JPH01166763A - Medical and dental curable material - Google Patents

Abstract

PURPOSE:To obtain a medical and dental curable material cured at temp. in the vicinity of the room temp. or bodily temp., made long in a curing time and harmless to a living body, by using a calcium phosphate, which contains alpha-tricalcium phosphate as an essential component, as a main material and using at least one kind of a substance selected from a group consisting of tannin, a tannin derivative and collagen as a curing retarder. CONSTITUTION:A medical and dental curable material is based on a calcium phosphate powder containing alpha-tricalcium phosphate (alpha-TCP) as an essential component and, as a curing retarder, at least one kind of a substance selected from a group consisting of tannin, a tannin derivative and collagen is used. The calcium phosphate powder pref. consists of 60-100wt.% of alpha-TCP and 0-30wt.% of hydroxyapatite (HAp). When alpha-TCP is below 60wt.% of the calcium phosphate powder, the physical strength of a cured substance after kneading is extremely lowered. When alpha-TCP and calcium phosphate other than HAp exceed 10wt.% of the powder, a curing time becomes short and sufficient kneading can not be performed.

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field] The present invention relates to medical and dental hardenable materials used for bone cement, dental cement, root canal filling materials, and the like.

[Background technology]

In recent years, dental cements have been produced in the form of powders such as hydroxyapatite (hereinafter referred to as rHApJ) and α-tricalcium phosphate [α-Ca s (P 04)i.

Hereinafter, [referred to as α-TCPJ] is used, and a polyacrylic acid aqueous solution is used as the curing solution. The powder and curing solution are mixed and kneaded to form a cured product. However, uncured and unreacted polyacrylic acid may remain, and the problem of harm to living organisms due to elution of this remains.

Bone cement has traditionally been made of polymethyl methacrylate (P
Products using polymeric materials such as MMA) and methyl methacrylate (MMA) are commercially available. However, bone cement using polymeric materials has the following three problems. First of all, the bone tissue of the host to be implanted and the bone cement are not directly bonded to each other, and fibrous tissue is interposed, so that when implanted in a living body for a long period of time, there are problems such as loosening. Second
Another problem is that the heat generated during curing reaches a temperature of about 90 to 100°C, resulting in necrosis of surrounding cells. Thirdly, unreacted hexamers and oligomers are eluted,
The problem is that it has a negative effect on bones.

On the other hand, biomaterials using α-TCP, which is a substance similar to HAp, which is the main inorganic component of biological hard tissues, have been proposed. α-TCP has high chemical activity and can be converted to HAp under conditions equivalent to those in the living body or the oral cavity. α
- Materials combining TCP powder and aqueous solutions of citric acid or malic acid have been reported to be useful in dental and bone cements. Although this material and its cured product are not harmful to living organisms, the calcium phosphate powder/curing solution ratio (hereinafter simply referred to as the "powder/liquid ratio") is
There is a problem that if the curing time is increased, the curing time becomes extremely short, making it impractical.

[Purpose of the invention]

In view of the above, it is an object of the present invention to provide a curable material for medical and dental applications that can be cured at room temperature or at a temperature close to the body temperature of a living body, has a long curing time, and is not harmful to living organisms. The purpose is to

[Disclosure of the Invention] In order to achieve the above object, the present invention provides a curable material for medical and dental use mainly composed of calcium phosphate powder containing α-TCP as an essential component, which contains tannin as a curing retarder. The object of the present invention is to provide a curable material for medical and dental use, characterized in that at least one selected from the group consisting of tannin derivatives and collagen is used.

The present invention will be explained in detail below.

The medical and dental curable material according to the present invention comprises at least a combination of calcium phosphate powder and a curing solution.

α-TCP occupies part or all of the calcium phosphate powder. The remainder of the powder is comprised of HAp, carbonate apatite, β-tricalcium phosphate, calcium hydrogen phosphate dihydrate, and the like. However, it does not contain tetracalcium phosphate. Calcium phosphate powder has 60 to 100% by weight of α-
TCP and preferably 0 to 30% by weight HAp. If α-TCP is less than 60% by weight of the calcium phosphate powder, a problem may arise in that the physical strength of the cured product after kneading is extremely reduced. If the amount of calcium phosphate other than α-TCP and HAp exceeds 10% by weight of the powder, the curing time may be shortened, resulting in a problem that sufficient kneading cannot be achieved.

