JP2010063872A - Bioabsorbable implant and method for manufacturing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a high-strength bioabsorbable implant including large pore communication to facilitate bone healing, and its manufacture method. <P>SOLUTION: The bioabsorbable implant includes a porous composite where a bioactive ceramic powder is evenly dispersed in bioabsorbable polymer. It is comprised so that the porosity may be 45-75%, the diameter of pore communicating parts may be 100-250 μm, the pores communicating with other pores may be 95% or more, and the compression strength may be 1 MPa or higher. The method of manufacturing the bioabsorbable implant includes heating and kneading both the bioabsorbable polymer and the bioactive ceramic powder at a temperature higher than the melting point of the bioabsorbable polymer in order to make the composite, granulating the composite into granules of 50 μm or above in diameter, mixing the obtained granulated composite with a granular soluble material of 200 μm or above in diameter in order to obtain a granular mixture, and pressing the obtained granular mixture at pressure of 10 MPa or above, while heating the obtained granular mixture at a temperature equal to and above the glass transition temperature of the polymer and equal to and below its melting point, in order to make a molding, and immersing the molding in a solvent where the soluble material is dissolved, in order to elute the soluble materials. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a bioabsorbable implant and a method for producing the same, and more particularly to a bioabsorbable implant that has excellent ability to bind to bone and can rapidly regenerate bone tissue and a method for producing the same.

  As a prior art related to a bioabsorbable implant, for example, a technique is known in which a surfactant is added to a ceramic slurry, and the mixture is stirred to foam, dried, and fired to produce a porous calcium phosphate (Patent Document 1). reference).

  As another prior art, a fiber assembly is made from a suspension in which an organic polymer is dissolved in a volatile solvent and inorganic particles are dispersed, and pressure-molding under heating to form a porous fiber assembly molded body, An organic-inorganic composite porous body in which a porous body is created by dipping in a volatile solvent to weld fibers together is known (see Patent Document 2).

  Further, as another prior art, a technique related to a biodegradable material member in which a bioactive filler is embedded on the surface of a bioadsorbable polymer component used in surgery and other medical fields (see Patent Document 3), a porous polymer Techniques relating to biocompatible implants comprising a composition or a thermoplastic composition and a growth promoting composition (see Patent Document 4), medical materials comprising lactide-containing polymers (see Patent Document 5), and bioabsorbable polymers and bioactivity A technique related to a bioabsorbable implant made of a composite material of ceramic filler (see Patent Document 6) is also known.

Patent No. 2597355 JP 2003-159321 A Special table 2005-508219 Special table 2004-531292 WO99 / 61082 Special table 2006-516435

  For example, in the thing of patent document 1, since the shape of the foam | bubble of ceramics slurry becomes the frame | skeleton part of a porous body as it is, it is excellent in the connectivity of a pore, but since it is ceramics, it is brittle and a crack etc. arise. It is easy and has a problem in durability. Further, when the porosity is increased in order to enlarge the communicating portion of the pores, there is a problem that the strength is extremely lowered.

  Moreover, in the thing of patent document 2, it has the structure where the fiber was entangled, and since the clearance gap between fibers becomes a pore part, it is excellent in the connectivity of a pore, and since it uses a polymer as a base material There is no brittleness like ceramics. However, since it is an aggregate of thin fibers, there is a problem that it is insufficient in strength.

  Therefore, the present invention aims to solve such problems of the prior art and to provide a bioabsorbable implant having a large pore communicating part that promotes bone fusion and having high strength, and a method for producing the same. .

  In order to solve the above problems, a bioabsorbable implant according to the first invention of the present invention is a porous body made of a composite in which a bioactive ceramic powder is dispersed in a bioabsorbable polymer, and has a porosity of 45 to 45. It is 75%, the diameter of the communicating part between pores is 100 to 250 μm, the communicated pores are 95% or more of the whole pores, and the compressive strength is 1 MPa or more.

According to a second invention of the present invention, a method for producing a bioabsorbable implant is provided, which comprises:
Step 1 for producing a composite by heating and kneading the bioabsorbable polymer and the bioactive ceramic powder at a temperature equal to or higher than the melting point of the bioabsorbable polymer;
Step 2 for granulating the composite obtained in Step 1 to a particle size of 50 μm or more;
Step 3 of mixing the composite granule obtained in Step 2 and a granule of a soluble substance having a particle size of 200 μm or more;
Step 4 for producing a compact by pressing the granule mixture obtained in Step 3 at a molding pressure of 10 MPa or more while heating at a molding temperature not lower than the glass transition temperature of the polymer and not higher than the melting point;
Step 5 of immersing the molded product obtained in Step 4 in a solvent in which the soluble substance dissolves to elute the soluble substance;
It is characterized by including.

