EP2291203A2

EP2291203A2 - Pmma paste

Info

Publication number: EP2291203A2
Application number: EP09772084A
Authority: EP
Inventors: Sebastian Vogt; Hubert Buechner
Original assignee: Heraeus Medical GmbH
Current assignee: Heraeus Medical GmbH
Priority date: 2008-06-30
Filing date: 2009-06-13
Publication date: 2011-03-09
Also published as: CA2728880A1; JP2011526171A; DE102008064657A1; US20110112210A1; AU2009266110A1; WO2010000384A3; WO2010000384A2

Abstract

A PMMA paste comprising a mixture of A methyl methacrylate that has a methacrylic acid content of less than 1% and a water content of less than 1% and B at least one polymethyl methacrylate that has a Tg of more than 65°C and a molar mass of greater than or equal to 200 000 g/mol, the methyl methacrylate fraction being sufficient for the PMMA paste to be autosterile, and the weight ratio of B to A being 10-50% B to 50-90% A, can be used to produce paste-like one-component bone cements and two-component bone cements.

Description

Paste PMMA

The invention relates to a PMMA paste (polymethyl methacrylate paste), their use and containing them paste-like one-component bone cements or bicomponent bone cements.

PMMA bone cements have been known for decades and are based on the fundamental work of Sir Charnley (Chamley, J .: Anchorage of the femoral head prosthesis of the shaft of the femur, J. Bone Joint Surg., 42 (1960) 28-30. ). The basic structure of the PMMA bone cements has remained basically the same since then. PMMA bone cements consist of a liquid monomer component and a powder component. The monomer component generally contains the monomer methyl methacrylate and an activator (N, N-dimethyl-p-toluidine) dissolved therein. The powder component consists of one or more polymers which are prepared on the basis of methyl methacrylate and comonomers, such as styrene and methyl acrylate, by polymerization, preferably suspension polymerization, an X-ray opaque and the initiator dibenzoyl peroxide. When the powder component is mixed with the monomer component, a plastically deformable dough is formed by swelling the polymers of the powder component in the methyl methacrylate. At the same time, the activator N ₁ N-dimethyl-p-toluidine reacts with the dibenzoyl peroxide, which decomposes to form free radicals. The radicals formed initiate the polymerization of the methyl methacrylate. As the polymerization of methyl methacrylate progresses, the viscosity of the cement paste increases until the dough solidifies and hardens.

Basic mechanical requirements for PMMA bone cements, such as 4-flexural strength, flexural modulus and compressive strength, are described in ISO 5833. For the user of the PMMA bone cements, the property of the freedom from tackiness of the bone cement is of essential importance. The term tack-free is defined in ISO5833. The tackiness shows for conventional PMMA bone cements, the cement has reached the processing phase after mixing the components by swelling the polymers in the cement powder contained in the cement powder. Basically, a PMMA bone cement must be tack-free so that the user can shape and apply the cement. The PMMA bone cement must not stick to the gloves and application aids, such as mixing systems, jars or spatulas.

A disadvantage of the conventional PMMA bone cements for the cement producer is that both the powder component and the monomer component have to be prepared in double sterile packaging. This means that at least four sterile packaging materials are required for a bone cement pack.

A further disadvantage of the previous PMMA bone cements for the medical user is that the liquid monomer component must be mixed with the powder component immediately before the cement application in a mixing system or in crucibles. In this case, mixing errors can easily occur, which can adversely affect the cement quality. After mixing the monomer component with the powder component, depending on the type of cement, it is necessary to wait a certain time until the cement paste is tack-free and can be applied. Thereafter, the user has a more or less short processing time available in the total endoprostheses can be positioned or bone cavities as in kyphoplasty and vertebroplasty can be filled. During the processing time, the viscosity of the cement dough changes due to the increasing swelling of the polymer particles in the monomer and the progressive polymerization of the monomer. The relatively short processing time is a major disadvantage of the previous bone cements. Particularly disadvantageous are short processing times in kyphoplasty and vertebroplasty. It would be desirable to have a cement, especially for vertebroplasty and kyphoplasty, in which the viscosity of the cement paste remains substantially constant over a period of several minutes during cement application.

