformed into its final form, which means an advantage over crosslinked materials, in which some of the reagents have functionality greater than two, and must be polymerized directly in their final or pre-finished form. When the resulting polyurethane material is not linear, the molar ratio between the isocyanate groups and the groups that react with the isocyanate group does not necessarily have to be 1: 1, and excess groups of any of the two types can be used, for example of isocyanate groups to give rise to crosslinking by formation of allophanate bonds with urethane groups or biuret bonds 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 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 starting from a salt chain extender, such as lysine ethyl ester dihydrochloride, a base that sequesters the acid groups from the reaction medium should be added to the reaction mixture, and that does not react with isocyanate groups. Tertiary amines, such as triethylamine, can be used as a base. If the acid groups are not sequestered, they greatly retard the polymerization reaction of the isocyanate group with the reactive groups of the spreader chain, while leading to a greater proportion of side reactions and therefore 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, solvents classified as Class 3 are preferably used 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 such as N, N-dimethylacetamide (DMAc), N, N-dimethylformamide (DMF ) and N-methyl-2-pyrrolidone (NMP), avoiding, whenever possible, Class 1 solvents such 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 becomes necessary. The catalyst preferably used is tin 2-ethyl hexanoate, usually called tin octoate. Any other substantially non-toxic amine or organometallic type catalyst is also valid. 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 high enough molecular weight of the final polymer is always reached so that it hardly influences, depends on the reagents chosen that constitute the polymer chain, and on the resulting morphology. For example, if the polyol crystallizes at the temperature of use, the polymer will have a plastic behavior, in which after a certain elongation the polymer will permanently deform, while if at the temperature of use the polyol remains amorphous, material may have, depending on another series of factors, an elastomeric behavior. Figure 3 shows polymers derived from several dihydroxy triblocks, some very soft with low mechanical properties, and others with better properties that behave like tough plastics, in which the stress increases greatly at the beginning, with a creep point at low deformation from which the deformation is permanent and the effort increases slowly with the increase in deformation until breakage. Likewise, it was proved, with models, that the 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 phase separation in the system was verified, or what is the same, the hard segments are mixed with the soft segments formed by the polyol and form a single phase. If the polyol crystallizes, a practically pure polyol phase is formed, while it is expected that the amorphous part of the polyol and the hard segments form a mixed phase. The structural irregularity introduced by the amino acid residues in the polymer chain prevents the crystallization of the hard segments, which would promote phase separation, and therefore, when the hard segments do not contain aromatic rings or other rigid structural units, it is expected that phase separation does not take place. If the hard segments contain aromatic rings or other rigid structural elements, for example using p-aminophenol as an extender, although crystallization remains highly unlikely, the thermodynamic incompatibility with the soft segments of the polyol is greater, and the separation of a Hard amorphous segment phase. Depending on the application, phase separation could be advantageous, since it generally improves the mechanical properties of the material, achieving in the best possible scenario an elastomeric material with an amorphous soft segment and a hard segment separated into phases with very good mechanical properties. . The biodegradable polyurethane material can be formulated with additives, including fillers and plasticizers, to adjust the properties of the material or its behavior under specific conditions, being biodegradable or removable additives and they and their non-toxic degradation products. 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 pharmacological or biotechnological products and for tissue engineering. BRIEF DESCRIPTION OF THE CONTENT OF THE FIGURES Figure 1. Scheme of the reaction of an amino acid with a molar excess of a diol to form a difunctional compound with an alcohol group and an amine group. Figure 2. Scheme of the reaction of an amino acid with a 2: 1 molar ratio to form a difunctional compound with two amine groups. Figure 3. Stress-strain curves for a series of PCL / PEG / PCL-LDI-lysine ethyl ester polymers. The nomenclature of polymers as in Table 3.
