WO2004029123A1

WO2004029123A1 - Method for the production of biocompatible polyurethanes

Info

Publication number: WO2004029123A1
Application number: PCT/DE2003/003081
Authority: WO
Inventors: Josef Jansen; Günter LORENZ; Engin Kocaman; Mario Krautschick
Original assignee: Adiam Life Science Ag
Priority date: 2002-09-20
Filing date: 2003-09-17
Publication date: 2004-04-08
Also published as: DE10243965A1; AU2003275919A1; EP1543055A1

Abstract

The invention relates to biocompatible polyurethanes and production thereof by reaction of an aliphatic and/or cycloaliphatic diisocyanate with a polyester, polyether, polysiloxane, or polysulphone with an average molecular weight of 500 to 6000. The prepolymer thus obtained is subsequently reacted with a chain extending agent, which is a low molecular weight diol or a mixture of the low molecular weight diol with a macrodiol of the polyester, polyether, polysiloxane or polysulphone type. According to the invention, the ratio of the NCO terminal groups of the prepolymer to the OH groups of the chain extending agent is 1.01: 1 to 1.05: 1. The subsequent molecular weight fractionation of the polymer obtained, for removal of the low molecular weight polyurethane fraction is achieved with a mass proportion of 10 to 55 wt. %. The invention further relates to the use of said polyurethane for the production of objects for medical use.

Description

Process for the production of biocompatible polyurethanes

The invention relates to a method for producing biocompatible polyurethanes, the polyurethanes thus produced and products for medical purposes which are produced from these polyurethanes.

Biocompatible polyurethanes have long been used in medicine, especially in applications that are in contact with blood. The reason for this is the very good mechanical properties, the a priori existing good blood tolerance and the good processability of the polyurethanes. However, most of the known polyurethanes have a number of disadvantages. For example, hydrolytic influences adversely affect mechanical properties such as strength, elongation and elasticity within more or less short periods of time. Many polyurethanes are even completely broken down over time. DE 33 18 730 describes polyurethanes which are generally referred to as biocompatible and biostable. However, these biocompatible and biostable polyurethanes have further disadvantages: low-molecular constituents can be washed out or diffuse to the surface, thereby negatively influencing the biocompatibility. In addition, there are, for example, no polyurethanes with a modulus of elasticity <15 N / mm ² (determined from the relationship σ = E • ε, σ is the tensile stress and ε is the elongation), so-called soft polyurethanes, which have a high linear elastic behavior have high tensile strength and tear strength with high long-term stability in vivo. These properties are particularly important for materials that are used for long-term implants that are subject to cyclic loading, for example as a heart valve sail.

It is an object of the invention to provide polyurethanes with improved properties compared to the previously known polyurethanes, which, particularly with a low modulus of elasticity, exhibit high linear elastic behavior, high tear and tear propagation resistance and high long-term stability in vivo. This object is achieved by a process in which at least one aliphatic and / or at least one cycloaliphatic diisocyanate is reacted with a macrodiol of the polyester, polyether, polysiloxane or polysulfone type with an average molecular weight of 500 to 6000 and the prepolymer obtained in this way is further processed reacted with a chain extender which is a low molecular weight diol or a mixture of low molecular weight diols or a mixture of the low molecular weight diol with a macrodiol of the type polyester, polyether, polysiloxane or polysulfone with an average molecular weight of 500 to 6000, characterized in that the ratio of NCO end groups of the prepolymer to OH groups of the chain extender is 1.01: 1 to 1.05: 1 and that the polymer obtained, if appropriate after treatment with a reagent to deactivate the NCO groups still present, is shown in a molecular weight fractionation throws, in which the low molecular weight polyurethane fraction with a mass fraction of 10 to 55% by weight, ie unusable fraction, is separated off and possibly discarded and the remaining high molecular weight fraction is obtained as biocompatible polyurethane with improved properties.

Suitable aliphatic diisocyanates are straight-chain or branched C ₂ -C ₁₀ -alkyl diisocyanates, which can be substituted by methyl, ethyl, n-propyl, i-propyl or butyl. Preferred are C - to C ₈ -alkyl isocyanates, particularly preferably C ₅ - and Ce-alkyl isocyanates, which can each be substituted by methyl, ethyl, n-propyl, i-propyl or butyl. Hexanediisocyanates, which can be substituted by methyl radicals, are very particularly preferred. 1, 6-diisocyanato-2,2,4,4-tetramethylhexane, 1, 6-diisocyanato-2,4,4-trimethylhexane and 1, 6-diisocyanato-2,2,4-trimethyl-hexane may be mentioned in particular.

