JP2000210377A - Amorphous biodegradable-absorptive implant material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide the subject implant material which has the decreased anisotropy in terms of strength accompanying the orientation of crystals, is highly tough as an amorphous material, is dense and has enhanced strength and fast hydrolyzability by forming the implant material of a dense molding which is an amorphous molding having specific % or below of degree of crystallinity and has the density higher than before molding. SOLUTION: This biodegradable-absorptive implant material is formed of the dense molding which is the amorphous molding having the degree of crystallinity of <5% and has the density higher than before molding. The implant material is formed of the amorphous molding of a biodegradable-absorptive polymer and, therefore, the absolute strength thereof is generally inferior compared with the crystalline implant material (the degree of crystallinity of >=70%) having the extremely high degree of crystallinity but the material is free of the brittleness derived from the excessive degree of crystallinity and the hardness accompanying the orientation thereof, is highly tough and hardly gives rise to cracking and chipping even when the material is subjected to impact force. Even more, the material is the dense molding having the density higher than before molding and, therefore, the strength of the molding itself is improved and the easy destruction does not occur.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to, for example, osteosynthesis,
The present invention relates to an amorphous biodegradable and absorbable implant material suitably used for bone grafting, osteotomy, bone reconstruction, ligament reconstruction, joint fusion, fixation and filling of fenestrations, and the like.

[0002]

2. Description of the Related Art In recent years, implant materials that are decomposed and absorbed in vivo have been studied, and orthopedic surgery, plastic surgery, thoracic surgery,
In the field of surgery such as oral surgery and neurosurgery, instead of conventional implant materials such as metal or ceramic osteosynthesis plates, screws, pins, sheets (mesh) and blocks, raw materials such as polyglycolic acid and polylactic acid are used. Implant materials consisting of biodegradable and absorbable polymers have been developed.

[0003] Since such biodegradable and absorbable implant materials are weaker than metal materials, they are stretched uniaxially to uniaxially orient molecular chains and crystals or self-reinforced by fibers. The prior art uses a high molecular weight polymer to improve the strength.

[0004]

However, the poly L
-A crystalline implant material made of lactic acid or the like, which is uniaxially oriented as described above to increase the strength, certainly exhibits a flexural strength higher than that of the cortical bone (flexural strength: about 200 MPa) of a living body. For this reason, decomposition in vivo by hydrolysis is slow, and a problem that a long period of 5 to 7 years is required for complete decomposition and absorption depending on the size, thickness or implantation site remains.

The present invention has been made in view of the above-mentioned problems, and has as its object to reduce the anisotropy in strength associated with the crystal orientation and to provide a toughness as an amorphous material.
It is an object of the present invention to provide a biodegradable and absorbable implant material that is dense and has high strength and that is rapidly hydrolyzed.

[0006]

In order to achieve the above object, the biodegradable and absorbable implant material according to claim 1 of the present invention is an amorphous molded article having a degree of crystallinity of less than 5%. It is characterized by comprising a dense compact having a higher density than the previous density.

The implant material according to claim 2 is characterized in that the amorphous molded body is forged. The implant material according to claim 3 is
The implant material according to claim 4, wherein the amorphous molded body is formed of a copolymer of L-lactic acid and D-lactic acid, or a copolymer of L-lactide and D-lactide. The copolymer is a random copolymer, and the ratio of L-lactic acid or L-lactide is 20 to
The implant material according to claim 5, characterized in that the amorphous molded body is formed of an amorphous homopolymer of poly L-lactic acid or poly D-lactic acid. The implant material according to claim 6 is characterized in that it contains a bioceramics powder.

The term "amorphous" as used in the present invention means that the degree of crystallinity is less than 5% as described above, and it is not always necessary to be completely amorphous. In the present invention, “poly L-lactic acid” refers to L-lactic acid, a cyclic dimer of L-lactic acid.
-Is a concept including poly-L-lactide which is a polymer of lactide, and "poly-D-lactic acid" also includes poly-D-lactide which is a polymer of D-lactide which is a cyclic dimer of D-lactic acid It is a concept.

