Bone regeneration material kit, paste-like bone regeneration material, bone regeneration material, and bone bonding material

Abstract

The present invention aims to provide a bone regeneration material kit, a paste-like bone regeneration material, a bone regeneration material, and a bone bonding material, which contain particles including a bioabsorbable polymer; and can fill a bone defect or damage and secure the mechanical strength of the bone in the short term and can promote regeneration of the patient's own bone in the long term. In addition, they can exhibit anti-washout properties after filling even when they are in contact with water such as blood or biological fluids. The present invention relates to a bone regeneration material kit comprising: a particle comprising a calcium salt and having an inositol phosphate or salt thereof adsorbed on the surface; a particle comprising a bioabsorbable polymer; and an aqueous medium.

Claims

1. A bone regeneration material kit comprising: a particle comprising a calcium salt and having an inositol phosphate or salt thereof adsorbed on the surface; a particle comprising a calcium phosphate compound and having no inositol phosphate or salt thereof adsorbed on the surface; wherein a blend ratio of the particle comprising a calcium salt and having an inositol phosphate or salt thereof adsorbed on the surface and the particle comprising a calcium phosphate compound and having no inositol phosphate or salt thereof adsorbed on the surface is within the range of 10:90 to 50:50 by weight; a particle comprising a bioabsorbable polymer; and an aqueous medium.

2. The bone regeneration material kit according to claim 1, wherein the inositol phosphate or salt thereof is inositol hexaphosphate.

3. The bone regeneration material kit according to claim 1, wherein the particle comprising a bioabsorbable polymer is a particle comprising crosslinked gelatin.

4. The bone material regeneration kit of claim 1, wherein the calcium salt is a hydroxyapatite.

5. The bone material regeneration kit of claim 1, wherein the calcium phosphate compound comprises -tricalcium phosphate and -tricalcium phosphate.

6. A paste-like bone regeneration material comprising the bone regeneration material kit according to claim 1, the paste-like bone regeneration material being a paste prepared by mixing the particle comprising a calcium salt and having an inositol phosphate or salt thereof adsorbed on the surface; the particle comprising a calcium phosphate compound and having no inositol phosphate or salt thereof adsorbed to the surface, the particle comprising a bioabsorbable polymer; and the aqueous medium.

7. A bone regeneration material prepared by curing the paste-like bone regeneration material according to claim 6.

Description

DESCRIPTION OF EMBODIMENTS

(1) The following describes examples to more specifically illustrate embodiments of the present invention. It should be noted that the present invention is not limited only to these examples.

Experimental Example 1

(2) (1) Preparation of Wet-Synthesized Hydroxyapatite Powder

(3) First, 1000 mL of a 0.5 M suspension of calcium hydroxide was prepared. To the suspension was added dropwise 1000 mL of a 0.3M aqueous solution of phosphoric acid. The concentrations of calcium hydroxide and phosphoric acid were adjusted so that they satisfy Ca/P=1.67 (molar ratio). The pH in a reaction chamber was adjusted with a pH adjuster (25% ammonia water) to meet 10<pH<11. After completion of the dropping of the aqueous solution of phosphoric acid, the mixture was further stirred for one hour and then allowed to stand in an incubator set at 37 C. for 24 hours for maturation. After maturation, the slurry was recovered by suction filtration and frozen overnight in a freezer at 80 C. The frozen slurry was dried for 48 hours using a freeze dryer (Free Zone (trademark), produced by Labconco) to give a wet-synthesized hydroxyapatite powder.

(4) (2) Preparation of Inositol Hexaphosphate-Adsorbing Hydroxyapatite Particles

(5) A 8.00 g portion of a 50% by weight aqueous solution of inositol hexaphosphate (produced by Wako Pure Chemical Industries) was accurately weighed, diluted to about 300 mL with purified water, then adjusted to pH 7.3 with an aqueous solution of sodium hydroxide and hydrochloric acid, and diluted to 500 mL in a measuring cylinder. Thus, a 8000 ppm aqueous solution of inositol hexaphosphate was prepared.

