NL8703115A - BIODEGRADABLE POLYURETHANS, PREPARATIONS BASED ON THESE, AND POLYESTER POLYOL PREPOLYMERS. - Google Patents

Description

VO 9477

Title: Biodegradable polyurethanes, articles based thereon, and polyester polyol prepolymers

The invention relates to a biodegradable polyurethane based on a polyol prepolymer and a polyisocyanate.

The invention further relates to articles of manufacture, in particular biomedical articles, such as artificial skin, wound coverings, artificial veins, vein joints, nerve joints and the like, which comprise such a polyurethane.

The invention further relates to a polyester polyol prepolymer which can be used for the preparation of the polyurethane.

Polyurethanes are considered to be excellent biomedical materials, which have good mechanical and physical properties and exhibit satisfactory blood compatibility. For these reasons, linear (thermoplastic) elastomeric polyurethanes are used, for example, in biodegradable polyurethane / poly (L-lactide) mixtures for the manufacture of biomedical products such as blood vessel inoculations, meniscus prostheses, artificial skin products and nerve joints. See e.g.

Gogolewski and Pennings, Makromol. Chem., Rapid Commun.

3 (1982) 839 and 4 (1983) 675.

The known polyurethane / poly (L-lactide) mixtures, however, exhibit a very low degradation rate in vivo, after an initial fragmentation. In addition, creep defects are observed under dynamic loading, which lead to aneurysms at blood vessel grafts. An even more serious drawback of the polyurethane elastomers known for biomedical applications with biodegradation, such as Biomer, Estane, etc., is that upon degradation, toxic, mutagenic and carcinogenic substances, such as 4,4'-methylenedianiline, when the polyurethane is prepared under. 87 031 15 9% -2 using 4,4'-methylenediphenyl diisocyanate may be released. It is known that this drawback can be mitigated by using non-aromatic polyisocyanates in the preparation of the polyurethanes. For example, it has been proposed by Szycher et al, J. Elastomers and Plastics 15 (1983) 81-95 to use cycloaliphatic diisocyanates such as 4,4'-methylene bis cyclohexyl diisocyanate. By reacting this diisocyanate with a poly tetramethylene ether glycol (with a molecular weight of about 1000) and 1,4-butanediol, cycloaliphatic polyurethane elastomers of biomedical quality are obtained, which are marketed under the trademark Tecoflex.

It has also been proposed to use non-cyclic aliphatic polyisocyanates, such as 1,6-hexanediisocyanate, in the polyurethane preparation. However, the corresponding diamines, which can be released upon degradation of the polyurethanes, are still toxic to a greater or lesser extent.

As for the polyols to be used for the preparation of polyurethanes, it is known to use polyester-20 polyol prepolymers therefor. For example, Schindler et al., J. Polym. Sci. (1982) 319, the formation of star-shaped polycaprolactone polymers described by an alcohol-initiated ring-opening polymerization of ε-caprolactone using a cyclic sugar such as sorbitol, xylitol or ribitol as the alcohol. By Pitt et al, J. Polym. Sci. 25 (1987) 955 describes the preparation of biodegradable polyurethanes from prepolymers with 3 terminal hydroxyl groups, obtained by a glycerol initiated ring-opening copolymerization of a 1: 1 mixture of δ-valerolactone and ε-caprolactone. These prepolymers were cross-linked with 1,6-hexanediisocyanate.

Furthermore, Schindler et al., In "Cont. Topics in Polym. Sci." (Eds. Pearce and Schaefgen) 35 Plenum Press N.Y., USA, vol. 2 (1977) and Kricheldorf. 8703115-3s et alr Macromolecules 17 (1984) 2173 biodegradable copolyesters of L-lactide or glycolide and ε-caprolactone.

Hitherto, however, no biodegradable polyurethane elastomers have been described which have a combination of properties suitable for various biomedical applications and which in particular do not yield toxic degradation products during degradation.

The invention now provides a biodegradable polyurethane based on a polyol prepolymer and a polyisocyanate, which does meet this need and is characterized in that the polyisocyanate is an L-lysine derivative with at least 2 isocyanate groups. More particularly, the invention relates to such a biodegradable polyurethane, in which the polyol prepolymer is a polyester polyol prepolymer.

