DE10242075B4 - Bone-adhesive polyurethane polymer, process for its preparation and its uses - Google Patents

Abstract

use at least one polyisocyanate component and at least one polyester polyol component with triglyceride structure for making a bone adhesive based on polyurethane.

Description

The The present invention relates to an improved bone-adhesive polyurethane polymer, Process for its preparation and its uses.

In In the 1950s, work on the anchoring of head prostheses began started in the femur with the help of bone cements (1). Since then predominantly Bone cements based on polymethyl methacrylate (PMMA) use. Today, bone cements are used especially in endoprosthesis implants, cavity fillings and composite osteosynthesis used (2). Frequent use of bone cements lies in the anchoring of hip prostheses.

Of the Use of conventional Bone cements, especially in composite osteosynthesis, but also in surgical treatments of bone fractures and mechanical unstable bones that are not yet or not yet alone can be treated with bone cements, subject to some limitations. The high brittleness the cements leads often to break the connection under load. Shrinkage of the cement during curing can limit his commitment as well as the training of necrotic Tissue in an exothermic polymerization reaction. PMMA cements do not have sufficient adhesive strength to their sole use without screws, pins, wires etc. to a sufficiently strong, in particular from the patient resilient, allow mechanical connection of bone fragments. Because PMMA cements not from the body can be resorbable, a compound consisting of PMMA cement or glued joint between two bone fragments not from regrowing Bones are replaced.

Except for PMMA cements In the prior art further attempts for the production of bone adhesives known with different chemical compositions. there Both polymers were natural Of origin such as chitosan or collagens, as well as synthetic polymers, e.g. based on epoxy or polyurethane. The use of calcium phosphates was studied to contain the hydroxyapatite Bones provide a building substance. However none of the new developments is an alternative to the PMMA cements (2).

From the publication US 5,266,608 A are biomedical adhesive compositions for calcified tissue known by reactions of aliphatic, alicyclic or aromatic diisocyanates or triisocyanates with Polyalkylenetherglykolen or polyester glycols having preferably 10 to 80 carbon atoms, preferably preferably from 25 to 55 carbon atoms, sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, octyl gallate, glycol monostearate, hexyl resorcinol, sorbitan monoesters of fatty acids, and especially polyoxyethylene (20) derivatives of sorbitan monoesters of fatty acids (TWEEN 20 ^™ , polyethoxysorbitan laurate). Only the glycol (mono) ester glycol monostearate with 20 carbon atoms is called. Furthermore, it is off US 5,266,608 an addition of glycerol monostearate to the biomedical adhesive composition is known. In part, calcium phosphate salts are also used to enhance bonding. From US 5,266,608 A However, known calcified tissue biomedical adhesive compositions have disadvantages that limit their use in the treatment of bone damage. They show in tensile tests with bonds of bone fragments only insufficient tensile strength, and their adhesive stability is sufficient only for bonding of bone, which are not exposed to shear forces, for example for bone

Skull. In addition, the reject US 5,266,608 A known adhesives only a slow biodegradability, which leads to a delay of Hei ment compared to mechanically, in particular with screws, supplied fractures.

WHERE 00/43050 A1 describes compositions of substrate / adhesive components, which is a biocompatible substrate with a covalent to the substrate include associated medical adhesive component, as well as with it related methods to attach substrates to native tissues or others To attach substrates.

WHERE 94/09048 A1 describes a new class cross-linked, glassy Polyurethanes or polyurethane networks for biomedical use, from low molecular weight polyols in the absence of a solvent getting produced.

In EP 0 988 851 A2 there is provided a transparent dental cement composition comprising at least one multifunctional oligomer or prepolymer as a binder, at least one finely divided filler, and at least one initiator system for the polymerization.

DE 4315173 A1 describes pure polyether and polyester urethanes based on aliphatic and / or cycloaliphatic diisocyanates, which are prepared without the addition of catalysts, and the use of these polyurethane plastics for biomedical applications.

In DE 19539653 A1 For example, there is provided a polyurethane reaction adhesive, a coupling agent layer based on the polyurethane reaction adhesive, and a method of making the adhesive layer that enables bonding of silicone and plastic.

US 5,266,608 A describes polymeric adhesive compositions for biomedical applications, in particular for the treatment of fractures and adhesions of calcified body tissues obtained from a network of the reaction of a polyisocyanate of the invention with a polyol of the invention.

Important requirements for bone cements are in particular (1, 2):
The cements should be chemically stable and biocompatible.

A carcinogenicity, mutagenicity or allergenicity educts, cements and decomposition products should be excluded be.

The viscosity and the curing time The cements should be variable, depending on the application.

The Cements should be in their ability surfaces of bone fragments, especially fractured surfaces, to wet and in the curing to make a firm connection with the bone, not by the Moisture of the bones impaired be in-situ in contact with body fluids, especially one Operating field, are located.

The Cements in the presence of body fluids, especially blood, lymph or tissue fluid, Harden.

The Cements should be treated under operating conditions within a few minutes, largely harden.

A exothermic polymerization reaction should be largely avoided.

Under Addition of X-ray contrast media or drugs should get the properties of the cements stay.

The mechanical stability and the elasticity Cements should be so coordinated, that firm Connection under load neither breaks nor permanent is subjected to mechanical deformation.

The physical properties of cements should also be under the influence of body fluids remain.

The Cements should be absorbable and replaceable with renewable bone be.

The Cements should be germ-free and sterilizable, easy to handle and cost-effective to manufacture be.

The Object of the present invention is achieved with the features of the independent claim 1 solved. Advantageous embodiments The invention comprises features of subclaims 2 and 3. Individual subtasks The present invention will be described with the features of the independent claims 4, 7, 22, 28 and 29 solved. Further advantageous embodiments The invention comprises features of subclaims 5, 6, 8-21 and 23-27.

According to the invention from the multitude of polyurethane polymers produced by polyaddition reactions of polyisocyanates with di- or higher functional nucleophiles and by the use of low molecular weight difunctional chain extender or higher functional Crosslinker in large Structural diversity are available, Polyurethane polymers provided with properties according to the invention, in the production process according to the invention are obtainable by reactions between educts according to the invention. The inventive, improved knochenadhäsiven Polyurethane polymers are characterized by reactions between at least one Polyesterpolyolkomponente invention and at least one polyisocyanate component of the invention available. In advantageous embodiments include the bone-adhesive polyurethane polymers of the invention additives according to the invention or inventive catalysts.

In In a first aspect, the present invention relates to the use at least one polyisocyanate component and at least one polyester polyol component with triglyceride structure for making a bone adhesive based on polyurethane, according to the claims. In In another aspect, the present invention relates to a bone adhesive polyurethane-based with at least one polyisocyanate component and at least one polyester polyol component having a triglyceride structure, which is obtainable by means of a method according to the claims.

One Bone-adhesive polyurethane polymer according to the invention comprises at least one polyester polyol component according to the invention with triglyceride structure and at least one polyisocyanate component according to the invention. In advantageous embodiments comprises a bone-adhesive polyurethane polymer according to the invention at least one inventive polymer Polysiocyanatkomponente. In further advantageous embodiments comprises a bone-adhesive polyurethane polymer according to the invention at least one additive according to the invention, in particular an additive according to the invention hexamethylene diisocyanate or phase-pure β-tricalcium phosphate. In still further advantageous embodiments, an inventive bone-adhesive polyurethane polymer comprises lymer at least one catalyst according to the invention, in particular a nitrogen-based catalyst.

The polyurethane polymers according to the invention are characterized in particular by a predetermined compromise between strength and elasticity. Too high a strength leads to brittle and thus fragile Plastics, too high elasticity, however, leads to too low Strength. The strength of the bone-adhesive polyurethane polymers according to the invention in particular by the polyisocyanate components according to the invention certainly. This applies in particular to the polymers according to the invention Polyisocyanate. The strength of the polyurethane polymers will also by the additives according to the invention, in particular of calcium salts, in particular hydroxyapatite or phase-pure β-tricalcium phosphate, influenced. The elasticity the bone-adhesive polyurethane polymers according to the invention is based in particular on aliphatic chains, which are used in the polyester polyol component according to the invention, on the other hand in the additive according to the invention of aliphatic hexamethylene diisocyanate are present.

The Polyesterpolyolkomponenten invention advantageously have a triglyceride structure with hydrolysable Ester bonds between a glycerol component of the polyester polyol component and one, two or preferably three with the glycerol component esterified fatty acid side chains. Favorable Wears way at least one fatty acid side chain a polyester polyol component according to the invention with triglyceride structure at least one hydroxyl group attached to a Can participate in addition reaction with a polyisocyanate component. Advantageously wearing the flexibility the hydroxyl-bearing fatty acid side chains of the polyester polyol components according to the invention to the elasticity the bone-adhesive polyurethane polymers according to the invention at.

