JP2017086814A - Adhesive bone prosthetic material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an adhesive bone prosthetic material having high compression strength, having excellent adhesiveness to biological tissue, and being suitable for vertebroplasty.SOLUTION: An adhesive bone prosthetic material comprises the following components: a. a polyethylene glycol ether of a branched alcohol having an amino group at the terminal; b. tris-succinimidyl citrate and/or tris-sulfosuccinimidyl citrate; c. α-tricalcium phosphate particle, d. hydroxy apatite nanoparticle; and e. buffer, wherein [component c + component d] (weight%) is 55-75 weight% of the total weight of the adhesive bone prosthetic material, and [component d/component c] (weight ratio) is 1/99-15/85.SELECTED DRAWING: None

Description

  The present invention relates to an adhesive bone filler containing calcium phosphate, and more specifically, a bone filler containing α-tricalcium phosphate and hydroxyapatite in a predetermined ratio to form a cured product having excellent adhesive strength and compressive strength to tissue. About.

  Vertebroplasty is performed in which a bone filling agent is injected into the vertebral body to reinforce the bone. The bone filling material mainly includes polymethacrylic and calcium phosphate. The former is quickly cured and easily shaped, but is not biocompatible and has been reported to cause complications such as pulmonary embolism and spinal cord injury. Calcium phosphate in the latter is a bone biomaterial and has no problem with biocompatibility, but does not have mechanical strength comparable to the former, and research is being conducted to increase the strength.

  The present inventor has developed a calcium phosphate-based bone filler and proposed various prescriptions in order to increase the mechanical strength and reduce the risk of fracture of the vertebral bone adjacent to the surgical site (for example, Patent Document 1). .

WO2014 / 142132

  The hardened material of the bone filling material shows excellent bending strength, but in vertebroplasty, compression strength is often more important than bending strength. Also, adhesion to living tissue is important. Then, this invention aims at improving the said bone filling agent from these viewpoints.

The present inventor has found that, while proceeding with the improvement of the bone filler, it can be remarkably improved in terms of compressive strength and adhesive strength by means such as prescription. That is, the present invention is as follows.
The following ingredients:
a. A polyethylene glycol ether of a branched alcohol having an amino group at the terminal b. Trissuccinimidyl citrate and / or trissulfosuccinimidyl citrate c. α-tricalcium phosphate particles d. Hydroxyapatite nanoparticles e. An adhesive bone filler containing a buffer solution,
[Component c + Component d] (wt%) is 55 to 75 wt% of the total weight of the adhesive bone filler, and
[Component d / Component c] (weight ratio) is 1/99 to 15/85,
Adhesive bone filler.

  The adhesive bone filler of the present invention (hereinafter sometimes referred to as “bone filler”) is excellent in compressive strength and adhesive strength. α-Tricalcium phosphate becomes hydroxyapatite by hydration and integrates with bone. Therefore, it is expected that the strength can be improved by adding a large amount of hydroxyapatite from the beginning. In fact, in Patent Document 1, when the ratio of hydroxyapatite to α-tricalcium phosphate is decreased, a decrease in the three-point bending strength is observed. Has been. However, in terms of compressive strength, it was found that it is better to reduce the proportion of hydroxyapatite, contrary to this expectation. In addition, by increasing the relative amount of α-tricalcium phosphate, the concentration of trissuccinimidyl citrate and / or trissulfosuccinimidyl citrate, which acts as a crosslinking agent and curing accelerator, is increased. It was also found that the adhesive strength can be improved exponentially.

FIG. 1 is a graph showing changes in compressive strength depending on the particle diameter of α-tricalcium phosphate. FIG. 2 is a graph showing changes in compressive strength according to [hydroxyapatite / (hydroxyapatite + α-tricalcium phosphate)] (%). FIG. 3 is a graph showing a change in injectability (injectability) according to [hydroxyapatite / (hydroxyapatite + α-tricalcium phosphate] (%). FIG. 4 shows changes in adhesive strength according to [trissuccinimidyl citrate and / or trissulfosuccinimidyl citrate / polyalkylene glycol ether of polyhydric alcohol having an amino group at its terminal] (equivalent ratio). It is a graph which shows. FIG. 5 is an electron micrograph (× 250) of the ivory substrate surface after the adhesive strength test. FIG. 6 is an electron micrograph (× 250) of a cross section of the ivory substrate after the adhesive strength test.