  The bioabsorbable implant according to the first invention of the present invention is a porous body made of a composite in which a bioactive ceramic powder is dispersed in a bioabsorbable polymer, and has a porosity of 45 to 75%. Since the diameter of the communicating portion is 100 to 250 μm, the communicating pores are 95% or more of the whole pores, and the compressive strength is 1 MPa or more, a large pore communicating portion can be formed and high strength is achieved. As a result, it is possible to prevent damage during or after the filling operation. Further, after filling, the living tissue can easily invade and bone union can be performed at an early stage, and a very useful implant can be provided as a bioabsorbable implant.

  According to the second aspect of the present invention, in the method for producing a bioabsorbable implant, the bioabsorbable polymer and the bioactive ceramic powder are heated and kneaded at a temperature equal to or higher than the melting point of the bioabsorbable polymer to form a composite. The composite is granulated to a particle size of 50 μm or more, and the resulting mixture is mixed with a granule of a soluble substance having a particle size of 200 μm or more. While being heated at the following molding temperature, pressurization is performed at a molding pressure of 10 MPa or more to produce a molded body, and the molded body is immersed in a solvent in which the soluble substance dissolves to elute the soluble substance to make a porous body. . Thereby, the part where the granules of the soluble substance are in contact with each other becomes a communicating part of the pores, and by making the particle diameter of the composite granule 50 μm or more, the composite granule becomes difficult to enter the gap between the granules of the soluble substance. A wide or large communication portion can be secured. In addition, the molding pressure is set to 10 MPa or more, and the molding temperature is set to be equal to or higher than the glass transition temperature of the polymer and equal to or lower than the melting point, thereby controlling the degree of collapse of the composite, and pressing the composite into the gap between the granules of the soluble substance. It can be adjusted, and the diameter of the communicating portion can be finely adjusted. As a result, substantially all of the soluble substance granules are connected to each other, and the connected pores can secure 95% or more of the total pores.

The graph which shows the example of a setting of the molding temperature in this invention. The figure which shows a pore part typically. FIG. 3 is an enlarged view of detail III in FIG. 2.

  The bioabsorbable implant according to the present invention is formed from a porous body containing a bioabsorbable polymer and a bioactive ceramic dispersed in the bioabsorbable polymer. This porous body is a porous body in which a large number of pores are formed in a composite containing a bioabsorbable polymer and a bioactive ceramic dispersed in the bioabsorbable polymer. In other words, the composite is mainly composed of the composite. It is a porous body having a skeleton. And the bioabsorbable implant which concerns on this invention is formed by shape | molding this porous body with this porous body as it is.

The porous body has a porous structure in which the composite is used as a main skeleton and a plurality of pores are formed on the surface and inside of the composite. This porous structure has a communication hole in which a communication portion in which a plurality of pores communicate with each other is formed. When the porous structure has communication holes, the living tissue can enter the porous body that is the bioabsorbable implant. The communication between the pores may be regular or irregular. Some of the pores may be independent, that is, not communicated with other pores, and some of the pores may communicate with several other pores.

  The porosity of the porous body having such a porous structure is 45 to 75%. When the porosity is less than 45%, the diameter of the communicating portion described later is remarkably small, and when the bioabsorbable implant is obtained, high bone healing properties may not be exhibited. If it exceeds, the amount of the complex may decrease and the strength may be significantly reduced. The porosity is preferably 45 to 65%, particularly preferably 45 to 55%, in that both the bone healing property and the strength can be achieved at a higher level. The porosity of the porous body is calculated from the true density calculated from each mass ratio and the respective density of the bioabsorbable polymer and the bioactive ceramic contained in the porous body, and the mass and volume of the porous body. From the apparent density, it is calculated by the formula (1-apparent density / true density) × 100 (%).

  In the porous body, the diameter of a communicating portion formed by communicating pores (hereinafter sometimes referred to as a communicating diameter) is 100 to 250 μm. If the communication diameter is less than 100 μm, it is not preferable because the invasion of living tissue may not be easy, and if it exceeds 250 μm, the strength of the porous body may be insufficient. The communication diameter is preferably 100 to 200 μm from the viewpoint of the balance between the penetration of living tissue and the strength of the porous body.

  The communication diameter is a portion having a smaller diameter than the pore diameter, usually a portion having the smallest diameter, formed by connecting adjacent pores, and is measured as an average converted diameter by a mercury porosimeter.