The implant material according to the first aspect of the present invention is made of an amorphous molded article of a biodegradable and absorbable polymer, so that it can be used as a crystalline implant material having a very high crystallinity (crystallinity of 70% or more). In comparison, although the absolute strength is generally inferior, it is rich in toughness without brittleness due to excessive crystallinity and hardness accompanying its orientation, and rarely cracks or chips even when subjected to impact force. It is. Moreover,
Since this amorphous molded body is a dense molded body having a higher density than that before molding, the strength of the molded body itself is improved, and the amorphous molded body is not easily broken. Also,
Because it is amorphous, it is morphologically more hydrophilic than crystalline one, and the opportunity for hydrolysis is blessed from the beginning of decomposition, so it may be decomposed, absorbed, and disappeared within one year in some cases. .

[0010] In particular, when the amorphous molded body is forged, as in the case of the implant material according to the second aspect, the domain or cluster of the molecular chain assembly of the biodegradable and absorbable polymer [forms a polymer chain at the molecular level. Intramolecular or intermolecular stereocomplexes between sequences formed of several contiguous consecutive isomers of L-lactic acid (L-lactide) or D-lactic acid (D-lactide) ), Which leads to an improvement in the strength]. However, since the multiaxially oriented body is oriented along a number of reference axes having different axial directions, the strength anisotropy is reduced, and the force from any direction is reduced. Harder to destroy,
The mechanical strength is improved overall. The forging will be described later.

Regarding the biodegradable and absorbable polymer, regardless of whether it is essentially amorphous or crystalline, an amorphous molded article having a crystallinity of less than 5% can be obtained by adjusting the molding conditions. Any of the above can be used as long as it can be used. Among them, a copolymer of L-lactic acid and D-lactic acid or L-lactide and D-lactic acid used in the implant material according to claim 3 can be used.
Lactide copolymers or homopolymers such as poly-L-lactic acid and poly-D-lactic acid used for the implant material according to claim 5 are suitable, and particularly used for the implant material according to claim 4. Such L-lactic acid or L-lactide is 20 to 8
Random copolymers occupying 0 mol% are very suitable.

Although the molecular weight of the polymer is not limited, it is preferable to use a polymer having an initial viscosity average molecular weight of 100,000 to 700,000. When a polymer having an initial viscosity average molecular weight of less than 100,000 is used, it is difficult to obtain an implant material having sufficient strength for practical use. On the other hand, when a polymer having a viscosity of more than 700,000 is used, unnecessary length for decomposition is required. Inconvenience such as requiring a long period of time occurs. More preferred viscosity average molecular weight of the polymer is in the range of 150,000 to 500,000.

The above-mentioned poly-L-lactic acid and poly-D-lactic acid are essentially crystalline polymers, but are rapidly cooled from a heated and melted state to quickly pass a crystallization temperature (Tc), and have a glass transition temperature (Tc). When the temperature is lowered to room temperature equal to or lower than Tg), an amorphous melt molded product having a crystallinity of less than 5% is obtained. On the other hand, a random copolymer of L-lactic acid and D-lactic acid, or L
-A random copolymer of lactide and D-lactide, wherein L-lactic acid or L-lactide occupies 30 to 70 mol%, is a crystal with an ordered sequence such as poly L-lactic acid or poly D-lactic acid Since it is essentially non-crystalline without exhibiting properties, an amorphous molten molded article can be obtained even when cooled slowly. However, the copolymer in which the proportion of L-lactic acid or L-lactide accounts for 20 to 80 mol% can be reduced to about 5% or less of L-lactic acid (L-lactide) or D when cooled slowly.
-Crystals due to repeating chains of lactic acid (D-lactide) may appear.