The Polyesterpolyolkomponenten invention advantageously have ester groups that are more sensitive across from hydrolysis are as the ether moieties of the polyether polyols the known in the art bone cements based on polyurethane. In accordance with the invention the polyester polyol component is the bone adhesive polyurethane polymer Sensitivity to a hydrolysis and thus improved over the prior art biodegradability. The improved biodegradability promotes a quick cure in which the polyurethane polymer degrades and through the body's own Tissue can be replaced. Due to its sensitivity to hydrolysis and biodegradability provides the bone-adhesive polyurethane polymer of the present invention no barrier to coalescence of adjacent bone fragments but a biodegradable and by the body's own Tissue replaceable solid compound.

In the following - without any limitation as to the technical scope of the invention - the invention will be described by means of embodiments, wherein the 1 to 10 and Tables 1 to 15 are referred to.

Abbreviations

• CERASORB ^® :

  phase-pure β-tricalcium phosphate

  DABCO:

  Diazabicyclo [2.2.2] octane

  Desmophen ^® 2200B:

  polyester polyol component according to the invention of the embodiment 5

  Desmophen 2400S ^® :

  polyester polyol component according to the invention of the embodiment 4

  DMAP:

  4-dimethylaminopyridine

  Elastoflex ^®:

  polyester polyol component according to the invention of the embodiment 8th

  GPCS:

  Glycerol-1-phosphate Calcium salt, glycerol-2-phosphate calcium salt, glycerol-3-phosphate Calcium salt or a mixture of at least two of these salts

  HDI:

  hexamethylene diisocyanate

  Lupranat® M20W ^®:

  inventive polymers Polyisocyanate component of the embodiment 1

  Lupranat M10R:

  inventive polymers Polyisocyanate component of the embodiment 2

  Lupranat® M50 ^®:

  inventive polymers Polyisocyanate component of the embodiment 3

  Lupraphen 8004 ^® :

  polyester polyol component according to the invention of the embodiment 7

  Lupraphen VP9267 ^®:

  polyester polyol component according to the invention of the embodiment 6

  MDI:

  4,4'-methylene-bis- (phenylisocyanate)

  Merginat® LV8570 ^®:

  polyester polyol component according to the invention of the embodiment 3

  Merginat® PV200 ^®:

  polyester polyol component according to the invention of the embodiment 9

  Merginat® PV204 ^®:

  polyester polyol component according to the invention of the embodiment 10

  Merginat® PV206 ^®:

  polyester polyol component according to the invention of the embodiment 11

  Merginat® PV235 ^®:

  polyester polyol component according to the invention of the embodiment 2

  Merginat® PV300 ^®:

  polyester polyol component according to the invention of the embodiment 12

  Merginat® VP8364 ^®:

  polyester polyol component according to the invention of the embodiment 13

  PMMA:

  polymethylmethacrylate

  TDI:

  4,4-tolylene diisocyanate

  TWEEN 20 ^TM :

  Polyoxyethylene (20) derivative of sorbitan laurate

  voranat

  inventive polymers Polyisocyanate component of the embodiment 4

  XDI:

  1,3-bis (isocyanatomethyl) benzene

The Figures show:

1 a general structural formula of polyester polyol components according to the invention having a triglyceride ester structure;

2 a structural formula of the polyester polyol component 2 according to the invention;

3 the structural formula of 1,3- (bis (isocyanatomethyl)) benzene (XDI);

4 a general structural formula of the polymeric polyisocyanate components 1 and 2 according to the invention;

5 the structural formula of terephthalic acid;

6 the structural formula of bisphenol A;

7 the structural formula of 2-ethylhexanoic tin (II) salt;

8th the structural formula of 1,1,4,7,10,10-hexamethylenetriethylenetetramine;

9 the structural formula of diazabicyclo [2.2.2] octane (DABCO);

10 the structural formula of 4-dimethylaminopyridine (DMAP).

in the following will be first components according to the invention, additions and catalysts of bone-adhesive polyurethane polymers of the invention described.

One first embodiment a polyester polyol component according to the invention for the Preparation of a bone-adhesive polyurethane polymer according to the invention is castor oil, its dominant fatty acid, the ricinoleic acid (~ 85%), in addition to a double bond carries a hydroxyl group, the to an addition reaction with an isocyanate group of a polyisocyanate component of the invention can participate. castor oil due to its triglyceride structure advantageously has good Wetting properties, and is because of its ester bonds sensitive to Hydrolysespaltungen and therefore easily biodegradable. When natural vegetable oil it is biologically well tolerated.

Table 1 (3, 4, 5, 6, 7, 8, 9, 10)

In Table 1 are further embodiments 2 to 7 of polyester polyol components according to the invention a bone-adhesive polyurethane polymer according to the invention shown. The embodiments 2 to 7 of the polyester polyol components according to the invention are in the present application also with their aforementioned Abbreviations designated.

The hydroxyl number in Table 1 describes the proportion of free OH groups in the Polyesterpolyolkom component. It is calculated according to Uhlig, p. 106 (15) as follows: OH number = 56000 / equivalent weight (polyol); % [OH] = OH number / 33.

The Polyesterpolyolkomponenten invention 2 and 3 in Table 1 are derived from vegetable oils and have a triglyceride ester structure with at least one aliphatic Side chain carrying at least one hydroxyl group. by virtue of the triglyceride structure they advantageously have good wetting properties. As derivatives of vegetable oils they have a good biocompatibility.

The ratio OH _primary : OH _secondarily in Table 1 serves for the closer characterization of polyester polyol components according to the invention having a triglyceride structure based on vegetable oil, in particular of working examples 2 and 3.

A general example of advantageous polyester polyol components of the invention having a triglyceride ester structure is disclosed in U.S. Pat 1 shown. The inventive polyester polyol component or similar polyester polyol components according to the invention, in particular the above-mentioned embodiments 2 and 3, are known in principle as chemical compounds in the prior art and are obtainable, for example, by a known process (3) in which, in a first step, oxygen is bonded to double bonds in fatty acids of an unsaturated vegetable oil to obtain an epoxidized oil. In a second step, the oxygen ring of the oil deepexdierten by hydrogen-active compounds, such as water, various alcohols or acids, opened. In each case, an OH group is formed with the introduced radical in neighboring position. If suitable alcohols are used, further OH groups can be introduced.

The polyester polyol component 2 according to the invention in Table 1 has the in 2 shown branched structure. It is based on soybean oil, epoxidized and esterified with ethylene glycol. It has the other properties mentioned in Table 1. Their chemical structure is additionally determined by means of the indicated key figures CAS no. and EINECS no. identifiable. It is under the name Merginat® PV235 ^® from Hobum fat chemistry and by the company Harburg fat chemistry Brinckman & Mergell GmbH, 21079 Hamburg, under product number 8106 and the product description "branched oleochemical polyol" available.

The polyester polyol component 3 according to the invention in Table 1 is produced on the basis of soybean oil, epoxidized and esterified with fatty acids from vegetable oils. She owns one. branched structure and the other properties mentioned in Table 1. Their chemical structure is additionally determined by means of the specified code CAS no. identifiable. It is under the name Merginat® LV8570 ^® from Hobum fat chemistry and by the company Harburg fat chemistry Brinckman & Mergell GmbH, 21079 Hamburg, under the product number LV 8570 and with the product description "branched oleochemical polyol" available.

at advantageous embodiments the bone-adhesive polyurethane polymer according to the invention own the polyester polyol components according to the invention a triglyceride structure, that of the polyester polyol component as such and also the whole freshly mixed, but not yet cured polyurethane polymer a good invention Wetting property confers and the formation of a solid according to the invention Connection between the polyurethane polymer and the bone tissue, Dental tissue, prosthetic metal or denture plastic promotes. The aliphatic branches the triglyceride structure have flexibility and contribute to the elasticity of the cured polyurethane polymer according to the invention at.

The polyester polyol component 4 according to the invention in Table 1 is a polyester based on adipic acid, phthalic acid, propylene glycol and trimethylolpropane having the properties mentioned in Table 1. Under the name Desmophen 2400 S ^® by Goldschmidt It is AG / Degussa, 45116 Essen, and available from Rhein Chemie.

The polyesterpolyol component 5 according to the invention in Table 1 is a partially branched polyester based on adipic acid, diethylene glycol and trimethylolpropane having the properties mentioned in Table 1. It is available from Goldschmidt AG / Degussa, 45116 Essen, and from Rhein Chemie under the name Desmophen 2200 B ^®.

The polyesterpolyol component 6 according to the invention in Table 1 is a higher functional, aromatic polyesterpolyol having the properties mentioned in Table 1. Their para. Specified in Table 1 meters can be determined in particular by means of the following test methods, which are incorporated by reference in the present patent application: hydroxyl number - DIN 53 240, viscosity at 75 ° C - DIN 53 015, water content - DIN 51 777, acid number - DIN 53 402, iodine color number - DIN 6162. the polyester polyol component 6 according to the invention is known as Lupraphen VP 9267 ^® by the company Elastogran GmbH BASF group and under the same name under the order no. 00235013 available from BASF Schwarzheide GmbH.