  The porous body has a compressive strength of 1 MPa or more. When the compressive strength is 1 MPa or more, the bioabsorbable implant is less likely to be damaged regardless of a part to be compensated in the living body and various uses. Therefore, the bioabsorbable implant formed of this porous body can be used without any problems in various filling sites and various uses. The compressive strength is preferably 8 MPa or more, and the upper limit is not particularly limited, but can be, for example, 25 MPa. The compressive strength is the same as that of a porous body forming a cylindrical body having a diameter of 10 mm × height of 10 mm or a porous body to be measured. Then, a compressive stress is applied at a speed of 1 mm / min to create a stress-strain curve, which is calculated from the point at which the stress is maximum in this curve.

  In the porous body, it is preferable that the compressive strength when the amount of displacement in the compression direction is 10% is 50% or more of the maximum compressive strength in that the porous body does not easily collapse when a load is applied during and after filling.

  The bioabsorbable polymer is superior in bioabsorbability and can be a bioabsorbable implant that is more easily decomposed and absorbed in the living body and can be replaced with living tissue more quickly. The polymer is preferably at least one polymer of acid and poly-ε-caprolactone, and poly-L-lactic acid is particularly preferable in that it can be a bioabsorbable implant that hardly causes damage during filling.

  The bioabsorbable implant of the present invention has a porous body made of a composite in which bioactive ceramic powder is uniformly dispersed in a bioabsorbable polymer. Examples of the bioabsorbable polymer include at least one polymer selected from the group consisting of polylactic acid, polyglycolic acid, poly-ε-caprolactone and polybutyl succinate, and / or lactic acid, glycolic acid, ε-caprolactone, And poly-L-lactic acid can be used. )

  The bioabsorbable polymer can appropriately adjust the degradation rate, strength, and the like of the bioabsorbable implant according to the type of polymer used and the average molecular weight, depending on the purpose of use. For example, when the bioabsorbable polymer is poly-L-lactic acid, the weight average molecular weight is preferably 30,000 to 300,000. Since the degradation rate can be adjusted by adjusting the weight average molecular weight within the above-mentioned range, the bioabsorbable implant is decomposed and absorbed at an appropriate rate in the living body, and is sufficiently and quickly replaced with the living tissue. be able to. A molecular weight of 300,000 or more is not preferable because decomposition and absorption in a living body are slow, and replacement with living bone is not performed promptly. On the other hand, when the molecular weight is less than 30,000, degradation and resorption in vivo becomes too fast, and the transplanted material is decomposed and absorbed before sufficient new bone is formed in the bone defect, thereby treating the bone defect. Is not preferable because it cannot be sufficiently performed.

  The crystallinity of poly-L-lactic acid is preferably 30 to 70%, more preferably 30 to 65%, and more preferably 30 to 55%, for the same reason as the weight average molecular weight. Is particularly preferred. When the degree of crystallinity exceeds 70%, decomposition and absorption in vivo are slow, and replacement with living bone cannot be performed quickly, which is not preferable. If the ratio is less than 30%, degradation and resorption in the living body become too fast, and the transplanted material is decomposed and absorbed before sufficient new bone is formed in the bone defect, so that the bone defect is sufficiently treated. It is not preferable because it cannot be performed. The weight average molecular weight is a standard polystyrene equivalent molecular weight measured by gel permeation chromatography (GPC), and the crystallinity is an endothermic amount accompanying crystal melting and exotherm accompanying crystal formation measured by a differential scanning calorimeter. It is a value calculated from the quantity.

The bioactive ceramics may be any ceramic that is replaced with a bioabsorbable implant in the living body and then bonded to a living tissue and replaced, and examples thereof include calcium phosphate ceramics, calcium carbonate ceramics, and bioglasses. The bioactive ceramic is preferably at least one selected from the group consisting of calcium phosphate ceramics, calcium carbonate ceramics, and bioglass. Among these, the bioactive ceramics are rapidly decomposed and absorbed in vivo and replaced with biological tissue. A calcium phosphate ceramic is preferable in that it can be a bioabsorbable implant. Examples of the calcium phosphate ceramic include α-tricalcium phosphate, β-tricalcium phosphate, hydroxyapatite, tetracalcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, and the like, particularly in vivo. Β-tricalcium phosphate is particularly preferable in that it can be a bioabsorbable implant that is rapidly decomposed and absorbed. Examples of the calcium carbonate ceramic include calcium carbonate, and examples of the bioglass include SiO ₂ —CaO—Na ₂ O—P ₂ O ₅ glass, SiO ₂ —CaO—Na ₂ O—. _{P 2 O 5 -K 2 O-} MgO based glass, _{and, SiO 2 -CaO-Al 2 O} 3 -P 2 O 5 based glass. The said bioactive ceramics can also be used individually by 1 type, and can also use 2 or more types together.

