HK40062997A

HK40062997A - Dental root canal filling material composition

Info

Publication number: HK40062997A
Application number: HK62022051628.5A
Authority: HK
Inventors: 横田兼欣; 坂野惠美; 伊藤祥作; 林美加子
Original assignee: 日本齿科药品株式会社
Filing date: 2019-05-10
Publication date: 2022-06-17

Description

Root canal filling material composition

Technical Field

The invention relates to a root canal filling material composition.

Background

Within the root canal of the tooth is the pulp, which contains nerves and blood vessels. When dental pulp infection or inflammation due to deep caries, broken crown, etc. is left alone, abscess may be formed at the apical end of the root canal, inflammation may spread in periapical tissue, gingiva may swell, or systemic symptoms such as swollen lymph nodes and fever may occur in some cases. Therefore, when the dental pulp is infected or inflamed, the dental pulp is removed as necessary, then the interior of the root canal is sterilized, and the pulp chamber is closed with a root canal filling material to block irritation to periapical tissue.

Conventional root canal disinfectants contain active ingredients such as formalin, paraformaldehyde, p-chlorophenol, guaiacol, eugenol, zinc oxide and calcium hydroxide.

Formalin and paraformaldehyde cause sclerostinal necrosis of proteins, thereby playing a role in protecting internal tissues, and also have a very strong bactericidal action or sterilization action. Has disinfectant and analgesic effects on chlorophenol, guaiacol and eugenol. The zinc oxide has disinfectant and antiinflammatory effects. However, these ingredients do not promote healing of root canal-periapical tissue.

In contrast, calcium hydroxide has a disinfecting action and an analgesic action, and is considered to have an action of promoting healing of the periapical tissue of the root canal. Therefore, calcium hydroxide has been widely used as an active ingredient of infected root canal treatment drugs in europe and the united states, and in japan, dental treatment preparations containing calcium hydroxide have been developed and improved.

The progress of the use of calcium hydroxide in the preparation for dental treatment is described in detail below. Calcium hydroxide is a white powder, and the aqueous solution of calcium hydroxide has a pH of 12.6 and is strongly basic, and thus has a strong disinfecting effect. Calcium hydroxide also has a hard tissue-forming action of promoting enamel, dentin and cementum, and thus has been included in a myeloplasty material, a live-cutting material, a root canal filling material and The like (dental outlook, 72(1), 63-74, 1988; The Journal of Japan endo-Association (Japanese society of dental therapy, 16(1), 47-51, 1995; The Japanese Journal of Pediatric dental department, 26(3), 611-620, 1988).

Calcium hydroxide is also widely used for root tip sealing of immature teeth of root canals, sealing of perforated sites and The like (The Journal of Japan Endodontic Association, 14(2), 89-95, 1993; The Journal of Japan Endodontic Association, 16(1), 70-73, 1995; The Japanese Journal of Pediatric dental department, 24(3), 459-.

Calcium hydroxide has also been actively used as a short-term disinfectant (temporary root canal filling material) during The treatment of infected root canals (The Japanese Journal of dental storage, 34 (3)), 986-.

The root canal therapeutic agent containing calcium hydroxide is considered to have less tissue irritation, and has a bactericidal action, a soft tissue-dissolving action, an analgesic action, a healing promoting action, an exudate-stopping action, a root absorption-inhibiting action, a hard tissue formation-inducing action, and the like due to strong alkalinity. As described above, calcium hydroxide is not only a bactericide but also an agent for improving the healing of periapical tissue of root canal.

The root canal filling material containing calcium hydroxide is useful because it has an excellent bactericidal action and a root canal-periapical tissue healing promoting action, but is insufficient in providing a healing promoting action of intractable pulpitis or periapical periodontitis, for example, intractable pulpitis or periapical periodontitis in which healing is inhibited by bacterial infection which is difficult to remove or by invasion of bacteria into periapical lesions or apical lesions. Therefore, there is a need for a root canal filling material that can promote healing of intractable pulpitis or periapical periodontitis.

Documents of the prior art

Patent document

Patent document 1: JP 3473879B

Patent document 2: JP 4614376B

Patent document 3: JP 5827086B

Disclosure of Invention

Problems to be solved by the invention

An object of the present invention is to provide a root canal filling material composition having a higher healing promoting effect than conventional root canal filling material compositions.

Means for solving the problems

The inventors of the present invention have conducted repeated studies in order to solve the above problems, and found that a root canal filling material composition containing a lithium salt promotes differentiation of dental pulp stem cells into osteoblasts to activate or stimulate bone metabolism in apical lesions and to activate or stimulate an immune response. The inventors of the present invention have further found that the root canal filling material composition thus has an excellent root canal-periapical tissue healing promoting effect and is effective in promoting healing of intractable pulpitis and periapical periodontitis that cannot be healed with conventional root canal filling materials.

The present invention has been accomplished based on the above findings, and provides the following root canal filling material composition.

[1] A root canal filling material composition comprising a lithium salt.

[2] The root canal filling material composition according to [1], wherein the concentration of the lithium salt is 0.0001 to 20% by weight with respect to the total amount of the composition.

[3] The root canal filling material composition according to [1] or [2], further comprising a calcium compound.

[4] The root canal filling material composition according to [3], wherein the concentration of the calcium compound is 2 to 70% by weight with respect to the total amount of the composition.

[5] The root canal filling material composition according to any one of [1] to [4], further comprising water.

[6] The root canal filling material composition according to [5], wherein the content of water is 1 to 2 times that of the lithium salt in terms of a weight ratio.

[7] The root canal filling material composition according to any one of [1] to [6], further comprising a polyhydric alcohol.

[8] The root canal filling material composition according to [7], wherein the concentration of the polyhydric alcohol is 1% by weight to 90% by weight with respect to the total amount of the composition.

[9] The root canal filling material composition according to any one of [1] to [8], further comprising alumina ultrafine particles having a particle size of 1nm to 1 μm and/or titanium oxide ultrafine particles having a particle size of 1nm to 1 μm.

[10] The root canal filling material composition according to [9], wherein the total content of the alumina ultrafine particles and/or the titania ultrafine particles is 0.1 to 20% by weight with respect to the total amount of the composition.

[11] The root canal filling material composition according to [1] or [2], wherein the root canal filling material composition is a combination of a paste A containing rosin and a paste B containing magnesium oxide and vegetable oil, and one or both of the paste A and the paste B contains a lithium salt.

[12] The root canal filling material composition according to [1] or [2], wherein the root canal filling material composition is a combination of paste A and paste B and is hardened by mixing paste A and paste B, one or both of paste A and paste B contains a lithium salt, one or both of paste A and paste B contains a glass powder containing calcium oxide and silicon dioxide in a total amount of 50 to 100% by weight relative to the total amount of the glass powder, and the weight ratio of calcium oxide to silicon dioxide (calcium oxide: silicon dioxide) in the glass powder is 6:4 to 3: 7.

[13] The root canal filling material composition according to [12], wherein the content of the glass powder is 20% by weight or more with respect to the total amount of the paste A and the paste B and 70% by weight or less with respect to the total amount of each of the paste A and the paste B.

[14] The root canal filling material composition according to [12] or [13], wherein the paste A further contains at least one component selected from the group consisting of eugenol, guaiacol, higher fatty acid, polyacrylic acid or a salt thereof, and phosphoric acid, and the paste B further contains at least one component selected from the group consisting of calcium oxide, magnesium oxide, strontium oxide, zinc oxide, calcium phosphate, and aluminosilicate glass.

[15] The root canal filling material composition according to any one of [1] to [14], which is used for immunostimulation in lesions of the root canal and/or periapical tissue.

[16] The root canal filling material composition according to any one of [1] to [14], which is used for inducing differentiation of dental pulp stem cells into osteoblasts in lesions of root canals and/or periapical tissues.

[17] Use of a lithium salt in the manufacture of a root canal filling material composition.

[18] Use of a lithium salt-containing composition for the manufacture of a root canal filling material.

[19] Use of a lithium salt in a root canal filling material composition.

[20] Use of a lithium salt-containing composition in a root canal filling material.

[21] A method of treating an infected root canal and/or infected periapical tissue, the method comprising filling a root canal of a patient infected with a root canal and/or infected periapical tissue with an effective amount of a lithium salt to treat the infected root canal and/or infected periapical tissue.

[22] A method of treating an infected root canal and/or infected periapical tissue, the method comprising filling a root canal of a patient infected with a root canal and/or infected periapical tissue with a composition comprising an effective amount of a lithium salt to treat the infected root canal and/or infected periapical tissue.

[23] Use of a lithium salt in the manufacture of an immunostimulant for root canal and/or periapical tissue lesions.

[24] Use of a composition comprising a lithium salt in the manufacture of an immunostimulant for root canal and/or periapical tissue lesions.