The adhesive bone filling material of the present invention comprises the following components:
a. A polyalkylene glycol ether of a polyhydric alcohol having an amino group at the terminal b. Trissuccinimidyl citrate and / or trissulfosuccinimidyl citrate c. Hydroxyapatite d. α-tricalcium phosphate, and e. Buffer solution.
Hereinafter, it demonstrates for every component.

<Component a. Polyalkylene glycol ether of polyhydric alcohol having amino group at terminal>
Component a (hereinafter sometimes referred to as “a.polyether”) is a polyethylene glycol ether of a polyhydric alcohol, and is a polymer having an amino group at the end of the polyethylene glycol chain. Examples of the polyhydric alcohol include divalent to hexavalent alcohols such as ethylene glycol, propylene glycol, neopentyl glycol, glycerin, trimethylolpropane, pentaerythritol, and sorbitol. Among these, trivalent or higher alcohols are preferable, Particularly preferred are glycerin and pentaerythritol.

  Examples of the polyalkylene glycol include polyethylene glycol, polypropylene glycol, and mixtures thereof, among which polyethylene glycol is preferable.

  A terminal amino group is present at the end of each ether chain and may be a primary, secondary, or tertiary amino group. From the viewpoint of reactivity, a primary amino group is preferred.

  Component a preferably has a molecular weight (Mw) of 5,000 to 100,000, more preferably 10,000 to 30,000. Note that the polyalkylene glycol ether chains extending by reacting with the hydroxyl groups of the polyhydric alcohol do not have to have the same chain length.

As component a, for example, tetraamine-polyethylene glycol (TAPEG) described in WO2010 / 070775 can be used, of which a polymer represented by the following formula (1) is preferable:


In the formula _(1), n 1 ~n ₄ is an integer of 25 to 250, preferably 50 to 150 integer. n _{1 to} n ₄ may be the same. R ^{1 to} R ⁴ are C _{2 to} C ₄ alkylene groups, preferably C ₃ alkylene groups. The polymer has high biocompatibility and has a clinical record.

<Component b. Trissuccinimidyl citrate and / or trissulfosuccinimidyl citrate>
Component b (hereinafter may be referred to as “b. Citric acid”) contains component a. Acts as a crosslinking agent for the polyether and acts as a curing accelerator after the succinimidyl group or sulfosuccinimidyl group is eliminated, component d. Promotes hydration hardening of calcium phosphate. These compounds have also been confirmed to be excellent in biocompatibility.

  As described above, the component b has both functions of a crosslinking agent and a curing accelerator. As shown in the examples described later, the adhesiveness of the cured product increases remarkably when the amount of component b is increased. However, if the amount is too large, there is a concern about irritation to the living body. Therefore, it is preferable that the maximum amount is contained in a range where the irritation does not occur.

<Component c. α-Tricalcium Phosphate Particles>
α-Tricalcium phosphate (hereinafter sometimes referred to as “α-TCP”) is represented by the formula: Ca ₃ (PO ₄ ) ₂ and is described later as a component e. It reacts with the buffer solution and water in the living body to form a hydrated cured product via hydroxyapatite. The average particle diameter (D ₅₀ ) of α-tricalcium phosphate is preferably small, but if it is less than 3.5 μm, it is difficult to obtain and handling is also somewhat difficult. Therefore, in practice, the average particle size is 3.5 μm to 9 μm, preferably 3.5 μm to 6 μm. Note that the surface of the α-TCP particles may be treated with a silane compound or the like as long as the object of the present invention is not impaired.

