DE102008030312A1 - Polymethylmethacrylate-based paste used in single- or two-component bone cements or active substance release systems, has self-sterile composition - Google Patents

Abstract

The paste comprises a mixture of two components, A and B. The first (A) has a methacrylic acid content less than 1% and a water content less than 1%. The second (B) includes at least one polymethylmethacrylate (PMMA) with a Tg exceeding 65[deg] C and a molecular weight of 200000 g/mol or more. The methyl methacrylate proportion is sufficiently high that the PMMA paste is auto-sterile. The mass ratio B:A is expressed as 10-50% to 50-90%. The polymethylmethacrylate molecular weight exceeds 300000 g/mol or 500000 g/mol. An independent claim is included for a method of making one- or two-component bone cements.

Description

object of the invention are a PMMA paste (polymethyl methacrylate paste), their use and containing single-component pasty bone cements or bicomponent bone cements.

PMMA bone cements have been known for decades and are based on the fundamental work of Sir Charnley ( Charnley, 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 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, 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 in the ISO 5833 described. 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 freedom is in the ISO5833 Are defined. The freedom from tack indicates in conventional PMMA bone cements that the cement has reached the processing phase after mixing of the components by swelling the polymers contained in the cement powder in the monomer. 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.

One Disadvantage of conventional PMMA bone cements for the Cement producers is that both the powder component as well as monomer component each produced double sterile packaged Need to become. That means there are at least four sterile ones Packaging for a bone cement package necessary.

One Another disadvantage of the previous PMMA bone cements for the medical user is that the liquid Monomer component with the powder component immediately before the cement application must be mixed in a mixing system or in crucibles. there Miscibility errors can easily occur which negatively affect the cement quality can influence. After mixing the monomer component with the powder component has a certain time depending on the type of cement Wait until the cement paste is tack-free and applied can. After that, the user has a more or less short processing time be positioned in the total endoprostheses or bone cavities as in kyphoplasty and Vertebroplasty can be filled up. While the processing time changes the viscosity of the cement paste as a result of the increasing swelling of the polymer particles in the monomer and the progressive polymerization of the monomer. The relatively short processing time is a significant disadvantage the previous bone cements. Particularly disadvantageous are short processing times in kyphoplasty and vertebroplasty. Desirable would be a cement, especially for vertebroplasty and kyphoplasty, where the viscosity of the cement paste during the cement application over a period of time remains largely constant for several minutes.

The The object of the invention is therefore to a PMMA paste develop as starting material for the production paste-type PMMA bone cements can be used, which overcome the problems of the known PMMA bone cements can.

The The object of the invention is achieved by a PMMA paste according to claim 1 solved. Advantageous embodiments will be apparent from the further claims.

• A Methylmethacrylat, das einen Methacrylsäuregehalt kleiner 1% und einen Wassergehalt kleiner 1% hat,
• B und mindestens einem Polymethylmethacrylat, das einen Tg (Glasübergangstemperatur) größer 65°C und eine Molmasse größer gleich 200.000 g/mol hat,

gebildet, wobei der Methylmethacrylat-Anteil so hoch ist, das die PMMA-Paste autosteril ist.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 of less than 1%,
• B and at least one polymethyl methacrylate having a Tg (glass transition temperature) greater than 65 ° C and a molecular weight greater than or equal to 200,000 g / mol,

formed, wherein the proportion of methyl methacrylate is so high that the PMMA paste is autosterilic.

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

Prefers is a polymethyl methacrylate with a molecular weight greater 300,000 g / mol, more preferably one molecular weight larger 500,000 g / mol.

advantageously, is the polymethyl methacrylate at least 80 weight percent in Methyl methacrylate soluble.

Surprised was found to be pastes containing a proportion of methyl methacrylate greater than or equal to 50% by weight autosteril are. This means that methyl methacrylate causes a killing of microbial germs in the PMMA paste. Corresponding PMMA pastes preferred in which a weight ratio of 10-50% Polymethyl methacrylate to 50-90% methyl methacrylate is present.