[25] Use of a lithium salt in an immunostimulant of lesions of the root canal and/or periapical tissue.

[26] Use of a composition comprising a lithium salt in an immunostimulant for root canal and/or periapical tissue lesions.

[27] Lithium salts for use in immunostimulants for root canal and/or periapical tissue lesions.

[28] A method of immunostimulating a root canal and/or periapical tissue lesion, the method comprising filling the root canal and/or root canal of a patient having a periapical tissue lesion with an effective amount of a lithium salt to immunostimulate the lesion of the root canal and/or periapical tissue.

[29] A method of immunostimulating a root canal and/or periapical tissue lesion, the method comprising filling a root canal and/or a root canal of a patient having a periapical tissue lesion with an effective amount of a composition comprising a lithium salt to immunostimulate the lesion of the root canal and/or the periapical tissue.

[30] Use of a lithium salt for producing an inducer of differentiation of dental pulp stem cells into osteoblasts in a lesion of root canal and/or periapical tissue.

[31] Use of a composition containing a lithium salt for producing an inducer of differentiation of dental pulp stem cells into osteoblasts in a lesion of a root canal and/or periapical tissue.

[32] Use of a lithium salt as an inducer of differentiation of dental pulp stem cells into osteoblasts in a lesion of root canal and/or periapical tissue.

[33] Use of a composition containing a lithium salt as an inducer of differentiation of dental pulp stem cells into osteoblasts in a lesion of root canal and/or periapical tissue.

[34] Lithium salt used as differentiation inducer of dental pulp stem cells into osteoblasts in root canal and/or periapical tissue lesion

[35] A method of inducing differentiation of dental pulp stem cells into osteoblasts in a root canal and/or periapical tissue lesion, the method comprising filling a root canal of a patient having the root canal and/or periapical tissue lesion with a lithium salt in an amount effective to induce differentiation of dental pulp stem cells into osteoblasts in the root canal and/or periapical tissue lesion.

[36] A method of inducing differentiation of dental pulp stem cells into osteoblasts in a root canal and/or periapical tissue lesion, the method comprising filling a root canal and/or a root canal of a patient of the periapical tissue lesion with a composition comprising a lithium salt in an amount effective to induce differentiation of dental pulp stem cells into osteoblasts in the root canal and/or periapical tissue lesion.

ADVANTAGEOUS EFFECTS OF INVENTION

For example, even if a root canal filling material containing calcium hydroxide, which is considered to have a healing promoting effect, is used, it is difficult to heal the root canal filling material because of a bacterial infection which is difficult to remove from the dental pulp or intractable pulpitis or apical periodontitis which hinders healing by invasion of bacteria into peri-root lesions or apical lesions.

In contrast, the root canal filling material composition of the present invention includes a lithium salt, thereby promoting or inducing differentiation of dental pulp stem cells into osteoblasts, and increasing leukocytes to stimulate immunity. Based on these activities, the root canal filling material composition of the present invention can suppress inflammation of lesions such as pustules in dental pulp or around the apex of the root and effectively promote healing even in refractory pulpitis or periapical periodontitis.

When the root canal filling material composition of the present invention contains calcium hydroxide in addition to the lithium salt, the composition has excellent bactericidal action and anti-inflammatory action derived from calcium hydroxide, and remarkably or synergistically improves the healing promoting action of root canal-apical periodontal tissue.

The inventors of the present invention have found that when a root canal filling material composition containing a lithium salt is filled into a root canal, the dissolution of the lithium salt is insufficient in some cases. In this case, it is necessary to contain a larger amount of the lithium salt, which may increase the price or may limit the formulation.

In contrast, a root canal filling material composition containing water and polyhydric alcohol in addition to lithium salt and calcium hydroxide readily dissolves the lithium salt after filling in the root canal, and a root canal filling material composition containing a small amount of lithium salt can provide a healing promoting effect on the periapical tissue of the root canal.

The root canal filling material composition containing calcium hydroxide may precipitate and separate when stored, and when used, the composition may dissolve out mainly only the liquid component, or the calcium hydroxide may solidify in a syringe, and the paste may be difficult to discharge. In contrast, the root canal filling material composition comprising a lithium salt, calcium hydroxide, water and a polyhydric alcohol can suppress such solid-liquid separation during storage.

The inventors of the present invention have also found that when calcium hydroxide is added to a root canal filling material composition containing a lithium salt, the paste after preparation may become hard or dry, such a preparation is difficult to grasp on a root canal paste spiral conveyor or difficult to smoothly discharge from a syringe container or the like and is difficult to apply. In contrast, when the root canal filling material composition of the present invention is a composition comprising a lithium salt, calcium hydroxide, water and a polyhydric alcohol, and contains water in a weight ratio of 1 to 2 times that of the lithium salt, the composition has an appropriate consistency, and the paste is not hardened and is not easily dried. Therefore, the composition can be smoothly discharged from a syringe container or the like and is excellent in operability. The composition is not easily dried, so that a container or package of the composition does not need to be specially designed, and the composition is easily produced.

As described above, according to the study of the inventors of the present invention, the root canal filling material composition containing a lithium salt may not sufficiently dissolve the lithium salt after the root canal filling material composition is filled into the root canal. When the double paste type root canal filling material composition comprises a combination of paste a containing a higher fatty acid and rosin and paste B containing magnesium oxide and vegetable oil, and one or both of paste a and paste B contains a lithium salt, the mixture of paste a and paste B readily dissolves the lithium salt after filling in the root canal, the root canal filling material composition comprising a small amount of lithium salt can provide an excellent root canal-periapical tissue healing promoting effect.

When the root canal filling material composition comprises a combination of the paste a containing the higher fatty acid and the rosin and the paste B containing the magnesium oxide and the vegetable oil, and one or both of the paste a and the paste B contain the lithium salt, the root canal filling material composition has an appropriate consistency and thus has high workability. For example, the composition is easy to fill into root canals and to grasp on instruments such as root canal paste augers and gutta percha points. Excellent handling properties include high stringing properties.

If the hardening time is too short, the paste is hardened during mixing, and the hardened paste is difficult to flow into the root canal. If the hardening time is too long, it may contaminate the apical area with surrounding exudates or blood and reduce the sealing properties of the apical portion. The combined composition has a suitable hardening time.

The combined composition has satisfactory storage stability and suppresses solid-liquid separation during storage.

When the root canal filling material composition comprises a combination of paste a and paste B and is hardened by mixing paste a and paste B, one or both of paste a and paste B comprise a glass powder containing calcium oxide and silicon dioxide in a total amount of 50 to 100% by weight relative to the total amount of the glass powder, the weight ratio of calcium oxide to silicon dioxide in the glass powder (calcium oxide: silicon dioxide) is 6:4 to 3:7, and one or both of paste a and paste B comprise a lithium salt, the lithium salt is easily dissolved after the mixture of paste a and paste B is filled in the root canal, and the root canal filling material composition comprising a small amount of lithium salt can provide a healing promoting effect of root canal-apical periodontal tissue.

The root canal filling material composition comprising the glass powder and the lithium salt has an appropriate consistency and thus is highly operable. For example, the composition is easy to fill into root canals and to grasp on instruments such as root canal paste augers and gutta percha points. Excellent handling properties include high stringing properties. The composition also has a suitable setting time. The composition has satisfactory storage stability and suppresses solid-liquid separation during storage.

The root canal filling material composition comprising the glass powder and the lithium salt forms P6 in vivo₃A crystalline phase of the/m space group, such as hydroxyapatite, or the formation of osteoid crystals. Bones and teeth, which account for the majority of hard tissues in the living body, contain hydroxyapatite as a main component. The root canal filling material composition generates a bone-like crystal having the same structure as the main component of a tooth from the surface thereof, then fills a small gap formed between the filling and dentin, and can integrate the dentin and bone tissue through the crystal. In particular, this property has a beneficial effect for filling root canals that are difficult to seal, such as non-apical teeth including deciduous and immature permanent teeth, teeth that do not form an apical seat in infected root canal treatment, and teeth whose apices cannot be opened by apicoectomy. Thus, even in cases where complete closure cannot be achieved clinically, the compositionBut also provides intimate contact with dentin and bone tissue to produce satisfactory sealing properties and induce hard tissue.

When the root canal filling material composition includes a glass powder and a lithium salt, the paste a includes one or more components selected from eugenol, guaiacol, higher fatty acids, polyacrylic acid, and phosphoric acid as a hardening property-imparting component, and the paste B includes one or more components selected from calcium oxide, magnesium oxide, strontium oxide, zinc oxide, calcium phosphate, and aluminosilicate glass as a hardening property-imparting component, consistency, workability, hardening time, storage stability, and osteoid formation inductivity are further improved.

