JP4555804B2 - Bioactive bone cement composition, method for producing the same, and kit for producing the same - Google Patents

Description

  The present invention relates to a bioactive bone cement composition having an apatite forming ability in a body fluid environment.

Bone cement is widely used around the world as a filler for bone defects or as an adhesive for fixing metal artificial joints such as artificial hip joints to surrounding bones. Among them, the PMMA bone cement does not form apatite in vivo like glass ceramics because it does not have biological activity in itself. As a result, since it is covered with a fibrous cap and isolated from surrounding bone, there has been a problem that loosening occurs between the artificial joint and the bone over a long period of time. So far, as an attempt to impart bone-binding property to cement, a PMMA bone cement mixed with glass containing calcium or crystallized glass powder has been proposed (see Patent Document 1). Although it exhibits apatite-forming ability, Ca ²⁺ ions are eluted from the glass or crystallized glass powder, so that the strength of the cement may decrease for a long time after being implanted in the living body. On the other hand, bone cement containing anatase-type titanium dioxide has been proposed as a technique for suppressing deterioration of cement strength due to long-term use (see Patent Document 2). Furthermore, bone cement containing rutile titanium oxide as an additional inorganic filler for strength enhancement, preferably in an amount in the range of 0.1 to 10% by weight has been proposed (see Patent Document 3).

JP-A-11-164879 JP 2004-201869 A International Publication No. 2002/102427 Pamphlet

  The bone cement described in the above-mentioned Patent Document 2 has (1) no elution of glass-derived ions, which is a problem when crystallized glass-containing bone cement is used, and no decrease in strength due to that, (2) artificial Although the function is improved in that the mechanical strength of the bone can be increased, a bone cement having further excellent apatite forming ability is demanded.

  As a result of diligent research to solve the above-mentioned problems, the present inventors have found that when at least 15% by weight of rutile type titanium dioxide is mixed in a bone cement material, it has an apatite forming ability, and the forming ability is the same amount. The knowledge that it is superior to the case of using anatase type titanium dioxide was obtained, and the present invention was completed. That is, the present invention comprises rutile titanium dioxide particles and a polymethacrylate polymer, and contains at least 15% by weight of rutile titanium dioxide particles based on the total amount of the rutile titanium dioxide particles and the polymethacrylate polymer. A bioactive bone cement composition.

  Since the bioactive bone cement composition of the present invention contains at least 15% by weight of rutile type titanium dioxide particles, it has excellent apatite forming ability in simulated body fluid.

  The present invention is a bioactive bone cement composition comprising rutile titanium dioxide particles and a polymethacrylate polymer, wherein at least the rutile titanium dioxide particles are contained in the total amount of the rutile titanium dioxide particles and the polymethacrylate polymer. It is used in vivo containing 15% by weight.

  The titanium dioxide particles to be blended in the bioactive bone cement composition of the present invention can be used without particular limitation as long as the crystal system is a rutile type. In addition, anatase type titanium oxide may be mixed in the range which does not impair the effect of this invention, or it may be a mixed phase of an anatase type and a rutile type. The particle shape is known in the form of plates, flakes, needles, rods, fibers, columns, etc. in addition to granular or indeterminate shapes obtained by ordinary industrial processes such as sulfuric acid method, chlorine method, gas phase hydrolysis method, etc. Various shapes can also be used. The particle size of titanium dioxide is not particularly limited, and a range of 0.01 to 100 μm can be used. However, in terms of affinity with a polymer to be blended with bone cement, the average particle size is 0.01 to The range of 10 μm is desirable. Further, in the case of using titanium dioxide having an anisotropic shape such as a plate shape, a flake shape, or a rod shape, it is desirable that the average longest diameter is in the range of 0.1 to 10 μm because the affinity with the polymer is excellent. Further, the titanium dioxide particles used may be those in which individual primary particles are dispersed, or those obtained by agglomerating primary particles into secondary particles. Furthermore, in the present invention, it is desirable to use high purity rutile titanium dioxide particles with few impurities. For example, it is desirable to use a known gas phase synthesis method such as a chlorine method or a gas phase hydrolysis method because high-purity rutile titanium dioxide particles can be easily obtained. In addition, in order to improve the affinity between the titanium dioxide particles and the polymer, the surface of the titanium dioxide particles may be a known organic substance such as a silane coupling agent, silica, alumina, etc. as long as the effects of the present invention are not impaired. You may use what coat | covered a small amount with the well-known inorganic substance.