The The invention also relates to the use of the PMMA pastes described above for the production of paste-like one-component bone cements and bicomponent bone cements. For this purpose, the PMMA paste with organic and / or inorganic fillers and with radical initiators and / or accelerators for the production mixed by one-component and two-component bone cements.

Preferably Be organic and inorganic fillers in methyl methacrylate not swelling and a methyl methacrylate uptake of less than 25% have mixed with the PMMA paste.

Especially is the PMMA paste according to the invention for the preparation a means for fixing total endoprostheses and revision endoprostheses used.

Especially advantageous is the use of the invention PMMA paste for the production of a self-hardening filling material for vertebroplasty, kyphoplasty and femoral neck augmentation.

The PMMA paste according to the invention can also be used for the production used by local drug release systems. So is it z. B. possible, containing an antibiotic from the PMMA bone cement prepared according to the invention PMMA paste spherical or bean-shaped implants forms used as local drug release systems can.

It can additionally pharmaceutical active ingredients the groups of antibiotics, hormones, growth factors and anti-inflammatory drugs mixed with the PMMA paste according to the invention become. As antibiotics are mainly aminoglycoside antibiotics, Glycopeptide antibiotics, fluoroquinolone antibiotics, lincosamide antibiotics and oxazolidinone antibiotics. Gentamicin, tobramycin, Amikacin, teicoplanin, vancomycin, ramoplanin, dalbavancin, moxifloxaxin, Ciprofloxacin, lincosamine, clindamycin and linezolid.

The Invention is illustrated by the following examples, but without limiting the invention. Parts and percentages refer to the weight as in the rest of the description, unless otherwise stated.

Example 1 Preparation of a PMMA paste 1

It were added 500 ml of methyl methacrylate (Fluka) together with 2.0 g of Dowex 50WX2 and 2.0 g sodium sulfate in a 500 ml Erlenmeyer flask 2 Stirred at room temperature for hours and then followed by a 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 certainly. The gas chromatographically determined methacrylic acid content was 0.08% and.

It were then in 195 g of pretreated methyl methacrylate 105th g Poylmethyl methacrylate (molecular weight about 500,000 g / mol, Tg 100-106 ° C) in a 500 ml two-necked flask with exclusion of air (nitrogen flow) at room temperature with gentle stirring. The result was a bubble-free, very viscous colorless paste.

to Examination of the autosterility of the paste were spore strips (Bacillus subtilis ATCC 6633) inserted into the paste. After 72 Hours of storage at room temperature, the spore strips were removed and tested for sterility by incubation. It no growth took place.

Example 2 Preparation of a PMMA paste 2

The Paste 2 was prepared analogously to the PMMA paste 1, but with a PMMA with a molecular weight of about 700,000 g / mol and a Tg of 100-106 ° C. has been 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 with a PMMA with a molecular weight of about 1200,000 g / mol and a Tg of 100-105 ° C. has been used. The PMMA concentration was adjusted to 28%.

Example 4 Preparation of a two-component paste cement

Paste A:

It 22.80 g of the PMMA paste 1 with 1.50 g of 1-cyclohex-5-ethyl-barbituric acid, 3.15 g zirconia and 5.00 g partially soluble in MMA Polymethylmethacrylate kneaded together.

Paste B:

It 22.80 g of PMMA paste 1 were mixed with 125 mg of Aliquat 336, 0.5 mg of copper (II) -2-ethxanoate, 1.50 g 1-Cyclohex-5-ethyl-barbituric acid, 3.15 g zirconia and 5.00 g in MMA partially soluble polymethylmethacrylate (particle size <63 μm, MMA intake approx. 10%) are kneaded together.

30 g of paste A were kneaded with 30 g of paste B. The resulting Cement dough was tack-free immediately and could over a period of time be shaped by about 5 minutes. After that took place within 4 Minutes of curing the cement.