[0014] These melt molded articles are all amorphous, but are not dense amorphous molded articles. Therefore, in order to further increase the strength, the melt molded body is subjected to secondary molding to obtain a high-density dense amorphous molded body (for example, increasing the density by about 2 to 3% to about 1.25 to 1.26 g / cm ^3). It is necessary to be). As a method for obtaining a dense amorphous molded body, a method such as ordinary compression molding may be adopted, but a method of forging molding in a cold state (in particular, in the case of a single polymer, at a low temperature at which crystallization does not proceed) is particularly preferred. It is preferably adopted.

[0015] The forging means cold-press-filling the above-mentioned melt-formed body (billet) into a mold having a bottom to perform secondary forming. Conditions such as (cross-sectional area / cross-sectional area of forged product) need to be adjusted depending on the type of polymer.

That is, when forging a billet made of an amorphous melt-molded product of poly-L-lactic acid or poly-D-lactic acid, the billet is formed in a mold at a cold temperature not lower than the glass transition temperature (Tg) and not higher than 110 ° C. In this case, it is preferable to set the deformation ratio in the range of 1.2 to 3.0. Also, when forging a billet composed of an amorphous melt-molded product of a copolymer in which L-lactic acid or L-lactide accounts for less than 20 mol% or more than 80 mol%, the above inherently crystalline nature is obtained. The temperature and the deformation ratio are set in the same range as the polymer.

On the other hand, when forging a billet made of an amorphous melt-molded product of a random copolymer in which L-lactic acid or L-lactide occupies 20 to 80 mol%, crystallization occurs during the molding. And the viscosity during processing is low, so it is higher than the glass transition temperature (Tg) and 90 ° C.
What is necessary is just to press-fit a billet into a shaping | molding die at the following temperature, and in that case, it is preferable to set the deformation ratio in the range of 1.5-5.0.

By performing forging as described above, a dense amorphous molded body having a higher density than that of the polymer before molding is obtained. As described above, the molded body is composed of the domain of the molecular chain of the polymer or the domain. The cluster is a multiaxially oriented body in which the clusters are oriented along many reference axes having different axial directions. The implant material made of a dense amorphous molded body having such multiaxial orientation has a strength improved by about 20 to 50% as compared with a melt molded body (a billet) before forging, and has a strong anisotropy. , It is hard to be broken by force from any direction.

In some cases, the billet of the melt-formed body may be cold forged as described above, and then the machine direction may be further changed to forge cold. When the forging is performed a plurality of times while changing the machine direction in this manner, the strength anisotropy is further reduced, and fatigue resistance characteristics such as repeated bending strength are remarkably improved.

The implant material of the present invention as described above is
Hydrolysis of the biodegradable absorbent polymer proceeds from the surface in contact with body fluids in the living body, is absorbed into the living body, and is excreted outside the body. It is highly hydrolyzed (has many chances of infiltration and wetting of bodily fluids), and is rapidly hydrolyzed. There is no. Therefore, it is not necessary to perform the operation again and remove the patient from the body like a metal implant material, so that the pain and the economic burden on the patient are reduced.

Further, when the bioceramic powder is contained as in the implant material of claim 6, the bioceramic powder which is exposed on the surface layer or the bioceramic which is exposed as the polymer is hydrolyzed. Since the powder conducts the bone tissue to the surface layer of the implant material, the implant material bonds with the living bone within a short period of time. Then, loosening and rattling do not occur, and the osteosynthesis and the like can be firmly fixed. Moreover, where the polymer decomposes and disappears, bone is formed with these ceramic powders as nuclei.

Examples of the bioceramics powder include fired hydroxyapatite having surface bioactivity, bioglass or crystallized glass for living organisms, non-fired hydroxyapatite bioabsorbable, dicalcium phosphate, tricalcium phosphate, and the like. Any one kind of powder such as tetracalcium phosphate, octacalcium phosphate, calcite, and diopsite, or a mixed powder of two or more kinds is used. Of these, unfired hydroxyapatite is most preferably used. Here, "non-fired" refers to one that has not been fired or prefired.