EJEMPLO DE REALIZACIÓN DE LA INVENCIÓNEXAMPLE OF EMBODIMENT OF THE INVENTION
Ejemplo 1.- Síntesis de tribloques de polietilenqlicol y caprolactona Materiales: El trietilenglicol (peso molecular 150), los polietilenglicoles (PEG) 400, 900 y 2000, el 2-etil-hexanoato de estaño y la epsilon-caprolactona (CL) se obtuvieron de Aldrich. Los glicoles se secaron a vacío y 75°C durante toda la noche, y se mantuvieron en desecador hasta su uso. Los otros reactivos se emplearon directamente. El peso molecular (Mn) de los polietilenglicoles se determinó por resonancia magnética nuclear (RMN) de protón en cloroformo deuterado y añadiendo unas gotas de anhídrido trifluoroacético para desplazar la señal de los grupos terminales. Los resultados obtenidos fueron 474, 912 y 2466 g/mol para los PEG 400, 900 y 2000 respectivamente. Síntesis del tribloque de polietilenglicol 400 y epsilon-caprolactona con un peso molecular aproximado de 2000 g/mol: En un matraz redondo de 250 mi seco se añaden 0,0241 moles de polietilenglicol 400, 0,3377 moles de epsilon- caprolactona y 0,0000241 moles de 2-etil-hexanoato de estaño. Se calienta la mezcla a 130°C con agitación durante 8 horas bajo atmósfera de nitrógeno. Tras ese tiempo se deja enfriar la masa de reacción y se obtiene un sólido blanco de consistencia pastosa que se caracteriza por RMN de protón, calorimetría diferencial de barrido (DSC), y difracción de rayos X de ángulo alto (WAXD). Siguiendo el mismo procedimiento se sintetizaron una serie de tribloques que se recogen en la tabla 1. La relación molar CUPEG se fue variando, y el catalizador de estaño se añadió siempre en una relación molar del 0,1% respecto a los moles de glicol. Por RMN de protón, y siguiendo el procedimiento usado para los PEG, se calculó el Mn para los tribloques, cuyo resultado se incluye en la tabla 1. La denominación del tribloque hace referencia al Mn del glicol de partida y a la relación molar CL/PEG de la alimentación. Todos los tribloques obtenidos resultaron sólidos blancos a temperatura ambiente, de consistencia más o menos pastosa para los de Mn menor o alrededor de 2000 g/mol.Example 1.- Synthesis of polyethylene glycol and caprolactone triblocks Materials: Triethylene glycol (molecular weight 150), polyethylene glycols (PEG) 400, 900 and 2000, tin 2-ethyl-hexanoate and epsilon-caprolactone (CL) were obtained from Aldrich. The glycols were dried under vacuum and 75 ° C overnight, and kept in desiccator until use. The other reagents were used directly. The molecular weight (Mn) of the polyethylene glycols was determined by proton nuclear magnetic resonance (NMR) in deuterated chloroform and adding a few drops of trifluoroacetic anhydride to displace the signal from the terminal groups. The results obtained were 474, 912 and 2466 g / mol for the PEG 400, 900 and 2000 respectively. Synthesis of the triblock of polyethylene glycol 400 and epsilon-caprolactone with an approximate molecular weight of 2000 g / mol: 0.0241 moles of polyethylene glycol 400, 0.3377 moles of epsilon-caprolactone and 0, are added in a 250 ml round flask. 0000241 moles of tin 2-ethyl hexanoate. The mixture is heated at 130 ° C with stirring for 8 hours under a nitrogen atmosphere. After that time the reaction mass is allowed to cool and a white solid of pasty consistency is obtained which is characterized by proton NMR, differential scanning calorimetry (DSC), and high angle X-ray diffraction (WAXD). Following the same procedure, a series of triblocks are summarized in Table 1. The CUPEG molar ratio was varied, and the tin catalyst was always added in a 0.1% molar ratio. regarding the moles of glycol. By proton NMR, and following the procedure used for the PEG, the Mn for the triblocks was calculated, the result of which is included in table 1. The denomination of the tribloque refers to the Mn of the starting glycol and the CL / PEG molar ratio of food. All triblocks obtained were white solids at room temperature, of a more or less pasty consistency for those of less than Mn or about 2000 g / mol.