• 4-Biegefestigkeit (Luft/24 h/Raumtemperatur): 49,9 ± 0,8 MPa
• Biegemodul (Luft/24 h/Raumtemperatur): 1985 ± 53 MPa
• 4-Biegefestigkeit (Wasser/24 h/37°C): 65,5 ± 1,1 MPa
• Biegemodul (Wasser/24 h/37°C): 2604 ± 29 MPa
• 4-Biegefestigkeit (Wasser/48 h/37°C): 71,8 ± 1,7 MPa
• Biegemodul (Wasser/48 h/37°C): 2726 ± 74 MPa
• Dynstat-Schlagzähigkeit (Luft/24 h/Raumtemperatur): 3,47 ± 0,35
• Dynstat-Biegefestigkeit (Luft/24 h/Raumtemperatur): 72,71 ± 2,33

The cement paste was used to test specimens for determining the 4-point flexural strength and the flexural modulus ISO5833 and manufactured to test the Dynstat impact resistance. The 4-point flexural strength and the flexural modulus were tested after storage of the test specimens at room temperature after 24 hours and additionally after storage of the test specimens in water at 37 ° C. for 24 and 48 hours.

• 4-flexural strength (air / 24 h / room temperature): 49.9 ± 0.8 MPa
• Flexural modulus (air / 24 h / room temperature): 1985 ± 53 MPa
• 4 flexural strength (water / 24h / 37 ° C): 65.5 ± 1.1 MPa
• Flexural modulus (water / 24 h / 37 ° C): 2604 ± 29 MPa
• 4-flexural strength (water / 48 h / 37 ° C): 71.8 ± 1.7 MPa
• Flexural modulus (water / 48 h / 37 ° C): 2726 ± 74 MPa
• Dynstat impact strength (air / 24 h / room temperature): 3.47 ± 0.35
• Dynstat bending strength (air / 24 h / room temperature): 72.71 ± 2.33

Example 5 Preparation of a two-component paste cement

Paste A:

It were 21.20 g of PMMA paste 2 with 1.50 g of 1-cyclohex-5-ethyl-barbituric acid, 3.15 g zirconia and 6.60 g partially soluble in MMA Polymethylmethacrylate kneaded together.

Paste B:

It were added 21.20 g of the PMMA paste 1 with 125 mg of Aliquat 336, 0.5 mg of copper (II) -2-ethxanoate, 1.50 g 1-Cyclohex-5-ethyl-barbituric acid, 3.15 g zirconia and 6.60 g in MMA partially soluble polymethylmethacrylate (particle size <63 μm, MMA intake approx. 10%) are kneaded together.

30 g of paste A were kneaded with 30 g of paste B. The resulting Cement dough was tack-free immediately and could over a period of time be shaped by about 5 minutes. After that took place within 4 Minutes of curing the cement.

• 4-Biegefestigkeit (Luft/24 h/Raumtemperatur): 52,0 ± 1,2 MPa
• Biegemodul (Luft/24 h/Raumtemperatur): 2080 ± 52 MPa
• 4-Biegefestigkeit (Wasser/24 h/37°C): 64,2 ± 2,3 MPa
• Biegemodul (Wasser/24 h/37°C): 2548 ± 51 MPa
• 4-Biegefestigkeit (Wasser/48 h/37°C): 72,1 ± 1,5 MPa
• Biegemodul (Wasser/48 h/37°C): 2803 ± 59 MPa
• Dynstat-Schlagzähigkeit (Luft/24 h/Raumtemperatur): 4,11 ± 0,29
• Dynstat-Biegefestigkeit (Luft/24 h/Raumtemperatur): 81,23 ± 1,77

The cement paste was used to test specimens for determining the 4-point flexural strength and the flexural modulus ISO5833 and manufactured to test the Dynstat impact resistance. The 4-point flexural strength and the flexural modulus were tested after storage of the test specimens at room temperature after 24 hours and additionally after storage of the test specimens in water at 37 ° C. for 24 and 48 hours.

• 4-flexural strength (air / 24 h / room temperature): 52.0 ± 1.2 MPa
• Flexural modulus (air / 24 h / room temperature): 2080 ± 52 MPa
• 4-flexural strength (water / 24 h / 37 ° C): 64.2 ± 2.3 MPa
• Flexural modulus (water / 24 h / 37 ° C): 2548 ± 51 MPa
• 4-flexural strength (water / 48 h / 37 ° C): 72.1 ± 1.5 MPa
• Flexural modulus (water / 48 h / 37 ° C): 2803 ± 59 MPa
• Dynstat impact strength (air / 24 h / 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:

It were 20.80 g of the PMMA paste 3 with 1.50 g of 1-cyclohex-5-ethyl-barbituric acid and kneaded with 13.0 g of zirconia.