It is preferable that the powder has an average particle diameter of 1 to 25 μm. If the average particle size of the powder is less than 1 μm, the physical strength of the cured product will improve, but the curing time may become shorter. The coating thickness of the object is 30
There may be a problem that the thickness is not smaller than μm.

α-'rcp is, for example, 7-c, a, P! O? It is obtained by firing an equimolar mixture of CaCOs and CaCOs at 1200° C. or higher and then pulverizing it, but it can also be obtained by other methods. HAp etc. are calcium phosphate derived from living organisms such as bone powder, or synthetic HAp obtained by well-known or publicly known methods, carbonate apatite, β
- Tricalcium phosphate, etc. may also be used. None of these calcium phosphates has biohazardous properties.

As the curing solution, a solution of a biologically related substance is used.

As the biologically related substance, at least one selected from the group consisting of tannins, tannin derivatives, and biologically relevant organic acids (hereinafter referred to as "organic acids") is used. The tannin, tannin derivative, and the organic acid are
All of these substances are biologically related substances and are not harmful to living organisms.

Any tannin or tannin derivative may be used, but it is preferable to use tannic acid. Although tannic acid will be explained below as an example, tannins and tannin derivatives other than tannic acid can be used in the same manner. Tannic acid is a curing agent that has a slower curing rate than conventional curing agents, that is, it is a curing agent and a curing retardant. In addition, when tannic acid is used in hardenable dental materials, it has a healing effect on inflammation of the oral cavity and pharyngeal mucosa.
It is expected to be effective in preventing tooth decay by inhibiting the dissolution of dental protein. The tannic acid concentration of the tannic acid solution is not particularly limited, but is preferably in the range of 0.1 to 70% by weight, preferably in the range of 0.1 to 30% by weight in the coexistence of an organic acid, and 0.1 to 30% by weight in the coexistence of collagen. The range is preferably from .1 to 20% by weight, and in the coexistence of organic acid and collagen, it is from 0.1 to 1% by weight.
The range of 0% by weight is preferable; below each of these ranges, the curing retardation effect may not be exhibited, and above each of these ranges, the cured product may disintegrate in the aqueous solution.

As the organic acid, one type selected from the group consisting of citric acid, malic acid, malonic acid, glyceric acid, and glutaric acid is used alone, or two or more types are used in combination.

These organic acids produce a hard cured product by mixing and kneading with calcium phosphate powder. The organic acid concentration of the organic acid solution is not particularly limited, but is preferably in the range of 0.1 to 90% by weight, and in the presence of tannic acid, it is 0.1% by weight.
A range of ~90% by weight is preferred, a range of 0.1 to 70% by weight is preferred in the coexistence of collagen, and a range of 0.1 to 70% by weight is preferred in the coexistence of tannic acid and collagen. If it is below these ranges, the physical strength of the cured product will be extremely reduced after kneading, and it may collapse in the aqueous solution.If it exceeds each of these ranges, crystals will precipitate in the hardening solution before kneading. There are things to do.

As the collagen, it is preferable to use atelocollagen, but other collagens may also be used. Atelocollagen is collagen in which part or all of the telopeptide at the terminal end of the molecule has been removed by enzymatic treatment, and is non-toxic to living organisms. Collagen may be used after being dissolved in a hardening solution, or may be used in a solution separate from the hardening solution, or may be used in a powdered state. The collagen concentration of the collagen solution is not particularly limited, but is 0.
The range is preferably from 0.01 to 35% by weight, preferably from 0.05 to 35% by weight in the coexistence of an organic acid, and preferably from 0.01 to 30% by weight in the coexistence of tannic acid.
In the coexistence of an organic acid and tannic acid, the range is preferably from 0.01 to 30% by weight.