The polyester polyol component 7 according to the invention in Table 1 is a branched polyester polyol based on aromatic dicarboxylic acids and aliphatic alcohols having the properties given in Table 1. Their parameters given in Table 1 can be determined in particular by means of the following test methods, which are incorporated by reference in the present patent application: hydroxyl number - DIN 53 240, viscosity at 75 ° C - DIN 53 015, water content - DIN 51 777, acid number - DIN 53 402, iodine color number - DIN 6162, alkali content - titrimetric. The polyester polyol component according to the invention 7 is under the name Lupraphen 8004 ^® by the company Elastogran GmbH BASF Group and under the same name under the order no. 00235013 available from BASF Schwarzheide GmbH.

Another embodiment 8 a polyester polyol component according to the invention is available under the name Elastoflex® ^® by BASF AG.

Further embodiments 9 to 12 of the present invention polyester polyol with triglyceride vegetable oil based are under the trade names Merginat® PV 200 ^®, Merginat® PV 204 ^®, Merginat® PV 206 ^® or Merginat® PV 300 ^® by the company Harburg Fettchemie Brinckman & Mergell GmbH.

Another embodiment 13 of a polyester polyol component according to the invention having a branched structure that is synthesized based on fatty acids, under the trade name Merginat® VP 8364 ^® by the company Harburg fat chemistry Brinckmann & Mergell GmbH is available.

Further Properties of the polyester polyol components according to the invention the embodiments 10, 11 and 13 are shown in Table 1.

Further embodiments of polyester polyol components according to the invention are polyester polyols based on poly (diethylene glycol-glycerol-adipic acid), the the person skilled in the art readily finds to become a bone-adhesive polyurethane polymer according to the invention to get.

The bone-adhesive polyurethane polymers of the invention include in addition to the at least one polyester polyol component according to the invention at least one polyisocyanate component.

First exemplary embodiments of the bone-adhesive polyurethane polymers according to the invention comprise at least one diisocyanate component or triisocyanate component which is selected according to the invention from any diisocyanate component or triisocyanate component known in the art, in particular from 4,4'-methylene-bis (phenyl isocyanate) (MDI) , 2,4-toluene diisocyanate (TDI), 1,6-diisocyanatohexane (hexamethylene diisocyanate, HDI), 4,4'-methylene (cyclohexyl isocyanate), 1,3-bis (1-isocyanato-1-methylethyl) benzene or 1, 3- (bis (isocyanatomethyl)) benzene (XDI, 3 ).

The abovementioned polyisocyanate components have the following further characteristics:
2,4-tolylene diisocyanate (TDI) - NCO content 48.2%, density 1.23 g / ml;
1,6-diisocyanatohexane (hexamethylene diisocyanate, HDI) - NCO content 49.9%, density 1.04 g / ml;
4,4'-methylene (cyclohexyl isocyanate) - NCO content 32.0%, density 1.07 g / ml;
1,3-bis- (1-isocyanato-1-methylethyl) benzene - NCO content 34.4%, density 1.06 g / ml;
1,3- (bis (isocyanatomethyl)) benzene (XDI, 3 ) - NCO content 44.6%, density 1.20 g / ml;
4,4'-methylene-bis (phenyl isocyanate) (MDI) - NCO content 33.6%.

advantageous embodiments of the bone-adhesive polyurethane polymers of the invention at least one inventive (prepolymerized) polymeric polyisocyanate component having a predetermined degree of polymerization having. Further advantageous embodiments of the bone-adhesive polyurethane polymers according to the invention comprise at least one polymeric polyisocyanate component according to the invention and additionally at least one monomeric diisocyanate or triisocyanate as the polyisocyanate component or supplement.

Table 2 (11.1, 11.2, 12, 13, 14)

Table 2 shows exemplary embodiments 1 to 4 of polymeric polyisocyanate components according to the invention for a bone-adhesive polyurethane polymer according to the invention. The embodiments 1 to 4 of the polymeric polyisocyanate components according to the invention are also referred to in the present application with their abovementioned abbreviations. The polymeric polyisocyanate components 1 to 4 according to the invention are prepolymerized polymeric polyisocyanates based on 4,4'-methylene-bis- (phenyl isocyanate) (MDI) with an in 4 shown general structure.

The in Table 2 isocyanate NCO content is the proportion free isocyanate groups in the polyisocyanate. It is calculated according to Uhlig, p. 106 (15) as follows:% [NCO] = 4200 / equivalent weight (Isocyanate).

The polymeric polyisocyanate component 1 according to the invention in Table 2 preferably has an average functionality and a high reactivity. It has the further properties mentioned in Table 2, in particular the average number of 4,4'-methylene-bis (phenyl isocyanate) (MDI) units given in the line "4,4 'MDI isomers". Under the name Lupranat® M 20 W ^® it is as a product 52,519,646 by BASF Antwerpen NV, B-2040 Antwerp 4, under the order number and the identification 00244129/01 UUH936 DNH816 available.

The polymeric polyisocyanate component 2 according to the invention in Table 2 preferably has a low functionality and a comparatively higher reactivity. It has the other properties mentioned in Table 2. In addition, the polymeric polyisocyanate component 2 according to the invention reacts with water at the interface slowly with release of CO ₂ to insoluble, high-melting polyurea. Their chemical structure is additionally determined by means of the specified code CAS no. identifiable. Under the name Lupranat® M 10 R ^® It is available from BASF Antwerpen NV, B-2040 Antwerp 4, as a product 08,051,415th

The polymeric polyisocyanate component 3 in Table 2 according to the invention preferably has a high functionality and a high reactivity. It has the other properties mentioned in Table 2. In addition, the polymeric polyisocyanate component 3 of the present invention reacts slowly with water at the interface to release insoluble, high melting polyurea to release CO ₂ . Their chemical structure is additionally determined by means of the specified code CAS no. identifiable. Under the name M Lupranat® she's 50 ^® as a product 08,050,971 by BASF Antwerpen NV, B-2040 Antwerp 4, available.

The inventive polymer Polyisocyanate components 1 to 3 in Table 2 are characterized with respect to their functionality and reactivity through a wide range of properties and allow Advantageously, the production of a plurality of bone-adhesive polyurethane polymers according to the invention with selected ones Properties.

The inventive polymers Polyisocyanate component 4 in Table 2 has in particular the in Table 2 mentioned properties. It is under the name Voranat available from Brenntag.

Further embodiments of polymeric according to the invention Polyisocyanate components are prepolymerized polymeric polyisocyanates based on at least one monomeric diisocyanate or triisocyanate, the invention of a any, in particular one known in the art, monomeric Diisocyanate or triisocyanate is selected, in particular prepolymerized polymeric polyisocyanates based on 4,4'-methylene-bis (phenyl isocyanate) (MDI), 2,4-tolylene diisocyanate (TDI), 1,6-diisocyanatohexane (hexamethylene diisocyanate, HDI), 4,4'-methylene (cyclohexyl isocyanate), 1,3-bis (1-isocyanato-1-methylethyl) benzene or 1,3- (bis (isocyanatomethyl)) benzene (XDI).

Inventive polymers Polyisocyanate components can by a person skilled in the art by means of prepolymerization, in particular by known methods from known educts, getting produced.

The inventive polymer Polyisocyanate components advantageously have a lower one Vapor pressure and lower toxicity than the non-prepolymerized Diiso- or triisocyanates of the known polyurethane-based bone cements. The polymers of the invention Polyisocyanate components therefore contribute to a lower toxicity and a better biocompatibility the bone-adhesive polyurethane polymers according to the invention in comparison with known polyurethane-based bone cements.

In further advantageous embodiments of the polymeric polyisocyanate components according to the invention, isocyanate groups are present separated from the aromatic by at least one aliphatic grouping. In particular, these are polymeric polyisocyanate components based on 1,3-bis (isocyanatomethyl) benzene (XDI) ( 3 ) and terephthalic acid ( 5 ) or bisphenol A ( 6 ). With bone-adhesive polyurethane polymers according to the invention, degradation to toxic aromatic diamines is thereby advantageously impossible.

Yet further advantageous embodiments of bone-adhesive polyurethane polymers according to the invention contain at least one prepolymerized polymer according to the invention Polyisocyanate component based on at least one isocyanate component 1,3-bis (1-isocyanato-1-methylethyl) benzene or 1,3-bis (isocyanatomethyl) benzene and at least one component terephthalic acid or bisphenol A, which is the Expert by means of, in particular in the prior art, known method manufactures.

Yet further advantageous embodiments of bone-adhesive polyurethane polymers according to the invention comprise at least one mixture according to the invention of at least terephthalic acid ( 5 ) and XDI ( 3 ) or of corresponding compounds which according to the invention make it possible to avoid the formation of aromatic diamines.

According to the invention, the degree of crosslinking of the polyurethane polymers is influenced in particular by the selection of polymeric polyisocyanate components according to the invention. The degree of vernet in turn affects the strength of the polyurethane polymers of the invention. The strength of the polyurethane polymers according to the invention can therefore be predetermined in particular by the selection of the polymeric polyisocyanate components.