Suitable cycloaliphatic diisocyanates are those with cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl groups, it being possible for the cycloaliphatic radicals to be linked via one or more methylene radicals. Cyclopentyl, cyclohexyl and dicyclohexyl methane are preferred diisocyanates, particularly preferred are cyclohexyl and dicyclohexyl methane diisocyanates. 4,4'-Dicyclohexylmethane diisocyanate, 1,4-cyclohexyl diisocyanate, 1,3-bis (isocyanatomethyl) cyclohexane, 1,4-bis (isocyanatomethyl) cyclohexane and isophorone diisocyanate may be mentioned in particular. 4,4'-Dicyclohexylmethane diisocyanate and 1,4-cyclohexyl diisocyanate are very particularly preferably used in the process according to the invention. Isomer mixtures of the diisocyanates mentioned are of course also suitable.

Suitable macrodiols are polyesters, polyethers, polysiloxanes or polysulfones which have two OH end groups with an average molecular weight of M _w = 500 to 6000 (M _w = weight average), preferably polyesters, polyethers, polysiloxanes or polysulfones with two OH end groups an average molecular weight of M _w = 500 to 4000 (M _w = weight average), particularly preferably polyester, polyether, polysiloxanes or polysulfones with two OH end groups with an average molecular weight of M _w = 1000 to 3000 (M _w = weight average) particularly preferably polyesters, polyethers, polysiloxanes or polysulfones with two OH end groups with an average molecular weight of M _w = 1000 to 2400 (M _w = weight average).

Examples of polyesters are those having C to C alkylene units, preferably those having C ₂ to C ₆ alkylene units, particularly preferably C ₂ to C ₄ alkylene units, where these can each be substituted by methyl groups.

Polyethers which may be mentioned are those with C to C ₁₀ alkylene units, preferably those with C ₂ to C ₆ alkylene units, particularly preferably C ₂ to C ₄ alkylene units, where these can each be substituted by methyl groups.

Polysiloxanes which may be mentioned are those with C to C ₀ alkylene units, preferably those with C ₂ to C 6 alkylene units, particularly preferably C ₂ to C alkylene units, where these can each be substituted by methyl groups. Polysulfones which may be mentioned are those with C to C 10 alkylene units, preferably those with C ₂ to C ₆ alkylene units, particularly preferably C ₂ to C ₄ alkylene units, where these can each be substituted by methyl groups.

Suitable low molecular weight diols are C ₂ to C 10 alkyl diols, which may optionally be substituted by lower alkyl radicals such as C 1 -C ₃ radicals. Ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,4-bis (hydroxymethyl) cyclohexane, 1,6-hexanediol, 2,2,4-trimethyl-1,6-hexanediol and 2,4,4-trimethyl-1,6-hexanediol, preferably 1,4-butanediol, 1,6-hexanediol, 2,2,4-trimethyl-1,6-hexanediol and 2,4,4-trimethyl-1 , 6-hexanediol, particularly preferably 1, 4-butanediol and 2,2,4-trimethyl-1, 6-hexanediol. A mixture of low molecular weight diols can of course also be used. A mixture of two diols is generally used. The diol can also be used in admixture with a macrodiol of the polyester, polyether, polysiloxane or polysulfone type as specified in detail above, the polyester, polyether, polysiloxane or polysulfone having an average molecular weight as mentioned above being used.

When the prepolymer is reacted with the chain extender, a catalyst can be used in a manner known per se. For example, dibutyltin dilaurate, tin octoate or diazabicyclooctane can be used as catalysts.

The ratio of NCO end groups of the prepolymer to OH groups of the chain extender is generally 1.01: 1 to 1.05: 1, preferably 1.02: 1 to 1.04: 1, particularly preferably 1.025: 1 to 1.035: 1.

The molecular weight fractionation of the process according to the invention is carried out in a manner known per se. Suitable processes are precipitation reactions, solid phase extraction, liquid phase extraction, adsorption chromatography, precipitation chromatography according to Baker-Williams, distribution fractionation, gel permeation chromatography (GPC) and continuous polymer fractionation (CPF). Precipitation reactions, gel permeation chromatography and continuous polymer fractionation are particularly suitable for molecular weight fractionation. In molecular weight fractionation, a low molecular weight fraction with a mass fraction of 10 to 55% by weight is generally separated, a low molecular weight fraction with a mass fraction of 20 to 50% by weight is preferred, particularly preferably one with a mass fraction of 30 to 45% by weight. separated and discarded.