  The polymethacrylate polymer blended in the bioactive bone cement composition of the present invention is obtained by polymerizing a methacrylate monomer, and the polymerized polymethacrylate polymer is blended in the bioactive bone cement composition in advance. May be. Examples of the methacrylate polymer include methyl methacrylate (MMA) such as methyl methacrylate monomer (Wako Pure Chemical Industries, Ltd.) and ethyl methacrylate (EMA). The polymethacrylate polymer is selected from the group consisting of polymethyl methacrylate (PMMA), polyethyl methacrylate (PEMA), polybutyl methacrylate (PBMA) and the like; methyl methacrylate and styrene, ethyl methacrylate and methyl acrylate Copolymers combining at least one type; 2,2-bis [4- (3-methacryloxy-2-hydroxypropoxy) phenyl] propane (Bis-GMA), 2,2-bis (4-methacryloxyethoxyphenyl) propane (Bis-MEPP), triethylene glycol dimethacrylate (TEGDMA), diethylene glycol dimethacrylate (DEGDMA), ethylene glycol dimethacrylate (EGDMA), etc. Including a polymer of acrylate-based monomers. When blending a pre-polymerized polymethacrylate polymer, it is desirable to use a polymer powder having a weight average molecular weight of at least 10,000. For example, trade name Techpolymer (registered trademark) MB-4C (weight average molecular weight: 1, 200,000, Sekisui Plastics Co., Ltd.) can be decomposed by γ-ray irradiation, and a polymethylmethacrylic polymer powder having a weight average molecular weight of 270,000 can be used.

  The compounding amount of the rutile type titanium dioxide particles is at least 15% by weight, preferably 15% by weight to 80% by weight, more preferably 20% by weight based on the total amount of the rutile type titanium dioxide particles and the polymethacrylate polymer. % To 80% by weight. The bone cement composition of the present invention is desirable in terms of mechanical strength and apatite forming ability when embedded in a living body at this blending weight ratio. If the blending amount of the rutile type titanium dioxide particles is less than the above range, the apatite forming ability is not sufficient, and if the blending amount is more than the above range, the apatite forming ability corresponding to the blending amount cannot be expected, but rather the strength is lowered. It will be easier to come.

  The bone cement composition of the present invention can be used as a so-called artificial bone in a paste-like or molded state according to its use form. The paste-like bone cement composition of the present invention can be applied, for example, to a bone defect part in a living body and cured to be used for filling the bone defect part. The paste-like composition becomes a cured body within a short time in the body, and can produce a strong bond with a bone or an artificial joint. The bone cement composition of the present invention that has become a hardened body exhibits bioactivity that forms an apatite layer in vivo and binds to bone via the apatite layer. In addition, when an artificial bone that is not bio-bonding or weak is embedded in a bone defect, the living body is surrounded by a fibrous coating and is isolated from the surrounding bone, so the artificial bone is combined with the surrounding natural bone. The pasty bioactive bone cement composition of the present invention is used to bind the two. The paste-like bone cement composition of the present invention can also be used for fixation of artificial joints.

  Further, the molded bone cement composition of the present invention is a paste-like composition that has been cured and molded in advance using a desired mold having good releasability in vitro, and embedded in a bone defect. Can be used.

  The following present invention is a method for producing the bioactive bone cement composition, characterized in that the methacrylate monomer is polymerized in the presence of rutile titanium dioxide particles and a polymerization initiator. When the polymerization initiator comes into contact with the methacrylate monomer, the polymerization reaction proceeds, and a paste-like composition having a viscosity effective for filling the bone defect or bonding the artificial joint to the surrounding bone is obtained. The pasty composition cures over time. The polymerization reaction may be performed ex vivo, or each of the above components may be introduced into a site requiring an artificial bone in vivo and polymerized in situ. A living body formed by in vitro forming a paste-like bioactive bone cement composition of the present invention in advance and then inserting it into a container having a desired shape and solidifying before hardening. An active bone cement composition may also be used.