  The ceramic is preferably a ceramic powder formed by pulverizing or crushing the ceramic in that it can be mixed substantially uniformly with the bioabsorbable polymer. The shape and average particle size of the ceramic powder may be any shape and average particle size that can be substantially uniformly mixed with the bioabsorbable polymer. For example, shapes such as a spherical shape, an elliptical shape, a flat spherical shape, and a polyhedral shape may be used. For example, the average particle diameter may be in the range of 0.1 to 5 μm. When the average particle diameter exceeds 5 μm, the ceramic particles are coarse, and uniform dispersion in the bioabsorbable polymer becomes difficult, which is not preferable. On the other hand, when the thickness is less than 0.1 μm, the ceramic particles are aggregated, and uniform dispersion in the bioabsorbable polymer becomes difficult. In addition, the said average particle diameter can be measured with the laser diffraction type particle size distribution measuring apparatus (Brand name "LA-750", Horiba Ltd. make).

  In addition to the bioabsorbable polymer and the bioactive ceramics, the composite may contain other components such as a dispersant, as long as the object of the present invention is not impaired.

  In the composite, the bioactive ceramic is preferably contained in an amount of 20 to 70% by mass with respect to the total mass of the bioabsorbable polymer and the bioactive ceramic. When the bioactive ceramic is contained in the bioabsorbable polymer within the above range, the bioabsorbable implant exhibits high bone healing properties. If the bioactive ceramic exceeds 70% by mass with respect to the total mass of the bioabsorbable polymer and the bioactive ceramic, the porous body becomes brittle and easily collapses, which is not preferable. Moreover, since less than 20 mass% cannot obtain sufficient bioactivity, it is not preferable. When the inorganic particles are mixed into the resin material, the strength is improved up to a certain ratio, but at the same time, the flexibility is lowered, and when the ratio is excessive, the strength becomes brittle and low strength. For example, even if a 60% by mass product has a higher strength than a bioabsorbable implant with a content of 30% by mass, the strength ratio at the time of 10% displacement may decrease (flexibility decreases).

  In the composite, the bioactive ceramics dispersed in the bioabsorbable polymer is preferably dispersed substantially uniformly on the surface and inside thereof. The fact that the bioactive ceramic is “substantially uniformly dispersed” in the bioabsorbable polymer means that the object of the present invention is observed at each observation point when a plurality of surfaces and interiors of the composite are observed. As long as it can be achieved, the bioactive ceramics may be dispersed with a non-uniform presence rate or the like, and it is not necessary that the bioactive ceramics be accurately dispersed with a constant presence rate or the like.

  The bioabsorbable implant is left as the porous body that satisfies the above characteristics, or is manufactured by molding the porous body into a desired shape. Therefore, the bioabsorbable implant according to the present invention satisfies the above-mentioned characteristics as well as this porous body. Examples of the desired shape include a shape similar to the shape of the portion to be compensated, or a shape corresponding to this shape, for example, a similar shape, and specifically, a granular shape, a powder shape, a fiber shape, a block shape, or the like. A film form etc. are mentioned.

  The bioabsorbable implant according to the present invention is formed from the porous body and has the above characteristics, and in particular, since it has a relatively large communication diameter, porosity and pore diameter in the above range, it is embedded in the living body. Then, the living tissue easily invades and is quickly replaced and can heal early. In addition, the bioabsorbable implant according to the present invention is formed from the porous body and has the above characteristics, and particularly has the compressive strength within the above range. Even if it is used, etc., it is difficult to break. Therefore, the bioabsorbable implant according to the present invention is very useful as a bioimplant to be filled in a living body. And the said porous body which satisfies the said characteristic is used very suitably as a bioabsorbable implant which has the outstanding bone fusion property and high intensity | strength, or its material.

The bioabsorbable implant of the present invention is manufactured as follows.
First, the bioabsorbable polymer and the bioactive ceramic powder are heated and kneaded at a temperature equal to or higher than the melting point of the bioabsorbable polymer to produce a composite. Next, this composite is granulated to a particle size of 50 μm or more. The composite granule thus obtained and a granule of a soluble substance having a particle size of 200 μm or more are mixed to prepare a granule mixture.

  The method of forming the “composite granule” using a bioabsorbable polymer powder and the like and a bioactive ceramic powder is not particularly limited. For example, the bioabsorbable polymer powder and the bioactive ceramic powder are dry blended. And the like, and then melt-kneaded at a predetermined temperature based on the melting point of the bioabsorbable polymer using an extruder or the like, and then pulverized by freeze pulverization or the like. When the bioabsorbable polymer powder is used for forming the composite granule, the average particle size of the powder is not particularly limited by the kind of the polymer and the like, but can be 100 to 500 μm, particularly 200 to 400 μm. Further, the average particle diameter of the bioactive ceramic powder is not particularly limited depending on the kind of ceramic or the like, but may be 0.5 to 10 μm, particularly 1 to 5 μm.

