JP4631012B2 - Flexible sheet-like bone filling material and method for producing the same - Google Patents

Description

  The present invention relates to a novel calcium phosphate for bone filling material having excellent biological activity, a fluid bone filling material composition containing the same, a sheet-like bone that is easy to handle and can be applied in a wide range of clinical applications. It is related with a filling material and its manufacturing method.

  Conventionally, the forms such as β-TCP and hydroxyapatite as artificial bone filling materials used to promote defect filling and bone formation are mainly in powder form and sintered blocks. However, the sheet-like bone prosthesis material in which these materials are provided in layers on the sheet-like support can be cut by sandwiching the entire support into a shape suitable for the affected area. Since there are few clinical cases, some have already been proposed.

  For example, Patent Document 1 discloses that a part of the particles are embedded in the base sheet by attaching and pressing particles made of a calcium phosphate compound on at least one side of the base sheet made of a bioabsorbable polymer substance. A bone-repairing sheet is described in which a communication hole is provided that communicates from the front surface to the back surface, and a plurality of communication holes having an average hole diameter of 10 to 2000 μm are provided by punching out the base sheet. 2 has a sheet made of a mixture of apatite and chitosan sol dissolved with acid, the sheet comprising at least one element selected from the group of Group I metal and Group II metal elements It is neutralized by a solution of the compound, is not toxic in vivo, and after completion of the chemical reaction, the product is a cured product near neutrality, A sheet-like bone filling agent excellent in formation is disclosed, and Patent Document 3 discloses poly-L-lactide (PLLA), poly-D-lactide (PDLA), poly-D, L-lactide (PD). , L-LA), polyglycolic acid, polycaprolactone, polydioxanone, L-lactide / glycolide copolymer, D-lactide / glycolide copolymer, L- and D-lactide / glycolide copolymer (P ( LA / GA)), L-lactide / caprolactone copolymer, D-lactide / caprolactone copolymer, L- and D-lactide / caprolactone copolymer (P (LA / CL)) A particle made of a calcium phosphate compound is attached to at least one side of a base material sheet made of a bioabsorbable polymer substance, and the sheet is pressed under heating. More, by embedded portions of said particles to said base sheet, the powder has been described bone filling sheet was to avoid scattered into the body.

  However, in the bone filling sheet described in Patent Document 1, there is no disclosure that pays attention to the particle size of the calcium phosphate compound, and the bone filling sheet described in Patent Document 2 is 3 to 800 ° C to 1100 ° C. 50 to 1% by weight of beef bone meal (which is faster than apatite) and 50 to 99% by weight of apatite, with a particle size of 100 μm or less, preferably 74 μm or less, baked for 7 hours A mixture of calcium phosphate compound composed of and chitosan sol dissolved with acetic acid, formic acid, lactic acid, malic acid, citric acid, adipic acid, tartaric acid, malonic acid and other acids to form a mixture and form it into a sheet The formed sheet contains a compound of at least one element selected from the group of at least Group I metal and Group II metal elements. Although it is described that it is produced by neutralization with an aqueous solution, there is no description about the particle size of the calcium phosphate compound itself, and β-TCP granules used in the technique described in Patent Document 3 The particle size of is not limited, and is preferably 0.1 to 10 mm, and relatively large particle size particles are recommended.

  However, the conventional technique for producing a sheet-like bone filling material by applying a calcium phosphate-based filling material such as apatite in a layered manner on the surface of a flexible sheet material generally pays particular attention to the particle size of the calcium phosphate-based material. However, the ratio of the calcium phosphate material is low, the amount of binder used is large, the long-term storage stability of the liquid composition or paste-like composition is not satisfactory, and the viscosity of the coating liquid or paste is too high. Therefore, it is difficult to adjust the coating operation, and it is easy to form a non-uniform coating layer. Also, the obtained sheet-like bone grafting material lacks wettability, and the bone grafting material layer is a sheet during normal handling. It is easy to exfoliate and fall off from the surface of the material, or it is not possible to exfoliate only the bone prosthetic material layer from the sheet accurately with the required shape of the exfoliation pattern, and the activity of the bone prosthetic material is poor, and therefore Problems went to require a long period of time the growth has not been overcome.

JP-A-2-241460 Japanese Patent Laid-Open No. 5-220211 JP 2000-126280 A

Accordingly, an object of the present invention is to provide a fine calcium phosphate for bone grafting material that has extremely high bioactivity and maintains high bioactivity even after long-term storage and does not give a sense of incongruity when administered to the affected area with fine texture, and a fluid containing the same Another object of the present invention is to provide a liquid or paste-like coating composition.
Another object of the present invention is that the amount of binder used is small, the ratio of the calcium phosphate powder material is high, the viscosity of the coating solution is low, and therefore the coating operation is easy to adjust and the coating layer is uneven. In addition, the obtained sheet-like bone grafting material is difficult to peel off from the surface of the sheet material in the normal handling mode, and the bone-shaped bone grafting material can be accurately removed from the sheet with a stripping pattern of the required shape when necessary. It is an object of the present invention to provide a method for producing a sheet-like bone prosthetic material that can peel only the prosthetic material layer, has high activity of the bone prosthetic material, and therefore does not require a long period of time for bone growth.

  When manufacturing a sheet-like bone filler by applying a calcium phosphate filler such as apatite in layers on the surface of the flexible sheet material, the amount of binder used is small and the ratio of the calcium phosphate material is high. The coating liquid viscosity is not too high. Therefore, the coating operation can be performed relatively easily, and a sheet-like bone filling material having a uniform and sufficiently thick coating layer can be obtained. The bone substitute material does not peel from the surface of the sheet material in the normal handling mode, and only the bone substitute material layer can be peeled from the sheet accurately with the peel pattern of the required shape only when necessary. It is preferable that it is a sheet-like bone grafting material having a layer of bone grafting material that is maintained in a dispersed state. To produce this, a fine particle calcium phosphate for bone grafting has a volume average particle size of 3.5 to Volume average at 8.0μm The diameter 9.0μm or more coarse particles was found that it is necessary to prepare as substantially free. Such a granular material composed of calcium phosphate fine particles retains high activity, has high bioreceptivity, and therefore has a high speed of transmitting living bone, and is particularly suitable as a bone grafting material for living aggregate.

  Furthermore, by using this, it is possible to prepare a coating liquid that has a relatively low binder amount ratio and therefore has a viscosity that is not too high and can maintain high bioreceptivity even during storage. It has been found that coating is preferred. It is preferable that the thin sheet-like support having flexibility (softness) is uniformly coated and dried without causing wrinkles and wound into a roll. The obtained sheet-like bone filling material can also maintain high bioreceptivity and activity.