If it is below each of these ranges, the hardening retardation effect of collagen and tannic acid may not be exerted, and if it exceeds each of these ranges, collagen may be degraded in the organic acid solution before kneading or the solution viscosity may be reduced. may rise too much. When collagen is used in powdered form, it is preferable to have the above average particle diameter for the above reasons.

In this invention, the progress of the hardening reaction of calcium phosphate powder is slowed down by using at least one selected from the group consisting of tannins, tannin derivatives, and collagen. This improves the operability during kneading, increases the powder/liquid ratio, and provides a cured product with higher strength. Furthermore, it can be used in applications that require a relatively long time for filling, such as a root canal filling material for filling cavities in tooth root canals. Note that the hardening retardation effect is greater when tannic acid and collagen are used together than when tannic acid and collagen are used separately.

The curable material for medical and dental purposes according to the present invention can be cured by mixing and kneading at room temperature or at a temperature near the body temperature, thereby preventing problems such as cell necrosis due to reaction heat. do not have.

Examples of the medical and dental curable materials according to the present invention include the following.

■ A system consisting of a combination of calcium phosphate powder and tannic acid.

For this type of material, a tannic acid solution is used as the curing solution. The powder/liquid ratio is not particularly limited, but is 0°1 to 5g/m
A range of z is preferred. If it is less than this range, curing may be insufficient, and if it exceeds this range, it may not be possible to mix it sufficiently at room temperature.

The reaction mechanism of the material of the type (2) is believed to be, for example, as follows, based on analysis results using X-ray powder diffraction, infrared absorption spectra, scanning electron microscopy images, etc. When calcium phosphate powder and tannic acid solution are mixed and kneaded at room temperature or at a temperature close to the body temperature, α in the powder
- Water coordinates with TCP to form amorphous calcium phosphate (Ca)
t (POaL ・nH* 0°, hereinafter referred to as rACPJ), and on the other hand, tannic acid forms an aggregate (considered to be fibrous). This ACP aggregates into a tannic acid aggregate. , ACP becomes H over time in this state.
It is converted to Ap and hardening progresses.

■ A system consisting of a combination of calcium phosphate powder, tannic acid and collagen.

In this system as well, tannic acid serves as a hardening agent and a hardening retardant, and collagen acts as a hardening retarder, similar to the system ① above. Tannic acid also acts on collagen to crosslink it. Since it contains collagen, it has good compatibility with surrounding living tissues. Collagen is
It may be used in a solution separate from the tannic acid solution, it may be used after being dissolved in the tannic acid solution, or it may be used in the form of a powder.

The ratio of the materials of type (2) to be used is not particularly limited, but 0.01 to 20 parts by weight of tannic acid and 0.01 to 2 parts by weight of collagen to 10 to 80 parts by weight of calcium phosphate powder.
Each range of 0 parts by weight is preferred.

When tannic acid is below this range, curing may be insufficient, and when it is above this range, calcium phosphate powder may not be sufficiently kneaded during kneading. If the collagen content is below this range, the strength of the cured product may be too low, and if it is above this range, it may not be possible to mix it sufficiently at room temperature.

The reaction mechanism of the material of the type (2) is believed to be, for example, as follows, based on analysis results using X-ray powder diffraction, infrared absorption spectra, scanning electron microscopy images, etc. When calcium phosphate powder, tannic acid solution, and collagen are mixed and kneaded at room temperature or at a temperature near the body temperature, water coordinates with α-TCP in the powder to produce ACP, and the interaction between collagen and tannic acid occurs. A cross-linked complex is formed. HAp converted from ACP crystallizes and aggregates in this composite (which is considered to be fibrous), and hardening progresses.

When the materials of the type (2) and the materials of the type (2) are mixed and kneaded as described above, the curing proceeds much more slowly than when an organic acid is used as a curing agent, and a soft cured product can be obtained. It will be done. For example, it hardens at room temperature or at a temperature around the body temperature of a living body in about 1 to 2 days after the start of kneading. For this reason,
The materials of type (1) or (2) can be used, for example, as a root canal filling material to fill a cavity in a tooth root canal.