Ejemplo 2.- Sínteis del polímero de LDI y éster etílico de L-lisina, L-omitina, L- serina y L-tirosina. Materiales: La L-lisina, la L-omitina, la L-serina, y la L-tirosina se obtuvieron de Fluka, el diisocianato del éster metílico de L-lisina (LDI) de Kyowa Hakko, el 2-etil-hexanoato de estaño de Aldrich, la trietilamina, el cloruro de tionilo, el etanol y la dimetilacetamida de Scharlau. A partir de la L-lisina, la L-omitina, la L-serina y la L-tirosina, por reacción con etanol y cloruro de tionilo, se sintetizaron los esteres etílicos correspondientes siguiendo el procedimiento encontrado en la bibliografía [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. Capítulo 14. 1991 ; Huang, S.L.; Bansleben, D.A.; Knox, J.R.. J. Appl. Polym. Sci., 23, 429-437, 1979]. Los esteres resultantes se caracterizaron por RMN de protón y análisis elemental, coincidiendo con los esteres etílicos correspondientes cristalizados, para la L-lisina y la L-ornitina con dos moléculas de HCI, y para la L-serina y la L-tirosina con una molécula de HCI. La trietilamina se secó por destilación sobre potasa, recogiéndose en un frasco topacio con tamices moleculares. La dimetilacetamida se purificó por destilación a presión reducida sobre isocianatos. Los isocianatos reaccionan con los restos de agua y de aminas presentes en el disolvente, que desequilibrarían el balance estequiométrico en la reacción de polimerización. La temperatura de destilación se mantuvo siempre por debajo de los 60°C de temperatura, y el disolvente destilado, almacenado bajo nitrógeno en un matraz sellado, se utilizó siempre dentro de los siete días siguientes al de destilación. El resto de reactivos se emplearon directamente. Síntesis del polímero de LDI y éster etílico de L-lisina: En un matraz redondo de 25 mi seco se añaden 0,004 moles del éster etílico de la L-lisina, 0,004 moles de LDI y 15 mi de dimetilacetamida. Se calienta la mezcla a 80°C con agitación bajo atmósfera de nitrógeno hasta que se disuelve el éster etílico de la L-lisina, se deja enfriar a temperatura ambiente y se añaden 0,008 moles de trietilamina. Aparece un precipitado de trietilamina. HCI, y tras unos minutos de reacción se comprueba por IR que el diisocianato se ha consumido, y la mezcla se vierte sobre hielo/agua. Se separa un sólido viscoso en forma de gel, la disolución se decanta, se lava el sólido con agua un par de veces, y se seca a vacío. El sólido resultante se caracteriza por RMN de protón y DSC. Siguiendo el mismo procedimiento se sintetizó el polímero de LDI+éster etílico de omitina. Para los polímeros LDI+éster etílico de L-serina y LDI+éster etílico de L-tirosina, el procedimiento varió simplemente en la adición de 0,00004 moles de 2-etil-hexanoato de estaño y la mitad de moles de trietilamina. Estos polímeros se prepararon para estimar las propiedades térmicas de los segmentos duros compuestos de LDI+éster etílico de los aminoácidos mencionados, en poliuretanos compuestos de estos segmentos duros+un poliol. En la Tabla 2 se recogen los modelos de segmentos duros preparados y su temperatura de transición vitrea (todos resultaron ser amorfos) obtenida por DSC.Example 2.- Synthesis of the LDI polymer and ethyl ester of L-lysine, L-omitin, L-serine and L-tyrosine. Materials: L-lysine, L-omitin, L-serine, and L-tyrosine were obtained from Fluka, L-lysine methyl ester diisocyanate (LDI) from Kyowa Hakko, 2-ethyl-hexanoate from Aldrich tin, triethylamine, thionyl chloride, ethanol and Scharlau dimethylacetamide. From the L-lysine, L-omitin, L-serine and L-tyrosine, by reaction with ethanol and thionyl chloride, the corresponding ethyl esters were synthesized following the procedure found in the literature [Shi, FY; Wang, LF; Tashev, E .; Leong, KW. "Polymeric Drugs and Drug Delivery Systems", RL Dunn and RM Ottenbrite Eds., ACS Symposium Series 469, ACS Washington DC. Chapter 14. 