In order to prepare the coating liquid of the present invention, it is preferable to use fine calcium phosphate obtained by milling calcium phosphate as a raw material in a water-soluble or water-miscible organic solvent, and obtained by such milling treatment. Fine calcium phosphate is extremely bioactive. Such high biological activity appears to be due mainly to the increase in specific surface area due to the new 劈 surface generation by潰砕action during milling (the size of a unit volume per surface area). The milling process can be more preferably performed in the presence of a binder material.

Thus, the above object is achieved by (1) “dicalcium phosphate dihydrate CaHPO ₄ .2H ₂ O (DCPD), octacalcium phosphate Ca ₈ H ₂ (PO ₄ ) ₆ · 5H ₂ O (OCP) of the present invention. ), White lockite or tricalcium phosphate Ca (PO ₄ ) ₂ (β-TCP, α-TCP), carbonate apatite, and calcium-OH-apatite Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (HA) Fine particle calcium phosphate (Ca-P) having a volume average particle size of 3.5 to 8.0 μm and a content of coarse particles having a volume average particle size of 9.0 μm or more of 0.1% by number or less. ) Fluidity including 100 parts by weight, 0.01-80 parts by weight of hydrophilic binder material and 50-500 parts by weight of aqueous liquid medium, and having a viscosity of 30-5000 centipoise (20-25 ° C.). It is achieved by replacement material composition ".

In addition, the object is (2) “dicalcium phosphate dihydrate CaHPO ₄ · 2H ₂ O (DCPD), octacalcium phosphate Ca ₈ H ₂ (PO ₄ ) ₆ · 5H ₂ O (OCP), From white rockite or tricalcium phosphate Ca (PO ₄ ) ₂ (β-TCP, α-TCP), carbonate apatite, and calcium-OH-apatite Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (HA) Fine particle calcium phosphate (Ca-P) 100 selected from the group consisting of: a volume average particle size of 3.5 to 8.0 μm and a content of coarse particles having a volume average particle size of 9.0 μm or more of 0.1% by number or less A sheet-like material comprising a flexible sheet-like support surface provided with a bone grafting material coating layer of calcium phosphate material containing 0.01 part by weight and 0.01 to 80 parts by weight of a hydrophilic binder material It is achieved by filling material ".

Further, the above object is achieved by (3) “dicalcium phosphate dihydrate CaHPO ₄ .2H ₂ O (DCPD), octacalcium phosphate Ca ₈ H ₂ (PO ₄ ) ₆ · 5H ₂ O (OCP), white of the present invention. It consists of rockite or tricalcium phosphate Ca (PO ₄ ) ₂ (β-TCP, α-TCP), carbonate apatite, and calcium-OH-apatite Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (HA). Calcium phosphate (Ca-P) selected from the group has a content of 0.1% by number or less of coarse particles having a volume average particle size of 3.5 to 8.0 μm and a volume average particle size of 9.0 μm or more. The calcium phosphate obtained was wet crushed to 20 to 25 parts, containing 0.01 to 80 parts by weight of a hydrophilic binder material and 50 to 500 parts by weight of an aqueous liquid medium per 100 parts by weight of the calcium phosphate. The coating solution having a viscosity of 30 centipoise to 5000 centipoise is applied to the surface of the flexible sheet-like support using a doctor blade coating device and dried to obtain phosphoric acid having a thickness of 10 to 5000 μm. Forming a bone-implanting material-coated layer of calcium material ”;
(4) “The method for producing a sheet-like bone filling material according to (3) above, wherein the wet crushing of the calcium phosphate (Ca—P) is performed in the presence of the hydrophilic binder material. Is achieved.

The fine calcium phosphate for bone filling material of the present invention has extremely high bioactivity and maintains high bioactivity even after long-term storage. Further, fluidity of the liquid or pasty bone substitute material composition comprising the fine calcium phosphate and Vine Da is excellent in dispersibility of the fine texture and grain, higher even after long-term storage in the case of the coating composition It maintains bioactivity and has good coatability. Furthermore, the sheet-like bone prosthetic material produced using this is fine in texture, excellent in surface smoothness and uniformity, and does not give a sense of incongruity when administered to the affected area.
Furthermore, the bone prosthetic material according to the present invention is in the form of a sheet, and further has flexibility, in addition to the known advantage that the clinical application range is expanded compared to conventional bone prosthetic materials, The method for producing a sheet-like bone filling material of the present invention uses a small amount of binder, has a high ratio of calcium phosphate-based material, and has a low coating solution viscosity. Therefore, adjustment of coating operation is easy and uneven. In the normal handling mode, the obtained bone-like bone filling material is difficult to peel off from the surface of the sheet material, and the necessary shape of the peeling pattern can be accurately obtained when necessary. In addition, only the bone grafting material layer can be peeled from the sheet, and the activity of the bone grafting material is high. Therefore, an excellent effect of providing a sheet-shaped bone grafting material that does not require a long period of bone growth is exhibited.

Hereinafter, the present invention will be described in detail.
As the calcium phosphate (Ca-P) bone filling material in the present invention, dicalcium phosphate dihydrate CaHPO ₄ · 2H ₂ O (DCPD), octacalcium phosphate Ca ₈ H ₂ (PO ₄ ) ₆ · 5H ₂ O ( OCP), white rockite or tricalcium phosphate Ca (PO ₄ ) ₂ (β-TCP, α-TCP), carbonate apatite, and calcium-OH-apatite Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ( Those selected from the group consisting of HA) can be used, and in particular, β-TCP can be preferably used.

Calcium phosphates (Ca-P) are normally present in the body as enamel, dentin, cementum and bone, and are present in calcified materials (tooth, calculus, calculus), and enamel and caries. formation, related to the progression and inhibition, but used in preventive dentistry and recovery dentistry, these Ca-P, amorphous calcium phosphate (ACP), brushite (brushite) or dicalcium phosphate dihydrate CaHPO ₄ · 2H ₂ O (DCPD), monetite (monetite) or dicalcium phosphate anhydrous CaHPO ₄ (DCP), phosphate octacalcium _{Ca 8 H 2 (PO 4)} 6 · 5H 2 O (OCP), whitlockite (whitlockite), or phosphoric acid tricalcium _{Ca (PO 4) 2 ((} β-TCP; biological whitlockite was usually magnesium substituted _{(Ca, Mg) 3 (PO} 4) 2 in the form der β-TCMP), carbonate apatite (in this specification, it means partially carbonated apatite containing carbonate ions, and calcium is substituted with various ions to maintain chemical equilibrium in the process of introduction of carbonate ions. As a result, apatite with calcium deficiency; literally “carbonic acid apatite” indicates that all the OH positions of the hydroxyapatite are replaced by carbonate ions, but in reality this does not exist), calcium − OH-apatite Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (HA) (biological apatite is not pure HA but calcium is substituted and calcium-deficient apatite) and oral calcification still calcium pyrophosphate unreported hydrate Ca ₂ P ₂ O ₇ · buccal biological systems occurs at H 2 _{O (CPPD)} is also included, not of interest in the sheet-like bone filler of the present invention. As another important calcium compounds, fluorides or calcium fluoride CaF _2, and calcite ( Calcite) -type calcium carbonate CaCO ₃ is also included, but it is not the same in the sheet-like bone filling material of the present invention.