The L-lysine derivative to be used according to the invention in the preparation of the polyurethane is preferably a compound of the structural formula OCN-CH-COOR

(CH2) 4

NCO

wherein R represents an alkyl, aryl, alkaryl or aralkyl group, which may be substituted by one or more isocyanate groups and / or inert groups, such as alkoxy groups, inert in the polyurethane forming reaction. Preferably R represents a lower alkyl group, most preferably the ethyl group, and this lower alkyl group is unsubstituted or substituted by an isocyanate group.

Such L-lysine polyisocyanates are known per se from French patent 1,351,368, which also describes their preparation and mentions their usefulness for the preparation of polyurethane foams, adhesives and elastomers. This publication. 8703 1 15 r t -4- does not, however, contain any suggestion for the conversion. of such L-lysine polyisocyanates with polyol prepolymers, in particular polyester polyol prepolymers, to polyurethanes which can be used medically.

The polyurethane according to the invention may be based on a polyester diol prepolymer and an L-lysine derivative with at least 3 isocyanate groups, preferably L-lysine aminoethyl ester triisocyanate of the structural formula

10 OCN-CH-COO (CHo) 2NCO

(CH2) 4 NCO

The polyester diol prepolymer is preferably a prepolymer obtained by a ring-opening polymerization reaction of L-lactide, glycolide, and / or one or more lactones, such as ε-caprolactone and δ-valerolactone, optionally initiated with a diol, such as glycol , 1,4-butane-diol, 1,6-hexanediol, etc. Most preferably, the prepolymer is obtained by optionally diol-initiated ring-opening copolymerization of L-lactide and / or glycolide with one or more lactones, such as ε-caprolactone and δ-valero-lactone.

However, the invention also includes linear or non-linear biodegradable polyurethanes based on an L-lysine derivative with 2 or more isocyanate groups, such as L-lysine ethyl ester diisocyanate and L-lysine aminoethyl ester triisocyanate; a diol prepolymer, for example a polyether diol such as polytetramethylene glycol with a molecular weight of about 1000-2000, or a polyester diol such as polycaprolactone diol with a molecular weight of about 1000-2000; and a chain extender such as 1,4-butanediol.

The polyurethane according to the invention, however, is preferably based on an L-lysine diisocyanate, most preferably L-lysine ethyl ester diisocyanate with the structure -8703115 ψ -5-formula OCN- (j; H-COOC2H5 ·? H2) 4

NCO

5 and a polyester polyol prepolymer with at least 3 hydroxyl groups. This prepolymer is preferably obtained by a ring-opening polymerization reaction of L-lactide, glycolide, and / or one or more lactones, such as ε-caprolactone 10 and δ-valerolactone, with a polyol containing at least 3 hydroxyl groups. Here, too, a copolymerization of L-lactide and / or glycolide with one or more lactones, such as ε-caprolactone and δ-valerolactone, is preferred. The polyol to be used for initiating the polymerization reaction is preferably a cyclic polyol, and especially myo-inositol has proved extremely suitable for this purpose, in relation to the intended uses of the polyurethane.

Most preferred is a polyurethane according to the invention, wherein the polyester polyol prepolymer is obtained by a ring-opening polymerization reaction of L-lactide or glycolide with ε-caprolactone and with myo-inositol, and the L-lysine polyisocyanate the compound L-lysine ethyl ester diisocyanate. The monomeric products which can be released upon complete degradation of such a polyurethane are myo-inositol (a human-occurring vitamin), L-lactic or glycolic acid, 6-hydroxyhexanoic acid, L-lysine and ethanol.