The bone-adhesive polyurethane polymers of the invention can at least one addition of monomeric aliphatic diisocyanate or triisocyanate. The elasticity of the aliphatic contributes Chains to the elasticity the polyurethane polymer according to the invention at. The elasticity of the polyurethane polymer according to the invention by selecting the type and the amount of an added aliphatic diisocyanate or Triisocyanate influenced. In advantageous embodiments the polyurethane polymer according to the invention a predetermined amount of hexamethylene diisocyanate (HDI) is added.

The Strength of the polyurethane polymer of the invention especially by additives other additives, in particular aliphatic diamines, aliphatic diols or amino acids affected especially increased, become. Examples of additives according to the invention of aliphatic diols are in particular additives of 1,3-butanediol, 1,4-butanediol, 1,6-hexanediol or 1,8-octanediol. Examples of additives of the invention Aliphatic diamines are in particular additions of 1,6-diaminohexane or 1,8-diaminooctane. Examples of further additives according to the invention are additives of especially glycolic acid or polyethyleneimine.

Further beneficial additives enable Interactions of the polyurethane polymer according to the invention with the bone and its surrounding tissue and thus increase the compatibility and the absorbability of the polyurethane polymer and support that Bone growth and healing. Examples of additives that interact with the bone or its surrounding tissue additions proteins, in particular casein or gelatine, protein degradation products, in particular casein degradation products or collagen degradation products or peptides derived therefrom, any amino acid, in particular leucine, serine, Lysine, glycine, alanine, asparagine and aspartic acid, of carbohydrates, in particular of polysaccharides, in particular of dextran, starch degradation products, Glucose or glycerin.

Additions from Increase calcium phosphate salts According to the invention, the strength the polyurethane polymer according to the invention and influence interactions according to the invention the polyurethane polymer according to the invention with bone or Tooth tissue in more favorable Wise. The bone-adhesive polyurethane polymer according to the invention can additives of glycerol-1-phosphate calcium salt, glycerol-2-phosphate calcium salt, Glycerol-3-phosphate calcium salt or a mixture thereof, tricalcium phosphate, in particular phase-pure β-tricalcium phosphate, Hydroxyapatite, at least one calcium salt of a phosphoglyceric acid, at least a calcium salt of glucose-1-phosphate or glucose-6-phosphate or contain at least one other calcium salt or salt of a phosphoric acid.

at advantageous embodiments of the invention the polyurethane polymer contains an addition of glycerol-1-phosphate calcium salt, Glycerol-2-phosphate calcium salt, glycerol-3-phosphate calcium salt or a mixture thereof, in particular glycerol-1-phosphate calcium salt. In further advantageous embodiments of the invention the polyurethane polymer is an addition of tricalcium phosphate, in particular of phase pure β-tricalcium phosphate. An addition of any of the foregoing salts, in particular glycerol-1-phosphate calcium salt or of phase-pure β-tricalcium phosphate to the polyurethane polymer according to the invention leads to an increase the tensile strength of adhesive bonds between bone fragments.

According to the invention introduces Addition of a granulate of phase-pure β-tricalcium phosphate with a granule size of approx. at least 150 μm up to a granule size of several 100 μm, in particular of about 500 μm, to a stronger one increase the tensile strength of the bone adhesive Polyurethane polymer as an additive of phase pure β-tricalcium phosphate with a granule size of at most 150 μm. apparently affect the structural properties of the added β-tricalcium phosphate granules the mechanical strength of the polyurethane polymer according to the invention.

Of the Addition according to the invention β-tricalcium phosphate granules also facilitates advantageously the ingrowth of new bone tissue into Pores of the polyurethane polymer of the invention in the healing and coalescence of bone fragments or Bone fragments and prostheses with the bone-adhesive polyurethane polymer according to the invention be firmly connected with each other.

According to the invention is in the selection of an additive to the invention bone adhäsi The polyurethane polymer, in particular, takes into account the functionality of the additive. Possible additives have in particular the following functionalities: GPCS, glycerol phosphate calcium (II) salt: 2; 1,3-butanediol: 2; 1,4-butanediol: 2; 1,6-hexanediol: 2; 1,8-octanediol: 2; Terephthalic acid: 2; Bisphenol A: 2; 1,6-diaminohexane: 2; 1,8-diaminooctane: 2; Glycolic acid: 2; Leucine: 2; Serine: 3; Lysine: 3; Glycine: 2; Alanine: 2; Asparagine: 3; Aspartic acid: 3; Glycerol: 3; Starch degradation products (eg "AgenaMalt 20223 ^®" or "AgenaMalt 20226 ^®" by the company Agrana GmbH): high; Starch, water-soluble or water-insoluble (Sigma): high; Gelatin: high; 2,4-diaminotoluene: 2; Polyethyleneimine: highly functional; Glucose: 5; Dextran: high.

Advantageous embodiments of the bone-adhesive polyurethane polymer according to the invention comprise at least one addition of a catalyst for accelerating the setting and solidification, in particular 2-ethylhexanoic acid stannous salt (US Pat. 7 ). A suitable catalyst according to the invention is, in particular, a catalyst known in the art for polyurethane polymers, in particular sodium trichlorophenate, sodium tetrachlorophenate, sodium pentachlorophenate, iron (II) ethylhexanoate, iron acetylacetonate, dibutyltin di-2-ethylhexanoate, tin II-ethylhexanoate, cobalt-II-ethylhexanoate. The person skilled in the art advantageously selects a catalyst which allows a predetermined setting and solidification time of the bone-adhesive polyurethane polymer according to the invention.

In advantageous embodiments of the invention, the bone-adhesive polyurethane polymers according to the invention comprise at least one nitrogen-containing catalyst according to the invention. A nitrogen-containing catalyst for the bone-adhesive polyurethane polymer according to the invention is, in particular, 1,1,4,7,10,10-hexamethylenetriethylenetetramine (US Pat. 8th ), Diazabicyclo [2.2.2] octane (DABCO, 9 ) or 4-dimethylaminopyridine (DMAP, 10 ). DABCO and DMAP are used according to the invention in particular as a 33% solution in ethylene glycol.

in the The following is the bone-adhesive polyurethane polymer according to the invention based on embodiments However, the present invention in no way described limited in their technical scope.

at the development of the bone-adhesive polyurethane polymer according to the invention tensile tests were initially carried out to determine the adhesive strength Bonding of wooden discs and subsequently with gluing to the Corticalis performed.

at The experiments with wooden discs were round wooden discs with a Diameter of 20 mm and a height of 10 mm used. The Wood discs were watered overnight before bonding to the moist body milieu to simulate. After bonding, the wooden discs were at 37 ° C in an aqueous medium stored and visually after a period of 14 to 22 hours examined.

The tensile strength F [N / mm ² ] was determined by means of a ZWICK tractor model TIRA-Test 28100. The exact diameter of the parts to be joined was determined to be 0.1 mm with a caliper gauge. The glued samples were removed from the buffer liquid and clamped in the tractor without torque. The load cell used was a 3 kN or 20 kN load cell. The test speed was 2 mm / min. The test end criterion was a force drop of 50 or 80%. The maximum of the absolute tensile force in Newton was taken from the test report and converted into the bond strength in N / mm ² .

at The studies on the tensile strength of the corticalis were fresh Used beef bones sourced from a butcher. It was bone from the front or hind leg. The bones were sawed in about 9 mm wide slices. With the help of a trephine drill were cylindrical bone pieces drilled with 10 mm diameter from the corticalis. For one Tensile strength test were two cylindrical bone pieces on their circular End faces with the bone-adhesive polyurethane polymer according to the invention glued together. Samples were phosphate buffered at 37 ° C for 14 to 72 hours Sodium chloride solution (pH 7.4, 0.137 mol / l NaCl). Subsequently, the tensile strength F the adhesive connection determined.

In the same tensile tests and the tensile strengths of the publication US 5,266,608 A determined, biomimetic adhesive compositions for calcified tissue. With the mentioned polyurethane adhesives based on the polyol TWEEN 20 and diisocyanate, it was only possible to determine adhesive stabilities (tensile strengths) of up to 0.62 N / mm ² in the in-vitro test.

Table 3, reproduced in the Annex, shows the results of the tests on glued wood panels. In the studies shown in Table 3 mixtures were verschie denerer Polyesterpolyolkomponenten, inventive polymeric polyisocyanate components and various additives produced and used for bonding wood discs. The catalyst used was 2-ethylhexanoic acid tin (II) salt. Also shown in Table 3 are the results of some prior art TWEEN 20 bonded polyurethane bone custody bonding tests.

In Table 3 shows the macroscopic properties of the investigated Polyurethane polymers specified, in particular the stirring and Aufstreichfähigkeit the polymer mixture before curing, the viscosity and any strong bleeding of the liquid mixtures during application on the surfaces to be bonded, the hardness and consistency of the cured Polymers, especially if it is an elastic, highly foamed foam polymer traded or a less elastic non-foamed plastic, the degree of swelling during hardening in a moist environment, brittleness and adhesion the surfaces to be bonded.