  It has been identified by X-ray diffraction (XRD) as early as 1926 that the enamel, dentin and bone of human teeth are calcium phosphates (Ca-P) having an apatite structure. Conventionally, most of the observation and measurement of calcified tissue is by microradiography. Although this method has been shown to be capable of quantitative measurement based on theoretical support, it is actually more convenient in recent years because it takes time to prepare samples, set irradiation conditions, and set reference materials. The use of reflected electron images has increased as a method for observing and semi-quantitatively measuring calcified tissues. In the present invention, in order to observe the bone guidance, the direction of bone formation and the arrangement of the bone formation in the interior and boundary surface portion of the bone prosthetic material, the back-scattering imaging by the three types of implants is observed, Interesting knowledge has been obtained.

Vitro calcium phosphate (Ca-P) and in vivo calcium phosphate (Ca-P) is not necessarily the same, also calcium phosphate in the same biological (Ca-P) be a human and beagle calcium phosphate (Ca -P) is reported to be different, and even though it is human calcium phosphate (Ca-P), there is also a report that healthy and caries are different, but β-TCP used in the present invention is usually magnesium. It is an alternative to substituted (Ca, Mg) ₃ (PO ₄ ) ₂ form of biological white rockite (β-TCMP).
It has been reported in the past that the carbonate component in carbonate apatite can be an important and complex factor in vivo as a calcium phosphate substance (T. Sakae, A. Ookubo, RZ LeGeros, Key Engineering Materials Vola. 240-242). (2003) pp.395-398), and magnesium in β-TCMP is reported to be a cause of the deterioration of calcium phosphate (RZ LeGeros, T. Sakae, C. Bautista, M. Retino, JP LeGreros, Advances in Dental Reserch, 10, 2, 225-231, 1996.) Further, as tricalcium phosphate, not only β-TCP but also α-TCP is a good sputter target material. Biological apatite is said to be apatite with a calcium deficiency due to substitution of calcium instead of pure HA.

The method for obtaining these sodium phosphates (Ca-P) will be described. The DCPD includes, for example, sodium phosphate or preferably ammonium phosphate NaH ₂ PO ₄ , NH ₄ H ₂ PO ₄ 100 ml, 0.1M, and the initial pH is room temperature. 250 ml of 0.04M Ca (Ac) ₂ was added dropwise under stirring to a 750 ml solution adjusted to 6 (adjusted with KOH or NH ₄ OH) at ˜37 ° C. to give the product in the form of a precipitate. Can be produced by the precipitation method obtained in It is preferable that the cation as a counter ion of phosphate ion is a volatile or decomposable ammonium ion or onium ion apart from the strength. Similarly, an anion as a counter ion of calcium ion is also an organic acid ion such as acetic acid. Can be. The resulting precipitate is washed with distilled water and dried in air.

  The OCP can be obtained in the same manner as in DCPD except that the initial pH is adjusted to 4 at 80 ° C. or 5 at 60 ° C. using acetic acid. The formation of the precipitate is completed within 30 minutes at 80 ° C and about 60 minutes at 60 ° C.

The pure β-TCP cannot be obtained directly from an aqueous system, and is synthesized by sintering amorphous calcium phosphate (ACP) at 800 to 1000 ° C. The raw pure amorphous calcium phosphate (ACP) (contains only calcium ions and phosphate ions) is obtained by adding 6 (NH ₄ ) ₂ HPO ₄ in a mixture of alkaline phosphoric acid solution (325 ml water and 10 ml concentrated aqueous ammonia). 0.5 g) is quickly dissolved in an alkaline Ca (NO ₃ ) ₂ solution (11.75 g of Ca (NO ₃ ) ₂ dissolved in a mixture of 137 ml of distilled water and 10 ml of concentrated aqueous ammonia) at room temperature. In addition, the product can be obtained by filtering and drying.

The carbonate apatite is classified into one in which CO ₃ is substituted with OH (type A) and one in which PO ₄ is substituted (type B), but type A carbonate apatite is heated to high-temperature HA (described later). Produced under very dry conditions by passing dry CO ₂ gas at about 1000 ° C.). Type B carbonate apatite has CO ₃ replaced with PO ₄ as well as Na replaced with Ca, which is produced by precipitation or hydrolysis from an aqueous system at 37-100 ° C. Is done. For example, 2 g of CaHPO ₄ (reagent purity) is hydrolyzed at 95-100 ° C. for 5 hours in 1 liter of 0.01-0.4 M NaHCO ₃ , and the precipitated product is filtered and overnight. It can be obtained by drying at 60 ° C. Type B carbonate apatite can also be produced by subjecting a CO ₃ -containing DCPD or OCP solution to a hydrolysis-precipitation treatment.

  For the production of the HA, pure HA cannot be obtained directly from the aqueous system, as in the case of β-TCP, but can be obtained in the solid phase, or preferably very high pH (KOH or concentrated aqueous ammonia). The apatite obtained by precipitation from (adjusted to a pH exceeding 11) can be obtained by firing. That is, it can be obtained by addition of hot steam at 375 ° C., or it can be obtained by heat-treating precipitated apatite from an aqueous system adjusted to pH 12 at a temperature of 900 ° C. or higher.

  FIG. 1 shows the pH dependence of the solubility of each of these calcium phosphates (Ca—P). In addition, the temperature and pH dependence of the precipitation of each of these calcium phosphates (Ca-P) from the aqueous liquid is shown in the following table.

  The form, purity (existence of trace amounts of heteroelements and heterogroups), and properties (for example, solubility and lattice constant, particularly expansion and contraction in the a-axis direction) of each of these calcium phosphates (Ca-P) can be determined by various analytical methods. In particular, X-ray diffraction (XRD) and infrared absorption (IR) measurements are useful. For example, in the case of a hexagonal crystal (a structure in which a hexagonal crystal is laminated in a plate shape is often found in tooth enamel and dentin), the relationship between the XRD measurement result and the lattice constant is as follows: Holds.