■ A system consisting of a combination of calcium phosphate powder, organic acids and tannic acid.

In this system, the organic acid acts as a curing agent and the tannic acid acts as a curing retarder. Tannic acid may be used in a solution separate from the organic acid solution, or may be used after being dissolved in the organic acid solution.

The proportion of the materials of type (1) to be used is not particularly limited, but is preferably in the range of 5 to 60 parts by weight of organic acid and 1 to 10 parts by weight of tannic acid to 30 to 80 parts by weight of powder. If the organic acid is below this range, curing may be insufficient, and if it is above this range, sufficient kneading may not be possible at room temperature. If the tannic acid content is below this range, the curing retardation effect may not be exhibited, and if it exceeds this range, it may not be possible to knead the product completely at room temperature.

The reaction mechanism of the material of the type (2) is believed to be, for example, as follows, based on analysis results using X-ray powder diffraction, infrared absorption spectra, scanning electron microscopy images, etc. When calcium phosphate powder, organic acid solution and tannic acid are mixed and kneaded at room temperature or at a temperature close to the body temperature,
A chelate bond is formed between the Ca of α-TCP in the powder and the carboxyl group of the organic acid, and the neutralization reaction progresses. On the other hand, tannic acid forms an aggregate (considered to be m-fiber-like), and a chelate of α-TCP and an organic acid aggregates in the aggregate. In the presence of water, the chelate and unreacted α-TCP undergo a hydration reaction at room temperature or at a temperature close to the body temperature, producing ACP, which is converted to HAp, and HAp is converted into tannic acid. It crystallizes into aggregates and hardening progresses.

■ A system consisting of a combination of calcium phosphate powder, organic acids and collagen.

In this system as well, organic acids serve as curing agents. Collagen acts as a set retarder. Collagen may be used in a solution separate from the organic acid solution, dissolved in the organic acid solution, or in powder form.

The proportion of the material of type (2) is not particularly limited, but 5 parts by weight of the organic acid is based on 30 to 80 parts by weight of calcium phosphate powder.
-70 parts by weight and 0.01 to 30 parts by weight of collagen are preferred. If the organic acid is below this range, curing may be insufficient, and if it is above this range, the curing retarding effect of collagen may not be exhibited.

If the collagen content is below this range, the strength of the cured product may not improve, and if it exceeds this range, it may not be possible to knead sufficiently at room temperature.

Based on the analysis results of X-ray powder diffraction, infrared absorption spectra, scanning electron microscopy images, etc., the reaction mechanism of the material in the system (2) is based on the collagen calcification model of biological hard tissue, as shown below. it is conceivable that. When calcium phosphate powder, organic acid solution, and collagen are mixed and kneaded at room temperature or at a temperature near the body temperature, a chelate bond is generated between the Ca of α-TCP in the powder and the carboxyl group of the organic acid, resulting in neutralization. The reaction progresses. On the other hand, collagen becomes fibrillar and a chelate of α-TCP and organic acid aggregates on the collagen fibers. In the presence of water, the chelate and unreacted α-TCP undergo a hydration reaction at room temperature or around the body temperature, resulting in AC.
This ACP is converted to HAp, which crystallizes into collagen fibers and hardening progresses.

■ A system consisting of a combination of calcium phosphate powder, organic acids, tannic acid and collagen.

In this system as well, the organic acid serves as the curing solution. Tannic acid and collagen are set retarders. Tannic acid and collagen may be used in a solution separate from the organic acid solution, dissolved in the organic acid solution, or used in a solution containing both tannic acid and collagen. Good too. Moreover, collagen may be used in powdered form.

The proportion of the material of type (2) is not particularly limited, but 5 parts by weight of the organic acid is based on 30 to 80 parts by weight of calcium phosphate powder.
-60 parts by weight, 0.05-10 parts by weight of tannic acid and 0.05-30 parts by weight of collagen are preferred.