  In the production method according to the present invention, first, a bioabsorbable polymer and a bioactive ceramic are prepared. The bioabsorbable polymer and the bioactive ceramic are basically the same as the bioabsorbable polymer and the bioactive ceramic in the bioabsorbable implant according to the present invention described above. The bioabsorbable polymer and bioactive ceramics may be in the form of granules (powder), pellets, etc., but they are preferably granules in that they can be easily mixed. It is also preferable that the bioactive ceramic has a smaller particle size. The bioabsorbable polymer and the bioactive ceramic are granulated by, for example, a known pulverization method such as freeze pulverization or a pulverization method, and the granule can be classified by, for example, a sieve if desired. The bioabsorbable polymer granules have a particle size of, for example, 100 to 500 μm, and the bioactive ceramics have a particle size of, for example, about 0.1 to 100 μm, preferably about 0.5 to 10 μm. Can be.

  In the production method according to the present invention, the bioabsorbable polymer thus prepared and the bioactive ceramic are mixed to prepare a composite. Examples of the mixing of the bioabsorbable polymer and the bioactive ceramic include a heat kneading method, more specifically, a method of melt kneading at a predetermined temperature using an extruder or the like after mixing by dry blending or the like. When the predetermined temperature is equal to or higher than the melting point of the bioabsorbable polymer, a composite in which bioactive ceramics are dispersed in the bioabsorbable polymer can be prepared. In this mixing step, the mixing ratio of the bioabsorbable polymer and the bioactive ceramic is preferably 20 to 70% by mass of the bioactive ceramic with respect to the total mass of these. When the bioactive ceramics are mixed with the bioabsorbable polymer in this range, the manufactured bioabsorbable implant exhibits high bone healing properties.

  In the production method according to the present invention, the prepared composite is then pulverized or crushed into granules. The composite is pulverized or pulverized by a known pulverization method such as freeze pulverization or the like, or crushed into granules, and the granules can be classified by, for example, a sieve if desired. The particle size of the composite granule can be 50 μm or more, and the upper limit can be set to 600 μm.

  In the production method according to the present invention, a granule mixture is prepared by mixing the granule of the composite prepared as described above and the granule of the soluble substance. The mixing method is not particularly limited as long as the composite granule and the soluble material granule can be mixed, and examples thereof include dry mixing such as a dry blend method.

  The particle size of the granule made of a soluble substance used in this step may be 200 μm or more, preferably 250 to 650 μm, particularly preferably 350 to 550 μm. When the particle size of the soluble substance is increased, it becomes difficult to uniformly mix with the composite granule, and the strength when the porous body is obtained is lowered. If the average particle diameter is 250 to 650 μm, pores having a predetermined porosity and having a predetermined pore diameter communicate in a three-dimensional manner, and this communication portion can be a porous body having a sufficient average communication diameter. . As a result, it has sufficient strength, does not break during the filling operation, has excellent handling properties, and after filling, the living tissue easily invades, is quickly replaced by the living tissue, and absorbs quickly. It can be set as an implantable implant material.

  The soluble substance may be any substance that dissolves in the solvent described later. Examples thereof include a water-soluble compound when the solvent is an aqueous solvent and an organic compound when the solvent is an organic solvent. Examples of the water-soluble compound include saccharides, celluloses, proteins, inorganic compounds, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, polyacrylate, polyethylene oxide, sulfonated polyisoprene, and sulfonated polyisoprene copolymers. Is mentioned. Examples of the saccharide include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dextrin, starch and other polysaccharides, sucrose, maltose, lactose, mannitol, and the like. Examples thereof include hydroxypropyl cellulose and methyl cellulose. Examples of the inorganic compound include salts such as sodium chloride and potassium chloride. Examples of the organic compound include resins such as polyacrylic acid esters and polymethacrylic acid esters. These soluble substances have a glass transition point or melting point that is welded at the molding temperature during molding of the granule mixture, which will be described later. Therefore, the soluble substance is preferably selected in consideration of the molding temperature at the time of molding. A soluble substance can also be used individually by 1 type, and can also use 2 or more types together.

  These soluble substances are granulated by pulverization or crushing in that they can be easily mixed with the complex. The soluble material is pulverized or pulverized by a known pulverization method such as freeze pulverization or the like, or crushed into granules, and the granules can be classified by, for example, a sieve if desired.