The Investigations shown in Table 3 prove that an additive of higher functionality Additives with chain-extending / -linking Features often too brittle, easily breakable plastics, while in the absence of additives often very soft, elastic plastics were obtained. Bone-adhesive polyurethane polymers according to the invention with beneficial properties were usually more likely to be bifunctional Preserved additives. An addition of highly functional polysaccharides led in a few cases to promising results.

at The investigations on wooden discs was based on possible effects of storage and curing the polyurethane polymers in the aqueous Milieu respected. It was observed that the moisture of the Wood discs do not negatively affect their wetting surfaces with the still liquid Reaction blends of the polyurethane polymers led and also the strength the bonds were not affected.

As expected due to the known reaction of isocyanates with water, which is known to lead to elimination of CO ₂ and foaming of the polymer, the samples swelled on storage and curing in aqueous solution. However, some porosity of the polyurethane polymers is desired to provide freedom of movement for the bone-forming cells and to facilitate ingrowth of the newly formed tissue into the adhesive bond during bone formation during healing. Too much swelling led either to very brittle, highly porous materials or to very flexible flexible foams. In the bone-adhesive polyurethane polymer of the present invention, the swelling of the glue line is minimized to a predetermined desired level, which particularly facilitates the healing process.

Table 4, reproduced in the Annex, gives the results of gluing with wooden discs, in which all the specimens shown in Table 3, which had promising optical and mechanical properties, were subjected to a tensile test. Also shown in Table 4 are the results of some prior art TWEEN 20 bonded cementitious polyurethane bone cements. With bone-adhesive polyurethane polymers according to the invention, tensile strengths of up to 1.82 N / mm ^{2 were} measured.

In of the column "starting materials" in Table 4 the individual components and additives of the examined polyurethane polymers specified. In the column "Ratio" are the relative Proportions of the individual components and additives in the reaction mixture specified. The column "Remarks" indicates which type of breaks when crossing the maximum tensile strength F with a bond of two wooden discs with occurred in each case examined polyurethane polymer. It will be so-called cohesive fractures, i. Breaks within of the adhesive joint in the polyurethane polymer, adhesion fractures, i. fractures the connection between a surface of a wooden disc and the adjacent polyurethane polymer in the glue line and breaks within a wooden disc, i. fractures outside the glue joint and not at the interface between wooden disc and Adhesive joint, differentiated.

In the investigation of gluing of wood slices, the fundamental trend was the observation that the character of the additives with chain-extending / crosslinking properties had a fundamental influence on the resulting adhesives. While in the absence of additives often very soft, elastic plastics were obtained, an addition of tri- or higher functional additives often led to very brittle, easy to break plastics. Excessive crosslinking of the resulting polyurethanes therefore appears to be generally disadvantageous. Particularly advantageous polyurethanes were obtained with difunctional additives. A few polyurethanes with advantageous properties were obtained with additions of highly functional polysaccharides. With regard to the degree of crosslinking of the bone-adhesive polyurethane polymers according to the invention, the investigations indicate that the polymeric polyisocyanate components according to the invention of Examples 1 to 3 in Table 2 lead to advantageous polymers, whereas a higher degree of crosslinking generally leads to brittle polymers.

Table 5

Table 5 shows the results of tensile tests with bonding of bone fragments (adhesions to the "corticalis") with particularly advantageous bone-adhesive polyurethane polymers according to the invention. The embodiments 1 to 6 of the bone-adhesive polyurethane polymers according to the invention are given as formulations for reaction mixtures. The polyesterpolyol component 2 according to the invention from Table 1, the polymeric polyisocyanate components 1 or 2 according to the invention from Table 2 and the additives of the linear aliphatic isocyanate hexamethylene diisocyanate, of glycerol 1-phosphate calcium salt and of phase-pure β-tricalcium phosphate according to the invention are with their given at the beginning of the abbreviations listed. The embodiments 1 to 6 of the bone-adhesive polyurethane polymers according to the invention contain as catalyst an addition of 2-ethylhexanoic acid tin (II) salt in a mass ratio of polyester polyol component: catalyst = 150: 1.

The in the Table 5 advantageous embodiments of bone-adhesive polyurethane polymers according to the invention are characterized by high tensile strength F. Here were high tensile strengths with the polyester polyol component according to the invention 2 with both the inventive polymer Polyisocyanate component 1 (embodiments 1, 3, 4 and 6) as well as with the polymeric polyisocyanate component according to the invention 2 (embodiments 2 and 5) and with both an addition of glycerol-1-phosphate calcium salt as well as with the addition of phase-pure β-tricalcium phosphate with a granule size of more than 150 μm up to several 100 μm, in particular in about 500 μm, achieved. The embodiments 1 to 6 of the bone-adhesive polyurethane polymer according to the invention generally have higher Tensile strengths on as embodiments, in which an addition of leucine, glycerol-1-phosphate calcium salt or phase-pure β-tricalcium phosphate is missing.

at the tensile tests shown in Table 5 with the bone-adhesive polyurethane polymers according to the invention the embodiments 1 to 6 were always adhesion breaks between the corticalis and the polyurethane polymer are observed in the glue line. This indicates a limit of adhesive interactions between the corticalis and the polyurethane polymers of the invention embodiments 1 to 6 out.

Table 6

In Table 6 shows the results of tensile tests at which adhesions of Corticalisknochen with bone-adhesive polyurethane polymers according to the invention with additives of phase pure β-tricalcium phosphate examined with different granule sizes were.

The 3rd column from the left shows the tensile strengths of the polyurethane polymers with β-tricalcium phosphate with a granule size of approximately 150-500 μm. In the 4th column from the left, the tensile strengths of the corresponding embodiments with β-tricalcium phosphate are indicated with a granule size of less than 150 microns. The tensile strength of the bonds with the polyurethane polymers with β-tricalcium phosphate with a granule size of 150-500 microns was always greater than the tensile strength of the bonds with the in üb identical identical polyurethane polymer with an addition of β-tricalcium phosphate with a granule size of less than 150 microns. The column on the right-hand side of Table 6 indicates the percentage of tensile force achieved in a polyurethane polymer of the invention when β-tricalcium phosphate having a granule size of less than 150 μm is substituted for β-tricalcium phosphate having a granule size of approximately 150 μm. 500 microns was used. Depending on the composition of the polyurethane polymer of the present invention, the tensile force decreased to 28-81% of the tensile force achieved with the β-tricalcium phosphate having a granule size of about 150-500 μm.

In Table 7, attached hereto, are the compositions of exemplary embodiments 1 to 66 of the bone-adhesive polyurethane polymers according to the invention with their respective adhesive strength "tensile force F", which in tensile tests at Bone cysts ("corticalis") was determined. The embodiments 4, 6, 8, 18 and 28 in Table 7 correspond to the embodiments 1 to 5 in Table 5.

at the bone-adhesive polyurethane polymers according to the invention can advantageously the OH numbers of the polyol components according to the invention and additives and the NCO contents of the polyisocyanate components according to the invention and additives for a Finding a stoichiometric to be used according to the invention ratio Polyol / polyisocyanate are used.

In particular, in the exemplary embodiments 1 to 52 in Table 7 with at least one prepolymerized polymeric polyisocyanate component according to the invention, a stoichiometric ratio of the OH content to the% [NCO] content according to the invention can advantageously be calculated as follows:
The% [NCO] content is given by the formula: % [NCO] = volume of polymeric polyisocyanate component 1 according to the invention (according to Table 2) × 31.2 × 1.23 + volume of polymeric polyisocyanate component 2 according to the invention (according to Table 2) × 31.4 × 1.23 + volume HDI × 49, 9 × 1.04.

The OH content is given by the formula: Content OH = volume of the polyester polyol component 2 according to the invention (according to Table 1) × 160 × 0.98.

at advantageous embodiments the bone-adhesive polyurethane polymers according to the invention is the stoichiometric to be used relationship OH content /% [NCO] content between 3.5 and 7, in particular between 4,5 and 5,8.

Examples 16 to 25 and 27 to 30 in Table 7 have, for example, stoichiometric ratios OH content /% [NCO] content between 4.5 and 5.8. For example, the embodiment 26 in Table 7 has a stoichiometric OH content /% [NCO] content of 3.7 to be used. The polyurethane polymer of Embodiment 26 of the present invention has a very high tensile strength F of 1.49 N / mm ² .

The embodiments in Table 7 selected by the skilled person directly on the basis of their specified properties and accomplished become. The person skilled in the art also takes from Table 7, for example, that in the case of the bone-adhesive polyurethane polymers according to the invention the embodiments 2 and 3 show an exchange of the glycerol phosphate calcium salt by the same amount in grams of the amino acid leucine with an otherwise identical Composition only a small effect on the high tensile strength F has these polyurethane polymers. The variety of in Table 7 illustrated embodiments allows the expert, on the basis of considerations, the implications of Table 7 attached variations of components and additives, others, not here specified with their exact formulation, inventive bone adhesive polyurethane polymers Find with comparable properties without significant effort.