(6) The inositol hexaphosphate was adsorbed on the hydroxyapatite using a planetary ball mill (type P-6, produced by FRITCH) under the following conditions. To a zirconia pot were added 50 mL of the resulting aqueous solution of inositol hexaphosphate, 10.0 g of the wet-synthesized hydroxyapatite powder (average particle size 10 m), and 180 g of 2 mm zirconia balls. They were stirred at a rotation speed of 300 rpm for one hour, followed by centrifugation at 9000 rpm for 30 minutes. The resulting residue was filtered to obtain a slurry. The slurry was frozen overnight at 80 C. The frozen slurry was freeze dried for 24 hours using a freeze dryer (Free Zone (trademark), produced by LABCONCO) to give inositol hexaphosphate-adsorbing hydroxyapatite particles.

(7) (3) Preparation of Ground Product of -Tricalcium Phosphate Particles

(8) -tricalcium phosphate was ground using a planetary ball mill (type P-6, produced by FRITCH) under the following conditions. To a zirconia pot were added 40 mL of purified water, 10.0 g of -tricalcium phosphate particles (average particle size 10 m, produced by TAIHEI CHEMICAL INDUSTRIAL CO., LTD.), and 180 g of 2 mm zirconia balls. They were stirred at a centrifugal acceleration of 300 rpm for one hour, followed by filtration. The resulting product was frozen overnight at 80 C. The frozen slurry was freeze dried for 24 hours using a freeze dryer (Free Zone (trademark), produced by LABCONCO) to give a ground product of -tricalcium phosphate particles.

(9) (4) Preparation of Powder Mixture of Inositol Hexaphosphate-Adsorbing Hydroxyapatite Particles and Ground Product of -Tricalcium Phosphate Particles

(10) A V-type mixer (produced by TSUTSUI SCIENTIFIC INSTRUMENTS CO., LTD.) was charged with the inositol hexaphosphate-adsorbing hydroxyapatite particles and the ground product of -tricalcium phosphate particles at a ratio of 0:100, 10:90, 20:80, 50:50, 80:20, or 100:0 by weight. They were stirred for 5 minutes to prepare a powder mixture.

(11) (5) Production of Crosslinked Gelatin Particles

(12) Uncrosslinked gelatin particles having an average particle size of 200 m were heat-treated under vacuum at 140 C. for 14 hours to prepare thermally crosslinked gelatin particles.

(13) (6) Production of Bone Regeneration Material Kit and Paste-Like Bone Regeneration Material

(14) A bone regeneration material kit was composed of the resulting powder mixture of the inositol hexaphosphate-adsorbing hydroxyapatite particles and the ground product of -tricalcium phosphate particles, the resulting thermally crosslinked gelatin particles, and an aqueous medium (10% chitosan, 2.5% sodium dihydrogen phosphate). To the resulting powder mixture was blended the thermally crosslinked gelatin particles in an amount of 10% by weight relative to the amount of the powder mixture. Then, 700 to 800 L of the aqueous medium was added to a 1.0 g portion of the resulting mixture. They were mixed for 120 seconds to prepare a paste-like bone regeneration material.

Experimental Example 2

(15) A bone regeneration material kit and a paste-like bone regeneration material were produced as in Experimental Example 1, except that the amount of thermally crosslinked gelatin particles was 5% by weight.

Comparative Examples 1 and 2

(16) A bone regeneration material kit and a paste-like bone regeneration material were produced as in Experimental Example 1 or 2, except that hydroxyapatite particles to which no inositol hexaphosphate was adsorbed were used instead of the inositol hexaphosphate-adsorbing hydroxyapatite particles.

(17) The hydroxyapatite particles to which no inositol hexaphosphate was adsorbed were prepared by stirring the wet-synthesized hydroxyapatite powder and purified water with a planetary ball mill.