Paste B:

It 20.80 g of PMMA paste 1 were mixed with 125 mg of Aliquat 336, 2.0 mg of copper (II) -2-ethoxanoate, 1.50 g of 1-cyclohex-5-ethyl-barbituric acid and 13.0 g of zirconia 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 ge over a period of about 7 minutes be formed. This was followed within about 6 minutes, the curing of the cement.

• 4-Biegefestigkeit (Luft/24 h/Raumtemperatur): 49,8 ± 1,4 MPa
• Biegemodul (Luft/24 h/Raumtemperatur): 2271 ± 112 MPa
• 4-Biegefestigkeit (Wasser/24 h/37°C): 62,0 ± 3,8 MPa
• Biegemodul (Wasser/24 h/37°C): 3001 ± 40 MPa
• Dynstat-Schlagzähigkeit (Luft/24 h/Raumtemperatur): 3,67 ± 0,24
• Dynstat-Biegefestigkeit (Luft/24 h/Raumtemperatur): 65,78 ± 4,41

The cement paste was used to test specimens for determining the 4-point flexural strength and the flexural modulus ISO5833 and manufactured to test the Dynstat impact resistance. The 4-point flexural strength and the flexural modulus were tested after storage of the test specimens at room temperature in air and at 37 ° C. in water after 24 hours.

• 4-flexural strength (air / 24 h / room temperature): 49.8 ± 1.4 MPa
• Flexural modulus (air / 24 h / room temperature): 2271 ± 112 MPa
• 4-flexural strength (water / 24 h / 37 ° C): 62.0 ± 3.8 MPa
• Flexural modulus (water / 24 h / 37 ° C): 3001 ± 40 MPa
• Dynstat impact strength (air / 24 h / room temperature): 3.67 ± 0.24
• Dynstat bending strength (air / 24 h / room temperature): 65.78 ± 4.41

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited non-patent literature

• - Charnley, J .: Anchorage of the femoral head prosthesis of the shaft of the femur. J. Bone Joint Surg. 42 (1960) 28-30. [0002]
• - ISO 5833 [0003]
• - ISO5833 [0003]
• - ISO5833 [0028]
• - ISO5833 [0032]
• - ISO5833 [0036]

Claims (11)

PMMA paste made from a mixture of a. methyl methacrylate, which has a methacrylic acid content of less than 1% and a water content has less than 1%, and b. at least one polymethylmethacrylate, the one Tg greater than 65 ° C and a molecular weight greater than or equal to 200,000 g / mol, the Methyl methacrylate content is so high that the PMMA paste autosteril is. A PMMA paste according to claim 1, wherein the polymethylmethacrylate has a molecular weight greater than 300,000 g / mol. PMMA paste according to claim 2, wherein the molecular weight is greater than 500,000 g / mol. PMMA paste according to one of the preceding claims, characterized in that the polymethyl methacrylate B at least to 80% by weight in methyl methacrylate A is soluble. PMMA paste according to claims 1-3 characterized in that a weight ratio of 10-50% B to 50-90% A is present. Paste-like one-component bone cements and bicomponent bone cements containing a PMMA paste after one of claims 1-5. Use of a PMMA paste according to one of the claims 1-5 for the preparation of a means for fixation of total endoprostheses and revision endoprostheses. Use of a PMMA paste according to one of the claims 15 for the preparation of a self-curing filling material for vertebroplasty, kyphoplasty and femoral neck augmentation. Use of a PMMA paste according to one of the claims 1-5 for the preparation of local drug delivery systems. Process for the preparation of paste-like One-component bone cements or two-component bone cements, characterized in that a PMMA paste after a of claims 1-5 with organic and / or inorganic Fillers and with radical initiators and / or Accelerators is mixed. Method according to claim 7, characterized in that organic and inorganic fillers in methylmethacrylate not swelling and a methyl methacrylate uptake of less than 25% have to be mixed with the PMMA paste.