ここで、ｄは反射面間の距離を表わし、ｈ，ｋ，ｌは反射面のmiller係数を表わす。
而して、ａ―軸の各長さは、（４１０）面及び（３００）面から、次のように計算される。

Here, d represents the distance between the reflecting surfaces, and h, k, and l represent the miller coefficients of the reflecting surfaces.
Thus, each length of the a-axis is calculated from the (410) plane and the (300) plane as follows.

2 to 7 show several XRD charts and IR spectrum charts as a reference for identifying these calcium phosphates. Here, FIG. 2 shows an XRD chart of dicalcium phosphate dihydrate CaHPO ₄ .2H ₂ O (DCPD), and FIG. 3 shows an IR spectrum chart of DCPD. The strongest peak of XRD (Bragg angle 2θ) is 11.7 °, and IR absorption indicates the presence of O—H (H ₂ O), P—O—H (HPO ₄ ), P—O (PO ₄ ). ing.
FIG. 4 shows diffraction peaks after calcination at commercially available calcium hydroxyapatite Ca ₁₀ (OH) ₂ (PO ₄ ) ₆ and 950 ° C., where FIG. 4 (a) is a graph of monetite CaHPO ₄ (M) and apatite. Diffraction peaks are shown, and FIG. 4 shows that the ratio of β-TCP and HA has changed due to the product of calcination.
FIG. 5 shows XRD charts of (a) and (c) before firing (b) and (d) of the apatite precipitated at 95 ° C. and after firing at 800 ° C. When comparing the chart (a) before firing and the chart (c) after firing, the ratio of β-TCP (T) / HA (A) is changed from 55/45 before firing to 35/65 after firing. I understand that.
FIG. 6 shows an XRD chart (a) and an IR absorption spectrum chart (b) of OCP precipitated at pH 5 at 60 ° C. or pH 4 at 70-80 ° C.
FIG. 7 shows an XRD chart of calcium hydroxyapatite Ca ₁₀ (OH) ₂ (PO ₄ ) ₆ (HA) obtained by firing the product obtained by the precipitation method at 950 ° C.

The pulverization of these calcium phosphates (Ca-P) is preferably performed in two stages, a dry pulverization or kneading stage and a wet dispersion stage. In the dry pulverization or kneading step, for example, coarse powder or pellets are pulverized by a jet mill or pulverized by applying shear stress using a three-roll mill. In the next wet dispersion stage, it is subjected to dispersion treatment in a dispersion together with a binder, and a volume average particle size of 3.5 to 8 . Finely pulverized and / or crushed until coarse particles having a volume average particle size of 9.0 μm or more at 0 μm are substantially not included, resulting in fine particles having a new active crushing surface. When micronized calcium phosphate (Ca-P) is applied to the affected area as it is or in a viscous liquid or paste form with a binder or as a bone grafting material layer provided on a sheet substrate, porous calcium phosphate (Ca It has been found in the present invention that a bone growth rate approximately comparable to -P) is obtained.

前記式中、Ｄは各チャネルに存在する粒子の代表粒径（μｍ）を示し、ｎは各チャネルに存在する粒子の総数を示す。
なお、チャネルとは、粒径分布図における粒径範囲を等分に分割するための長さを示すもので、本発明の場合には、後述のような各チャンネルのチャンネル長さを採用した。また、各チャネルに存在する粒子の代表粒径としては、各チャネルに保存する粒子粒径の中央値を採用した。

In the above formula, D represents the representative particle size (μm) of particles present in each channel, and n represents the total number of particles present in each channel.
The channel indicates a length for equally dividing the particle size range in the particle size distribution diagram. In the present invention, the channel length of each channel as described later is adopted. Further, as the representative particle size of the particles existing in each channel, the median particle size stored in each channel was adopted.

As a particle size analyzer for measuring the particle size distribution, a laser diffraction particle size analyzer (
Shimadzu Corporation model SALD-7000) was used.
The measurement conditions are as follows.
(1) Particle size range: 500 to 0.015 μm
(2) Number of channels: 52
(3) Channel length (channel width) of each channel: as described later (4) Representative particle diameter of each channel: as described later Volume average particle diameter is, for example, COULTERTA-II (COULTER ELECTRONICS, INC), micro It can also be similarly measured using a track particle size analyzer (model HRA 9320-X100: manufactured by Honeywell, refractive index: 2.42).

  Commercially available calcium phosphate is usually composed of secondary particles in which a large number of fine primary particles are aggregated, and these are milled in the present invention. In the present invention, the calcium phosphate can be wet-dispersed using a known dispersing device such as a paint shaker, ball mill, attritor, keted mill, sand mill, dyno mill, colloid mill, and particularly preferably a ball mill or a sand mill. High specific gravity (for example, zirconia spheres) that can achieve so-called under ten (average particle size of 10 μm or less) relatively easily and reliably can be used, and in this case, smaller spherical zirconia is required to obtain smaller particle size particles. For example, in order to make the particles substantially free of coarse particles having a volume average particle diameter of 3.5 to 8.0 μm and 9.0 μm or more, it is necessary to use a high speed dispersion. Circulate and disperse, or coarsely pulverize (primary dispersion) using zirconia media with a diameter of 0.5 mm to 1.0 mm, then In 0.5mm it is preferably achieved by distributing (secondary dispersion) using a medium of the following diameters. However, in the present invention, it is not always indispensable to divide the dispersion processing into primary dispersion and secondary dispersion.

  Ball milling for primary dispersion and secondary dispersion is preferably performed wet rather than dry, and in that case, it is preferable to perform ball milling together with an appropriate amount of a binder used in subsequent coating. . The binder is also effective in preventing secondary agglomeration of highly active ultrafine powder (which must release excess surface energy as heat of aggregation, and thus is prone to agglomeration), thus The liquid after ball mill treatment containing calcium phosphate and a binder component or a paste derived therefrom can withstand long-term storage.

  In any case, when the force cannot be accurately applied only to a limited local area, it is difficult to pulverize into particles with the minimum particle size as in the present invention only by the stress due to the impact force. In order to mechanochemically pulverize the particles having a particle size, it is preferable to perform a dispersion treatment while applying a shear stress in the stirring dispersion process. For this purpose, for example, it is preferable that the dispersion is kneaded in a state of being captured by a binder in the dispersion. From the viewpoint of imparting shear stress, it is effective to use a slightly less soluble or swellable binder as a binder when dispersed by a ball mill than a readily soluble one. The liquid viscosity depends on the correlation between the nature and amount of the binder and the dispersion medium liquid. For example, when a hydrophilic and readily water-soluble binder is dissolved in water and subjected to a dispersion operation, the dispersion viscosity should be adjusted by adding a small amount of a water-miscible and binder-insoluble easily volatile solvent such as methanol or acetone. Can do.