Drawings

Fig. 1 is each an X-ray micro CT image of the left mandibular first molar 4 weeks after filling the root canal filling material composition of example 18 or comparative example 1 into the lesion apical foramen of the rat.

FIG. 2 is a graph showing changes with time in lesion volume after each of the tube filling material compositions of example 5 and comparative example 1 was filled into lesion apical foramen of rats.

FIG. 3 is a graph showing changes with time in lesion volume after each of the tube filling material compositions of example 3 and comparative example 1 was filled into lesion apical foramen of rats.

FIG. 4 is a graph showing changes with time in lesion volume after each of the tube filling material compositions of examples 1 to 3 and comparative example 1 was filled into lesion apical foramen of rats.

Fig. 5 is a histopathological section image prepared as follows: the respective root canal filling material compositions of example 18 and comparative example 1 were filled in the lesion apical hole of the mouse; tissue sections of root tip lesions were prepared after 4 weeks and hybridized in situ. Arrows indicate Colla1 or Runx2 positive cells.

Fig. 6 is an image prepared as follows: each of the tube-filling material compositions of example 18 and comparative example 1 was filled in a lesion apical hole of a mouse; after 4 weeks, tissue sections of root tip lesions were immunofluorescent stained for cell surface markers on B cells.

Detailed Description

The present invention will now be described in detail.

The root canal filling material composition of the present invention

The root canal filling material composition of the present invention is a root canal filling material composition containing a lithium salt.

The root canal filling material is also referred to as, for example, a sealer for root canal filling, an endodontic drug, a pore filler, or a puncture repair material.

(lithium salt)

The lithium salt may be any of inorganic acid salts and organic acid salts. Examples of the inorganic acid salt include hydrochloride, carbonate, sulfate, phosphate, hydrobromide and nitrate. Examples of the organic acid salt include polycarboxylates such as orotate (also referred to as "orotate" or "uracil 6-carboxylic acid"), citrate, fumarate, maleate, succinate and malonate, lactate, tartrate, acetate, butyrate, palmitate, stearate, methanesulfonate, toluenesulfonate (tolumenoate), toluenesulfonate (tosylate), and napadisylate.

Specifically, inorganic acid salts are preferable, and hydrochloride and carbonate are more preferable.

The lithium salt may be used alone or in combination of two or more thereof.

The concentration of the lithium salt may be, for example, 0.0001 wt% or more, 0.001 wt% or more, or 0.005 wt% or more, and is preferably 0.01 wt% or more, more preferably 0.05 wt% or more, and still more preferably 0.1 wt% or more, relative to the total amount of the composition. The composition containing the lithium salt at a concentration within the above range can sufficiently promote healing of pulpitis or periapical periodontitis. The concentration of the lithium salt is preferably 20% by weight or less, more preferably 15% by weight or less, still more preferably 12% by weight or less, even more preferably 10% by weight or less, and further preferably 6% by weight or less, relative to the total amount of the composition. The composition comprising the lithium salt at a concentration within the above range does not cause symptoms of lithium poisoning, such as anorexia and vomiting.

(use of)

When the root canal filling material composition of the present invention is filled in a diseased site of a root canal or periapical tissue, the composition induces differentiation of dental pulp stem cells into osteoblasts and increases leukocytes to activate immunity. Therefore, the root canal filling material composition of the present invention can be used as a composition for inducing osteoblast differentiation (specifically, for inducing osteoblast differentiation in a diseased site of a root canal and/or periapical tissue), a composition for increasing leukocytes (specifically, for increasing leukocytes in a diseased site of a root apex and/or periapical tissue), and an immunostimulatory (specifically, for stimulating immunity in a diseased site of a root apex and/or periapical tissue) composition.

The differentiation of osteoblasts by the root canal filling material composition of the present invention is induced by promoting the expression of Colla1 or promoting the expression of Runx2, and thus the root canal filling material composition of the present invention can be used as a composition for promoting the expression of Colla1 (specifically, a composition for promoting the expression of Colla1 in lesions in root canals and/or periapical tissues) or as a composition for promoting the expression of Runx2 (specifically, a composition for promoting the expression of Runx2 in lesions in root canals and/or periapical tissues).

As mentioned above, pulpitis and apical periodontitis are involved in bacterial infections. Accordingly, the present invention includes a method of treating an infected root canal and/or infected periapical tissue, the method comprising filling a root canal of a patient infected with a root canal and/or infected periapical tissue with a lithium salt-containing composition in an amount sufficient to treat the infected root canal and/or infected periapical tissue.

The invention also includes a method of immunostimulation in a lesion of the root canal and/or periapical tissue, the method comprising filling the root canal of a patient having a lesion of the root canal and/or periapical tissue with a composition comprising a lithium salt in an amount sufficient for immunostimulation in the root canal and/or periapical tissue.

The present invention also includes a method of inducing differentiation of dental pulp stem cells into osteoblasts in a lesion of the root canal and/or periapical tissue, the method comprising filling the root canal of a patient having a lesion of the root canal and/or periapical tissue with a composition comprising a lithium salt in an amount sufficient to induce differentiation of dental pulp stem cells into osteoblasts in the lesion of the root canal and/or periapical tissue.

The dose or filling amount of the lithium salt-containing composition sufficient to treat the infected root canal and/or infected periapical tissue depends on the type of tooth or the shape of the root canal, and about 0.01 to 0.03mL of the composition containing the lithium salt at the above-mentioned concentration may be used. The dosage or filling amount of the composition containing a lithium salt sufficient to immunostimulate or induce differentiation of dental pulp stem cells into osteoblasts in the lesion of root canal and/or periapical tissue is substantially the same as described above.

The patient may be a non-human animal or a human being, particularly preferred a human being.

(elution of lithium salt)

The root canal filling material composition of the present invention is preferably 0.02 μ g or more, more preferably 0.05 μ g or more, and still more preferably 0.1 μ g or more of the absolute amount of lithium per day in the impregnation solution, as determined by the method in the "lithium elution test from apical pores" in the examples. The amount may be 1 μ g or more. The amount is preferably 5mg or less, more preferably 1mg or less, and still more preferably 0.1mg or less. The amount may be 10 μ g or less.

First embodiment of the root canal filling material composition of the present invention

(calcium compound)

In the first embodiment, the root canal filling material composition of the present invention may further include a calcium compound.

Examples of the calcium compound include calcium hydroxide, calcium carbonate, calcium sulfate, calcium chloride, calcium acetate, calcium oxide, tricalcium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, and calcium dihydrogen pyrophosphate. Specifically, calcium hydroxide and calcium carbonate are preferred, and calcium hydroxide is more preferred.

The calcium compound may be used alone or in combination of two or more thereof.

In the calcium compound (particularly, calcium hydroxide) containing composition, the concentration of the calcium compound (particularly, calcium hydroxide) is preferably 2% by weight or more, more preferably 5% by weight or more, still more preferably 10% by weight or more, and even more preferably 20% by weight or more, relative to the total amount of the composition. When calcium hydroxide is contained in a concentration within the above range, the composition sufficiently provides medicinal effects, particularly medicinal effects of calcium hydroxide. The concentration of the calcium compound (particularly, calcium hydroxide) is preferably 70% by weight or less, more preferably 50% by weight or less, and still more preferably 40% by weight or less, relative to the total amount of the composition. When the calcium compound is contained at a concentration within the above range, the hardness of the composition is moderate, and the composition can be easily discharged even from a syringe container.

(Water)

The root canal filling material composition of the present invention in the first embodiment may further contain water.

In the aqueous composition, the concentration of water is preferably 1 time or more, more preferably 1.1 times or more, still more preferably 1.2 times or more, and even more preferably 1.3 times or more the concentration (wt%) of the lithium salt. When water is contained in a concentration within the above range, the paste is not hard. The concentration of water is preferably 2 times or less, more preferably 1.8 times or less, still more preferably 1.7 times or less, and even more preferably 1.6 times or less the concentration (wt%) of the lithium salt. Compositions with too high a water content ratio dry easily, while compositions with a water content ratio in the above range prevent drying during storage.

The concentration of water is preferably 0.001 wt% or more, more preferably 0.005 wt% or more, still more preferably 0.01 wt% or more, even more preferably 0.1 wt% or more, and further preferably 1 wt% or more, based on the total amount of the composition. The concentration is preferably 70% by weight or less, more preferably 50% by weight or less, still more preferably 40% by weight or less, and even more preferably 30% by weight or less, and further preferably 25% by weight or less.

(polyhydric alcohol)

The root canal filling material composition according to the present invention in the first embodiment may further contain a polyhydric alcohol.