If the organic acid is below this range, curing may be insufficient, and if it is above this range, a large amount of unreacted organic acid may be eluted. If the tannic acid content is below this range, the curing retardation effect may not be exhibited, and if it exceeds this range, sufficient kneading may not be possible at room temperature.

If the collagen content is below this range, the hardening retardation effect may not be exhibited, and if it is above this range, sufficient kneading may not be possible at room temperature.

Based on the analysis results of X-ray powder diffraction, infrared absorption spectra, scanning electron microscopy images, etc., the reaction mechanism of the material in the system (2) is found to be similar to the collagen calcification model of bone tissue, as shown below. Conceivable. When calcium phosphate powder, organic acid solution, tannic acid and collagen are mixed and kneaded at room temperature or at a temperature close to the body temperature,
A chelate bond is formed between the Ca of α-TCP in the powder and the carboxyl group of the organic acid, and the neutralization reaction progresses. On the other hand,
A chelate of α-TCP and an organic acid, which forms a cross-linked complex (considered to be fibrous) of tannic acid and collagen, aggregates into the complex. In the presence of water, the chelate and unreacted α-TCP undergo a hydration reaction at room temperature or at a temperature near the body's body temperature to generate ACP, which is converted to HAp, and HAp is converted into the complex. It crystallizes in the body and hardens.

When the materials from each prefecture (■ to ■) are mixed and kneaded, the hardening progresses more slowly than when tannic acid and collagen are not used. For example, at room temperature or at a temperature about the body temperature of a living body, it hardens within 5 to 60 minutes after the start of kneading, and a hard cured product is obtained. Therefore, the calcium phosphate powder/organic acid ratio can be increased, thereby increasing the strength of the cured product. In particular, when collagen is used, the compressive strength increases without increasing the calcium phosphate powder/organic acid ratio, and even after the hardening, the compressive strength increases over time and becomes highly elastic. The materials from each of the prefectures ① to ② can be used, for example, as bone cement, dental cement, and other materials for filling biological hard tissues and for prosthetics.

The initial hardened product obtained by mixing and kneading each material of
BS: Phosphate Buffered
5aline), the crushing resistance improves over time. That is, when each of the above-mentioned materials ① and ② is used as a bone cement, the strength improves over time even after implantation. This is considered to be due to the use of collagen.

When the materials from ■ to ■ are used as bone cement and implanted into the bone of a living body, α-TCP becomes biosoluble (biodegradable).
e), it can be gradually replaced with new bone in about 6 months to 1 year. That is, among the curable materials according to the present invention, if one using an organic acid as a curing agent and at least one of tannic acid and collagen as a curing retarder is used as a bone cement, the Over time, it replaces bone tissue and integrates with the existing part.

It should be noted that the materials from each of the prefectures (1) to (2) above may contain materials other than those mentioned above, as long as they do not impede achievement of the purpose of the present invention.

Further, the usage is not limited to the above example.

Examples of the present invention are shown below along with comparative examples, but the invention is not limited to the following examples.

(Examples 1 to 10 and Comparative Examples 1 to 4) A solution containing tannic acid, collagen, and an organic acid at the concentrations shown in Table 1 was prepared, and this solution was mixed with calcium phosphate powder having the composition shown in Table 1. The mixture was mixed at the powder/liquid ratio shown in Table 1 and kneaded manually for about 1 minute. Using this kneaded mud, the following measurements were carried out and the results are shown in Table 1. Note that all measurements below were performed under conditions of a temperature of 23±2° C. and a relative humidity of 50±10% according to ADAS 1lh61. However, in Examples 1 and 2, measurements were performed using ADAS m57.

(a) Initial hardening time measurement Pour each linear clay into a cylindrical stainless steel mold with an inner diameter of 10n and a height of 5mm placed on a glass plate with a length and width of 15tm x 15tm x 15n to flatten the surface and finish kneading. One minute after that, the temperature was 37±1℃ and the relative humidity was 1.
The sample was transferred to a thermostat at 0.00% and used as a test piece. Quality N2.94
N (300g) picker needle (cross-sectional area of needle 1f18)
was gently dropped onto the surface of the test piece, and the time when no needle marks were left was defined as the initial curing time starting from the start of kneading.