1991; Huang, SL; Bansleben, DA; Knox, JR. J. Appl. Polym Sci., 23, 429-437, 1979]. The resulting esters were characterized by proton NMR and elemental analysis, coinciding with the corresponding crystallized ethyl esters, for L-lysine and L-ornithine with two HCI molecules, and for L-serine and L-tyrosine with one HCI molecule. The triethylamine was dried by distillation on potash, collected in a topaz bottle with molecular sieves. The dimethylacetamide was purified by distillation under reduced pressure on isocyanates. The isocyanates react with the remains of water and amines present in the solvent, which would unbalance the stoichiometric balance in the polymerization reaction. The distillation temperature was always kept below the 60 ° C temperature, and the distilled solvent, stored under nitrogen in a sealed flask, was always used within seven days of the distillation. The remaining reagents were used directly. Synthesis of the LDI polymer and L-lysine ethyl ester: 0.004 mol of the L-lysine ethyl ester, 0.004 mol of LDI and 15 ml of dimethylacetamide are added in a 25 ml round flask. The mixture is heated at 80 ° C with stirring under a nitrogen atmosphere until the L-lysine ethyl ester is dissolved, allowed to cool to room temperature and 0.008 moles of triethylamine are added. A precipitate of triethylamine appears. HCI, and after a few minutes of reaction it is verified by IR that the diisocyanate has been consumed, and the mixture is poured onto ice / water. A viscous solid is separated into a gel, the solution is decanted, the solid is washed with water a couple of times, and dried under vacuum. The resulting solid is characterized by proton NMR and DSC. Following the same procedure, the polymer of LDI + omitin ethyl ester was synthesized. For the 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 half moles of triethylamine. These polymers were prepared to estimate the thermal properties of the hard segments composed of LDI + ethyl ester of the aforementioned amino acids, in polyurethanes composed 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.
Ejemplo 3.- Síntesis de poliuretano a partir de tribloques de PEG/CL, LDI y éster etílico de L-lisina. Materiales: Los tribloques dihidroxílicos obtenidos según el ejemplo 1 se secaron por el mismo procedimiento empleado en el ejemplo 1 para los PEG. El resto de reactivos como en ejemplo 1 y ejemplo 2. Síntesis del polímero de 150-16, LDI, y éster etílico de la lisina con relación molar 1 :2,5:1 ,5 (PU 150-16): En un matraz se añaden el tribloque 150- 16 y el LDI en relación molar 1 :2,5, dimetilacetamida para dar una disolución de aproximadamente 1 M de concentración de tribloque, y 0,01 moles de 2-etil- hexanoato de estaño. La mezcla se calienta a 80°C con agitación y bajo corriente de nitrógeno durante 3 horas para efectuar la pre-polimerización. Transcurrido ese tiempo, que por pruebas anteriores se sabe es suficiente para que reaccionen completamente los grupos alcohol, se deja enfriar, se añaden 1 ,5 moles de éster etílico de lisina y 4,5 moles de trietilamina, y se vuelve a calentar la mezcla de reacción a 80°C durante 2,5 horas. Transcurrido ese tiempo, se comprueba por IR que la reacción ha llegado a término y se enfría la dispersión resultante (el hidrocloruro de trietilamina formado durante la reacción se mantiene precipitado) y se vierte sobre una mezcla de hielo/agua destilada. El precipitado resultante se decanta, se lava con agua destilada y se filtra con ayuda de un embudo Büchner. Se vuelve a lavar con agua en el embudo y el polímero blanco que queda se seca a vacío. Las muestras de polímero para la realización de ensayos de caracterización se prepararon mediante casting a partir de una disolución al 10% peso/volumen del polímero en cloroformo. La película se extendió sobre un vidrio nivelado y se cubrió con un embudo para evitar la contaminación con polvo y una evaporación demasiado rápida del disolvente. Tras 48 horas de evaporación a temperatura ambiente dentro de una vitrina se despegó la película de polímero y se secó a vacío otras 24 horas a temperatura ambiente. De la película seca se cortaron las muestras para la caracterización de las propiedades térmicas por DSC (temperatura de