<Component d. Hydroxyapatite nanoparticles>
Hydroxyapatite (hereinafter sometimes referred to as “HAp”) is represented by the formula: Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ and is also the main component of bone. The nanoparticles used in the present invention are preferably spherical and have an average particle diameter (D ₅₀ ) of 10 nm to 100 nm, more preferably 10 nm to 50 nm.

  The nanoparticles may be added or doped with a metal in order to further promote the bone forming ability. Examples of the metal include zinc, titanium, strontium, copper, and silver. These metals are added on the nanoparticles in the form of a salt, for example, a phosphate, and the amount thereof is preferably about 0.01 to 0.5 mol% based on hydroxyapatite.

<Component e. Buffer>
The buffer contains component c. In addition to the action of hardening the α-tricalcium phosphate particles, it gives fluidity to the bone filler and improves the injectability to the application site. The buffer may be any buffer as long as the pH is 5.8 to 8.0, preferably 7.0 to 8.0. For example, phosphate buffer, Tris buffer, HEPES buffer, and borate buffer can be mentioned, and phosphate buffer is preferably used.

<Other additives>
In addition to the above components, the bone filling material of the present invention may contain a conventional additive in an amount that does not impair the object of the present invention. Examples of the additive include a surfactant, a viscosity modifier, an antibacterial agent, a dye, and an antioxidant.

About the compounding quantity of said each component, it is as follows. First, component c. α-tricalcium phosphate particles and components d. Hydroxyapatite nanoparticles have the following relationship:
[Component c + Component d] (% by weight) is 55 to 75% by weight of the total weight of the bone filler, and
[Component d / Component c] (weight ratio) is 1/99 to 15/85,
Meet.
When satisfy | filling the said relationship, it becomes a hardened | cured material excellent in compressive strength and adhesive strength. Preferably, [Component c + Component d] (wt%) is 59 to 67 wt% of the total weight of the bone filler, and [Component d / Component c] (weight ratio) is 2/98 to 4/96.

  Component a. The blending amount of the polyether is preferably 5 to 10% by weight, more preferably 5 to 8% by weight, based on the total weight of the bone filling material.

  Component a. Polyether and component b. Citric acid can obtain a cured product if [component b / component a] (equivalent ratio) is 0.8 or more, preferably the corresponding ratio is 1.5 to 9, more preferably 1. .9-9. When the amount ratio is 1.5 or more, the adhesive strength of the cured product is significantly improved. This is considered to be because a synergistic effect of an increase in the crosslinking density by the polyether and an increase in the hydration hardening of α-TCP is obtained.

  Component e. The blending amount of the buffer solution is preferably adjusted as appropriate in consideration of the injectability (injectability) and applicability of the bone filling material when [component c + component d] is dispersed. Typically, [component c + component d] / [component e] (weight / volume) is 1.5 / 1 to 3/1, preferably 2/1 to 2.5 / 1.

  The bone filling material of the present invention weighs each of the above components so as to have the above quantitative ratio, and mixes them by a known mixing or kneading means such as a kneader, roll, extruder, propeller mixer, high speed mixer, dissolver, homogenizer, etc. Can be made by doing. There is no limitation on the order of mixing, for example component a. Only polyether is used as component e. You may prepare by melt | dissolving in a buffer solution, adding another component to this solution, and knead | mixing.

  When the storage period from the preparation of the bone filling material to its use is long, it is preferably provided as a two-drug type. In that case, for example, component a and component e may be used as a liquid first agent, component b may be used as a powdery second agent together with components c and d, and both may be mixed immediately before use. Alternatively, component e. The buffer solution may be divided into both the first agent and the second agent, and the second agent may also be liquid, for example, in the form of a dispersion, and both may be applied simultaneously to the affected area with a syringe.

  The bone filling agent is applied by applying or injecting into a fracture part or a bone defect part. After the operation, it is confirmed by X-ray examination etc. that the intended location is covered. Although it depends on the degree of bone defect etc., the change in adhesive strength is about 70-80% cured in 5 minutes, 90% or more cured in about 6 hours, There was no significant increase. Actually, since water exists in the structure, it is considered that the hardness can be reached with a few tens of minutes and no problem.

  EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to these.

[Reference Examples 1-3]
Component c. In order to investigate the influence of the average particle diameter of α-tricalcium phosphate, the change in the compressive strength of the cured product was examined when only the particle diameter of component c was changed without compounding component d.
<Preparation of bone filler>
Each component was mixed with the composition shown in Table 1 to prepare a bone filling material. First, component a was dissolved in component e to form a solution, and the remaining components were added to the solution and mixed. The results are shown in Table 1 and FIG.
Details of each component are as follows.
Component a. Tetraamine-polyethylene glycol (TAPEG), Mw 20,000
Component b. Trissuccinimidyl citrate component c. α-tricalcium phosphate, D ₅₀ : 3.5 μm, 4.4 μm, 8.8 μm
Component e. Phosphate buffer, pH: 7.0

<Measurement of compressive strength>
The prepared bone filling material was poured into a cylindrical mold and allowed to stand in a 37 ° C. incubator in a saturated steam atmosphere for 24 hours, and then removed from the mold to obtain a cylindrical cured sample having a diameter of 6 mm and a height of 12 mm. Using an autograph (manufactured by Shimadzu Corporation), the compressive strength was measured at a crosshead speed of 0.5 mm / min. The results are shown in Table 1 and FIG.

  From the above results, it can be seen that as the average particle size of α-tricalcium phosphate decreases, the compressive strength increases rapidly. However, from the viewpoint of handleability, it was determined that the particle size is preferably 3.5 μm or more. Therefore, in all the following experiments, those having a particle size of 3.5 μm were used.

[Examples 1-6, Comparative Examples 1-18]
The effects of [component c + component d] and [component d / component c] on compressive strength and injectability were examined.
<Preparation of bone filler>
Each component was mixed with each composition of Tables 2-4, and the bone filling agent was prepared. First, component a was dissolved in component e to form a solution, and the remaining components were added to the solution and mixed.
Details of each component are as follows.
Component a. Tetraamine-polyethylene glycol (TAPEG), Mw 20,000
Component b. Trissuccinimidyl citrate component c. α-tricalcium phosphate, D ₅₀ : 3.5 μm
Component d. Hydroxyapatite nanoparticles, spherical, D ₅₀ : 40 nm
Component e. Phosphate buffer, pH: 7.0

The compressive strength was evaluated as described above, and the injectability was evaluated by the following method.
<Measurement of injectability>
1 mL of the prepared bone filling material was filled into a 2.5 mL plastic luer lock syringe. The syringe is set on an autograph, and the plunger of the syringe is pushed into the microtube until the force of pushing the plunger reaches 250 N at a crosshead speed of 24 mm / min. %). The results are shown in Tables 2-4. In the table, each data is an average value repeated three times, and "-" indicates that data was not taken.

  The result of compressive strength is shown in FIG. 2, and the result of injectability is shown in FIG. In these drawings, the horizontal axis represents [component d / (component c + component d)] (%). For example, 10% corresponds to [component d / component c] = 10/90. From these figures, it can be seen that when [d / c] (weight ratio) is 5/95 or less, both the compressive strength and the injectability are excellent.

[Examples 7 to 10, Comparative Examples 19 to 22]
Component b. Changes in the adhesive strength of the cured product due to [component b / component a] (equivalent ratio) were examined with the amount of components other than citric acid almost fixed.
<Preparation of bone filler>
Each component was mixed with the composition shown in Table 5 to prepare a bone filling material. First, component a was dissolved in component e to form a solution, and the remaining components were added to the solution and mixed.
Details of each component are as follows.
Component a. Tetraamine-polyethylene glycol (TAPEG), Mw 20,000
Component b. Trissuccinimidyl citrate component c. α-tricalcium phosphate, D ₅₀ : 3.5 μm
Component d. Hydroxyapatite nanoparticles, spherical, D ₅₀ : 40 nm
Component e. Phosphate buffer, pH: 7.0

  Furthermore, Biopex (trade name: calcium phosphate bone cement) was used as Comparative Example 21, and Endurance (trade name: polymethacrylic bone cement) was used as Comparative Example 22.