It is preferable to adjust the dispersion viscosity of the dispersion with a ball mill during secondary dispersion to 50 to 6000 centipoise. The ball mill treatment time is usually 15 minutes to 3 weeks (about 500 hours).
In such a dispersion, a dispersion medium liquid phase component is used in an amount of 30 to 300 parts by weight, preferably 40 to 200 parts by weight, more preferably 50 to 120 parts by weight, per 100 parts by weight of calcium phosphate. For example, those having a ratio of pure water to organic solvent of 35 to 70; 65 to 30 (volume ratio) can be preferably used.

  In the case of calcium phosphate (Ca-P), which has high hardness and is difficult to be finely pulverized by ball milling, an angular grinding aid such as sodium chloride is pulverized by putting it in a ball mill process together with these insoluble organic solvents. Then, water is added to the treated dispersion to dissolve and remove the grinding aid, followed by washing with water and filtration to obtain calcium phosphate (Ca-P) having a desired particle size.

  However, from the viewpoint of avoiding the disadvantage that the ratio of the calcium phosphate (Ca-P) as an effective component for bone replenishment is decreased due to an increase in the ratio of the binder in the formation layer on the sheet, an excessive amount of binder is dispersed at the time of dispersion. It is desirable to refrain from use.

For that purpose, it can be preliminarily pulverized with a conventional pneumatic milling device such as a jet mill having a coarse powder circulation path between the pulverizing means and the air bag filter classifying means, and then subjected to ball mill dispersion treatment, and preferable. In this case, in the primary dispersion process by the ball mill, it is only necessary to loosen the coarse powder in which the ultrafine powder (high activity) is secondary-agglomerated, so the total dispersion time of the primary dispersion and the secondary dispersion is usually 15 minutes to 24 hours. It's short.
Alternatively, it is possible and preferable to perform a ball mill treatment using a dispersion after sufficiently crushing by applying shear stress in a melt binder in advance with a three roll.

  As the binder material in the present invention, hydrophilic polymer materials such as polyvinyl acetate, vinyl chloride vinyl acetate copolymer, acrylic (co) polymers such as acrylic acid and acrylonitrile, natural rubber latex, maleic acid ( Co) polymer, polyester, starch or modified product thereof, polyvinyl alcohol or modified product thereof, SBR latex, NBR latex, carboxymethylcellulose, hydroxymethylcellulose, polyvinylpyrrolidone, polyol resin having epoxy resin part and polyoxyalkylene part, urea series Initial polycondensate, melamine-based initial polycondensate, phenolic resin, polyvinylpyrrolidone, gelatin, collagen, fibrin, albumin and other polypeptides, starch, pullulan, hyaluronic acid, chitin, dextrin, etc. Polyphosphates such as glycosides, nucleic acids, oxidized cellulose, poly-L-lactide (PLLA), poly-D-lactide (PDLA), poly-D, L-lactide (PD, L-LA), polyglycolic acid, Polycaprolactone, polydioxanone, L-lactide / glycolide copolymer, D-lactide / glycolide copolymer, L- and D-lactide / glycolide copolymer (P (LA / GA)), L-lactide / Examples include caprolactone copolymers, D-lactide / caprolactone copolymers, L- and D-lactide / caprolactone copolymers (P (LA / CL)), and among these, acrylic (co) polymers, Polypeptide such as polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, albumin, dextri Polyglycosides can be used preferably equal, particularly acrylic (co) polymer, polyvinyl pyrrolidone, can be used more preferably polyvinyl alcohol.

Activated carbon purified gelatin, rice starch, chitin, dextrin as a natural product with bioabsorbable properties and poly-L-lactide (PLLA), poly-D-lactide (PDLA), poly-D, L-lactide ( PD, L-LA), polyglycolic acid, polycaprolactone, polydioxanone, L-lactide / glycolide copolymer, D-lactide / glycolide copolymer, L- and D-lactide / glycolide copolymer (P (LA / GA)), L-lactide / caprolactone copolymer, D-lactide / caprolactone copolymer, L- and D-lactide / caprolactone copolymer (P (LA / CL)) are also preferably used. It is done.
These binder components are added in an amount of 0.1 to 90 parts by weight, preferably 1.0 to 80 parts by weight, more preferably 10 to 60 parts by weight per 100 parts by weight of calcium phosphate to be dispersed. It is.

  It is preferable to add a surfactant to the dispersion treatment liquid in the present invention. As the surfactant, an anionic surfactant, a nonionic surfactant, a cationic surfactant, or a betaine surfactant can be used, and a nonionic surfactant can be particularly preferably used. Further, polylactic acid, polylactide lactic acid, polylysine, and polyglutamic acid used as food additives can be used in combination. These surfactants contribute to promotion of wetting of calcium phosphate particles, suppression of foaming, promotion of dispersion, and improvement of wettability, flexibility and surface smoothness of the sheet-like bone filler. The addition amount of the surfactant is 0.001 to 20 parts by weight, preferably 0.01 to 10 parts by weight, more preferably 0.1 to 5 parts by weight per 100 parts by weight of calcium phosphate to be dispersed.

After the dispersion treatment, the dispersion liquid is filtered through a filter having an 8-mesh opening to obtain a volume average particle size of 3.5 to 8 . A purified dispersion containing calcium phosphate substantially free of coarse particles having a volume average particle size of 9.0 μm or more at 0 μm can be obtained. Here, substantially not containing coarse particles having a volume average particle size of 9.0 μm or more means that when 100 particles are observed 10 times with a microscope (that is, 1000 observations), the content of coarse particles is It means 1 or less (the content of the coarse particles is 0.1 number% or less).

  The purified dispersion thus obtained is adjusted to a viscosity suitable for coating operation. Viscosity adjustment is due to dilution by addition of the dispersion medium and / or increase in viscosity by vacuum removal of the liquid portion or addition of other auxiliary components. The viscosity suitable for the coating operation is usually in the range of 30 centipoise to 6000 centipoise, preferably 100 centipoise to 5000 centipoise at 25 ° C., more preferably 500 to 3000 centipoise.