transición vitrea - Tg, en el segundo barrido - y temperatura de fusión - Tf, en el primer barrido -) y mecánicas a tracción según la norma ISO 37. Siguiendo el mismo procedimiento de reacción en dos pasos se sintetizaron el resto de polímeros. La relación molar tribloque:LDI:éster etílico de lisina se mantuvo siempre 1 :2,5:1 ,5, la concentración de dimetilacetamida 1 M respecto al poliol, los moles de 2-etil-hexanoato de estaño 0,01 , y los moles de trietilamina 4,5. Para la obtención de las películas de polímero se empleó siempre cloroformo como disolvente. En la tabla 3 se recoge la denominación y composición de los polímeros sintetizados y sus propiedades térmicas y mecánicas. La denominación de los polímeros consta de las letras PU, que indican poli(uretano-urea), seguidas de la referencia al tribloque según se encuentra en la tabla 1. TABLA 1.- Tribloques sintetizados de la combinación de PEG-CL.Example 3.- Synthesis of polyurethane from tribes of PEG / CL, LDI and ethyl ester of L-lysine. Materials: The 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. Synthesis of the polymer of 150-16, LDI, and lysine ethyl ester with 1: 2.5: 1, 5 molar ratio (PU 150-16): In a flask tribloque 150-16 and the LDI in 1: 2.5 molar ratio, dimethylacetamide are added to give a solution of approximately 1 M triblock concentration, and 0.01 moles of tin 2-ethylhexanoate. The mixture is heated to 80 ° C with stirring and low nitrogen stream for 3 hours to carry out the pre-polymerization. After this time, it is known from previous tests that it is sufficient for the alcohol groups to react completely, it is allowed to cool, 1.5 moles of lysine ethyl ester and 4.5 moles of triethylamine are added, and the mixture is reheated reaction at 80 ° C for 2.5 hours. After that time, it is verified by IR that the reaction has come to an end and the resulting dispersion is cooled (the triethylamine hydrochloride formed during the reaction is kept precipitated) and poured onto a mixture of ice / distilled water. The resulting precipitate is decanted, washed with distilled water and filtered with the help of a Büchner funnel. It is washed again with water in the funnel and the remaining white polymer is dried under vacuum. Polymer samples for characterization tests were prepared by casting from 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 too rapid evaporation of the solvent. After 48 hours of evaporation at room temperature inside a showcase, the polymer film was peeled off and dried under vacuum for another 24 hours at room temperature. Samples were cut from the dry film for the characterization of the thermal properties by DSC (glass transition temperature - Tg, in the second scan - and melting temperature - Tf, in the first scan -) and mechanical tensile according to the standard ISO 37. Following the same reaction procedure in two steps, the rest of the polymers were synthesized. The tribloque molar ratio: LDI: lysine ethyl ester was always maintained 1: 2.5: 1, 5, the concentration of 1 M dimethylacetamide with respect to the polyol, the moles of tin 2-ethylhexanoate 0.01, and the moles of triethylamine 4.5. To obtain the polymer films, chloroform was always used as solvent. Table 3 shows the name and composition of the synthesized polymers and their thermal and mechanical properties. The name of the polymers consists of the letters PU, which indicate poly (urethane-urea), followed by the reference to the triblock as found in Table 1. TABLE 1.- Synthesized triblocks of the PEG-CL combination.
Figure imgf000021_0001
Figure imgf000021_0001
TABLA 2.- Modelos de segmentos duros preparados y su temperatura de transición vitrea obtenida por DSC.TABLE 2.- Models of prepared hard segments and their glass transition temperature obtained by DSC.
Figure imgf000021_0002
Figure imgf000021_0002
TABLA 3. - Denominación y composición de los poliuretanos sintetizados y sus propiedades térmicas y mecánicas.TABLE 3. - Denomination and composition of synthesized polyurethanes and their thermal and mechanical properties.