The polyhydric alcohol is added to prepare a calcium compound into a paste preparation. Examples of the polyhydric alcohol include dihydric alcohols such as propylene glycol, polypropylene glycol and polyethylene glycol, and trihydric alcohols such as glycerin. Specifically, propylene glycol, polyethylene glycol and glycerin are preferred.

The polypropylene glycol preferably has a polymerization degree of 100 to 1,000, more preferably 200 to 600, and still more preferably 300 to 400.

The polyethylene glycol preferably has a polymerization degree of 100 to 1,000, more preferably 200 to 600, and still more preferably 300 to 400.

The polyhydric alcohols may be used alone or in combination of two or more thereof. "two or more types thereof" includes, for example, a case where two or more polypropylene glycols having different polymerization degrees are contained and a case where two or more polyethylene glycols having different polymerization degrees are contained, in addition to a case where two or more types of polyols having different compound types are contained.

In the polyol-containing composition, the concentration of the polyol is preferably 1% by weight or more, more preferably 5% by weight or more, still more preferably 10% by weight or more, even more preferably 20% by weight or more, and further preferably 30% by weight or more, based on the total amount of the composition. The concentration of the polyhydric alcohol is preferably 90% by weight or less, more preferably 70% by weight or less, still more preferably 60% by weight or less, and even more preferably 50% by weight or less, relative to the total amount of the composition. The composition containing the polyhydric alcohol in a concentration within the above range can be prepared into a viscous paste-like preparation which is easy to handle.

(ultrafine particles of alumina/titanium oxide)

The root canal filling material composition of the present invention in the first embodiment may further comprise alumina ultrafine particles having a particle size of 1nm to 1 μm and/or titania ultrafine particles having a particle size of 1nm to 1 μm.

When stored in a container, the root canal filling material composition containing a calcium compound (particularly, calcium hydroxide) may be separated into the calcium compound (particularly, calcium hydroxide) and a liquid component, and may be difficult to be pushed out from the container such as a syringe container. When the composition of the present invention comprises the above-mentioned ultrafine alumina particles and/or ultrafine titania particles, solid-liquid separation during storage of the composition is suppressed.

The ultrafine particles may have a particle size of 1nm or more and a particle size of 5nm or more or 10nm or more. The ultrafine particles may have a particle size of 1 μm or less and a particle size of 500nm or less, 300nm or less, 50nm or less, or 20nm or less. When the particle size of the ultrafine particles is within the above range, separation between the calcium compound (particularly calcium hydroxide) and the liquid component can be sufficiently suppressed.

In the present invention, the particle size of the ultrafine particles is the average particle size of the primary particles and is determined by observation under a transmission electron microscope.

In the composition containing the ultrafine alumina particles and/or ultrafine titania particles, the total concentration of the ultrafine particles may be, for example, 0.1% by weight or more, preferably 0.5% by weight or more, more preferably 1% by weight or more, and still more preferably 2% by weight or more, relative to the total amount of the composition. When the ultrafine particles are contained in a concentration within the above range, the thickening effect is sufficiently achieved, and solid-liquid separation is suppressed. The total concentration of the ultrafine particles may be, for example, 20 wt% or less, preferably 10 wt% or less, more preferably 5 wt% or less, and still more preferably 4 wt% or less, with respect to the total amount of the composition. When the ultrafine particles are contained in a concentration within the above range, the composition has moderate hardness and is easily discharged from a syringe container.

(other Components)

The root canal filling material composition of the present invention in the first embodiment may further comprise an ointment base such as liquid paraffin, petrolatum, oil (vegetable oil such as olive oil, peanut oil), wax, resin and syrup, and a thickener such as cellulose and ester gum to control the consistency of the paste. When the composition comprises an ointment base, it is preferred to use a surfactant in combination.

The inventive root canal filling material composition in the first embodiment may contain an X-ray contrast agent or a radiopaque medium such as barium sulfate, zirconium oxide, bismuth subnitrate, bismuth trioxide, bismuth carbonate, zinc oxide, and iodoform. The X-ray contrast or opacity required for the root canal filling material composition is "an aluminum plate having a thickness of 3mm or more" according to JIS-T6522[ Dental root canal sealing materials ], and varies depending on the type of X-ray contrast agent or radiopaque medium used. For example, the content of barium sulfate contained is 10% by weight or more based on the total amount of the composition.

In addition, the composition may contain a component usable in the root canal filling material, such as an antimicrobial agent, as long as the effects of the present invention are not impaired.

Other components (components other than the lithium salt, the calcium compound, water, the polyol, the alumina ultrafine particles and the titania ultrafine particles) may be used alone or in combination of two or more thereof.

(consistency)

The root canal filling material composition of the present invention in the first embodiment preferably has a consistency (spread average) of 25 to 50mm, more preferably 25 to 40mm, wherein the consistency is determined as follows: sandwiching 75 μ L of the composition between glass plates; a load of 2.5kg was applied thereto for 7 minutes; and the maximum and minimum distances between parallel tangent lines in contact with the spread paste were measured. When the consistency is within the above range, solid-liquid separation of the composition during storage is more effectively suppressed, and the composition has fluidity suitable for application.

(preparation method)

The inventive root canal filling material composition of the first embodiment may be prepared by mixing and kneading a liquid component (including, for example, water and polyhydric alcohol) and a solid component (including a lithium salt and, for example, a calcium compound).

(method of use)

The root canal filling material composition of the present invention of the first embodiment may be, for example, filled into a syringe container, and then an 18 to 25 gauge blunt needle may be attached to the syringe container, and the composition may be filled into a root canal.

In order to take out the composition from the root canal, the composition may be alternately washed using 5 to 20 wt% (particularly about 10 wt%) of hypochlorous acid and 1 to 5 wt% (particularly about 3 wt%) of hydrogen peroxide water, or ultrasonic cleaning using purified water and an ultrasonic tip may be performed to remove the composition. When the root canal filling material composition of the present invention contains alumina ultrafine particles and/or titanium oxide ultrafine particles, the paste is not hardened for several days to several weeks after filling and thus can be easily removed.

The root canal filling material composition according to the second embodiment of the present invention

In a second embodiment, the root canal filling material composition of the present invention is a composition of paste a containing higher fatty acid and rosin and paste B containing magnesium oxide and vegetable oil, and one or both of paste a and paste B contains a lithium salt. The composition is used after mixing paste a and paste B.

(lithium salt)

The lithium salt is contained in one or both of the paste a and the paste B. The lithium salt is preferably contained only in the paste B, which can prevent hardening due to saponification with the higher fatty acid or rosin in the paste a.

As described above, the concentration of the lithium salt is preferably 0.0001 to 20 wt% with respect to the total amount of the composition, and in the second embodiment, the "total amount of the composition" is the total amount after mixing of the paste a and the paste B.

(higher fatty acid)

The higher fatty acid in paste a undergoes a saponification reaction when it comes into contact with the magnesium oxide in paste B, and as a result, the mixed paste as a sealing agent is hardened. The higher fatty acid preferably has a carbon number of 15 or more so as not to emit an offensive odor, and is preferably liquid at around room temperature because of making the paste a easily into a paste. The higher fatty acid may be any of saturated fatty acids and unsaturated fatty acids. More preferred is a higher fatty acid having 15 or more carbon atoms and being liquid at around room temperature. Among the saturated fatty acids, saturated fatty acids having a branched carbon chain, such as isostearic acid, are particularly preferred. Among the unsaturated fatty acids, linoleic acid, linolenic acid, arachidonic acid, clupanodonic acid, palmitoleic acid, etc. can be particularly preferably used.

The content of the higher fatty acid may be 20 to 50 mass%, preferably 30 to 40 mass%, with respect to the total amount of the paste a. If the content of the higher fatty acid is too low, the hardening time is prolonged, exudate or blood outside the apical pore may contaminate the inner wall of the root canal, or the apical sealing performance may deteriorate. In addition, the reduction of the liquid component increases the viscosity of the paste a itself, making the paste too thick and difficult to use at the time of use. If the content of the higher fatty acid is too high, the hardening time is too short, so that the paste is solidified during the root canal filling operation, the paste is difficult to be fed into the root canal, or the operation allowance time may be shortened.

(rosin)

The rosin in the paste a is a solid resin made by removing essential oil from secretions of various plants belonging to the genus pinus, and is not particularly limited, and any rosin conventionally used in the dental field may be used. Rosin is generally composed of 90% resin acids and 10% neutral species. The resin acids contain as a main component (about 90%) rosin acids which are isomerized by heating, and rosin contains as other components pimaric and isopimaric acids and contains almost no essential oils. Rosin from france contains a high content of pimaric acid. Also included are rosins prepared by hydrogenating the unsaturated bond portion of these rosins.

The rosin also undergoes saponification reactions when in contact with the magnesium oxide, which promotes the hardening reaction of the mixed paste.