  In the production method according to the present invention, the obtained granule mixture is then pressure-molded under heating to obtain a molded body. The molding method is not particularly limited, and examples thereof include a method using a mold press. The molding temperature should just be more than the temperature which the granule of a composite body fuses, for example, is more than the glass transition point Tg of the said bioabsorbable polymer. The upper limit is not particularly limited, and can be set, for example, below the melting point of the bioabsorbable polymer. Regarding the molding temperature, if the molding temperature exceeds the melting point, the bioabsorbable polymer melts during molding, and molding becomes impossible. If the molding temperature is lower than the glass transition temperature, the bioabsorbable polymer is not easily deformed and molding is impossible. For example, when the bioabsorbable polymer is poly-L-lactic acid, the glass transition temperature measured by DMA is 60 ° C. and the melting point is 167 ° C. as shown in FIG. The glass transition point Tg of the bioabsorbable polymer can be measured according to JIS K7121. The molding pressure is not particularly limited and can be 10 MPa or more, and the upper limit can be set to 100 MPa, for example. When the pressure is less than 10 MPa, the composite granules are not sufficiently welded to each other, and the strength of the obtained porous body is remarkably lowered.

  The molded body thus formed is composed of a skeleton part formed by welding the bioabsorbable polymer of the composite and a pore-forming part formed by welding a soluble substance, and the living body is formed inside or on the surface of the skeleton part. The active ceramics are substantially uniformly dispersed.

  In the production method according to the present invention, the obtained molded body is then immersed in a solvent in which the soluble substance dissolves to elute the soluble substance. The method for immersing the molded body is not particularly limited, and the molded body may be immersed in the solvent as it is, or the solvent may be stirred. At this time, the molded body immersed in the solvent may be an amount that can elute the soluble substance, and is, for example, a ratio of 1 to 10% by mass with respect to the mass of the solvent. The immersion conditions are not particularly limited, and can be performed, for example, at room temperature until the soluble substance is eluted.

  The solvent used in this step is selected according to the type of the soluble substance. For example, when a water-soluble compound is used as the soluble substance, an aqueous solvent for dissolving the water-soluble compound, for example, water, alcohol, alcohol water and the like can be mentioned. On the other hand, when an organic compound is used as the soluble substance, an organic solvent that dissolves the organic compound and does not dissolve the bioabsorbable polymer, for example, when poly-L-lactic acid is used as the bioabsorbable polymer. , Acetone, isopropanol and the like. Since the bioabsorbable implant is filled in the living body, the solvent is preferably an aqueous solvent, and particularly preferably water.

  When the molded body is immersed in the solvent, the soluble material constituting the molded body, that is, the pore-forming portion gradually elutes, forming three-dimensionally communicating holes, and the skeleton portion made of the composite remains. A porous body having a porous structure is obtained. The porous body has a plurality of continuous air holes having a porosity, a pore diameter, and a communication diameter in the above ranges, and exhibits a compressive strength of 1 MPa or more.

  In the production method according to the present invention, if desired, post-treatment such as a washing step and a drying step of the obtained porous body can be performed after the immersion treatment. The drying process can employ, for example, vacuum drying at 20 to 60 ° C. and heat drying.

  In the production method according to the present invention, the thus produced porous body or the dried porous body can be used as the bioabsorbable implant according to the present invention as it is. In addition, in the production method according to the present invention, if desired, the porous body produced as described above or the dried porous body is shaped into the same shape as the shape of the filling portion, etc. It can also be a bioabsorbable implant.

  The bioabsorbable implant and the method for producing the same according to the present invention are not limited to the above-described disclosure, and various modifications are possible within the scope that can achieve the object of the present invention.

  Hereinafter, some examples are shown in Table 1 together with comparative examples.

  Granules of poly-L-lactic acid (sometimes referred to as PLLA) having an average particle size of about 350 μm, a weight average molecular weight of 280,000 and a crystallinity of 70%, and β-tricalcium phosphate having an average particle size of about 2 μm (Hereinafter sometimes referred to as β-TCP) are mixed so as to have a mass ratio of 70:30, kneaded while heating to 200 ° C., and β- A composite comprising TCP dispersed therein was produced. Thereafter, the composite was pulverized by freeze pulverization, and granules having a particle size of 100 to 600 μm were sieved to obtain composite granules.

  The composite granules and sucrose granules having a particle size of 350 to 500 μm were mixed at a volume ratio of 50:50 to prepare a granule mixture.

  Subsequently, the granule mixture was pressure-molded at a pressure of 40 MPa while being heated at 160 ° C. to obtain a molded body. Then, 1 g of this molded body was immersed in 100 mL of pure water for 12 hours to elute sucrose to obtain a porous body having a complex composed of poly-L-lactic acid / β-TCP as a main skeleton. This porous body was dried to produce the bioabsorbable implant of Example 1. The poly-L-lactic acid constituting this bioabsorbable implant had a weight average molecular weight of 230,000 and a crystallinity of 42%.