Figure imgf000021_0003
Figure imgf000021_0003

Claims

REIVINDICACIONES
1.- Material de poliuretano biodegradable caracterizado porque está constituido por el producto resultante de la reacción entre un poliol, un poliisocianato y un extendedor de cadena, y porque su estructura incluye al menos un resto aminoácido natural, donde el poliol es un copolímero de bloque o al azar constituido por la combinación de monómeros de carácter hidrofílico e hidrofóbico antagónicos como: a) óxido de etileno y caprolactona, óxido de etileno y ácido láctico, óxido de etileno y ácido glicólico, óxido de etileno y carbonato de alquilo, óxido de etileno y valerolactona, óxido de etileno y butirolactona, óxido de etileno-óxido de propileno y caprolactona, óxido de etileno- óxido de propileno y ácido láctico, óxido de etileno-óxido de propileno y ácido glicólico, óxido de etileno-óxido de propileno y carbonato de alquilo, óxido de etileno-óxido de propileno y valerolactona, óxido de etileno-óxido de propileno y butirolactona, polietilenglicol y caprolactona, una mezcla de ellos o una mezcla con los homopolímeros, o b) óxido de etileno (u óxido de etileno-óxido de propileno)/diácido o anhidrido/glicol, siendo el diácido o anhídrido el malónico, succínico, glutárico, adípico, pimélico, subérico, azelaico, sebácico, maleico, fumárico, y siendo el glicol el etilenglicol, propilenglicol, butilenglicol, hexametilenglicol, dietilenglicol, trietilenglicol, glicerina, trimetilolpropano, o una mezcla de ellos o con los polioles del apartado a) y/o con los homopolímeros.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 consisting of the combination of antagonistic hydrophilic and hydrophobic monomers such as: a) ethylene oxide and caprolactone, ethylene oxide and lactic acid, ethylene oxide and glycolic acid, ethylene oxide and alkyl carbonate, ethylene oxide and valerolactone, ethylene oxide and butyrolactone, ethylene oxide-propylene oxide and caprolactone, ethylene oxide-propylene oxide and lactic acid, ethylene oxide-propylene oxide and glycolic acid, ethylene oxide-propylene oxide and carbonate alkyl, ethylene oxide-propylene oxide and valerolactone, ethylene oxide-propylene oxide and butyrolactone, polyethylene glycol and caprolactone, a mixture thereof or a mixture with homopolymers, or b) ethylene oxide (or ethylene oxide-propylene oxide) / diacid or anhydride / glycol, the malonic, succinic, glutaric, adipic, diacid or anhydride being the diacid or anhydride; 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 thereof or with the polyols the homopolymers.
2.- Material de poliuretano biodegradable según reivindicación 1 caracterizado porque el poliol tiene un peso molecular entre 150 y 6000 gr mol"1, preferentemente entre 1000 y 3000 gr mol"1.2. 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.- Material de poliuretano biodegradable según reivindicación 1 a 2 caracterizado porque el contenido relativo de los monómeros en el poliol es mayor que 0 y menor que 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.- Material de poliuretano biodegradable según reivindicación 1 a 3 caracterizado porque el poliol es preferentemente un copolímero tribloque resultante de la combinación de polietilenglicol y caprolactona de manera que se obtenga una estructura caprolactona-polietilenglicol-caprolactona. 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 so that a caprolactone-polyethylene glycol-caprolactone structure is obtained.
5.- Material de poliuretano biodegradable según reivindicación 1 caracterizado porque el poliisocianato es: a) un diisocianato o triisocianato, preferentemente butanodiisocianato y hexametilendiisocianato o b) un diisocianato o triisocianato derivado del éster de un monoalcohol, preferentemente metílico o etílico, de un aminoácido como la L-lisina o la L-ornitina. 5. Biodegradable polyurethane material according to claim 1 characterized in that the polyisocyanate is: a) 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.- Material de poliuretano biodegradable según reivindicación 1 caracterizado porque el extendedor de cadena es: a) un glicol difuncional como etilenglicol, propilenglicol, butanodiol y hexanodiol, un glicol polifuncional como glicerina, trimetilolpropano, glucosa, fructosa, ribosa y desoxirribosa, una diamina como etilendiamina, propilendiamina, butilendiamina, hexametilendiamina, piperacina, diaminodifenilsulfona y Polacure 740M o una molécula con grupos alcohol y amina como la etanolamina y el p-aminofenol, o b) un éster de un monoalcohol, preferentemente metílico o etílico, de un aminoácido portador de dos o más grupos susceptibles de reaccionar con el grupo isocianato, como la L-lisina o la L-ornitina, con dos grupos amina, la L-serina o la L-treonina, con