The process according to the invention is generally carried out as follows. In a suitable apparatus, e.g. In a three-necked flask equipped with a stirrer, nitrogen supply and cooler with a discharge pipe, the diisocyanate is mixed with the macrodiol to form the prepolymer and heated with constant stirring. The temperature is generally 50 to 120 ° C, preferably 60 to 100 ° C, particularly preferably 70 to 90 ° C. The reaction time for the prepolymer formation is at least 5 h, a reaction time for the prepolymer formation of 10 to 20 h is preferred, particularly preferably 14 to 19 h.

In the meantime, the chain extender is mixed in another vessel, if appropriate after adding a catalyst, for example dibutyltin dilaurate, tin octoate or diazabicyclooctane, and then added to the prepolymer. The reaction mixture is then heated at a temperature of 50 to 120 ° C., preferably 60 to 100 ° C., particularly preferably 70 to 90 ° C., with constant stirring for at least 48 hours. After the excess NCO groups have been deactivated, the resulting polymer is purified and dried with a suitable deactivation reagent, for example secondary amines, preferably dibutylamine. It is also possible to carry out the reaction described above in the presence of one or more solvents. The solvents are dimethylacetamide, dimethylformamide, chloroform, methylene chloride, trichlorethylene, tetrahydrofuran and dioxane, dimethylacetamide, dimethylformamide and chloroform are preferred, dimethylacetamide and chloroform are particularly preferred. Dimethylacetamide is very particularly preferably used as the solvent. Will the implementation Carried out in solution, the polymer formed can be separated off by drying in a suitable precipitant, for example i-propanol or water, and dried.

The polymer obtained is then subjected to a molecular weight fractionation. The molecular weight fractionation is explained using precipitation reactions. For this purpose, the polymer is first brought into solution. Suitable solvents for the polymer are dimethylacetamide, dimethylformamide, chloroform, methylene chloride, trichlorethylene, tetrahydrofuran and dioxane, dimethylacetamide, dimethylformamide and chloroform are preferred, and dimethylacetamide is particularly preferred. A non-solvent, such as i-propanol and / or water, preferably i-propanol, is slowly added to such a polymer solution in a manner known per se. This slowly lowers the solubility of the polymer. As a result, molecules with the highest degree of polymerization precipitate out first and shorter chains remain in solution. The polymer solution is at constant temperature, e.g. Held at room temperature and added the precipitant with stirring. As soon as the solution becomes cloudy, the temperature is increased until the precipitating polymer dissolves. The solution is then cooled to the original temperature, the polymer thus precipitated is separated off and dried. Suitable combinations of solvents and precipitants can be determined by turbidity titrations in addition to other methods known to those skilled in the art.

The invention furthermore relates to biocompatible polyurethanes produced by the process according to the invention, and to their use for producing products for medical purposes.

Surprisingly, it was found that the high molecular weight fraction obtained in the molecular weight fractionation, regardless of the method used for the molecular weight fractionation, has a modulus of elasticity which is 10 to 50%, for example 20 to 40%, lower than that of the starting material the secant module is to be understood, which can be seen in the stress-strain diagram the slope of the straight line can be determined by the origin and the end point of the quasilinear area. In addition, it was observed that in the stress-strain diagram the quasilinear area of the high-molecular fraction increases according to the relationship σ = E • ε by approx. 15 to 45%, eg 20 to 40%, compared to the starting material. In addition, the tear strength and tear resistance improve by about 10 to 20% [for terminology cf. DIN 53455, ISO 527.2-1985].

example 1

In a three-necked flask equipped with a stirrer, nitrogen supply and cooler with a discharge pipe, 0.54val 1, 4-cyclohexyldiisocyanate, 0.54val 4,4'-dicyclohexylmethane diisocyanate and 0.08val anhydrous polyether diol M _w ~ 2000 are filled and min Heated for 10 hours at 85 ° C with constant stirring. The addition reaction for the preparation of the pre-adduct is continued until the theoretically calculated isocyanate content of 21.7% by weight is reached. Meanwhile, 0.42val anhydrous polyether diol and 0.55val anhydrous 1,4-butanediol are mixed in another sealed vessel with the tin catalyst (0.12val dibutyltin dilaurate) to produce the chain extender. This mixing also takes place at approx. 80 ° C. For the production of the polyurethane, the two mixtures are stirred at a temperature of 85 ° C, degassed and poured into a curing mold. The curing takes place at 80 ° C and takes about 3 days. The polymer obtained in this way is described by the following characteristic values: molecular weight M _w = 82400, polymolecularity index 1.71, modulus of elasticity 21.0 N / mm ² , linearity 3.5%, tear propagation resistance 28 N / mm.