  The weight average molecular weight of poly-L-lactic acid was measured by GPC. GPC (manufactured by Tosoh Corporation, model “HLC-8120GPC”), and two column names “TSKgel Super HM-H” (manufactured by Tosoh Corporation) and a brand name “TSKgel Super 2000” (manufactured by Tosoh Corporation) 1 Used in series with the book. The measurement was performed using chloroform as a solvent under conditions of a flow rate of 0.3 mL / min, a sample concentration of 0.5 mg / mL, a sample amount of 10 μL, and a column temperature of 40 ° C. Further, the poly-L-lactic acid crystallinity was measured using a differential scanning calorimeter (manufactured by Rigaku Corporation, model “DSC8230”) under the conditions of a measurement temperature of 30 to 200 ° C. and a temperature increase rate of 5 ° C./min.

  A bioabsorbable implant of Example 2 was produced in the same manner as in Example 1 except that the granule mixture was heated at 120 ° C. and pressure-molded at a pressure of 20 MPa. The poly-L-lactic acid constituting this bioabsorbable implant had a weight average molecular weight of 250,000 and a crystallinity of 40%.

  A bioabsorbable implant of Example 3 was produced in the same manner as in Example 1 except that the mixing ratio of the composite granule and sucrose granule was changed to 30:70 by volume and the molding pressure was changed to 60 MPa. did. The poly-L-lactic acid constituting the bioabsorbable implant of Example 3 had a weight average molecular weight of 220,000 and a crystallinity of 45%.

  A bioabsorbable implant of Example 4 was produced in the same manner as in Example 1 except that the particle size of the composite granules was changed to 63 to 600 μm and the molding pressure was changed to 60 MPa. The weight average molecular weight of poly-L-lactic acid constituting the bioabsorbable implant of Example 4 was 230,000, and the crystallinity was 41%.

  Example 5 was carried out in the same manner as in Example 1 except that the mixing ratio of the granules of poly-L-lactic acid and the granules of β-tricalcium phosphate was changed to 40:60 by mass ratio and the molding pressure was changed to 60 MPa. A bioabsorbable implant was manufactured. The weight average molecular weight of the poly-L-lactic acid constituting the bioabsorbable implant of Example 5 was 210,000, and the crystallinity was 40%.

  Example 6 was carried out in the same manner as in Example 1 except that the mixing ratio of the poly-L-lactic acid granules to the β-tricalcium phosphate granules was changed to 80:20 by mass ratio and the molding pressure to 60 MPa. A bioabsorbable implant was manufactured. The poly-L-lactic acid constituting the bioabsorbable implant of Example 6 had a weight average molecular weight of 240,000 and a crystallinity of 43%.

  A bioabsorbable implant of Example 7 was produced in the same manner as in Example 1 except that the particle size of the composite granules was changed to 200 to 500 μm, the particle size of sucrose was changed to 200 to 500 μm, and the molding pressure was changed to 60 MPa. . The weight average molecular weight of the poly-L-lactic acid constituting the bioabsorbable implant of Example 7 was 220,000, and the crystallinity was 38%.

  A bioabsorbable implant of Example 8 was produced in the same manner as in Example 1 except that sucrose had a particle size of 350 to 500 μm, and the granule mixture was heated at 120 ° C. and pressed at a pressure of 20 MPa. . The weight average molecular weight of poly-L-lactic acid constituting the bioabsorbable implant of Example 8 was 240,000, and the crystallinity was 40%.

(Comparative Example 1)
A bioabsorbable implant of Comparative Example 1 was produced in the same manner as in Example 1 except that the particle size of the composite granule was changed to 200 μm or less and the molding pressure was changed to 60 MPa. The poly-L-lactic acid constituting the bioabsorbable implant of Comparative Example 1 had a weight average molecular weight of 210,000 and a crystallinity of 45%.

(Comparative Example 2)
A bioabsorbable implant of Comparative Example 2 was produced in the same manner as Example 1 except that the sucrose particle size was 350 μm or less and the molding pressure was changed to 60 MPa. The poly-L-lactic acid constituting this bioabsorbable implant had a weight average molecular weight of 220,000 and a crystallinity of 39%.

(Comparative Example 3)
A bioabsorbable implant of Comparative Example 3 was produced in the same manner as in Example 1 except that the granule mixture was heated at 120 ° C. and pressed at a pressure of 5 MPa. The poly-L-lactic acid constituting this bioabsorbable implant had a weight average molecular weight of 250,000 and a crystallinity of 45%.

(Comparative Example 4)
A bioabsorbable implant of Comparative Example 4 was produced in the same manner as in Example 1 except that the granule mixture was heated at 50 ° C. and pressure-molded at a pressure of 60 MPa. The poly-L-lactic acid constituting this bioabsorbable implant had a weight average molecular weight of 250,000 and a crystallinity of 38%.