  Examples of the polymerization initiator include benzoyl peroxide, tert-butyl peroxide, lauroyl peroxide, azobisisobutyronitrile, and the like. Of these, it is desirable to use benzoyl peroxide as a polymerization initiator because the polymerization reaction starts quickly and the reaction is easily sustained.

  In the present invention, the polymerizable monomer is further added in the presence of a polymethacrylate polymer and / or a polymerization accelerator, that is, in the presence of rutile-type titanium dioxide particles, a polymerization initiator, and further a polymer and / or a polymerization accelerator. Polymerization is desirable because the polymerization reaction proceeds more rapidly and a bioactive bone cement composition is obtained.

  By using the polymethacrylate polymer in advance, the amount of the methacrylate monomer used can be reduced, and the polymerization reaction time can be shortened. A desirable range of the blending ratio of the methacrylate monomer and the polymethacrylate polymer is 5: 1 to 1: 5 by weight. In addition, the presence of a polymerization accelerator allows the polymerization reaction to proceed more rapidly. Examples of the polymerization accelerator include N, N-dimethyl-p-toluidine, tri-dimethylaminomethylphenol and the like. Of these, N, N-dimethyl-p-toluidine is preferably used as a polymerization accelerator because the polymerization reaction proceeds rapidly.

  The blending amounts of the polymerization initiator and the polymerization accelerator are both 0.1 to 10 parts by weight, preferably 1 to 5 parts by weight with respect to 100 parts by weight of the methacrylate monomer. If the blending amount is less than the above range, the polymerization reaction is difficult to proceed, and even if the blending amount is increased, the polymerization initiator and the polymerization accelerator tend to remain in the final bioactive bone cement composition, which is not desirable.

  Furthermore, the present invention includes a kit for producing the bioactive bone cement composition containing rutile titanium dioxide particles, a methacrylate monomer and a polymerization initiator. Among these kits, those containing rutile titanium dioxide particles, a methacrylate monomer and a polymerization initiator and at least a methacrylate monomer and a polymerization initiator are separately packaged are desirable. In each of the above components, at least the methacrylate-based monomer that reacts by contacting with each other and the polymerization initiator are separately packaged and stored, and when necessary, they are mixed at a necessary place to obtain the present invention. A bioactive bone cement composition can be obtained. When the polymethacrylate-based polymer and / or polymerization accelerator is further included, these additional components may be additionally provided. Usually, those components that do not react by contact with each other are enclosed and stored. It is convenient to take the form of carrying. For example, rutile titanium dioxide particles, polymethacrylate polymers and polymerization initiators are usually in a solid state and do not react with each other, so they are stored together in one container, while methacrylate monomers and polymerization accelerators are stored. Since they are normally in a liquid state and do not react with each other, it is convenient to carry them if they are stored in two separate containers in a separate package, and the reaction operation is also simple, so the necessary scenes The bioactive bone cement of the present invention can be produced quickly.

  The bioactive bone cement of the present invention can form apatite in vivo and can be combined with bone via the apatite. In addition, apatite formation ability can be normally evaluated by being immersed in a simulated body fluid. As a simulated body fluid, T.W. Kokubo, H .; Kushitani, S .; Sakka, T .; Kitsugi and T.K. Yamamuro, “Solutions ble to reproductive in vivo surface-structure changes in bioactive glass-ceramic A-W”, J. Am. Biomed. Mater. Res. 24, 721-734 (1990) and the like (SBF: Simulated Body Fluid). The simulated body fluid refers to an aqueous solution having an inorganic ion concentration almost equal to that of human plasma, and the composition thereof is as shown in Table 1.

  Next, examples of the present invention will be described, but the present invention is not limited thereto.