These monomeric compounds are all non-toxic, which is of great significance for the use of the polyurethane as a degradable biomedical material. A second advantage due to the use of L-lysine ethyl ester diisocyanate is that the carboxyl group formed on hydrolysis of the ethyl ester has a catalytic effect on the further degradation of the polymer. The advantage of L-lactide (or glycolide) / ε-caprolactone copolyester prepolymers is that the polyurethanes based thereon combine good elastomer properties with a high biodegradation rate. Polyurethanes based on L-lacti-5 de / myo-inositol or glycolide / myo-inositol prepolymers have glass transition temperatures (Tg) above room temperature, while polyurethanes based on poly (ε-caprolactone) prepolymers have a low biodegradation rate, which for many applications is undesirable. The polyurethanes based on copolyester prepolymers, which according to the invention are preferred, preferably containing approximately equimolar amounts of L-lactide (or glycolide) and ε-caprolactone, combine low glass transition temperatures, for example in the range of 0-10 ° C, with a relative 15 high biodegradation rate. The glass transition temperature can be adjusted to a desired value by controlling the chain lengths of the copolyester prepolymers; longer chain lengths lead to lower values of the glass transition temperature. However, it should be taken into account that residues of unreacted monomers and oligomers exhibit a plasticizing action, so that an extraction treatment of the polymer, e.g. with chloroform, as a result of the removal of such monomers and oligomers will lead to a slightly higher glass transition temperature.

These monomer and oligomer residues also affect the gel content of the polyurethanes of the invention. The highest gel contents are achieved when the prepolymer, before reacting with the L-lysine polyisocyanate, is freed from such low molecular weight residues by precipitating the prepolymer from a solution of the non-solvent such as ethanol. prepolymer in an organic solvent, such as chloroform. Higher gel contents can also be achieved by using a small excess of the .87031 -7- isocyanate groups over the hydroxyl groups. In addition to the formation of urethane bonds, an additional cross-linking can take place through the formation of allophanate groups.

In connection with various biomedical applications, such as use as a bottom layer of artificial skin products for covering (burn) wounds, or use as an internal layer of blood vessel and nerve connections, the polyurethane according to the invention preferably consists of a porous network. Such a porous polyurethane network is available by carrying out the reaction between polyester-polyol prepolymer and L-lysine polyisocyanate in the presence of a salt, such as sodium chloride, and later removing this salt, for example by treatment with water, thereby creating pores stay behind.

The invention also includes articles which consist wholly or partly of a polyurethane according to the invention, in particular sheet-shaped biomedical articles such as artificial skin, wound covers, etc. and tubular biomedical articles such as arteries, vein connectors, nerve connectors, etc. Furthermore, the polyurethanes according to the invention can also be used as a biodegradable carrier for medicines, etc., as a (component of) biodegradable suture, etc.

The invention also extends to a polyester polyol prepolymer based on (1) a cyclic polyhydroxy compound with at least 3 functional hydroxyl groups, (2) L-lactide and / or glycolide, and (3) one or more lactones, such as ε- caprolactone and 5-valerolactone, especially over such a prepolymer in which the polyhydroxy compound is myo-inositol and / or the lactone is ε-caprolactone.

The invention is further elucidated by means of an example 35.

.8703115 (-8- «

Example (a) Preparation of the prepolymers 5 L-lactide (available from C.C.A.

Gorinchem, the Netherlands; after recrystallization from dry toluene) or glycolide (available from Dupont), as well as ε-caprolactone (available from Janssen Chemical, Belgium; after distillation) and myo-inositol (available from Merck) at 140 ° C in dry dimethylformamide. 0.5% by weight of tin (II) octoate (available from Sigma Chem. Corp., USA) was added as the catalyst and polymerization was carried out at 120-130 ° C for 20 hours under a nitrogen atmosphere. After the solvent was removed under reduced pressure, a tacky, yellowish-colored prepolymer remained. Part of this prepolymer was precipitated in ethanol (-70 ° C) from a chloroform solution and dried under reduced pressure at room temperature.

(B) Preparation of L-lysine ethyl ester diisocyanate

L-lysine monohydrochloride (available from Janssen Chemical, Belgium) was converted to reflux in L-lysine ethyl ester di-hydrochloride in ethanol while passing HCl gas through the solution.

Phosgenation of this L-lysine ethyl ester dihydrochloride in ortho-dichlorobenzene at 100-110 ° C for about 8 hours gave L-lysine ethyl ester diisocyanate, which was purified by vacuum distillation (bp 125 ° C at 0 ° C). 1 mm Hg).