The object of the invention is therefore to develop a PMMA paste which can be used as starting material for the production of paste-like PMMA bone cements, which can overcome the problems of the known PMMA bone cements. The object of the invention is achieved by a PMMA paste according to claim 1. Advantageous embodiments emerge from the other claims.

The PMMA paste according to the invention is composed of a mixture

A methyl methacrylate, which has a methacrylic acid content of less than 1% and a

Water content less than 1%,

B and at least one polymethyl methacrylate having a Tg (glass transition temperature) greater than 65 ^C C and a molecular weight greater than or equal to 200,000 g / mol formed, wherein the methyl methacrylate portion is so high that the PMMA paste is autosterilic.

The term methyl methacrylate is understood as meaning both pure methyl methacrylate and methyl methacrylate contaminated with small amounts of other monomers such as ethyl methacrylate, propyl methacrylate and styrene, provided that these impurities do not exceed a total content of 5%.

Preference is given to a polymethyl methacrylate having a molar mass greater than 300,000 g / mol, more preferably having a molar mass greater than 500,000 g / mol.

Advantageously, the polymethyl methacrylate is at least 80 percent by weight soluble in methyl methacrylate.

Surprisingly, it has been found that pastes with a proportion of methyl methacrylate greater than or equal to 50% by weight are autosterly. This means that methyl methacrylate causes a killing of microbial germs in the PMMA paste. Accordingly, preference is given to PMMA pastes in which a weight ratio of 10-50% of polymethyl methacrylate to 50-90% of methyl methacrylate is present.

The invention also relates to the use of the above-described PMMA pastes for the production of single-component paste-like bone cements and two-component bone cements. For this purpose, the PMMA paste is mixed with organic and / or inorganic fillers and with radical initiators and / or accelerators for the production of one-component and two-component bone cements. Preferably, organic and inorganic fillers which do not swell in methyl methacrylate and have a methyl methacrylate uptake of less than 25% are mixed with the PMMA paste.

In particular, the PMMA paste according to the invention is used for the preparation of an agent for the fixation of total endoprostheses and revision endoprostheses.

Particularly advantageous is the use of the PMMA paste according to the invention for the production of a self-hardening filling material for vertebroplasty, kyphoplasty and femoral neck suction.

The PMMA paste according to the invention can also be used for the production of local drug release systems. So it is z. For example, it is possible to form spherical or bean-shaped implants containing PMMA bone cement prepared from the PMMA paste of the present invention which can be used as local drug delivery systems.

In addition, pharmaceutical active ingredients from the groups of antibiotics, hormones, growth factors and anti-inflammatory drugs can be mixed with the PMMA paste according to the invention. Suitable antibiotics are, in particular, aminoglycoside antibiotics, glycopeptide antibiotics, fluoroquinolone antibiotics, lincosamide antibiotics and oxazolidinone antibiotics. Preferred are gentamicin, tobramycin, amikacin, teicoplanin, vancomycin, ramoplanin, dalbavancin, moxifloxaxin, ciprofloxacin, lincosamine, clindamycin and linezolid.

The invention is illustrated by the following examples without, however, limiting the invention. Parts and percentages are by weight unless otherwise indicated, as in the remainder of the description.

Example 1: Preparation of a PMMA Paste 1

500 ml of methyl methacrylate (Fluka) together with 2.0 g of Dowex 50WX2 and 2.0 g of sodium sulfate were stirred in a 500 ml Erlenmeyer flask for 2 hours at room temperature, followed by separation of the ion exchanger and the sodium sulfate by filtration. The water content of the methyl methacrylate of 0.1% was determined by Karl Fischer titration. The methacrylic acid content determined by gas chromatography was 0.08% and. There were then dissolved in 195 g of pretreated methyl methacrylate 105 g Poylmethylmethacrylat (molecular weight about 500,000 g / mol, Tg 100-106 ⁰ C) in a 500 ml two-necked flask with exclusion of air (nitrogen stream) at room temperature with gentle stirring. The result was a bubble-free, very viscous colorless paste.