After the reaction has ended, the polymer is subjected to a molecular weight fractionation by means of a precipitation reaction. For this purpose, a solution of 6.8 g of polymer in 70 g of dimethyl acetamide is mixed with 100 g of i-propanol and heated to 50 ° C. After cooling, the polymer is isolated from the lower gel phase and dried. The The analytical characteristics of the fractionated polymer have changed as follows: molecular weight M _w = 101700, polymolecularity index 1, 38, modulus of elasticity 13.2 N / mm ² , linearity 4.8%, tear propagation resistance 36 N / mm. -

Example 2

The polymer is prepared in analogy to Example 1. Preparative gel permeation chromatography is used for molecular weight fractionation. A dilute polymer solution is prepared for this. The concentration of the solution is a maximum of 8 g / L. Chloroform is used as the solvent. Parts of the polymer solution are injected into the G PC separation system. The concentration of the molecules separated from the separation columns by molecular weight is measured with a concentration-sensitive detector and divided into two fractions, which are collected separately. The polymer fractions in the three fractions are isolated and dried. Polymers with the following characteristics result:

GPC-M _w PMI ⁾ E-module in linearity in tear resistance

Fraction N / mm ² % in N / mm

1 108 100 1, 36 13.7 5.5 39

2 71900 1, 46 19.5 3.80 19

¹⁾ M _w = weight average molecular weight

²⁾ PMI = polymolecularity index

Fraction 1 is fed to its further determination as a fraction obtained by the process according to the invention. Examples 3 to 10

In a procedure analogous to Example 1, polyurethanes were produced from the starting materials listed in the following table and then subjected to molecular weight fractionation by means of precipitation reactions:

E.g. prepolymer chain extender no. Diisocyanate 1 diisocyanate 2 macrodiol macrodiol diol 1 diol 2

0.21 val

3 2.1val CHDI ¹⁾ - - - 1, 8val TMHD ⁵⁾ PED ³⁾ 1000

0.3val 2.0val

4 2.6val CHDI ¹⁾ 0.13val BD ⁴⁾ - PED ³⁾ 600 PED ³⁾ 600

1, 1 val 0.18val 0.5val

5 1.0val CHDI ¹⁾ 0.7val BD ⁴⁾ 0.7val TMHD ⁵⁾ DCHMDI ² 'PED ³⁾ 2000 PED ³⁾ 2000

1.6val 0.12val 0.64val

6 - 0.82val BD ⁴⁾ DCHMDI ² »PESD ⁶⁾ 2000 PESD ⁶⁾ 2000

0.15val 0.17val 0.1val

7 1, 4val CHDI ¹⁾ - 1, 24val TMHD ⁵⁾ CHMDI ²⁾ PSiD ⁷ '2000 PSiD ⁷⁾ 2000

0.19val 0.16val

8 0.38val CHDI ¹⁾ - 0.02vai BD ⁴⁾ - PESD ⁶⁾ 600 PESD ⁶ '600

5.4val 0.4val 0.5val

- - 4.5val TMHD ⁵⁾ DCHMDI ²⁾ PSD ^8> 2000 PSD ^8> 2000

0,22va

10 1, 20val CHDI ¹⁾ - - - 0.96val TMHD ⁵⁾ PSD ⁸⁾ 2000

¹⁾ CHDI = cyclohexane diisocyanate (1, 4)

²⁾ DCHMDI = 4,4'-dicyclohexylmethane diisocyanate

³⁾ PED = polyether diol ⁴⁾ BD = 1,4-butanediol

⁵⁾ TMHD = 2,2,4-trimethyl-1,6-hexanediol ⁶⁾ PESD = polyester diol ⁷⁾ PSiD = polysiloxane diol ⁸⁾ PSD = polysulfone diol

Preferred uses for the polyurethanes according to the invention are in the Claims 12 and 13 listed. In particular, polyurethane patches can be used for skin burns to provide a "second skin" for a short time, which saves the daily change of dressing. There are other areas of application for children who, for example, have to undergo cardiac surgery annually: The patch is placed under the skin here So that the surgeon only has to advance to the patch, the patch is removed so that the surgeon can operate directly on the heart without removing the connective tissue.Finally, patches can be used as surgical nets for heart, abdominal and chest wall defects.