(Comparative Example 5)
A bioabsorbable implant of Comparative Example 5 was produced in the same manner as in Example 1 except that the particle size of the composite granules was changed to 50 μm or less and the molding pressure was changed to 60 MPa. The poly-L-lactic acid constituting this bioabsorbable implant had a weight average molecular weight of 210,000 and a crystallinity of 41%.

  The porosity, the communication diameter, the communication ratio, the compressive strength, and the strength ratio of the bioabsorbable implants of Examples 1 to 8 and Comparative Examples 1 to 5 manufactured as described above were measured by the measurement method, and the results were measured as the first. Shown in the table. The communication diameter was measured using a mercury porosimeter (manufactured by Micromeritics, model “Autopore IV 9510”) under a measurement pressure of 2 to 207 MPa. The pore size of the bioabsorbable implant was almost the same as the particle size of the sucrose granules. The strength ratio in Table 1 indicates the ratio of strength at a displacement of 10% with respect to the maximum compressive strength.

  As shown in Table 1, in all of Examples 1 to 8, the bioabsorbable polymer and the bioactive ceramic powder were heated and kneaded at a temperature equal to or higher than the melting point of the bioabsorbable polymer to produce a composite. The body is granulated to a particle size of 50 μm or more, the composite granule and a granule of a soluble substance having a particle size of 200 μm or more are mixed, and the granule mixture is heated to a molding temperature of not less than the glass transition temperature of the polymer and not more than the melting point, and 10 MPa or more. The bioabsorbable implant is manufactured by pressurizing with molding pressure. Therefore, all of the bioabsorbable implants of Examples 1 to 8 have a porosity in the range of 45 to 75%, the diameter of the communicating portion between the pores is 100 to 250 μm or more, and the connected pores are the entire pores. Of 95% or more. Thus, since all of these bioabsorbable implants have relatively large values of porosity, pore diameter, and communication diameter, biological tissues can easily enter when supplemented in the living body. As a result, it is easily estimated that excellent bone healing properties are exhibited. In addition, these bioabsorbable implants all have a compressive strength of 1 MPa or more despite the relatively large porosity, pore diameter and communication diameter, and various filling sites and during and after filling. It is easily estimated that it is difficult to break regardless of the application.

  In contrast, the bioabsorbable implant of Comparative Example 1 had a small communication diameter because the particle size of the composite granule was small. In Comparative Example 1, since composite granules smaller than 200 μm are used, composite granules smaller than 50 μm are also included. When the communication diameter is small in this way, it is presumed that even if the communicating diameter is compensated in the living body, the living tissue hardly penetrates into the inside of the bioabsorbable implant, and high bone healing properties cannot be exhibited. On the other hand, the bioabsorbable implant of Comparative Example 2 had a small communication diameter because the particle size of sucrose was small. In Comparative Example 2, sucrose smaller than 350 μm is used, and sucrose smaller than 200 μm is included.

  The bioabsorbable implant of Comparative Example 3 had a low compression pressure and a poor compressive strength because the composite granules were not sufficiently welded together. The bioabsorbable implant of Comparative Example 4 had a low molding temperature and could not be molded. Furthermore, the bioabsorbable implant of Comparative Example 5 had a small communication diameter because the composite particle size was small.

  Thus, if any of the porosity, the pore diameter, and the communication diameter is not within the above range, even if the porosity is compensated in the living body, the living tissue cannot enter the bioabsorbable implant, and excellent bone healing is achieved. It is easily guessed that it is not possible to exert the properties.

Claims (2)

    It is a porous body composed of a composite in which bioactive ceramic powder is dispersed in a bioabsorbable polymer, the porosity is 45 to 75%, the diameter of the communicating portion between the pores is 100 to 250 μm, and the communicating pores are A bioabsorbable implant characterized by being 95% or more of the entire pores and having a compressive strength of 1 MPa or more. A method for producing a bioabsorbable implant according to claim 1,
Step 1 for producing a composite by heating and kneading the bioabsorbable polymer and the bioactive ceramic powder at a temperature equal to or higher than the melting point of the bioabsorbable polymer;
Step 2 for granulating the composite obtained in Step 1 to a particle size of 50 μm or more;
Step 3 of mixing the composite granule obtained in Step 2 and a granule of a soluble substance having a particle size of 200 μm or more;
A step 4 in which the granule mixture obtained in step 3 is heated at a molding temperature not lower than the glass transition temperature of the polymer and not higher than the melting point while being pressed at a molding pressure of 10 MPa or more to produce a molded body;
Step 5 of immersing the molded product obtained in Step 4 in a solvent in which the soluble substance dissolves to elute the soluble substance;
A method for producing a bioabsorbable implant, comprising:

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