To test the autosterility of the paste, spore strips (Bacillus subtilis ATCC 6633) were introduced into the paste. After 72 hours of storage at room temperature, the spore strips were removed and checked for sterility by incubation. There was no growth.

Example 2: Preparation of a PMMA Paste 2

The paste 2 was prepared analogously to the PMMA paste 1, but a PMMA having a molecular weight of about 700,000 g / mol and a Tg of 100-106 ⁰ C was used. The PMMA concentration was adjusted to 30%.

Example 3: Preparation of a PMMA Paste 3

The paste 2 was prepared analogously to the PMMA paste 1, but a PMMA having a molecular weight of about 1200,000 g / mol and a Tg of 100-105 ⁰ C was used. The PMMA concentration was adjusted to 28%.

Example 4 Preparation of a Two-Component Paste Cement Paste A:

22.80 g of the PMMA paste 1 were kneaded together with 1.50 g of 1-cyclohex-5-ethyl-barbituric acid, 3.15 g of zirconia and 5.00 g of polymethyl methacrylate partially soluble in MMA. Paste B:

There were 22.80 g of the PMMA paste 1 with 125 mg of Aliquat 336, 0.5 mg of copper (II) -2-ethxanoate, 1.50 g of 1-cyclohex-5-ethyl-barbituric acid, 3.15 g of zirconium dioxide and 5.00 g in MMA partially soluble polymethylmethacrylate (particle size <63 .mu.m, MMA uptake about 10%) kneaded together.

30 g of paste A was kneaded with 30 g of paste B. The resulting cement dough was immediately tack-free and could be molded over a period of about 5 minutes. This was followed within 4 minutes, the curing of the cement.

The cement paste was used to produce test specimens for determining the 4-point bending strength and the flexural modulus according to ISO5833 and for testing the Dynstat impact strength. The 4-point flexural strength and the flexural modulus were tested after storage of the test specimens at room temperature after 24 hours and in addition after storage of the test specimens in water at 37 ⁰ C for 24 and 48 hours.

4-flexural strength (air / 24h / room temperature): 49.9 ± 0.8 MPa flexural modulus (air / 24h / room temperature): 1985 ± 53 MPa 4 flexural strength (water / 24h / 37 ° C): 65.5 ± 1 , 1 MPa flexural modulus (water / 24h / 37 ° C): 2604 ± 29 MPa 4 flexural strength (water / 48h / 37 ° C): 71, 8 ± 1, 7 MPa flexural modulus (water / 48h / 37 ° C): 2726 ± 74 MPa Dynstat impact strength (air / 24h / room temperature): 3.47 ± 0.35 Dynstat flexural strength (air / 24h / room temperature): 72.71 ± 2.33

Example 5: Preparation of a Two-Component Paste Cement Paste A:

21.20 g of the PMMA paste 2 were kneaded together with 1.50 g of i-cyclohex-5-ethyl-barbituric acid, 3.15 g of zirconium dioxide and 6.60 g of MMA-soluble polymethyl methacrylate. Paste B:

There were 21, 20 g of PMMA paste 1 with 125 mg of aliquat 336, 0.5 mg of copper (II) -2-ethxanoate, 1.50 g of 1-cyclohex-5-ethyl-barbituric acid, 3.15 g of zirconium dioxide and 6.60 g in MMA partially soluble polymethylmethacrylate (particle size <63 .mu.m, MMA uptake about 10%) kneaded together.

The cement paste was used to produce test specimens for determining the 4-point bending strength and the flexural modulus according to ISO5833 and for testing the Dynstat impact strength. After testing the test specimens at room temperature after 24 hours and after storage of the test specimens in water at 37 ^° C. for 24 and 48 hours, the 4-point flexural strength and flexural modulus were tested.