Claims

claims

1. A process for the preparation of biocompatible polyurethanes with improved properties, in which at least one aliphatic and / or at least one cycloaliphatic diisocyanate is reacted with a macrodiol of the polyester, polyether, polysiloxane or polysulfone type with an average molecular weight of 500 to 6000 and the resultant is obtained Prepolymer further reacted with a chain extender which is a low molecular weight diol or a mixture of low molecular weight diols or a mixture of the low molecular weight diol with a macrodiol of the type polyester, polyether, polysiloxane or polysulfone with an average molecular weight of 500 to 6000, characterized in that the ratio of NCO end groups of the prepolymer to OH groups of the chain extender is 1.01: 1 to 1.05: 1 and that the polymer obtained, if appropriate after treatment with a reagent to deactivate the still present to which NCO groups are subjected to a molecular weight fractionation, in which the low molecular weight polyurethane fraction with a mass fraction of 10 to 55% by weight is separated and discarded and the remaining high molecular weight fraction is obtained as biocompatible polyurethane with improved properties.

2. The method according to claim 1, characterized in that 2 to 10 moles of diisocyanate are used per mole of macrodiol.

3. The method according to claim 1 and 2, characterized in that the ratio of NCO groups of the prepolymer to OH groups of the chain extender is 1.02: 1 to 1.04: 1.

4. The method according to claim 1 to 3, characterized in that one uses as polyester, polyether, polysiloxane or polysulfone one with an average molecular weight of M _w = 1000 to 2500.

5. The method of claim 1 to 4, characterized in that one as ^"chain extenders 2,2,4-trimethyl-1, 6-hexanediol are used.

6. The method according to claim 1 to 4, characterized in that a mixture of 2,2,4-trimethyl-1, 6-hexanediol and a macrodiol of the type polyester, polyether, polysiloxane or polysulfone with an average molecular weight of M _w as chain extender = 1000 to 2500 uses.

7. The method according to claim 1 to 4, characterized in that the chain extender used is a mixture of 1,4-butanediol and a macrodiol of the polyester, polyether, polysiloxane or polysulfone type with an average molecular weight of M _w = 1000 to 2500.

8. The method according to claim 1 to 4, characterized in that the chain extender is a mixture of 1, 4-butanediol, 2,2,4-trimethyl-1, 6-hexanediol and a macrodiol of the type polyester, polyether, polysiloxane or polysulfone an average molecular weight of M _w = 1000 to 2500.

9. The method according to claim 1 to 8, characterized in that 4,4'-dicyclohexylmethane diisocyanate or 1,4-cyclohexyldiisocyanate or a mixture of the two is used as the diisocyanate.

10. The method according to claim 1 to 9, characterized in that one uses for the molecular weight fractionation precipitation reactions or the continuous polymer fractionation.

11. Biocompatible polyurethanes which can be produced by reacting an aliphatic and / or cycloaliphatic diisocyanate with a polyester, polyether, polysiloxane or polysulfone with an average molecular weight from M _w = 500 to 6000 and subsequent reaction of the prepolymer thus obtained with a low molecular weight diol or a mixture of low molecular weight diols or a mixture of low molecular weight diols with a macrodiol of the type polyester, polyether, polysiloxane or polysulfone with an average molecular weight of M _w = 500 to 6000, the ratio of NCO groups of the prepolymer to OH groups of the chain extender being 1.01: 1 to 1.05: 1, and subsequent molecular weight fractionation of the polymer obtained to remove the low molecular weight polyurethane content with a mass fraction of 10 to 55 wt.%.

12. Use of the polyurethanes according to claim 11 for the manufacture of products for medical purposes, in particular for the manufacture of blood pumps, including VAD systems (cardiac support systems for adequate blood supply), annuloplasty rings, conduit valves, vein valves, tendon threads, heart valve balloons , Vascular prostheses, stents (vascular supports) including vascular stents or stent grafts (vascular prostheses with additional braiding), patches (tissue patches) including ductus botalli closure, mesh tissue for reconstructive measures including tissues for the reconstruction of blood vessels, testicular implants, Breast implants, miniscus replacement, urether prostheses including stents, vena cava filters.

13. Use of the polyurethanes according to claim 11 for the production of heart valves.