The content of rosin may be 40 to 80 mass%, preferably 50 to 70 mass%, relative to the total amount of the paste a. If the content of rosin is too low, the hardening time is prolonged, and exudate or blood outside the apical pore may cause contamination, thereby degrading the sealing property of the apical portion. If the rosin content is too high, the consistency of the paste at the time of use is too high, and it may be difficult to deliver the paste into the root canal.

(magnesium oxide)

The magnesium oxide in the paste B undergoes a saponification reaction immediately upon contact with the higher fatty acid and the rosin, hardening the mixture. The hardening time is therefore influenced by the magnesium oxide content. If the content of magnesium oxide is too low, the hardening reaction is slow. If the content of magnesium oxide is too high, the hardening reaction becomes rapid, making it difficult to fill the mixture into the root canal. The content of magnesium oxide suitable for the optimum hardening time (about 10 to 30 minutes) varies depending on the kind or content of other components contained in the composition, and is, for example, 5 to 30 mass%, particularly preferably 10 to 20 mass%, relative to the total amount of the paste B.

(vegetable oil)

The vegetable oil in paste B may be any natural component intended to serve as a base in the paste, examples of which include vegetable oils such as olive oil, peanut oil, rapeseed oil, soybean oil, safflower oil, cottonseed oil, corn oil, and evening primrose oil. Ester compounds of glycerin and higher fatty acids such as linoleic acid, oleic acid, linolenic acid, palmitic acid, isostearic acid, and the like are also contained in vegetable oils at high contents, and therefore are also contained in the vegetable oils of the present invention.

The paste prepared by mixing paste a and paste B preferably has a moderately high consistency and a consistency such that the paste does not flow in the root canal. If the vegetable oil content is too low, the consistency of the paste at the time of use is too high, making it difficult to deliver the paste into the root canal, or to prepare paste B. If the vegetable oil content is too high, the consistency of the composition at the time of use is too low and it is difficult to handle. The vegetable oil content which satisfies the desired paste consistency may be 10 to 40 mass%, particularly preferably 15 to 30 mass%, relative to the total amount of the paste B.

(other Components)

Other components that may be contained in the root canal filling material composition of the present invention of the second embodiment are substantially the same as those of the first embodiment. In addition to the "other components" listed in the first embodiment, polyhydric alcohols such as propylene glycol, polypropylene glycol, polyethylene glycol, glycerin, and the like may be contained as the thickener. Water may also be present.

An X-ray contrast agent or radiopaque medium may be included in one or both of paste a and paste B, and is preferably included in paste B to prevent solid-liquid separation of the composition. As for the content of the X-ray contrast agent or the radiopaque medium, for example, the concentration of barium sulfate may be 10% by weight or more relative to the total amount of the composition after mixing of paste a and paste B.

When an ointment base or thickener is used in order to control the viscosity of paste a and paste B, the ointment base or thickener may be included in one or both of paste a and paste B. Vegetable oil is included in paste B and may also be included in paste a to control viscosity.

In the root canal filling material composition of the present invention of the second embodiment, in addition to the "other components" of the first embodiment, one or both of the paste a and the paste B may contain silica ultrafine particles having a particle size of 1nm to 1 μm in order to control the viscosity.

When the ultrafine particles are contained, the content thereof may be 0.1 wt% or more, preferably 1 wt% or more, and more preferably 2 wt% or more, relative to the total amount of each of the paste a and the paste B. The content is preferably 10 wt% or less, more preferably 8 wt% or less, and still more preferably 5 wt% or less, with respect to the total amount of each of the pastes a and B. When the content is within the above range, the thickening effect is sufficiently obtained, and solid-liquid separation is suppressed.

The root canal filling material composition of the present invention according to the second embodiment may contain eugenol, but preferably does not contain eugenol.

The root canal filling material composition of the present invention of the second embodiment is preferably free of calcium oxide, calcium hydroxide or magnesium hydroxide. If such a component is contained, saponification (hardening) reaction with fatty acid or rosin proceeds immediately, and thus hardening starts at the time of mixing the paste, and the mixing operation or filling operation may be difficult. If such a component is contained in the paste B, the saponification reaction with the vegetable oil proceeds, and the paste B may be solidified (hardened) in a container such as a syringe in storage.

In the present invention, "free" of some components includes the case where the component is contained in an inevitable amount.

In the root canal filling material composition of the present invention of the second embodiment, the combined weight ratio of the paste a to the paste B (paste a: paste B) is preferably 1:0.5 to 1.5, more preferably 1:0.8 to 1.2, and particularly preferably 1: 1.

(preparation method)

Each of the paste a and the paste B of the root canal filling material composition of the present invention of the second embodiment may be prepared by mixing and kneading a liquid component and a solid component.

(Container)

The paste a and the paste B may be stored in separate containers, or may be stored in respective storage portions of a one-pack type container having two storage portions.

Examples of the one-pack type container having two storage portions include containers each having two compartments. In the container, the two chambers are separated by a partition wall, and the paste A and the paste B are filled in the respective chambers and mixed by breaking the partition wall at the time of use. In another container, each storage portion has a discharge port or a portion as a discharge port, and the paste a and the paste B are discharged from the respective discharge ports and mixed at the time of use. Examples of the latter container include a double syringe container from which a load of paste a and paste B can be pushed out in a desired ratio by a single push, and a double syringe container having a mixing tip at a discharge port from which a mixture of paste a and paste B in a desired ratio can be filled into a root canal by a single push.

(method of use)

According to the root canal filling material composition of the present invention of the second embodiment, the paste a and the paste B may be mixed and filled into, for example, a root canal. After filling, the magnesium oxide undergoes saponification with the higher fatty acid and rosin, and the composition hardens within about 5 minutes to 2 hours (preferably about 10 minutes to 30 minutes).

Third embodiment of the root canal filling material composition according to the present invention

In the third embodiment, the root canal filling material composition of the present invention is a root canal filling material composition which is a combination of paste a and paste B and is hardened by mixing paste a and paste B. One or both of paste a and paste B contain a lithium salt, and one or both of paste a and paste B contain a glass powder. The glass powder contains calcium oxide and silicon dioxide in a total amount of 50 to 100 wt% with respect to the total amount of the glass powder, and a weight ratio of calcium oxide to silicon dioxide (calcium oxide: silicon dioxide) in the glass powder is 6:4 to 3: 7.

(lithium salt)

The lithium salt is contained in one or both of the paste a and the paste B. Particularly when the paste a contains a component (specifically, a higher fatty acid, polyacrylic acid or a salt thereof, and/or phosphoric acid) that imparts hardening properties described later, the lithium salt is preferably contained only in the paste B to prevent hardening due to a saponification reaction with the component in the paste a.

As described above, the concentration of the lithium salt is preferably 0.0001 to 20 wt% with respect to the total amount of the composition, and "the total amount of the composition" is the total amount of the paste a and the paste B after mixing and is the total amount of the paste a and the paste B.

(Glass powder)

In the root canal filling material composition of the present invention, one or both of the paste a and the paste B contains powdered glass having the above-described specific composition as a filler. The composition containing a larger amount of powdered glass has higher performance of precipitating bone-like crystals and higher sealing performance. Therefore, the content of the powdered glass is preferably 20% by weight or more, and may be 30% by weight or more or 40% by mass or more, relative to the total amount of the paste a and the paste B.

A composition containing an excessive amount of powdered glass may have a low hardenability or a poor workability when used. Therefore, when the powdered glass is contained in one of the paste a and the paste B or when the powdered glass is contained in both the paste a and the paste B, the content of the powdered glass is preferably 70 wt% or less and may be 60 wt% or less or 50 wt% or less with respect to each paste.

There have been many studies and patents in which powdered glass is mixed with an inorganic material such as bioceramics, biodegradable polymers, organic resins or the like to improve the workability of the resulting composite material or the strength of a hardened body, and it is known that apatite-like crystals are formed from the surface of glass in vivo and the crystals are bonded to bone or teeth. Such properties are referred to as "bioactivity" and a variety of bioactive glass formulations have been examined and studied. As a constituent and a formulation, calcium oxide and silicon dioxide are contained at a weight ratio of calcium oxide to silicon dioxide of 6:4 to 3:7 in an amount of 50 to 100 mass%. In addition, the alkali metal oxide may be contained in an amount of 0 to 40% by weight, and the phosphoric acid may be contained in an amount of 0 to 10% by weight. An X-ray contrast medium such as lanthanum oxide may also be contained.

The powdered glass may be prepared by a conventional method or may be a commercially available product.