(c) Formation of the polyurethane network. Crosslinked L-lactide / ε-caprolactone copolyester. 8705115-9 prepolymers by treatment with L-lysine ethyl ester diisocyanate in toluene. The cross-linking of glycolide / ε-caprolactone copolyester prepolymers was performed in dichloromethane. The molar ratio of hydroxyl groups to isocyanate-5 groups was 1. By a reaction of one day at room temperature under nitrogen in a Petri dish and after curing for 3 hours at 100-110 ° C, thin films were obtained. The elastic transparent films were dried under reduced pressure at 50 ° C.

Porous films with a pore volume of about 85% were obtained by curing a viscous suspension of prepolymer, diisocyanate, solvent and an amount of dry NaCl powder of variable particle size in the manner indicated above and the salt 15 by washing the NaCl polymer mixture with water.

(d) Results. The gel contents (% w / w) were determined by extracting the networks with chloroform. The extracted networks were dried at 50 ° C under reduced pressure for several days.

Swelling tests were performed on the extracted networks at room temperature in chloroform.

The degree of swelling was calculated from the weight gain after the swelling, using the densities of chloroform (p = 1.48 g / cm3) and the dry extracted networks (p = 0.90-0.95 g / cm3).

A thermal analysis of the networks was performed using a Perkin-Elmer DSC-7, which had been calibrated with the I.C.T.A. (International Confederation for Thermal Analysis) certified reference materials and used at a scan rate of 10 ° C / min.

.8703115 c «-10-

Mechanical properties were determined at room temperature using an Instron (4301) tensile tester equipped with an ION load cell, at a drawing speed of 12 mm / min. Samples of 15 x about 0.75 x about 0.25 mm were cut for this purpose from thin films extracted or not.

For the porous materials, the microstructure was examined using an I.S.I.-DS130 scanning electron microscope.

The results of the studies described above, with the exception of the electron microscopic study, are summarized in the table below.

Polyester urethane network data 15 polyurethane prepolymer T (° C) gel tensile swelling, a), ^ -i „b) ° content breaking strength _, c) network chain length & elongation degree (%) (%) 20 1 2 , 1 91 300 8 6.3 2 8.2 400 30-36 2.70 3 7.7 95 300 11-12 6.3 25 4 8.3 425 28-34 3.05 5 - 94.2 350 16-20 9, 5 6 2.3 500 40 4.75 30 1 = myo-inositol / glycolide / e-caprolactone prepolymer + L-lysine-ethyl ester diisocyanate 2 = extracted network 1 3 = precipitated myo-inositol / glycolide / ε-caprolactone-prepolymer + L-lysine ethyl ester diisocyanate. 8703 115 -11- 4 = extracted network 3 5 = myo-inositol / L-lactide / e-caprolactone prepolymer + L-lysine ethyl ester diisocyanate 6 = extracted network 5 5 ^ chain length = amount of lactones lactide, glycolide, ε-caprolactone) per OH group, calculated from the amount of myo-inositol 10 in chloroform used, 20 ° C.

Fig. 1 shows the stress-strain curves for the glycolide / ε-caprolactone copolyester urethane networks before (dotted line) and after (solid line) extraction with chloroform, specifically networks 3 and 4 of the table.

All polyurethane networks exhibited a rubber-like behavior, with the extracted polyurethane networks exhibiting better mechanical properties, a higher elongation at break and a higher tensile strength (30-40 MPa) than the non-extracted networks.