un grupo alcohol y un grupo amina, la L-tirosina con un grupo fenol y un grupo amina, o la L-cisteina, con un grupo tiol y un grupo amina, o c) un compuesto resultante de la reacción entre un aminoácido, entre los que se incluyen los aminoácidos proteicos frecuentes como la lisina, la tirosina, la serina, la treonina, la cisteina, la glicina, la alanina, la valina, la leucina, la isoleucina, la fenilalanina, la prolina, la asparagina, la glutamina, el triptófano, la metionina, el ácido aspártico, el ácido glutámico, la arginina y la histidina, proteicos poco frecuentes como la 4-hidroxiprolina, la 5- h id roxi lisina, la desmosina, la isodesmosina, la epsilon-N-metil- lisina, la epsilon-N-trimetil-lisina y la 3-metil-histidina, no-proteicos como la omitina, la beta-alanina, el ácido gamma-aminobutírico, la homocisteína, la homoserina y la citrulina, y un gran exceso molar de un diol, como el etilenglicol o propilenglicol para obtener extendedor de cadena derivado de aminoácido con un grupo alcohol y un grupo amina, o la mitad en moles de dicho diol para obtener extendedor de cadena derivado de aminoácido con dos grupos amino.6. Biodegradable polyurethane material according to claim 1 characterized in that the chain extender is: a) a difunctional glycol such as ethylene glycol, propylene glycol, butanediol and hexanodiol, a polyfunctional glycol such as glycerin, trimethylolpropane, glucose, fructose, ribose and deoxyribose, 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) an ester of a monoalcohol, preferably methyl or ethyl, of a carrier amino acid two or more groups capable of reacting with the isocyanate group, such as L-lysine or L-ornithine, with two amine groups, L-serine or L-threonine, with an 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, or c) a compound resulting from the reaction between an amino acid, among which s and include frequent protein amino acids such as lysine, tyrosine, serine, threonine, cysteine, glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, asparagine, glutamine, tryptophan, the methionine, aspartic acid, glutamic acid, arginine and histidine, rare proteins such as 4-hydroxyproline, 5- h id roxy lysine, desmosin, isodesmosin, epsilon-N-methyl-lysine, epsilon -N-trimethyl-lysine and 3-methyl-histidine, non-proteins such as omitin, beta-alanine, gamma-aminobutyric acid, homocysteine, homoserine and citrulline, and a large molar excess of a diol, such as ethylene glycol or propylene glycol to obtain an amino acid derived chain extender with an alcohol group and an amine group, or half a mole of said diol to obtain an amino acid derived chain extender with two amino groups.
7.- Material de poliuretano biodegradable según reivindicaciones 1 a 6 caracterizado porque el resto de aminoácido se incorpora preferentemente por cada molécula de poliisocianato o de extendedor de cadena siendo ocasionalmente deseable su incorporación en un contenido menor o en localizaciones al azar en la cadena de poliuretano para lo cual se combinan dos poliisocianatos distintos, uno que contenga al menos un resto de aminoácido y otro que no contenga restos de aminoácido, o dos extendedores de cadena distintos, uno que contenga al menos un resto de aminoácido y otro que no contenga restos de aminoácido.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 lower content or at random locations in the polyurethane chain for which two different polyisocyanates are combined, 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. amino acid
8.- Material de poliuretano biodegradable según reivindicaciones 1 a 7 caracterizado porque puede formularse con aditivos biodegradables, entre los que se incluyen, cargas y plastificantes, para ajustar las propiedades del material o su comportamiento bajo condiciones específicas. 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.- Uso del material de poliuretano biodegradable según reivindicaciones 1 a 8 para la elaboración de productos aplicados en el sector farmacéutico y biotecnológico.9. Use of the biodegradable polyurethane material according to claims 1 to 8 for the elaboration of products applied in the pharmaceutical and biotechnological sector.
10.- Uso del material de poliuretano biodegradable según la reivindicación 9 caracterizado porque el producto es un biomaterial para el transporte y liberación de productos farmacológicos o biotecnológicos.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.- Uso según la reivindicación según la reivindicación 9 caracterizado porque el producto es un biomaterial utilizable en ingeniería de tejidos. 11. Use according to claim according to claim 9 characterized in that the product is a biomaterial usable in tissue engineering.
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