The initial curing time was expressed as the average of three measurements, rounded to the nearest 15 seconds.

(b) Measurement of Crushing Drag A cylindrical stainless steel mold with an inner diameter of 6 mm and a height of 12 mm was filled with each wire, and both ends were sandwiched between thick glass plates and pressurized. 2.5 minutes after the start of kneading, the temperature was increased to 37±1℃ while keeping the pressure applied.
It was transferred to a thermostat at 100% relative humidity. After 1 hour, the cured product was taken out of the mold and immersed in distilled water at 37±1°C, and 24 hours after the start of kneading, it was taken out from the distilled water and used as a test piece. This test piece was tested using Autograph AG-2000A.
The crushing drag force was measured using The crosshead speed was 1 m/min, and measurements were made on 6 test pieces, and the average value of the remaining values after excluding the values that were less than 15% of the total average value was taken as the measured value. However, if two or more values were less than 15% of the total average value, a retest was conducted.

As shown in Table 1, the materials of Examples 1 and 2 exhibited slower initial curing than those using organic acids as curing agents;
Initial curing time suitable for root canal filling material was shown. Example 3~
Comparing Example 8 and Comparative Example 1.3, the initial curing time was longer in Example.

Even if the crushing resistance of the cured product was increased by increasing the powder/liquid ratio as in Examples 9 and 10, the initial curing time was long enough to cause no practical problems. However, in Comparative Example 2.4, the initial curing time was extremely short due to the increased powder/liquid ratio, making it difficult to put it to practical use. Furthermore, in the cases where collagen was used (Examples 4, 5, 7, 8, and 10), the crushing resistance of the initially cured product was clearly improved, and this was particularly remarkable when it was used in combination with tannic acid.

When each of the materials of Examples 3 to 10 and Comparative Examples 1 to 4 was immersed in PBS, it was found that the crush resistance of the materials using collagen improved over time even after initial hardening.

In addition, each of the materials of Examples 3 to 10 and Comparative Examples 1 to 4 was initially hardened into a cylindrical piece measuring φ6fi x length 12mm, and the pieces were implanted into the femoral bone defect of a dog for 2 weeks and 4 weeks. ,
After 6 weeks, they were taken out, and the tissue of the adhesion surface with the bone tissue was observed and the adhesion force with the bone was evaluated by extrusion method. As a result, two weeks after transplantation, with the materials of Comparative Examples 1 to 4,
Although direct integration with bone had begun, slight round cell infiltration was observed. In contrast, the materials of Examples 3 to 10 had no such inflammatory reaction, and direct bonding with the bone had already progressed. 4 and 6 weeks after transplantation, Comparative Example 1
In materials No. 4 to 4, the inflammatory symptoms gradually disappeared, and bone formation gradually increased in this area. In each of the materials of Examples 3 to 10, bone cells were also present at the interface with the bone tissue. In particular, those using collagen (Example 4.5.7.8.1
In case 0), a large number of bone cells were present around the interface, and the adhesion force with the bone was also dramatically enhanced.

〔Effect of the invention〕

As described above, the medical and dental curable materials according to the present invention are mainly composed of calcium phosphate powder containing α-TCP as an essential component, and contain tannin and tannin as hardening retarders.
Since at least one type selected from the group consisting of tannin derivatives and collagen is used, it cures at room temperature or at a temperature close to the body's body temperature, can extend the curing time, and is not harmful to the body. Therefore, the medical and dental curable material according to the present invention can be used in applications that require a long time to cure,
By increasing the ratio of calcium phosphate powder to curing agent, it can be used in applications requiring a cured product with high strength.

Agent: Patent Attorney Takehiko Matsumoto

Claims (1)

[Claims] (1) A hardening material for medical and dental purposes whose main material is calcium phosphate powder containing α-tricalcium phosphate as an essential component, which is selected from the group consisting of tannins, tannin derivatives, and collagen as a hardening retarder. A curable material for medical and dental use, characterized in that at least one selected type is used.