The content ratio of the bioceramic powder is 10
It is appropriate to set it to about 60% by weight. If the amount is less than 10% by weight, the ability of the bioceramic powder to form conduction of bone tissue is not sufficiently exhibited. If the amount is more than 60% by weight, there is a disadvantage that the toughness of the implant material is reduced and the implant material becomes brittle.

The implant material of the present invention described above is
It is preferably applicable as an implant material for applications requiring toughness superior to viscoelasticity rather than rigidity, such as an interference screw and an anchor sooter.

[0025]

Next, specific examples of the present invention and comparative examples will be described.

Example 1 Poly L-lactic acid (PLLA) having a viscosity average molecular weight of 300,000 was melt-extruded to obtain a columnar amorphous billet having a viscosity average molecular weight of 200,000 and a diameter of 10 mm. This billet was heated to 70 ° C., forged, and quenched to obtain a columnar amorphous forged body having a diameter of 8 mm (deformation ratio: 1.6).

A rod having a diameter of 3.2 mm and a length of 40 mm was prepared from this forged product, and the bending strength, crystallinity and density were measured. The results are shown in Table 1 below. Table 1 also shows the bending strength, crystallinity, and density of rods of the same dimensions made from the billet before forging.

As shown in Table 1, the rod produced from the forged product had a crystallinity of 4.0% and had a higher density than the rod produced from the billet before forging. The bending strength was improved by forging. This is because the microvoids present in the billet before forging were lost due to the compression effect of forging, resulting in a compact body as a whole, and the domains or clusters of the polymer molecular chain aggregates were formed by forging. This is because a multiaxially oriented body oriented along a number of reference axes along the flow of the polymer during molding was obtained.

The rod was immersed in a phosphate buffer at 37 ° C. to conduct an in vitro hydrolysis experiment.
As a result, the molecular weight of the rod sharply decreased and showed rapid decomposition. However, the rod crystallized with a decrease in molecular weight, and reached about 50% after one year. This suggests that the time to complete absorption is longer compared to PDLLA, which is essentially amorphous. However, when compared to crystallized implant materials, degradation is faster and the time to complete absorption is reduced.

Example 2 L having a viscosity average molecular weight of 400,000
-A random copolymer of lactide and D-lactide (PD
LLA) [D / L (molar ratio) = 50/50] was melt-extruded to obtain a columnar amorphous billet having a viscosity average molecular weight of 200,000 and a diameter of 10 mm.

A rod having a diameter of 3.2 mm and a length of 40 mm, which is the same as that of Example 1, was prepared from a cylindrical forged product (deformation ratio: 3.0) obtained by heating the billet to 65 ° C. and forging. The bending strength, crystallinity and density were measured. The results are shown in Table 1 below. Table 1 also shows the bending strength, crystallinity, and density of rods of the same dimensions made from billets before forging.

The rod produced from the forged molded article of Example 2 is an amorphous rod having a crystallinity of 0% as shown in Table 1, and has a higher density than the rod produced from the billet before forging. It had a high density and the bending strength was improved by forging. This is because, as in the case of Example 1, a dense compact was obtained.

Using this rod, an in vitro test was performed under the same conditions as in Example 1. The rod decomposed rapidly, and its speed was much higher than that of the amorphous PLLA rod of Example 1. Further, the viscosity average molecular weight of the rod was reduced to about 10,000 to 30,000 after 12 weeks. Therefore, it is completely decomposed in one to two years after implantation, as it degrades faster in vivo.

Example 3 L having a viscosity average molecular weight of 400,000
-A random copolymer of lactide and D-lactide (PD
LLA) [D / L (molar ratio) = 30/70] was melt-extruded to obtain a columnar amorphous billet having a viscosity average molecular weight of 200,000 and a diameter of 10 mm.