Table 8

For example, in Table 8, Embodiments 6, 2 and 5 are summarized in Table 7, which is a system of bone-adhesive polyurethane polymers of the present invention based on the polyester polyol component 2 of Table 1 of the invention, the polymeric polyisocyanate component 1 of Table 2 of the present invention Polyisocyanate component HDI and lysine can be selected. For example, the person skilled in the art will understand from the system in Table 8 that increasing the amount of the polymeric polyisocyanate component from 0.50 ml in Embodiment 5 to 0.60 ml in Example 2 increases the tensile force F from 0.81 N / mm ² to 1 , 54 N / mm ² leads. In contrast, only a slight increase in the polymeric polyisocyanate component of 0.50 ml in Example 5 to 0.55 ml in Example 6 with simultaneous increase in the polyisocyanate component HDI of 0.15 ml and the leucine of 0.30 g in Example 5 to 0, 22 ml HDI or 0.33 g leucine in Example 6 to a doubling of the tensile force F.

Table 9

In Table 9 are the embodiments 8 and 3 are summarized in Table 7. This corresponds to a system "Polyesterpolyolkomponente invention 2 in Table 1 / inventive polymers Polyisocyanate component 1 in Table 2 / additive polyisocyanate component HDI / additive glycerol-1-phosphate Calcium salt. "Here leads one increase the added amount of the polyisocyanate component HDI to another increase the strong tensile force F.

Table 10

In Table 10 are the embodiments 4, 9, 1 and 7 from Table 7. This matches with a selected one System "Polyesterpolyolkomponente invention 2 in Table 1 / inventive polymers Polyisocyanate component 2 in Table 2 / additive polysiocyanate component HDI / additive glycerol-1-phosphate calcium salt "of bone-adhesive polyurethane polymers according to the invention.

For example, those skilled in the art will appreciate that increasing the amount of the polymeric polyisocyanate component from 0.50 ml in Example 9 to 0.60 ml in Example 4 with an otherwise identical composition of the polyurethane polymer of the present invention increases the tensile force F by 1.25 N / mm ^{2 leads} to 1.62 N / mm ² .

The increase in the amount of the polyisocyanate component HDI of 0.15 ml in Embodiment 7 to 0.20 ml in Embodiment 4 results in the otherwise identical composition of the polyurethane polymer according to the invention to an increase in the tensile force F of 0.91 N / mm ² 1.62 N / mm ² .

The increase of the amount of the polymeric polyisocyanate component from 0.60 ml in Embodiment 7 to 0.70 ml in Embodiment 1 merely results in an increase of the tensile force F from 0.91 N / mm ² to 0.95 N / mm ² . However, Embodiments 1 and 7 contain only 0.15 ml of the polyisocyanate component HDI, whereas Embodiments 4 and 9 each contain 0.20 ml of HDI.

this cohere in particular, the expert takes the hint that in the in Table 10 combined system the low amount of the polyisocyanate component HDI in the embodiments 1 and 7 a pronounced limiting influence on the traction force F exerts.

The in the reproduced in the Annex Table 11 embodiments with the exception of the embodiment 24 correspond to the embodiments in Table 7. The embodiment 24 in Table 11 corresponds to the embodiment 6 in the table 5th

The in the table 11 assembled embodiments correspond a selected system "Polyesterpolyolkomponente invention 2 in Table 1 / inventive polymers Polyisocyanate component 1 in Table 2 / additive polyisocyanate component HDI / Supplement Leucine / Supplement Phase-pure β-tricalcium phosphate according to the invention with a granule size of at least 150 μm up several 100 μm, in particular in about 500 μm of the bone-adhesive polyurethane polymers according to the invention.

The in the table 12 summarized in the appended embodiments correspond to the equally numbered embodiments in Table 7 and provide a selected system "Polyesterpolyolkomponente invention 2 in Table 1 / inventive polymeric polyisocyanate component 2 in Table 2 / Additive HDI / additive according to the invention phase-pure β-tricalcium phosphate with a granule size of at least 150 μm up several 100 μm, in particular in about 500 μm of the bone-adhesive polyurethane polymers according to the invention represents.

The embodiments summarized in the table 13 reproduced in the appendix correspond to the similarly numbered embodiments in Table 7 and represent a selected system "Polyesterpolyolkomponente 2 invention in Table 1 / inventive polymers Polyisocyanate component 1 in Table 2 / Addition HDI / additive according to the invention phase-pure β-tricalcium phosphate having a granule size of at least 150 microns to several 100 microns, especially in about 500 microns "of the bone-adhesive polyurethane polymers of the invention.

at further advantageous embodiments contains the bone-adhesive polyurethane polymer according to the invention at least one polymeric polyisocyanate component having at least one separated from the aromatic by an aliphatic grouping Isocyanate group. In a bone-adhesive polyurethane polymer according to the invention with the inventive polymer Polyisocyanate component with the by an aliphatic grouping The isocyanate group separated from the aromatics are degradation processes according to the invention aromatic diamine not possible. An embodiment a polyisocyanate component according to the invention with at least one by an aliphatic grouping of aromatics separated isocyanate group is in particular a polyisocyanate component based on 1,3-bis (isocyanatomethyl) benzene (XDI) and terephthalic acid and / or Bisphenol A.

In the embodiment 57 of a bone-adhesive polyurethane polymer according to the invention shown in Table 14, tensile forces of 0.92 N / mm ^{2 were} measured.

Tries, to bone-adhesive polyurethane polymers according to the invention to arrive, whereby terephthalic acid and bisphenol A in molar ratio 1: 2 were reacted with XDI at room temperature or at 50 ° C, led to no polyaddition reaction. For a reaction of terephthalic acid became in solution with XDI not a suitable solvent for the Diol component found.

at the embodiments shown in Tables 14 and 15 has been the Catalyst ethylhexanoic acid Tin (II) salt of the polyester polyol component according to the invention 2 in a mass ratio of 1: 150 added.

Table 14

The in the table 14 assembled embodiments correspond the similarly numbered embodiments in the table 7 and make a selected one System "Polyesterpolyolkomponente invention 2 in Table 1 / terephthalic acid / XDI "of the bone-adhesive polyurethane polymers according to the invention represents.

Table 15

The in the table 15 assembled embodiments correspond the similarly numbered embodiments in the table 7 and make a selected one System "Polyesterpolyolkomponente invention 2 in Table 1 / terephthalic acid / additive Leucin / XDI "the bone-adhesive polyurethane polymers of the invention represents.

The bone-adhesive polyurethane polymers of the invention advantageously have a polymerization or setting time from a few minutes, especially from about 5 to about 20 minutes, within which a substantial strength of the polymers with a largely fixed connection of the glued together bone, Tooth or implant surfaces is reached.

The The present invention also relates to methods for producing the bone-adhesive polyurethane polymers of the invention.

One first production method according to the invention comprises a first optional step in which at least one polyester polyol component according to the invention, polymeric polyisocyanate component or at least one additive the polymerization dried in vacuo and then under Exclusion of moisture is stored. In a first step is a mixture of at least one polyester polyol component according to the invention triglyceride structure obtainable by a process according to the claims, and at least one catalyst. In case of use in particular the polyester polyol component according to the invention 2 in Table 1 as a polyester polyol component and 2-ethylhexanoic tin (II) salt as a catalyst the mass ratio Polyester polyol component: Catalyst 150: 1. In an optional second step, the solid additives are weighed into a reagent vessel and with the polyol catalyst mixture by means of a mixing device intimately mixed. In a third step, at least one inventive polymer Polyisocyanate component and / or at least one diisocyanate component or a Triisocyanatkomponente added and the reaction mixture with mixed the blender until it's a semi-solid, but still has spreadable consistency. Depending on the educts used the reaction time in the third step varies between 2 and 20 minutes. In a fourth step, the reaction mixture is two-sided, especially in approx. 0.5 mm thick layers, on which adhesive surfaces are applied, the adhesive surfaces are brought into mutual contact and pressed firmly together.

at the attempts to produce the bone-adhesive polyurethane polymers according to the invention were the glued parts in further steps depending on the consistency of the adhesive between Stored for 10 and 20 minutes in the air, then simulating body-like Conditions in one at 37 ° C tempered, phosphate buffered saline inserted and there to stored for further examination between 14 and 72 hours.

One another embodiment relates to a production process according to the invention for the knochenadhäsive Polyurethane polymer of the embodiment 4 in Table 5: 1.1 ml of the polyester polyol component according to the invention 2 in Table 1 are added 0.01 ml of 1,1,4,7,10,10-Hexamethylentriethylentetramin and with 0.2 g of phase-pure β-tricalcium phosphate stirred. There are 0.6 ml of the polymeric polyisocyanate component of the invention 1 in Table 2 and 0.15 ml of hexamethylene diisocyanate (HDI) were added and touched, until a creamy mass is present. The mass is, in particular, with a layer thickness of about 0.5 mm, for example, two together firmly attached bone fragments are applied, and these become together.

In tensile testing to determine the tensile strength of the glue line, the bone samples treated as described above were placed in phosphate buffered saline after 15 minutes at 37 ° C. After 5 days, the sample was subjected to a tensile test; the tensile force was 1.18 N / mm ² .