  In the coating solution, as other auxiliary agents, pH regulators such as acetic acid, formic acid, lactic acid, malic acid, citric acid, adipic acid, tartaric acid, malonic acid and the like, and sodium carbonate, potassium carbonate, calcium hydroxide, Alkaline aqueous solutions such as barium hydroxide and magnesium hydroxide, dispersion stabilizers such as polyethylene glycol, antioxidants such as ascorbic acid, surfactants such as lysine and lecithin, surface active poorly water-soluble liquid organic materials such as nonyl cellosolve A silicon-based antifoaming agent such as dimethylsilicone, methylisobutylsilicone or particularly trifluoromethyl group-containing silicon may be added as desired.

  The coating solution is preferably adjusted to have a pH value in the range of 6-8. The pH value usually decreases slightly as the calcium phosphate dispersion treatment (milling) proceeds. In addition, polyethylene glycol not only acts as a dispersion stabilizer, but also acts as a plasticizer or a wetting agent, and the coating layer after drying can be easily peeled off from the sheet substrate by, for example, hand contact. Also plays a role to prevent.

The dispersion or paste thus obtained is stored as it is or after the viscosity is adjusted, administered to the affected area, or coated on the surface of the sheet-like substrate as a coating liquid. It is preferable that the solid content concentration in the coating liquid for the sheet-like bone substitute material is 65% or more (dry weight).
The sheet-like substrate is preferably flexible and flexible, and can be imparted with flexibility by supplying a plasticizer directly or from a coating liquid when it is rigid and lacks resistance to bending stress. . The thickness of the sheet-like substrate is preferably 5 μm to 100 μm. If it is less than 5 μm, it may be damaged during production and subsequent handling, and if it exceeds 100 μm, it tends to be rigid, and when applied to an affected area, the ratio of calcium phosphate (Ca—P) as an effective component is reduced. The sheet-like substrate can be obtained by, for example, irradiating an excimer laser and punching a large number of fine air-permeable holes having a diameter of less than 1.0 μm.

  Coating is a variety of known coating devices such as spin planar coaters, bead coaters, die coaters, roll coaters, wire bar coaters, air knife coaters, blade coaters, rod coaters, comma coaters, dip coaters, curtain flow coaters, silks. A spin-printer coater that can be used alone or in combination with a screen printer, gravure coater, etc. (for example, air knife treatment for smoothing the surface of an undried coating layer after coating with a blade coater) A roll coater, a wire bar coater, a blade coater, a curtain flow coater, a silk screen printer, a gravure coater or the like can be preferably used.

  Especially blade coaters, such as valido blade coaters, bellbaba blade coaters, short dwell blade coaters, trailing blade coaters, flexible blade coaters, roll application blade coaters, flooded nip blade coaters, fonten blade coaters, bill blade coaters A suitable blade coater can be preferably used. Blade coating using such a coater is suitable for forming a coating layer having a layer thickness on a sheet using a viscous coating solution of 30 to 6000 centipoise (300 to 60000 mPa · sec) in the present invention. ing.

  There are no particular restrictions on the sheet-like substrate, polyethylene film, polypropylene film, PVC-vinyl acetate copolymer film, styrene-butadiene copolymer film, acetate film, polyester film, polyamide film, polyvinyl chloride film, polycarbonate film. In order to prevent re-opening after healing of the affected area, various films formed from a water-soluble material, particularly calcium phosphate (Ca-P) used for forming a coating layer can be used. ) Film of the same material as the binder material, for example, a polyvinyl alcohol film carboxymethyl cellulose film is preferably used. At this time, the affinity between the sheet-like substrate and the binder material is too high, and calcium phosphate (Ca-P) is in the form of a sheet. Not much in the substrate In order to prevent osmotic embedding, a water-miscible and binder-insoluble easily volatile solvent such as methanol or acetone is effectively used as described above (for example, these are applied to a sheet-like substrate in advance). Coating liquid).

  After coating, it is dried, and a small hole (contributing to speeding and smoothing of the passage of bodily fluid and bone formation when administered by wrapping around the affected area) is perforated at an appropriate frequency without winding or winding in a roll shape. Then cut to the required size and package the desired number. The thickness of the coating layer is preferably 10 to 3000 μm after drying.

  Hereinafter, the present invention will be specifically described by way of examples. However, these examples are intended to help understanding of the present invention and are not intended to limit the present invention. In each example, “parts” indicates parts by weight.

[Example 1]
(Primary dispersion)
β-TCP (β-TCP-100, manufactured by Taihei Chemical Industry Co., Ltd., chemical formula = Ca ₃ (PO ₄ ) ₂ , molecular weight = 310.18, specific gravity = 3.07, white powder, nominal particle size = 1 to 2 μm 20 g of sintered particles), 0.4 parts (0.08 g) of dispersant (AQ-2559, Lion Corporation), and 40 parts (8 g) of distilled water (Wako Pure Chemical Industries) , 40 parts (8 g) of ethanol (Wako Pure Chemicals) and two kinds of alumina balls (AL-45-1, Showa Denko, 100 parts in total) of φ5 mm (10 g) and φ3 mm (20 g) in an alumina container (80 ml) ) And mixed and dispersed for 18 hours at a rotation speed of 90 rpm using a planetary ball mill (P5 / 2, Fridge Japan). pH = 7.75 (by Corning, pH meter M-220), viscosity 45 . A dispersion of 7 mPas (by CBC Materials, Viscometer, VM-10A-M) was obtained.

(Secondary dispersion)
Next, 10 parts of ethanol was added to the primary dispersed slurry, and an acrylic hydrophilic binder (HB-500, viscosity = 2000-20000 mPas / 25 ° C., pH = 7.0-9.0, Mw = 80,000, Tg = −10 ° C., 16 parts (3.2 g) of Lion Co., Ltd., a plasticizer (PEG # 600, Lion) for imparting flexibility and handling properties to the bone substitute layer of the sheet-like bone substitute 2 parts (0.4 g) and 0.2 g of an antifoaming agent (Leocon 1020H manufactured by Lion Corporation) were added, and the mixture was uniformly dispersed by ball milling for 2 hours. In order to adjust the viscosity of the slurry and defoam, it was treated under reduced pressure using a rotary evaporator, pH = 7.18 (by Corning, pH meter M-220), viscosity 228 mcPa (CBC Materials, Viscometer, VM- 10A-M) was obtained as a coating solution. This liquid did not change in dispersion state after 90 days of storage (sealed state, room temperature). Even when separated from the binder and stored in the dry state as well, it is expected that there will be no or very little change. Of course, the quality of the distributed state is based on the total performance of the primary distributed processing and the two-hour distributed processing. However, as seen in this example, the burden of the secondary distribution is reduced when the primary distribution takes a considerable part. .
Also, balls or beads is not limited to the course alumina, customary other high density dispersion medium can be, for example, preferably Jill co near or barium titanate balls or beads, as these dispersing media balls or beads, conventional If it is desired to disperse more finely, it is preferable to use a sphere having a smaller diameter.