Example 1
Rutile type titanium dioxide fine particles (trade name CR-EL; Ishihara Sangyo Co., Ltd., average particle size 0.25 μm) 3 g, PMMA powder as polymethacrylate polymer (average molecular weight: 270000, Techpolymer (registered trademark) MB-4C (Sekisui) Chemical Co., Ltd. Co) γ-irradiated product) 1.2 g and benzoyl peroxide 0.072 g as a polymerization initiator were mixed, and 1.8 g of MMA as a methacrylate monomer and N, N- After adding 0.036 g of dimethyl-p-toluidine, it was placed in a Teflon (registered trademark) jig and cured. A 15 × 10 × 2 mm sample piece was cut out from the cured product to obtain a bioactive bone cement composition (sample A) of the present invention. The content of the rutile titanium dioxide particles of Sample A (the amount of rutile titanium dioxide particles based on the total amount of rutile titanium dioxide particles and PMMA) is 50% by weight.

Comparative Example 1
A biological sample of a comparative sample was treated in the same manner as in Example 1 except that anatase type titanium dioxide fine particles (trade name ST-41; Ishihara Sangyo Co., Ltd., average particle size 0.15 μm) were used instead of the rutile type titanium dioxide fine particles. An active bone cement composition (Sample B) was obtained.

  Sample A and Sample B obtained in Example 1 and Comparative Example 1 were immersed in a simulated body fluid having the composition shown in Table 1 for a predetermined period. Scanning electron microscope observation of the sample surface after 3 days and 6 days after immersion was performed, and electron micrographs of both samples are shown in FIGS. 1 and 2, when 50% by weight of titanium dioxide particles are blended, sample A containing rutile type titanium dioxide has a faster apatite formation on its surface than sample B containing anatase type titanium dioxide. It was found that they were formed densely.

Example 2
5.4 g of rutile type titanium dioxide fine particles (trade name CR-EL; Ishihara Sangyo Co., Ltd., average particle size 0.25 μm), PMMA powder as polymethacrylate polymer (average molecular weight: 189000, Sekisui Plastics Co., Ltd.) 6 g and 0.45 g of benzoyl peroxide as a polymerization initiator were mixed, and 9.52 g of MMA as a methacrylate monomer and 0.08 g of N, N-dimethyl-p-toluidine as a polymerization accelerator were added to the mixed powder, and then Teflon was added. It was put into a (registered trademark) jig and cured. A 15 × 10 × 4 mm sample piece was cut out from the cured product to obtain a bioactive bone cement composition of the present invention (Sample C). The content of the rutile type titanium dioxide particles in Sample C is 17.7% by weight.

Comparative Example 2
A biological sample of a comparative sample was treated in the same manner as in Example 2 except that anatase-type titanium dioxide fine particles (trade name ST-41; Ishihara Sangyo Co., Ltd., average particle size 0.15 μm) were used instead of rutile-type titanium dioxide fine particles. An active bone cement composition (Sample D) was obtained.

  Sample C and Sample D obtained in Example 2 and Comparative Example 2 were immersed in a simulated body fluid in the same manner as in Example 1. Scanning electron microscope observations of the sample surface after 3 days, 7 days and 14 days after immersion were shown in FIG. 3 and FIG. 3 and 4, even when 17.7 wt% of titanium dioxide particles were blended, sample C blended with rutile titanium dioxide compared to sample D blended with anatase titanium dioxide (Comparative Example 2) It was found that not only apatite was formed quickly, but also densely formed.

Comparative Example 3, Examples 3 and 4
In accordance with the composition of Table 2 below, the rutile type titanium dioxide fine particles (trade name CR-EL; Ishihara Sangyo Co., Ltd., average particle size 0) are adjusted so that the compounding amount of rutile type titanium dioxide is 10% by weight, 15% by weight and 20% by weight. .25 μm), PMMA powder (average molecular weight: 135000, Sekisui Kasei) and benzoyl peroxide are mixed, MMA and N, N-dimethyl-p-toluidine are added to the mixed powder, and then Teflon (registered trademark) Seiji is used. It was put into a tool and cured. A 15 mmφ × 4 mm sample piece was cut out from the cured product to obtain a bioactive bone cement composition (samples E, F and G).