<Measurement of adhesive strength>
Place a 4x5x12mm Teflon (registered trademark) mold on an ivory section with a diameter of 6mm, inject each bone filler into it, and let it stand at room temperature for 24 hours. A piece was made. Using a texture analyzer (TA.XT Plus, manufactured by Eihiro Seiki Co., Ltd., peel rate: 0.1 mm / second), the adhesive strength between the cured specimen and the ivory slice was measured. The test was performed at n = 6, and the average value was calculated.

The results are shown in Table 5 and FIG. With the bone filling material not containing component b (Comparative Example 19), the cured product and the ivory slice did not adhere. The adhesive strength rapidly increased when [b / a] (equivalent ratio) exceeded 2, and was almost saturated at about 8.5. Biopex (Comparative Example 3) and Endurance (Comparative Example 4) hardly adhered to the ivory slice, and the adhesive strength could not be measured.

<Electron microscope (SEM) observation of ivory section after measurement of peel strength>
FIG. 5 (× 250) shows an electron microscope image of the ivory surface after the adhesion test, and FIG. 6 (× 250) shows an electron microscope image of a cross section of the ivory slice.
As shown in FIG. 5, as the amount of the component b is increased from a low concentration to a high concentration, the shape of the remaining bone filler cured product is changed from a granular shape to a lump shape, and the lump size is also increased. In Examples 9 and 10, it can be seen that the cured product remained on the entire surface of the ivory slice, and the adhesive strength was superior to the cohesive fracture strength of the cured bone filler material.
On the other hand, in Biopex (Comparative Example 21), a small amount of the cured product remained in the form of particles, and no residual cured product was found at Endurance (Comparative Example 22).
The SEM observation of the cross section shown in FIG. 6 also showed the same result, and there was a surface where the component b was adhered in a granular or small lump when the concentration was low, and the cured product was not adhered. It can be seen that as the concentration of the component b increases, the cured product remains on the entire surface, and the thickness thereof increases to change from interfacial peeling to cohesive failure.

  The bone filling material of the present invention is excellent in adhesive strength and compressive strength, and is suitably used for vertebroplasty for bone reinforcement.

Claims (8)

The following ingredients:
a. A polyethylene glycol ether of a branched alcohol having an amino group at the terminal b. Trissuccinimidyl citrate and / or trissulfosuccinimidyl citrate c. α-tricalcium phosphate particles d. Hydroxyapatite nanoparticles e. An adhesive bone filler containing a buffer solution,
[Component c + Component d] (wt%) is 55 to 75 wt% of the total weight of the adhesive bone filler, and
[Component d / Component c] (weight ratio) is 1/99 to 15/85,
Adhesive bone filler.   The adhesive bone filling material according to claim 1, wherein [component b / component a] (equivalent ratio) is 1.5 to 9.   The adhesive bone filler according to claim 1 or 2, wherein the amount of component a is 5 to 10% by weight based on the total weight of the adhesive bone filler.   The adhesive bone filling material according to any one of claims 1 to 3, wherein the molecular weight (Mw) of component a is 10,000 to 50,000. The adhesive bone filling material according to any one of claims 1 to 4, wherein component a is represented by the following formula (1).

In the formula _(1), n 1 ~n ₄ is an integer of ^25~250, R 1 ~R ⁴ is a _C 2 -C ₄ alkylene group. The average particle size of component c _{(D 50)} is 3.5Myuemu～9myuemu, adherent bone filling agent according to any one of claims 1 to 5. The average particle size of component d _{(D 50)} is 10 nm to 100 nm, adhesion bone filling agent according to any one of claims 1 to 6.   The adhesion according to any one of claims 1 to 7, wherein the bone filling composition is a two-component type, the first agent contains components a and e, and the second agent contains components b, c and d. Sexual bone filler.