. 87031 15

Claims (22)

Biodegradable polyurethane based on a polyol prepolymer and a polyisocyanate, characterized in that the polyisocyanate is an L-lysine derivative with at least 2 isocyanate groups. The polyurethane according to claim 1, wherein the polyol prepolymer is a polyester polyol prepolymer. Polyurethane according to claim 1 or 2, wherein the L-lysine derivative satisfies the structural formula OCN-CH-COOR 10 (h h2) 4 NCO in which R represents an alkyl, aryl, alkaryl or aralkyl group, which may be substituted groups, such as alkoxy groups, inert groups in the polyurethane forming reaction, by one or more isocyanate groups and / or. Polyurethane according to claim 2 or 3, wherein the polyester polyol prepolymer is a polyester diol prepolymer and the L-lysine derivative contains at least 3 isocyanate groups. 4 -12- CONCLPSIONS The polyurethane according to claim 4, wherein the L-lysine derivative is the compound L-lysine-aminoethyl ester triisocyanate having the structural formula 0CN- <uHH-C00 (CH2) 2NC0 25 (CH2) 4 NCO 6. Polyurethane according to claim 4 or 5, wherein the polyester diol prepolymer is obtained by a ring-opening polymerization reaction of L-lactide, glycolide, and / or one or more lactones, such as ε-caprolactone and δ-valero-lactone, if desired. with a diol. . 87 03 1 15 -13- « Polyurethane according to claim 4 or 5, wherein the polyester diol prepolymer is obtained by a ring-opening polymerization reaction of L-lactide and / or glycolide with one or more lactones, such as ε-caprolactone 5 and δ-valerolactone, and optionally with a diol. The polyurethane according to claim 2 or 3, wherein the polyester polyol prepolymer contains at least 3 hydroxyl groups and the L-lysine derivative is an L-lysine diisocyanate. The polyurethane according to claim 8, wherein the L-lysine diisocyanate is the compound L-lysine ethyl ester diisocyanate of the structural formula 0CN- <jJH-C00C2 h5 (fH2) 4 Polyurethane according to claim 8 or 9, wherein the polyester polyol prepolymer is obtained by a ring-opening polymerization reaction of L-lactide, glycolide, and / or one or more lactones, such as ε-caprolactone and δ-valerolactone, with a polyol containing at least 3 hydroxyl groups. 11. Polyurethane according to claim 8 or 9, wherein the polyester polyol prepolymer obtained is obtained by a ring opening polymerization reaction of L-lactide and / or glycolide with one or more lactones, such as ε-caprolactone and δ-valerolactone, and with a polyol containing at least 3 hydroxyl groups. 12. Polyurethane according to claim 10 or 11, wherein the polyol is a cyclic polyol with at least 3 hydroxyl groups. The polyurethane according to claim 12, wherein the cyclic polyol is myo-inositol. The polyurethane material of claim 1, wherein the polyol prepolymer is a polyester polyol prepolymer,. 87031 15 &; -14- obtained by a ring-opening polymerization reaction * of L-lactide or glycolide with ε-caprolactone and with myo-inositol, and the L-lysine polyisocyanate is the compound L-lysine ethyl ester diisocyanate. Polyurethane according to any one of the preceding claims, consisting of a porous network. 15 NCO Polyurethane according to claim 15, obtainable by carrying out the reaction between polyester polyol prepolymer and L-lysine polyisocyanate in the presence of a salt, such as sodium chloride, and later removing this salt, for example by treatment with water, leaving pores. Polyurethane according to any of the preceding claims, wherein the polyester-polyol prepolymer is precipitated from a solution of the prepolymer in an organic solvent, such as chloroform, using a non-solvent, such as ethanol. 18. Articles, wholly or partly consisting of a polyurethane according to any one of the preceding claims. 19. Sheet-shaped biomedical articles such as artificial skin, wound covering, etc. and tubular biomedical articles such as artificial veins, vein connectors, nerve connectors, etc., consisting wholly or partly of a polyurethane according to any one of claims 1-17. 20. Biomedical articles according to claim 19, comprising one or more layers of a porous polyether urethane as well as one or more layers of a polyurethane according to any one of claims 1-17. 21. Polyester polyol prepolymer based on (1) a cyclic polyhydroxy compound with at least 3 functional hydroxyl groups, (2) L-lactide and / or glycolide, and (3) one or more lactones, such as ε-caprolactone and 35 <5-valerolactone . .8703115 i '-15- The polyester polyol prepolymer of claim 21, wherein the cyclic polyhydroxy compound is myo-inositol. Polyester polyol prepolymer according to claim 21 or 22, wherein the lactone is ε-caprolactone. . 87031 15