  The samples (E, F, and G) obtained in Comparative Example 3 and Examples 3 and 4 were immersed in the simulated body fluid in the same manner as in Example 1. The sample after 14 days of immersion was observed with a scanning electron microscope, and an electron micrograph of each sample is shown in FIG. The formation of apatite was confirmed in samples (F and G) containing 15% by weight or more of titanium dioxide, and was not observed in sample (E) containing 10% by weight. From this, it was found that in the bone cement composition containing rutile type titanium dioxide, in order to express bioactivity (apatite forming ability), the blending amount is required to be at least 15% by weight. It was also found that a bone cement composition containing at least 20% by weight of rutile type titanium dioxide has excellent bioactivity.

Scanning electron micrographs of the surface of Sample A (Example 1) after 3 days and 6 days after immersion in simulated body fluid are shown. Scanning electron micrographs of the surface of Sample B (Comparative Example 1) after 3 days and 6 days after simulated body fluid immersion are shown. Scanning electron micrographs of the surface of Sample C (Example 2) after 3 days of simulated body fluid immersion (SBF3d), after 7 days (SBF7d) and after 14 days (SBF14d) are shown. Scanning electron micrographs of the surface of Sample D (Comparative Example 2) after 3 days of simulated body fluid immersion (SBF3d), after 7 days (SBF7d) and after 14 days (SBF14d) are shown. Scanning electron micrographs of the surfaces of Sample E (Comparative Example 3), F (Example 3), and G (Example 4) 14 days after simulated body fluid immersion (SBF14d) are shown.

Claims (16)

It contains rutile titanium dioxide particles having an apatite-forming ability and a polymethacrylate polymer, and contains at least 15% by weight of rutile titanium dioxide particles based on the total amount of the rutile titanium dioxide particles and the polymethacrylate polymer. Bioactive bone cement composition.   2. The bioactive bone cement composition according to claim 1, comprising 15 to 80% by weight of rutile titanium dioxide particles based on the total amount of rutile titanium dioxide particles and polymethacrylate polymer.   2. The bioactive bone cement composition according to claim 1, comprising 20 to 80% by weight of rutile titanium dioxide particles based on the total amount of rutile titanium dioxide particles and polymethacrylate polymer.   The bioactive bone cement composition according to claim 1, which is in a paste form.   The bioactive bone cement composition according to claim 1, wherein the bioactive bone cement composition is molded.   The method for producing a bioactive bone cement composition according to claim 1, wherein a methacrylate monomer is polymerized into a polymethacrylate polymer in the presence of rutile titanium dioxide particles and a polymerization initiator.   The method according to claim 6, further comprising polymerizing a methacrylate monomer in the presence of a polymethacrylate polymer and / or a polymerization accelerator to form a polymethacrylate polymer.   The production method according to claim 7, wherein the methacrylate monomer is polymerized in the presence of a polymethacrylate polymer having a weight average molecular weight of at least 10,000 and / or a polymerization accelerator.   The production method according to claim 6, wherein the polymerization initiator is benzoyl peroxide.   The production method according to claim 7, wherein the polymerization accelerator is N, N-dimethyl-p-toluidine.   The production method according to claim 7, wherein the blending ratio of the methacrylate monomer and the pre-existing polymethacrylate polymer is in the range of 5: 1 to 1: 5 by weight ratio.   The manufacturing method according to claim 6, further comprising a step of molding after polymerization.   The production method according to claim 6, wherein polymerization is performed in vivo.   The kit for producing the bioactive bone cement composition according to claim 1, comprising at least rutile titanium dioxide particles, a methacrylate monomer, and a polymerization initiator.   The kit according to claim 14, wherein at least the methacrylate monomer and the polymerization initiator are separately packaged.   The kit according to claim 15, further comprising a polymethacrylate polymer and / or a polymerization accelerator.