4-flexural strength (air / 24h / room temperature): 52.0 ± 1.2 MPa flexural modulus (air / 24h / room temperature): 2080 ± 52 MPa 4 flexural strength (water / 24h / 37 ° C): 64.2 ± 2 , 3 MPa flexural modulus (water / 24h / 37 ° C): 2548 ± 51 MPa 4-flexural strength (water / 48h / 37 ° C): 72.1 ± 1.5 MPa Flexural modulus (water / 48h / 37 ° C): 2803 ± 59 MPa Dynstat impact strength (air / 24h / room temperature): 4.11 ± 0.29 Dynstat bending strength (air / 24 h / room temperature): 81, 23 ± 1, 77

Example 6 Preparation of a Two-Component Paste Cement for Vertebroplasty / Kyphoplasty

Paste A:

There were 20.80 g of PMMA paste 3 with 1.50 g of 1-cyclohex-5-ethyl-barbituric acid and with

13.0 g of zirconium dioxide are kneaded together.

Paste B:

There were 20.80 g of PMMA paste 1 with 125 mg of Aliquat 336, 2.0 mg of copper (II) 2-ethxanoate,

1, 50 g of 1-cyclohex-5-ethyl-barbituric acid and 13.0 g of zirconium dioxide are kneaded together.

30 g of Paste A were mixed with 30 g of Paste B using a double cartridge system with static mixer attached. The resulting cement dough was immediately tack-free and could be molded over a period of about 7 minutes. This was followed within about 6 minutes, the curing of the cement.

The cement paste was used to produce test specimens for determining the 4-point bending strength and the flexural modulus according to ISO5833 and for testing the Dynstat impact strength. The testing of the 4-point flexural strength and the flexural modulus was carried out after storage of the test specimens at room temperature in air and at 37 ° C. in water after 24 hours.

4-flexural strength (air / 24h / room temperature): 49.8 ± 1.4 MPa flexural modulus (air / 24h / room temperature): 2271 ± 112 MPa 4-flexural strength (water / 24h / 37 ° C): 62.0 ± 3 , 8 MPa flexural modulus (water / 24h / 37 ° C): 3001 ± 40 MPa Dynstat impact strength (air / 24h / room temperature): 3.67 ± 0.24 dynstat flexural strength (air / 24 h / room temperature): 65, 78 ± 4.41

Claims

claims

1. PMMA paste from a mixture of

A methyl methacrylate, which has a methacrylic acid content of less than 1% and a water content of less than 1%, and B at least one polymethyl methacrylate having a Tg greater than 65 ^C C and a

Molar mass greater than or equal to 200,000 g / mol, wherein the proportion of methyl methacrylate is so high that the PMMA paste is autosterilic and a weight ratio of 10-50% B to 50-90% A is present.

2. PMMA paste according to claim 1, wherein the polymethyl methacrylate has a molecular weight greater than 300,000 g / mol.

3. PMMA paste according to claim 2, wherein the molecular weight is greater than 500,000 g / mol.

4. PMMA paste according to one of the preceding claims, characterized in that the polymethyl methacrylate B is at least 80 weight percent in methyl methacrylate A soluble.

5. paste-like one-component bone cements and two-component bone cements containing a PMMA paste according to any one of claims 1-4.

6. Use of a PMMA paste according to any one of claims 1-4 for the preparation of an agent for the fixation of total endoprostheses and revision endoprostheses.

7. Use of a PMMA paste according to any one of claims 1-4 for the preparation of a self-curing filling material for vertebroplasty, kyphoplasty and Femurhalsaug- mentation.

8. Use of a PMMA paste according to any one of claims 1-4 for the preparation of local drug release systems.

9. A process for the preparation of paste-like one-component bone cements or two-component bone cements, characterized in that a PMMA paste according to any one of claims 1-4 is mixed with organic and / or inorganic fillers and with free-radical initiators and / or accelerators.

10. The method claim 7, characterized in that organic and inorganic fillers which do not swell in methyl methacrylate and have a methyl methacrylate uptake of less than 25%, are mixed with the PMMA paste.