(Manufacture of sheet-like bone substitute)
The obtained coating solution was applied and dried on a polyvinyl alcohol film having a thickness of 500 μm and a width of 600 mm using a test coater (fonten blade coater whose coating speed and coating film thickness can be adjusted). to produce a sheet-shaped bone filling material of the thickness of about 200 [mu] m, drilled at a rate of 200 pieces / mm ² by puncher having a circular blade with a diameter of 80μm on this sheet-like bone graft material, producing a sheet-like bone filler of interest did. In addition, a thinner support body may be adopted and perforation may be performed by irradiation with infrared laser light having a beam waist of 80 to 150 μm and an output of 2 to 30 W.

(Test of calcium phosphate and sheet-like bone substitute)
FIG. 8 shows the FT-IR absorption spectrum (by Horiba, Fourier transform infrared spectrometer, FT-210) of the binder used in the above example. The absorption spectrum in the band of wavelength 700-1500 cm ⁻¹ attributed to the OH group, CO group, and COOH group of this binder is remarkable. FIG. 12 shows an FT-IR absorption spectrum chart of β-TCP powder (a) and a sheet-like bone filler (b) prepared as described above using β-TCP powder (a).

Particle size distribution data of raw material β-TCP powder, β-TCP in slurry after primary dispersion treatment, and β-TCP in slurry after secondary dispersion treatment (by Laser diffraction particle size analyzer, SALD-7000, Shimadzu Corporation) Each is shown in the following Table 2 (raw material β-TCP powder), Table 3 (β-TCP after primary dispersion) and Table 4 (β-TCP after secondary dispersion) , respectively . These distribution graphs are shown. The volume average particle diameter of the raw material β-TCP powder calculated from these results was 88.86 μm (Table 2 and FIG. 9A) , and the volume average particle diameter of β-TCP after primary dispersion was 6.51 μm (Table 3). And FIG. 9 (b)) , the volume average particle size of β-TCP after secondary dispersion was 6.45 μm (Table 4 and FIG. 9 (c)) . The volume average particle size of β-TCP after secondary dispersion is pulverized to a fine and narrow particle size distribution compared to the volume average particle size of the raw material β-TCP powder in which the secondary aggregates of the primary particles are the majority. You can see that.

FIG. 10 also shows the XRD measurement results of the raw material β-TCP powder (a) and the sheet-like bone substitute β-TCP (b) (manufactured by Rigaku Corporation, X-ray Diffractometer, radiation source = CuKα, wavelength = A spectrum chart as 1.541 Å) is shown.
From these charts, β-TCP of the sheet-like bone prosthesis in the present invention disappears or decreases some sharp Bragg angles (2θ ± 0.2 degrees) that the raw β-TCP powder had, Strongest peak at 30.5 °, strong peaks at 27.5 ° and 33.5 °, peaks at 25 °, 32 °, 43 ° and 53 °, 11 °, 13 °, 25 ° The peak does not show at 35 ° or has changed to a very small peak, the maximum peak changes from 35 ° to 30.5 ° of the raw β-TCP powder, and the ratio of each peak to the maximum peak also changes You can see that The crystal structure of β-TCP is clearly changed by milling.

FIG. 11 shows a tension-strain curve as a result of a tensile test (by a Shimadzu Corporation tensile tester) of a bone substitute layer obtained by peeling the support from the sheet-like bone substitute obtained in the above example. The tensile strength of this sheet is 0.409 ± 0.041 (MPa), the tensile elastic modulus (the ratio of the internal force (tension) to the length of the sheet-like bone substitute) is 0.107 ± 0.015 (GPa), the maximum The deformation rate (−) was 0.035 ± 0.006. It can be seen from these graphs that the bone prosthetic layer of Example 1 exhibits non-linear deformation with respect to stress.
This sheet-like bone filling material was wound around the jaw bone from which the rabbit was cut, and the postoperative course was observed. It was confirmed that the growth of new bone was remarkably restored to the original shape in appearance after 10 days.

[Example 2]
(Dry grinding of calcium phosphate (Ca-P))
Crushing β-TCP blob obtained by crushing β-TCP synthesized by sintering amorphous calcium phosphate (ACP) at 900 ° C. to a particle size of about 2 mm is pulverized using a jet mill. Machine (I-type mill; manufactured by Nippon Pneumatic Kogyo Co., Ltd.) and wind classification (DS classifier; manufactured by Nihon Pneumatic Kogyo Co., Ltd.) by swirling flow, β-TCP particles having a volume average particle size of 6.5 μm were obtained. Instead, a small amount of water is added to the sintered β-TCP and mixed with a Henschel mixer to obtain a mixture in which water is soaked in the aggregate, and this is obtained by a two roll set at a roll surface temperature of 130 ° C. Kneading for 45 minutes, rolling and cooling, pulverizing with a pulverizer to obtain a master batch β-TCP, mixing this with a mixer, melting and kneading three or more times with a two-roll mill, rolling cooling and coarsely pulverizing the kneaded product Thus, β-TCP particles having an average particle diameter of 5 to 10 μm can be obtained. For coarse pulverization, a jet mill manufactured by Hosokawa Micron Corporation can be used.

(Wet grinding of calcium phosphate (Ca-P))
Next, this β-TCP particle powder was weighed together with the following materials in the following proportions, dispersed in zirconia beads having a media diameter of 1.0 mm for one week in a 2-liter centrifugal ball mill, Dispersion treatment was further performed for 1 week with zirconia beads having a diameter of 0.5 mm. Instead of the centrifugal ball mill, a circular motion ball mill, a high swing ball mill, or a supercritical ball mill can be used (these are more convenient than a pot ball mill, a tube ball mill, or a conical ball mill).
β-tricalcium phosphate Ca (PO ₄ ) ₂ 100 parts ovalbumin 0.5 parts ascorbic acid 1 part lecithin 0.02 parts pure water 300 parts

(Preparation of calcium phosphate coating solution)
The obtained dispersed liquid was passed through a sieve having an opening size of 3, 2 μm to remove aggregates, and then a required amount of ovalbumin, ascorbic acid, triethylenetetraglycol, sodium citrate (2%) was added with stirring. Aqueous solution), methanol is added, and water is distilled off by suction, and the following composition and viscosity containing β-tricalcium phosphate,
β-tricalcium phosphate Ca (PO ₄ ) ₂ 100 parts ovalbumin 3 parts ascorbic acid 1 part triethylenetetraglycol 1 part sodium citrate (2% aqueous solution) 1 part lecithin 0.02 parts pure water 50 parts methanol 50 Part Appropriate amount of viscosity 660 mPa · s (26 ° C)
The coating liquid which has was adjusted.