One another embodiment relates to a production method for the bone-adhesive polyurethane polymer according to the embodiment 5 in Table 5: 1.1 ml of the polyester polyol component according to the invention 2 in Table 1 are added 0.01 ml of diazabicyclo [2.2.2] octane and with 0.31 g of phase-pure β-tricalcium phosphate according to the invention stirred. There are 0.63 ml of the polymeric polyisocyanate component of the invention 2 in Table 2 and 0.27 ml of hexamethylene diisocyanate (HDI) and stirred until a creamy mass is present. The mass is, especially with a Layer thickness of about 0.5 mm, for example, two together applied to connecting bone samples and these are joined together.

In tensile tests to determine the tensile strength of the glue line, the bone samples treated as described above were stored in phosphate buffered saline after 15 minutes at 37 ° C. After 7 days, the sample was subjected to tensile testing. The bond strength was about 1.66 N / mm ² .

One another embodiment relates to a method of making the bone-adhesive polyurethane polymer according to the embodiment 6 in Table 5: 1.1 ml of the polyester polyol component according to the invention 2 in Table 1 are added with 0.01 ml of 4-dimethylaminopyridine and with 0.24 g of phase-pure β-tricalcium phosphate according to the invention and 0.31 g of leucine. There are 0.63 ml of the polymeric polyisocyanate component of the invention 1 in Table 2 and 0.16 ml of hexamethylene diisocyanate (HDI) and stirred until a creamy mass is present. The mass is, in particular, with a layer thickness of about 0.5 mm, for example, two together applied to connecting bone samples and these are joined together.

In tensile tests to determine the tensile strength of the glue line, the bone samples treated as described above were stored in phosphate buffered saline after 15 minutes at 37 ° C. After 5 days, the sample was subjected to tensile testing. The tensile force was approximately 1.49 N / mm ² .

One another embodiment relates to the preparation of the bone-adhesive polyurethane polymer according to the embodiment 3 in Table 5: 1.1 ml of the polyester polyol component according to the invention 2 in Table 1 are added with 0.01 ml of 4-dimethylaminopyridine and stirred with 0.33 g of leucine. There are 0.55 ml of the polymeric polyisocyanate component of the invention 1 in Table 2 and 0.22 ml of hexamethylene diisocyanate (HDI) and stirred until a creamy mass is present. The mass is, in particular, with a Schichtdikke of about 0.5 mm, for example, two together applied to be joined bone fragments and these are joined together.

In tensile testing to determine the tensile strength of the glue line, the bone samples treated as described above were placed in phosphate buffered saline after 15 minutes at 37 ° C. After 3 days, the sample was subjected to a tensile test. The tensile force was 1.62 N / mm ² .

embodiments for further Manufacturing process arise in a similar manner from the Formulations of the further bone-adhesive polyurethane polymers according to the invention.

The The present invention also relates to the provision of uses the bone-adhesive polyurethane polymers according to the invention. In one aspect, the invention relates to the use of at least one Bone adhesive of the invention for fixing bone fragments, for fixation of dental fragments, for cavity fillings in bones, for cavity fillings in teeth, in composite osteosynthesis, in dental reconstruction, in endoprosthesis implantations, for anchoring hip prostheses. First embodiments of uses according to the invention are advantageous uses of the bone-adhesive polyurethane polymers according to the invention together with or instead of known bone cements containing a have lower tensile strength or biodegradability. The first embodiments of uses according to the invention the bone-adhesive polyurethane polymers according to the invention affect all known and future Uses of Known Bone Cements.

Further embodiments of uses according to the invention of the bone-adhesive polyurethane polymers according to the invention are novel uses which are familiar with the known bone cells previously inaccessible due to their lower tensile strength or biodegradability. Because of their higher tensile strength, the bone-adhesive polyurethane polymers according to the invention allow, in particular, firmer connections of bone fragments, dental fragments or endoprostheses with bone or teeth than the known bone cements. Therefore, solid compounds can be prepared alone with the bone-adhesive polyurethane polymers according to the invention, which were hitherto only possible by metallic means for solid compound or, in Verbundosteosynthesen, only together with metallic agents for solid Ver bond. In particular, the predeterminable biodegradability of the bone-adhesive polyurethane polymers according to the invention is also advantageous.

Yet further embodiments of uses according to the invention the bone-adhesive polyurethane polymers according to the invention partially or completely from the bone-adhesive polyurethane polymers according to the invention manufactured endoprostheses for partial or complete replacement of bones or teeth. In particular, the predeterminable biodegradability of the bone-adhesive polyurethane polymers of the invention advantageous.

adhesive joints of bone fragments bound with a bone-adhesive polyurethane polymer according to the invention, in particular one of the embodiments 2, 3, 5 or 6 in Table 5, have been firmly joined, show in studies with the electron microscope, a favorable ultrastructure.

to scanning electron microscopic examination was the adhesive layer clean detached from the bone and divided with a scalpel parallel to the glue joint. Both the the bone-bonded side as well as the center of the adhesive layer, were examined by scanning electron microscopy. All examined Samples showed a consistent picture: while facing the bone Page appeared very smooth and only a few small pores with a diameter of about 5 to 20 microns, was the interior the polyurethane polymer according to the invention interspersed with pores. Here, the pore diameter was up to 200 microns. In the event of the introduction of phase-pure β-tricalcium phosphate into the reaction mixture of the polyurethane polymer was incorporation β-tricalcium phosphate granules in the form of islands in the porous Adhesive layer to recognize well.

The formation of the pores is effected by the CO ₂ release during the curing process of the polyurethane polymer in the aqueous medium. The pores are well placed to allow bone-forming cells to impart into the polyurethane polymer layer to form new bone with the absorption of β-tricalcium phosphate and to gradually replace the polyurethane polymer layer with endogenous bone material.

The bone-adhesive polyurethane polymers according to the invention advantageously have only a low residual isocyanate content, which also decreases sharply within application-relevant periods. In polyurethane syntheses, unreacted isocyanate moieties are often observed in the polymer due to excess use of isocyanate or steric shielding of isocyanate moieties. IR spectroscopy provides a simple method for the qualitative detection of residual isocyanate in polyurethanes: the NCO band at 2270 cm ^-1 is a very intense band that is virtually unaffected by absorption by other molecular groups (16).

IR spectroscopy were used in all examined bone-adhesive polyurethane polymers according to the invention Observed bands that indicated free isocyanate groups in the polymer. In a long-term trial, the samples were phosphate buffered at 37 ° C Saline stored. Every 7 days the samples were dried and one more Subjected to IR spectroscopic examination. In this way were Even after 2 months still free isocyanate groups in the polyurethane demonstrated.

Around To quantitatively detect the free isocyanate were UV spectroscopic Investigations used. Basis of this very sensitive Investigations are the reaction of malachite green with butylamine to the colorless malachite green butylamine complex on the one hand, as well as the reaction of isocyanate with butylamine on the other hand: a standard solution of Butylamine in tetrahydrofuran is combined with the free isocyanate groups reacted in the polyurethane. The excess butylamine is mixed with malachite green in pyridine implemented; the degree of decolorization to be detected by UV spectroscopy the malachite green solution (comparison with a calibration curve) stands for the proportion of free isocyanate in the polymer in direct connection. A short description of the Quantitative NCO detection can be found in (17).

For the quantitative determination of residual isocyanate, the bone-adhesive polyurethane polymers of embodiments 5 and 6 according to the invention in Table 5 were investigated. 48 hours after the synthe In the case of the polyurethane polymers according to the invention, a residual isocyanate content of about 2% by mass was detectable. After a further 20 days, the proportion of free isocyanate groups had decreased to 0.7 percent by mass. This value was confirmed by comparative measurements with various polymer weighers. At the moment of the polyurethane polymer formulation, the isocyanate mass fraction was 13.5% and 10.8%, respectively.