(hardening Property imparting component of paste A)

Paste a may contain a component that imparts hardening properties to facilitate hardening by mixing paste a and paste B. Examples of the components include eugenol, guaiacol, higher fatty acids, polyacrylic acid or a salt thereof, and phosphoric acid. Preferred examples of the higher fatty acid are the same as those of the root canal filling material composition of the present invention according to the second embodiment. The hardening property imparting component may be used alone or in combination of two or more thereof.

The content of the hardening property-imparting component is determined by a relationship with the content of the powdered glass contained as the filler. That is, the content is required to be a content at which the mixture of the paste is hardened and a content suitable for causing the powder glass to provide a function of precipitating osteoid crystals and maintaining satisfactory sealing properties. From this viewpoint, the content of the hardening property-imparting component is preferably 5% by weight or more, more preferably 10% by weight or more, still more preferably 20% by weight or more, and even more preferably 40% by weight or more, relative to the total amount of the paste a. Paste a may not contain powdered glass, and thus paste a may contain a hardening property-imparting component in an amount of 100 wt% of the total amount of paste a.

(hardening Property imparting component of paste B)

Paste B may contain a component that imparts hardening properties to promote hardening by mixing paste a and paste B. Examples of such components include calcium oxide, magnesium oxide, strontium oxide, zinc oxide, calcium phosphate, and aluminosilicate glasses. The hardening property imparting component may be used alone or in combination of two or more thereof.

The content of such a component is determined by the relationship with the content of the powdered glass contained as a filler in the paste B. The content of the component imparting hardening property is preferably 5% by weight or more, more preferably 10% by weight or more, still more preferably 20% by weight or more, and even more preferably 40% by weight or more, relative to the total amount of the paste B. Paste B may not contain powdered glass, and thus paste B may contain a hardening property-imparting component in an amount of 100 wt% of the total amount of paste B.

Unlike the above-mentioned powdered glass, aluminosilicate glass does not have a function of forming bone-like crystals in vivo. However, it is known in the dental field that aluminosilicate glass is a hardenable material that hardens when mixed with polyacrylic acid or phosphoric acid, and may be selected as a component that imparts hardening properties by mixing.

(other Components)

Other components that may be contained in the root canal filling material composition of the present invention of the third embodiment are substantially the same as those of the first embodiment. In addition to the "other components" listed in the first embodiment, polyhydric alcohols such as propylene glycol, polypropylene glycol, polyethylene glycol, glycerin, and the like may be contained as the thickener. Water may also be present.

When an ointment base or thickener is used in order to control the viscosity of paste a and paste B, the ointment base or thickener may be included in one or both of paste a and paste B.

In the root canal filling material composition of the present invention of the third embodiment, in addition to the "other components" of the first embodiment, one or both of the paste a and the paste B may contain silica ultrafine particles having a particle size of 1nm to 1 μm in order to control the viscosity.

When the ultrafine particles are contained, the content thereof may be 0.1 wt% or more, preferably 1 wt% or more, and more preferably 2 wt% or more, relative to the total amount of each of the paste a and the paste B. The content is preferably 10% by weight or less, more preferably 8% by weight or less, and still more preferably 5% by weight or less. When the content is within the above range, the thickening effect is sufficiently obtained, and solid-liquid separation is suppressed.

In the root canal filling material composition of the present invention of the third embodiment, the combined weight ratio of the paste a to the paste B (paste a: paste B) is preferably 1:0.5 to 1.5, more preferably 1:0.8 to 1.2, and particularly preferably 1: 1.

(preparation method)

Each of the paste a and the paste B of the inventive root canal filling material composition of the third embodiment may be prepared by mixing and kneading a liquid component and a solid component.

(Container)

The containers filled with the paste a and the paste B are the same as those in the second embodiment.

(method of use)

According to the root canal filling material composition of the present invention of the third embodiment, the paste a and the paste B may be mixed and filled into, for example, a root canal. After filling, the composition hardens within about 5 minutes to 3 hours.

The root canal filling material composition of the present invention contains at least a lithium salt, and may be any composition other than the first to third embodiments exemplified above.

Examples

The present invention will be described in further detail below with reference to examples, but the present invention is not limited thereto.

(1) Preparation of root canal filling material composition

As a first embodiment of the present invention, paste-like root canal filling material compositions each having a formulation shown in tables 1 to 4 were prepared by mixing a liquid component mixed in advance and a solid component mixed in advance and kneading in a porcelain mortar.

As the second and third embodiments of the present invention, pastes a each having a formulation shown in table 5 and pastes B each having a formulation shown in table 6 were prepared by kneading all the respective components in a porcelain mortar. The formulation of the powdered glass in table 6 is shown in table 7.

TABLE 1 (Unit:% by weight)

TABLE 2 (Unit:% by weight)

TABLE 3 (Unit:% by weight)

TABLE 4 (Unit:% by weight)

TABLE 5 (Unit:% by weight)

Components of paste A	Formulation 1	Formulation 2
			Isostearic acid	40.0	39.0
Bismuth subcarbonate	56.0	-
			Ultrafine silica particles	4.0	-
Rosin	-	54.0
			Ester glue	-	5.0
Benzoic acid	-	2.0

TABLE 6 (Unit:% by weight)

TABLE 7 (Unit:% by weight)

Powder glass	Formulation 1	Formulation 2
			CaO	52.0	54.0
SiO₂	38.0	36.0
			P₂O₅	10.0	10.0
CaO/SiO₂Ratio of	1.37	1.50

TABLE 8

(2) Evaluation method

As the compositions shown in tables 1 to 4, 1mL of the paste was charged into a plastic syringe container. Paste a having the formulation shown in table 5 and paste B having the formulation shown in table 6 were used in equal amounts in the combination shown in table 8 and mixed. The following tests were carried out for each product.

The root canal filling material compositions of examples 1 to 3, 5 and 18 and comparative example 1 were each examined for their root tip lesion healing promoting effects using 4 rats per group according to the following procedure.

1. Male Wister rats of 10 weeks old were placed under general anesthesia and the occlusal surface of the mandibular first molar was incised with a round drill (#1/2) to expose the dental pulp.

2. The root tip is penetrated with a K file (# 10). By exposing the penetrated root tip to the oral cavity, root tip lesions were formed after 4 weeks.

3. After 4 weeks of pulp exposure, the rats were subjected to general anesthesia and the working length was set with an electric root canal length measuring instrument under rubber dam isolation for the mandibular first molar where pulp was exposed.

4. While washing with sodium hypochlorite solution, the root canal was enlarged with K files (#15 and # 20).

5. Root canal irrigation was performed with sodium hypochlorite aqueous solution in combination with ultrasonic vibration and the root canal was dried with paper tips.

6. A root canal filling material as a test sample was filled in the root canal and reached the apex of the root by applying ultrasonic vibration.

7. Filling composite resin to seal the pulp cavity.

8. To prevent the tested teeth from breaking, the maxillary first molars were extracted.

9. One, two, three and four weeks after the test sample was applied into the root canal, X-ray micro CT images were recorded and the volume of the root tip lesion was measured.

The same procedure as in < effect of promoting healing of root tip lesion > was performed except that mice were used instead of rats, and tissue sections of root tip lesions were prepared. As the root canal filling material composition to be applied to the root canal, the compositions of example 18 and comparative example 1 were used.

In situ hybridization was performed to identify that promotion of differentiation of dental pulp stem cells into odontoblasts is a factor promoting healing of apical lesions.

Specifically, paraffin sections were dewaxed, washed with 0.01M PBS, fixed with 4% PFA for 10 minutes, and washed with PBS. The sections were reacted with 1. mu.g/mL proteinase K (Takara Bio) for 5 min and post-fixed with 4% PFA. The sections were acetylated with 0.1M triethanolamine containing 0.25% acetic anhydride and washed with 0.01M PBS. Sections were prehybridized with cRNA probes (Axin 2: Addgene #21277, NM-015732, nt1774-2787, Col1a 1: NM-007742, nt29553415, Runx 2: AF010284, nt 922-1746) at 55 ℃ for 1 hour and allowed to stand in 5-fold concentrated sodium citrate solution (5-SSC) for 20 minutes. The sections were reacted with 0.2-SSC at 70 ℃ for 20 minutes, and allowed to stand in 0.2-SSC for 5 minutes and in maleic acid buffer (MBA) for 5 minutes. Sections were then blocked with blocking solution containing 5% goat serum (Vector Laboratories, california, usa) for 2 hours. Sections were reacted with Alkaline Phosphatase (AP) -labeled anti-digoxigenin antibody (1:5000) (Roche, Basel, Switzerland) at 4 ℃ for 24 hours, then washed with MBA containing 0.1% Tween 20, and washed with deionized distilled water containing 0.1% Tween 20. The sections were reacted with BM pure AP (Roche) as a substrate at room temperature for 6 hours, then washed with PBS, followed by mounting with 50% glycerol/PBS, and observed under an optical microscope.