(Manufacture of sheet bone substitute)
The coating solution is applied and dried on a polyvinyl alcohol film having a thickness of 500 μm using a Fonten blade coater to produce a sheet-like bone substitute material having a layer thickness of about 200 μm. A puncher having a circular blade with a diameter of 80 μm was used to punch at a rate of 200 pieces / mm ² , thereby producing a target sheet-like bone filling material. The perforation may be performed by irradiation with an infrared laser beam having a beam waist of 80 to 150 μm and an output of 2 to 30 W. In the coating with a blade coater, the coating layer can be freely adjusted from a minimum of several 50 μm to a maximum of about 2 mm.
Similar to the sheet-like bone substitute material according to Example 1, this sheet-like bone substitute material was excellent in terms of surface condition and bioactivity.

[Comparative Example 1]
In the same manner as in Example 2, calcium phosphate (Ca-P) was dry-pulverized to obtain β-TCP particles having a volume average particle size of 6.5 μm.
This β-TCP powder is used as it is without being pulverized again, as in Example 2,
β-tricalcium phosphate Ca (PO ₄ ) ₂ 100 parts ovalbumin 3 parts ascorbic acid 1 part triethylenetetraglycol 1 part sodium citrate (2% aqueous solution) 1 part lecithin 0.02 parts pure water 50 parts methanol 50 Part Appropriate amount of viscosity 660 mPa · s (26 ° C)
A coating solution having the following composition was prepared, applied onto a 500 μm-thick polyvinyl alcohol film using a Fonten blade coater, dried, perforated, and a sheet-like bone filling material having a layer thickness of about 200 μm. Manufactured.
This sheet-like bone filling material was wound around the jaw bone from which the rabbit was cut, and the postoperative course was observed. It was confirmed that it takes about 14 days for bone growth to recover to its original shape.

As described above, as is clear from the detailed and specific description, when the bone grafting material according to the present invention is administered to an affected affected part, it does not require a long period of time for bone growth and the amount of binder used is small. The ratio of the calcium phosphate-based material is high, the viscosity of the coating solution is low, and therefore the coating operation is easy to adjust, and a non-uniform coating layer is not produced. In the normal handling mode, the bone grafting material layer is difficult to peel off from the surface of the sheet material, and when necessary, only the bone grafting material layer can be peeled off from the sheet with a stripping pattern of the required shape. to exert an extremely excellent effect that the high activity.

It is a figure which shows the pH dependence of the solubility of the calcium phosphate (Ca-P) used by this invention. 2 is an XRD chart and an IR spectrum chart of calcium phosphate used in the present invention. 2 is an XRD chart and an IR spectrum chart of calcium phosphate used in the present invention. 2 is an XRD chart and an IR spectrum chart of calcium phosphate used in the present invention. 2 is an XRD chart and an IR spectrum chart of calcium phosphate used in the present invention. 2 is an XRD chart and an IR spectrum chart of calcium phosphate used in the present invention. 2 is an XRD chart and an IR spectrum chart of calcium phosphate used in the present invention. 2 is an FT-IR absorption spectrum of a binder used in Example 1. 3 is a graph showing the particle size distribution of β-TCP used in Example 1. 2 is an XRD spectrum chart of β-TCP used in Example 1. FIG. It is a figure which shows the tension test result of the sheet-like bone substitute obtained in Example 1. FIG. It is a FT-IR chart of (beta) -TCP powder (a) and a sheet-like bone grafting material (b).

Claims (4)

Dicalcium phosphate dihydrate _{CaHPO 4 · 2H 2 O (DCPD} ), phosphate octacalcium _{Ca 8 H 2 (PO 4)} 6 · 5H 2 O (OCP), whitlockite (whitlockite), or tricalcium phosphate Ca (PO ₄ ) selected from the group consisting of ₂ (β-TCP, α-TCP), carbonate apatite, and calcium-OH-apatite Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (HA); 100 parts by weight of fine calcium phosphate (Ca-P) having a coarse particle size of 5 to 8.0 μm and a volume average particle size of 9.0 μm or more of 0.1% by number or less, and a hydrophilic binder material of 0.01 to 80 A fluid bone prosthetic composition comprising 30 parts by weight and 50 to 500 parts by weight of an aqueous liquid medium and having a viscosity of 30 to 5000 centipoise (20 to 25 ° C). Dicalcium phosphate dihydrate _{CaHPO 4 · 2H 2 O (DCPD} ), phosphate octacalcium _{Ca 8 H 2 (PO 4)} 6 · 5H 2 O (OCP), whitlockite (whitlockite), or tricalcium phosphate Ca (PO ₄ ) selected from the group consisting of ₂ (β-TCP, α-TCP), carbonate apatite, and calcium-OH-apatite Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (HA); 100 parts by weight of fine calcium phosphate (Ca-P) having a coarse particle size of 5 to 8.0 μm and a volume average particle size of 9.0 μm or more of 0.1% by number or less, and a hydrophilic binder material of 0.01 to 80 A sheet-like bone grafting material, characterized in that a bone grafting material coating layer of calcium phosphate material containing parts by weight is provided on the surface of a flexible sheet-like support. Dicalcium phosphate dihydrate _{CaHPO 4 · 2H 2 O (DCPD} ), phosphate octacalcium _{Ca 8 H 2 (PO 4)} 6 · 5H 2 O (OCP), whitlockite (whitlockite), or tricalcium phosphate Ca (PO ₄ ) Calcium phosphate (Ca-P) selected from the group consisting of ₂ (β-TCP, α-TCP), carbonate apatite, and calcium-OH-apatite Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (HA) Is wet-crushed until coarse particles having a volume average particle size of 3.5 to 8.0 μm and a volume average particle size of 9.0 μm or more have a content of 0.1% by number or less, and the obtained calcium phosphate is 30 to 100 centipoise at 20 to 25 ° C. containing 0.01 to 80 parts by weight of hydrophilic binder material and 50 to 500 parts by weight of aqueous liquid medium per 100 parts by weight of calcium phosphate A coating solution having a viscosity of centipoise is formed, and this coating solution is applied to the surface of the flexible sheet-like support using a doctor blade coating device, dried, and bone-filled with a calcium phosphate material having a thickness of 10 to 5000 μm. A method for producing a sheet-like bone filling material, comprising forming a material coating layer. The method for producing a sheet-like bone filling material according to claim 3, wherein the wet crushing of the calcium phosphate (Ca-P) is performed in the presence of the hydrophilic binder material.

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