publications

• (1) Ege, W., Bone cement, in: Plastics and elastomers in medicine, Verlag W. Kohlhammer, Stuttgart, 1993; and there quoted pamphlets
• (2) Quack, R., Yaacoub, C., Adhesives in Pharmacy and Medicine, in: Adhesives from Renewable Resources, Franz Patat Center, Braunschweig, 1998; and there cited pamphlets US 5,266,608 A
• (3) Harburger Fettchemie Brinckman & Merell GmbH, polyols from renewable Raw materials, Product Information No. 2, as of 04/14/2000
• (4) Harburger Fettchemie Brinckman & Merell GmbH, EEC Material Safety Data Sheet, 91/155 / EEC, Product Name and Number: 8106 MERGINATE PV 235, Date: 08.03.01, Revision Date: 10.01.00
• (5) Harburger Fettchemie Brinckman & Merell GmbH, product specification MERGINAT PV 235, Reg. 8106-00-05, as of: 20.12.1999
• (6) Harburger Fettchemie Brinckman & Merell GmbH, EC Safety Data Sheet, 91/155 / EEC, product number and name: LV 8570, printed date: 08.03.01, revised on: 26.07.00
• (7) Harburger Fettchemie Brinckman & Merell GmbH, product specification LV 8570, Reg. LV8570-00-03, as of: 25.01.2001
• (8) "http://www.elastogran.de/cgi-win/Produkt.exe?S4Lupraphen": Elastogran GmbH, Lupraphen - product overview, 27/3/01
• (9) Elastogran GmbH, EC Safety Data Sheet, 91/155 / EEC, Product: Lupagraph 9267, date / revised on: 05.02.1999
• (10) Elastogran GmbH, EC Safety Data Sheet, 91/155 / EEC, Product: Lupraphen 8004, date / revised on: 05.02.1999
• (11.1) Lupranat M 20 W, Technical Data Sheet, Version 02, Stand: 06.01, pages 1-3, Elastogran GmbH, PO Box 11 40, 49440 Lemförde
• (11.2) Elastogran GmbH, EC Safety Data Sheet, 91/155 / EEC, Product: Lupranat M 20 W, date / revised on: 15.07.2002, printed date: 04.09.2002
• (12) "http://www.elastogran.de/cgi-win/Produkt.exe?S4Lupranat": Elastogran GmbH, Lupranat - product overview, 27/3/01
• (13) Elastogran GmbH, EC Safety Data Sheet, 91/155 / EEC, Product: Lupranat M 10 R, date / revised on: 01.11.2000
• (14) Elastogran GmbH, EC Safety Data Sheet, 91/155 / EEC, Product: Lupranat M 50, Date / revised on: 01.11.2000
• (15) Uhlig, K., Polyurethane-Taschenbuch, Hanser Fachbuchverlag, Munich, 1998
• (16) Oertel, G. (ed.), Polyurethane, 3rd ed., Hanser Fachbuchverlag, Munich, 1993
• (17) Kubitz, K, Determination of Traces of Isocyanates in Urethane-Based Polymers, Anal. Chem., 29, 818 (1957)
• (18) shepherds, H, polyurethanes from vegetable oil-based polyols, in: Gülzower Fachgespräche, volume 16: Modern polymers - carbohydrates and vegetable oils as innovative raw materials, Agency for Renewable Resources (FNR), 2001
• (19) Silbermann, M., A New Polyurethane-Based Adhesive for Injured Bones: An In Vitro Characterization Study, Research Report, Haifa, 1998th
• (20) Silbermann, M., A New Polyurethane-Based Adhesive for Injured Bones: A Biocompatibility Study, Research Report, Haifa, 1998.

Table 3

Table 4

TABLE 7

Table 11

Table 12

Table 13

Claims (29)

Use of at least one polyisocyanate component and at least one polyester polyol component having a triglyceride structure for the production of a bone adhesive based on polyurethane. Use according to claim 1, at least one polyester polyol component on vegetable oil basis. Use according to claim 2, at least the polyester polyol component Castor oil. Bone adhesive based on polyurethane with at least a polyisocyanate component and at least one polyester polyol component with triglyceride structure obtainable by a process wherein in a first step, oxygen at double bonds in fatty acids of a unsaturated vegetable oil is attached to obtain an epoxidized oil, and in one second step of the oxygen ring of the epoxidized oil hydrogen-active compounds is opened, wherein an OH group arises. Bone adhesive according to claim 4 having at least one polyester polyol component according to formula 1:

Bone adhesive according to claim 4 having at least one polyester polyol component according to formula 2:

Bone adhesive based on polyurethane with at least a polyester polyol component based on poly (diethylene glycol-glycerol-adipic acid). Bone adhesive according to one or more of claims 4 to 7 with at least one polymeric polyisocyanate component on the Base of hexamethylene diisocyanate, 2,4-tolylene diisocyanate, 4,4'-methylenebis (cyclohexyl isocyanate), 1,3-bis (1-isocyanato-1-methylethyl) benzene, 1,3-bis (isocyanatomethyl) benzene or 4,4'-methylene bis (phenyl isocyanate). Bone adhesive according to claim 8 with at least one polymeric polyisocyanate component based on 4,4'-methylene bis (phenyl isocyanate). Bone adhesive according to claim 9, comprising at least a polymeric polyisocyanate component having an NCO content of 30 to 32% by mass. Bone adhesive according to one or more of claims 4 to 7 with at least one aromatic polyisocyanate component with at least one by means of an aliphatic. Group of aromatics separated isocyanate group. Bone adhesive according to claim 11 with a polymeric Polyisocyanate component based on at least one isocyanate component 1,3-bis (1-isocyanato-1-methylethyl) benzene or 1,3-bis (isocyanatomethyl) benzene and at least one component terephthalic acid or bisphenol A. Bone adhesive according to one or more of claims 4 to 12 with an OH number / NCO content ratio from 3.5 to 7. Bone adhesive according to one or more of claims 4 to 13 with at least one addition of a calcium salt, salt of a Phosphoric acid, Protein, protein degradation product, peptides, an amino acid, one Carbohydrate, polysaccharide, starch degradation product, aliphatic Diols, aliphatic diamines, 1,3-bis (isocyanatomethyl) benzene, terephthalic acid, Bisphenol A, 2,4-diaminotoluene. Bone adhesive according to claim 14 with at least one addition of phase-pure β-tricalcium phosphate, glycerol-1-phosphate, glycerol-2-phosphate or glycerol-3-phosphate, hydroxyapatite, calcium phosphoglycerate, calcium salt of glycerol-1-phosphate or glycerol-3-phosphate, of Casein, a casein degradation product, gelatin, a collagen degradation product, leucine, serine, lysine, glycine, alanine, asparagine, aspartic acid, glucose, dextran, glycerol, glycolic acid, 1,3-butanediol, 1,4-butanediol, 1, 6-hexanediol, 1,8-octane diol, 1,6-diaminohexane, 1,8-diaminooctane, polyethylen lenimin. Bone adhesive according to claim 15, comprising at least an addition of phase-pure β-tricalcium phosphate with a granule size of at least 100-150 μm to several one hundred microns, in particular 500 microns. Bone adhesive according to one or more of claims 4 to 16 with at least one catalyst 2-ethylhexanoic acid stannous salt, Sodium trichlorphenate, sodium tetrachlorophenate, sodium pentachlorphenate, Iron (II) ethylhexanoate, iron acetylacetonate, dibutyltin di-2-ethylhexanoate, Tin (II) ethylhexanoate or cobalt (II) ethylhexanoate. Bone adhesive according to one or more of claims 4 to 16 with at least one nitrogen-based catalyst. Bone adhesive according to claim 18, comprising at least a catalyst 1,1,4,7,10,10-hexamethylenetriethylenetetramine, Diazabicyclo [2.2.2] octane, 4-dimethylaminopyridine, Diazabicyclo [5.4.0] undec-5-ene, piperidine, triisobutylamine, 2-mercapto-5-methyl-1,3,4-thiadiazole, Benzotriazole or tris- (2-aminoethyl) amine. Bone adhesive according to claim 19 with 2-ethylhexanoic acid tin (II) salt as a catalyst, up to a mass ratio of polyesterpolyol of the formula 2: Catalyst of 150: 1. Bone adhesive according to one or more of claims 4 to 20 with a tensile strength F of more than 0.62 N / mm ² . Method for producing a bone adhesive Polyurethane based according to one or more of claims 4 to 21, where a) in a first step, a mixture at least a polyester polyol component having a triglyceride structure and at least a catalyst is prepared, wherein the polyester polyol component available by a process is, wherein in a first step oxygen to double bonds in fatty acids an unsaturated one vegetable oil is attached to obtain an epoxidized oil, and in one second step of the oxygen ring of the epoxidized oil hydrogen-active compounds is opened to form an OH group; b) in a further step at least one polymeric polyisocyanate component and / or at least one diisocyanate component or a triisocyanate component is added; and c) in a further step with mixing a spreadable reaction mixture is prepared. The method of claim 22, further comprising Step a) at least one polyester polyol component, polymeric polyisocyanate component or at least one additive dried in vacuo and then under Keep moisture out. The method of claim 22 or 23, wherein further after step a) the solid. additions weighed into a reaction vessel and with the polyol catalyst mixture be intimately mixed by means of a mixing device. Method according to one or more of claims 22-24, wherein in step b) added an addition of hexamethylene diisocyanate becomes. Method according to one or more of claims 22-25 wherein the reaction mixture applied to firmly bonded surfaces or in one to be filled Bone, tooth or prosthesis cavity is introduced, and a subsequent Step in which the bone adhesive hardens. A method according to claim 26 for producing a Endoprosthesis, wherein the liquid Reaction mixture of an adhesive according to one or more of claims 4 to 21 is introduced into a mold which is a negative of the endoprosthesis or a polyurethane component or portion of the endoprosthesis corresponds, and the cured Polyurethane polymer finally is removed from the mold. Use of at least one bone adhesive after one or more of the claims 1 to 21 for the fixation of bone fragments, for the fixation of Tooth fragments, for cavity fillings in bones, for cavity fillings in teeth, in composite osteosynthesis, in dental reconstruction, in endoprosthesis implantations, for anchoring hip prostheses. Use of at least one bone adhesive after one or more of the claims 4 to 21 for the partial or complete preparation of endoprostheses.