Reference Example

(18) A bone regeneration material kit was composed of calcium phosphate particles having an average particle size of 10 m to which no inositol hexaphosphate was adsorbed (75% by weight of -tricalcium phosphate, 18% by weight of tetracalcium phosphate, 5% by weight of calcium hydrogen phosphate dihydrate, and 2% by weight of hydroxyapatite), thermally crosslinked gelatin particles, and an aqueous medium (aqueous solution containing 5.4% chondroitin sodium sulfate, 13% disodium succinate anhydrous, and 0.3% sodium bisulfite). To the calcium phosphate particles was blended the thermally crosslinked gelatin particles in an amount of 10% by weight relative to the amount of the calcium phosphate particles. Then, 700 L of the aqueous medium was added to a 1.5 g portion of the resulting mixture. They were mixed for 120 seconds to prepare a paste-like bone regeneration material.

(19) (Evaluation)

(20) The paste-like bone regeneration materials prepared in the experimental examples, the comparative examples, and the reference example were evaluated in the following way. Table 1 shows the results.

(21) (1) Evaluation of Setting Time of Paste-Like Bone Regeneration Material

(22) The paste-like bone regeneration material immediately after production was packed in a split mold with a diameter of 6.0 mm and a height of 12 mm, and cured for a specific time in a thermo-hygrostat at 37 C. and a relative humidity of 100%.

(23) The hardness of the product was measured for every curing time in accordance with JIS T 6602. The time required to achieve gillmore (lighter) was defined as the initial setting time, and the time required to achieve gillmore (heavier) was defined as the final setting time.

(24) (2) Evaluation of Anti-Washout Property

(25) The paste-like bone regeneration material immediately after production was packed in a split mold with a diameter of 6.0 mm and a height of 12 mm, and cured at room temperature for five minutes. The resulting cured product immediately after curing was put into distilled water, and allowed to stand at room temperature for 24 hours. Then, the state of the cured product in the distilled water was visually observed, and the anti-washout property was evaluated based on the following criteria.

(26) Good (): little disintegration was observed

(27) Fair (): slight disintegration was observed at an end area

(28) Bad (x): a product completely disintegrated

(29) (3) Evaluation of Compressive Strength and Bulk Density of Cured Product

(30) The paste-like bone regeneration material immediately after production was packed in a split mold with a diameter of 6 mm and a height of 12 mm, and aged in a thermo-hygrostat at 37 C. and relative humidity of 100% for 24 hours. Then, a sample was taken out from the split mold. Thus, a cured product was obtained.

(31) The compressive strength of the resulting cured product was measured using a universal tester (EZ-Graph, produced by SHIMADZU CORPORATION) at a test speed of 0.5 mm/min.

(32) The bulk density (g/cm.sup.3) was calculated by measuring the diameter, height, and weight of the cured product.

(33) TABLE-US-00001 TABLE 1 Paste-like bone regeneration material Powder mixture (ratio by weight) Inositol Hydroxyapatite Ground Amount of Evaluation hexaphosphate- particles with no product of crosslinked Cured product adsorbing adsorption of -Tricalcium gelatin Setting time Compressive Bulk hydroxyapatite inositol phosphate particles (min) Anti-washout strength density particles hexaphosphate particles (% by weight) Initial Final property (MPa) (g/cm.sup.3) Experimental 0 100 10 5 6 x 10.5 1.3 Example 1 10 90 10 6 7 20 80 10 6 7 12.1 1.3 50 50 10 12 25 8.6 1.3 80 20 10 22 40 or 3.7 1.2 more 100 0 10 100 or 100 or 2.7 1.4 more more Experimental 20 80 5 6 7 17.0 1.4 Example 2 Comparative 20 80 10 6 7 x 6.1 1.3 Example 1 Comparative 20 80 5 6 7 10.0 1.4 Example 2 Reference Calcium phosphate particles 10 8 100 or x 2.7 1.4 Example more

INDUSTRIAL APPLICABILITY

(34) The present invention can provide a bone regeneration material kit, a paste-like bone regeneration material, a bone regeneration material, and a bone bonding material, which contain particles comprising a bioabsorbable polymer; and can fill a bone defect or damage and secure the mechanical strength of the bone in the short term and can promote regeneration of the patient's own bone in the long term; and can exhibit anti-washout properties after filling even when they are in contact with water such as blood or biological fluids.