In addition, immunofluorescent staining of cell surface markers on B cells was performed to identify activation of immune responses that also promoted healing of root tip lesions.

Specifically, after paraffin sections were dewaxed, the sections were washed with Tris Buffered Saline (TBS), then reacted in a citric acid buffer at 100 ℃ for 10 minutes, and left to stand at room temperature for 30 minutes. Sections were blocked with blocking solution containing 10% goat serum (10% goat serum/TBS) for 1 hour and then reacted with primary antibody overnight at room temperature. CD45R (Abcam) was used as a primary antibody and experiments were performed at an antibody concentration of 1: 50. After reaction with primary antibody, sections were washed with TBS, then reacted with 1:500 Alexa 488-goat anti-rat TgG (Invitrogen, Calif., USA) for 2 hours at room temperature and washed. Sections were reacted with 1:1000 DAPI (4', 6-diamidino-2-phenylindole) (Sigma) for 15 min. After the reaction was complete, the sections were washed and mounted with 50% glycerol. The stained tissue sections were observed under a fluorescence microscope (Axioskop 2 plus: Carl Zeiss, Allen, Germany (Aalen)).

The root canal model (END1001-30#20, NISSIN) was enlarged to form a root canal having a bore size of 0.6mm and a root canal volume of 0.03 mL. About 0.05g of each composition shown in tables 1 to 4 was filled into the root canal. As a combined composition shown in table 8, equal amounts of paste a and paste B were used and mixed, and then the mixture was charged into a plastic syringe, and about 0.05g of the mixture was filled into a root canal. The upper part of the root canal of each specimen was sealed with a scotch tape. Each specimen was placed in a plastic container, then 10mL of purified water was added to immerse the root tips, and the whole was allowed to stand in a 37 ℃ thermostat. After each specimen was stored for 7 days, the maceration extract was collected, placed in an evaporation dish, and allowed to stand at 110 ℃ for 1 hour and 30 minutes for concentration. The tip of the platinum wire was dipped into the concentrate, then pulled up gently and placed in a colorless flame. When the flame color was observed through cobalt glass, a composition which produced a red flame was evaluated as acceptable (. smallcircle.), and a composition which did not produce a red flame was evaluated as unacceptable (. smallcircle.).

With respect to the compositions of examples 1, 3, 5, 24 and 26, the amount of eluted lithium in the immersion liquid was measured by ICP-AES, and the 1-day absolute amount (g) of the lithium eluted from the root tips was calculated. A composition having a 1-day released amount of lithium of 0.014 μ g or more was evaluated as "pass" (. smallcircle "), and a composition having a 1-day released amount of lithium of not 0.014 μ g or more was evaluated as" fail "(. ×).

For the compositions shown in tables 1 to 4, 75 μ L of the paste was sandwiched between glass plates (thickness 5mm, 70 × 70mm), and then a load of 2.5kg was applied for 7 minutes, and the maximum and minimum distances between parallel tangent lines in contact with the spread paste were measured. Compositions having a consistency (spread average) of 25 to 50mm (the upper limit increased since the consistency of example 16 was about 50 mm) were rated as acceptable (. largecircle.), while compositions having a consistency (spread average) of not 25 to 50mm were rated as unacceptable (. times.).

The combination compositions shown in Table 8 were tested by the test method specified in JIS-T6522-Dental root canal sealer (JIS-T6522-Dental root canal sealing materials). That is, the paste A and the paste B were used in equal amounts and mixed, and after 3 minutes, the mixture was sandwiched between glass plates in an amount corresponding to 0.05 mL. The diameter of the spread sample was measured in an environment of 23 ℃ and 50% relative humidity with a 120g weight (including the weight of the glass plate) applied for 7 minutes. Compositions having a paste consistency of 20 to 35mm were rated as acceptable (. largecircle.), while compositions having a paste consistency of not 20 to 35mm were rated as unacceptable (. largecircle.).

As an index of the paste hardness, a test method specified in JIS-T6522-Dental root canal sealer (JIS-T6522-Dental root canal sealing materials) was used as a reference. For the compositions shown in tables 1 to 4, about 0.07g of the paste was sandwiched between glass plates (thickness 5mm or more, contact surface area 200. + -. 25 mm)²) A load of 150. + -.3N was applied for 7 minutes using a small bench precision universal tester. For the combination compositions shown in table 8, paste a and paste B were used and mixed in equal volumes, then about 0.07g of the mixture was sandwiched between glass plates, and 3 minutes after the start of mixing, a load of 150 ± 3N was applied for 7 minutes using a mini bench top precision universal tester. The total thickness of the two glass plates and the paste film was measured, and the difference in thickness (film thickness) was calculated from the thickness without any paste film. Compositions having a film thickness of 50 μm or less were evaluated as good (. largecircle.), and compositions having a film thickness exceeding 50 μm were evaluated as bad (. smallcircle.).

The compositions shown in tables 1 to 4 did not harden and were therefore not tested. For the combination compositions shown in Table 8, tests were carried out with reference to the test method specified in JIS-T6522-Dental root canal sealing materials (JIS-T6522-Dental root canal sealing materials). That is, the paste A and the paste B were used in equal amounts and mixed, and the mixture was charged into a mold having a diameter of 10mm and a height of 2 mm. From 2 minutes after the mixing, the mold was placed in an environment at 37 ℃ and a relative humidity of 95% or more, and it was checked at predetermined time intervals whether a 100g Vicat needle having a diameter of 2mm was unblocked. A composition having a curing time of 6 hours or less was evaluated as acceptable (∘), and a composition having a curing time of 6 hours or less was evaluated as unacceptable (×).

For the compositions shown in tables 1 to 4, about 0.1g of the paste was placed on a mixed paper pad, left in a room (room temperature 23 ± 1 ℃, relative humidity 50 ± 5%) for 10 minutes, and whether the paste could be caught on the root canal paste auger or not was visually observed. Compositions that could be grasped were rated as good (o) and combinations that could not be grasped were rated as bad (x).

For the combination compositions shown in table 8, paste a and paste B were used in equal amounts and mixed, and then the mixture was pulled up with a spatula and visually observed for stringiness. The composition in which the stringiness occurred was evaluated as good (O), and the composition in which the stringiness did not occur was evaluated as bad (X).

For the compositions shown in tables 1 to 4, 1mL of the paste was filled in a plastic syringe container, and 3 days after loading, a 21-gauge blunt needle was mounted on the tip of the plastic syringe container. Using a small bench top precision universal tester, the syringe was displaced to 10mm at a crosshead speed of 20mm/min, and whether the paste was easily discharged from the syringe container was observed. Compositions having a resistance value of 40N or less were evaluated as good (. largecircle.), and compositions having a resistance value exceeding 40N were evaluated as bad (. smallcircle.).

About 1g each of the compositions shown in tables 1 to 4 and the composition shown in table 6 (paste B) was placed in a 2mL glass screw tube, and left at room temperature for one week to observe whether or not the compositions separated. The composition not separated was evaluated as good (. largecircle.), and the separated composition was evaluated as bad (. largecircle.).

(3) Results

The results are shown in tables 1 to 4, table 8, and fig. 1 to 3.

As shown in table 1, the compositions in examples 1 to 5 were different in lithium salt concentration, and each composition dissolved the lithium salt in the apical pore of the root canal model. Each composition had the appropriate consistency for direct application from the syringe container into the root canal and had satisfactory film thickness, pushout properties from the syringe container, and handling. No separation was observed even when each composition was stored at room temperature for one week.

In examples 6 to 11 in table 2, the ratio of water/lithium salt was varied.

Each of the compositions of examples 8 to 10 readily dissolved the lithium salt from the apical pore, had an appropriate consistency for direct application from the syringe vessel into the root canal, and had satisfactory film thickness, ejection property from the syringe vessel, and handling property. Even when each composition was stored at room temperature for one week, no separation was observed. The composition of example 6 was hard because of its small amount of water relative to the lithium salt, and was slightly difficult to be pushed out from the syringe container, but was practical. The composition of example 7 had a poor consistency, but could be formed into a film, and was easily pushed out from a syringe without separation, and thus was practically usable. The composition of example 11 was poor in consistency and became a putty-like material when left for 10 minutes, but could be practical in a quick operation.

The composition of example 12 in table 3 was the same as that of example 2 except that lithium carbonate in the composition of example 2 was changed to lithium chloride. Regardless of the kind of salt, the composition gave good performance in all tests of dissolution of lithium salt from the apical pore, consistency, film thickness, resistance to ejection from the syringe vessel, handling and separation.

In examples 13 to 16 of table 3, the concentration of the polyol was varied.

The compositions of examples 13 to 16 gave substantially satisfactory results in terms of dissolution of lithium salt from the apical pores, consistency, resistance to ejection from the syringe vessel and handling. Even when each composition was stored at room temperature for one week, no separation was observed. The compositions of examples 13 and 14 having a low polyol concentration gave slightly greater film thickness and became putty-like after standing for 10 minutes, but could be practical when handled quickly.

The composition of example 17 in Table 3 was the same as that of example 5 except that the calcium hydroxide in the composition of example 5 was changed to calcium carbonate. The composition has a healing promoting effect on apical lesions even when calcium hydroxide is not contained, and dissolves lithium from the apical pores of the root canal model. The composition has a suitable consistency for direct application from a syringe container into a root canal, and has satisfactory film thickness, pushout properties from a syringe container, and handling properties. No separation was observed even when the composition was stored at room temperature for one week.

The compositions of examples 19 and 20 in table 4 are the same as those of example 8 except that the polyethylene glycol in the composition of example 8 is changed to propylene glycol and glycerin, respectively. Regardless of the kind of polyol, the composition gave good performance in all tests of dissolution of lithium salt from the apical pore, consistency, film thickness, resistance to ejection from the syringe vessel, handling and separation.

The composition of example 21 in Table 4 contained a large amount of alumina ultrafine particles, whereas the composition of example 22 contained no alumina ultrafine particles. The composition gave good performance in all tests of dissolution of lithium salt from the apical pore, consistency, film thickness, resistance to extrusion from the syringe vessel, handling and separation, regardless of the content of the alumina microfine particles.

The composition of example 23 in table 4 contains no water and is therefore hard and somewhat difficult to push out of a syringe container.

The composition of example 24 in Table 4 produced a thick film that became a putty-like material when left for 10 minutes, but could be practical for rapid handling.

As shown in table 8, the compositions of examples 25 to 29, in which the compositions a1 and a2 as the paste a and the compositions B1 to B5 as the paste B were used in combination, had a consistency and a film thickness suitable for filling in a root canal, had good hardenability and workability, and dissolved lithium from an apical pore at the time of filling in a root canal model. No separation after storage was observed.

In examples 1, 2, 3, 5 and 18 in which elution of lithium from the apical foramen was observed, reduction in lesion volume was observed in evaluation of the effect of promoting healing of apical lesions.

Figure 1 shows X-ray micro CT images of the left mandibular first molars 4 weeks after application of the composition containing the lithium salt of example 18 but no calcium hydroxide and the composition containing no lithium salt of comparative example 1. In example 18, the radiopaque image showing the lesion of the root tip near the root tip was reduced, which indicates bone restoration, while in comparative example 1, the radiopaque image near the root tip was still large. In other words, in example 18 containing a lithium salt, a lesion volume-reducing effect was observed.

Fig. 2 to 4 show the change in lesion volume over time after application of the test composition to the root canal. As shown in fig. 2, in example 5 in which the lithium carbonate concentration was 12.0 wt%, the lesion volume was significantly reduced after two weeks or more. In fig. 3, example 3 having a lithium carbonate concentration of 1.0 wt% is compared with comparative example 1. As with the results in fig. 2, in example 3, the lesion volume was significantly reduced after three weeks or more as compared with comparative example 1. As shown in fig. 4, in examples 1 to 3 in which the lithium carbonate concentration was 0.01 to 1.0 wt%, the lesion volume was significantly reduced after three weeks or more, compared to comparative example 1 containing no lithium salt. The effect of reducing the lesion volume can be sufficiently achieved even at an extremely low lithium salt concentration of 0.01%. The lesion reduction effect is not significantly affected by the lithium salt concentration.

Fig. 5 shows a histopathological section image prepared as follows: the respective root canal filling material compositions of example 18 and comparative example 1 were filled in the lesion apical hole of the mouse; tissue sections of the root tip lesions were hybridized in situ 4 weeks later. Arrows indicate Colla1 or Runx2 positive cells. In example 18, an increase in the number of Colla1 or Runx2 positive cells indicated by arrows was observed. Runx2 is an osteoblast specific transcription factor that regulates differentiation of pluripotent mesenchymal cells into osteoblasts. Osteoblasts produce type I collagen, which is the main component in the bone matrix. Colla1 (type I collagen. alpha.I) is one of the types I collagen. Thus, the results indicate that the root canal filling material composition of example 18 induces differentiation of mesenchymal stem cells (dental pulp stem cells) around the apex of the root into osteoblasts to promote osteogenesis, which may be attributed to the inclusion of lithium salt.

Fig. 6 shows a histopathological section image prepared as follows: each of the tube-filling material compositions of example 18 and comparative example 1 was filled in a lesion apical hole of a mouse; after 4 weeks, tissue sections of root tip lesions were immunofluorescent stained for cell surface markers on B cells. In example 18, the number of CD45R positive (red) cells was increased compared to comparative example 1. CD45R is the most abundant hematopoietic marker expressed on all leukocytes, and expresses multiple isoforms in a cell-specific pattern. In mice, the CD45R/B220 isoform is expressed at various levels on B cells at all stages, predominantly from progenitor B cells to activated B cells. Thus, the results show that the root canal filling material composition of example 18 promotes the production of leukocytes to stimulate an immune response, which is attributable to the lithium salt contained therein.

The composition of comparative example 1 in table 1 was the same as that of example 3 except that lithium carbonate (1 wt%) was not contained, but the amount of calcium hydroxide (1 wt%) was increased accordingly.

The composition of comparative example 1 gave good performance in all tests of consistency, film thickness, ejection resistance from a syringe vessel, operability and separation, but did not provide a root tip lesion healing promoting effect and did not dissolve lithium from the apical foramen of the root canal model.

Industrial applicability

The root canal filling material composition of the present invention contains a lithium salt, and thus can effectively promote healing of refractory pulpitis or periapical periodontitis, which is very different from conventional root canal filling material compositions.

Claims

1. A root canal filling material composition comprising a lithium salt.

2. The root canal filling material composition according to claim 1, wherein the concentration of the lithium salt is 0.0001 to 20% by weight with respect to the total amount of the composition.

3. The root canal filling material composition according to claim 1 or 2, further comprising a calcium compound.

4. The root canal filling material composition according to claim 3, wherein the concentration of the calcium compound is 2 to 70% by weight with respect to the total amount of the composition.

5. The root canal filling material composition according to any one of claims 1 to 4, further comprising water.

6. The root canal filling material composition according to claim 5, wherein the content of water is 1 to 2 times that of the lithium salt in terms of a weight ratio.

7. The root canal filling material composition according to any one of claims 1 to 6, further comprising a polyol.

8. The root canal filling material composition according to claim 7, wherein the concentration of the polyhydric alcohol is 1% by weight to 90% by weight with respect to the total amount of the composition.

9. The root canal filling material composition according to any one of claims 1 to 8, further comprising alumina ultrafine particles having a particle size of 1nm to 1 μm and/or titanium oxide ultrafine particles having a particle size of 1nm to 1 μm.

10. The root canal filling material composition according to claim 9, wherein the total content of the alumina ultrafine particles and/or the titania ultrafine particles is 0.1 to 20% by weight with respect to the total amount of the composition.

11. The root canal filling material composition according to claim 1 or 2, wherein the root canal filling material composition is a combination of paste a containing a higher fatty acid and rosin and paste B containing magnesium oxide and a vegetable oil, and one or both of the paste a and the paste B contains a lithium salt.

12. The root canal filling material composition according to claim 1 or 2, wherein the root canal filling material composition is a combination of paste a and paste B and is hardened by mixing paste a and paste B, one or both of the paste a and the paste B contains a lithium salt, one or both of the paste a and the paste B contains a glass powder containing 50 to 100% by weight of calcium oxide and silica in total relative to the total amount of glass powder, and the weight ratio of calcium oxide to silica, i.e., calcium oxide to silica, in the glass powder is 6:4 to 3: 7.

13. The root canal filling material composition according to claim 12, wherein the content of the glass powder is 20 wt% or more with respect to the total amount of the paste a and the paste B and 70 wt% or less with respect to the total amount of each of the paste a and the paste B.

14. The root canal filling material composition according to claim 12 or 13, wherein the paste a further contains at least one component selected from the group consisting of eugenol, guaiacol, higher fatty acids, polyacrylic acid or a salt thereof, and phosphoric acid, and the paste B further contains at least one component selected from the group consisting of calcium oxide, magnesium oxide, strontium oxide, zinc oxide, calcium phosphate, and aluminosilicate glass.

15. The root canal filling material composition according to any one of claims 1 to 14, which is used for immunostimulation in lesions of the root canal and/or periapical tissue.

16. The root canal filling material composition according to any one of claims 1 to 14, which is used for inducing differentiation of dental pulp stem cells into osteoblasts in lesions of root canals and/or periapical tissues.