A rod having a diameter of 3.2 mm and a length of 40 mm, which is the same as that of Example 1, was prepared from a cylindrical forged product (deformation ratio: 3.0) obtained by heating the billet to 65 ° C. and forging. The bending strength, crystallinity and density were measured. The results are shown in Table 1 below. Table 1 also shows the bending strength, crystallinity, and density of rods of the same dimensions made from billets before forging.

The rod produced from the forged molded article of Example 3 is an amorphous rod having a crystallinity of 0% as shown in Table 1, and has a higher density than the rod produced from the billet before forging. It had a high density and the bending strength was improved by forging.

This rod was also rapidly decomposed in vitro, but its speed was D / L = 50/50 in Example 2.
Which tended to be slightly slower than those of the above, because the content of L-lactide was high, so that the domain or cluster of the continuous molecular chain aggregate of L-lactide in the molecular chain constituting the polymer was D / L. = 50/50, presumably because the decomposition of that portion occurs at a relatively slow rate.

Example 4 L having a viscosity average molecular weight of 200,000
-A random copolymer of lactide and D-lactide (PD
LLA) [D / L (molar ratio) = 15/85] is melt-extruded and then quenched to give a viscosity average molecular weight of 100,000 and a diameter of 10
Thus, an amorphous billet having a columnar shape of mm was obtained.

A rod having a diameter of 3.2 mm and a length of 40 mm, which is the same as that of Example 1, was prepared from a cylindrical forged product (deformation ratio: 1.6) obtained by heating the billet to 65 ° C. and forging. The bending strength, crystallinity and density were measured. The results are shown in Table 1 below. Table 1 also shows the bending strength, crystallinity, and density of rods of the same dimensions made from billets before forging.

As shown in Table 1, the rod produced from the forged body of Example 4 was an essentially amorphous rod having a crystallinity of 2.0%, and was produced from a billet before forging. It has a density slightly higher than that of the rod, and the bending strength has been improved by forging.

From the above measurement results of Examples 2 to 4, L-
In an amorphous rod made of a forged product of a random copolymer of lactide and D-lactide, the bending strength increases and the hydrolysis rate tends to decrease as the molar ratio of L-lactide increases. Of course, this tendency is the same when the molar ratio of D-lactide is increased. However, when the ratio of D-lactide or L-lactide is 8
Above 0%, essentially crystalline phases intervene in the polymer.

[0042]

[Table 1]

Example 5 The viscosity average molecular weight was 400,000, and
PDLLA having a D / L (molar ratio) of 50/50 and 30/70, respectively, and an HA / PDLLA composite in which non-calcined hydroxyapatite (HA) is uniformly dispersed in these PDLLA at a ratio of 30% by weight. These were each subjected to heat compression molding to obtain columnar amorphous billets having a viscosity average molecular weight of 200,000 and a diameter of 8 mm.

Next, each of these billets was heated to 75 ° C.
And forged by heating to a columnar amorphous (crystallinity: 0%) cylindrical forged body with a diameter of 4.6 (deformation ratio: 3)
I got

Then, a diameter of 3.2 m is obtained from each forged product.
Each rod having a length of m and a length of 40 mm was prepared, and the bending strength of each rod was measured. The results are shown in Table 2 below.
Table 2 below also shows the bending strength of rods of the same dimensions produced from each billet before forging.

As shown in Table 2, the bending strength of each of the rods produced from the forged products containing HA was dramatically improved.

As a result of performing an in vitro test on each of the rods produced from the forged products, the rods were promptly decomposed in about one year as in Example 2 or Example 3. Since the rod contains HA in the material, the amount of the polymer is smaller than that of a rod of the same shape consisting of only a polymer. Therefore, the period until complete absorption is further reduced. In addition, the non-fired HA is a resorbable HA and has osteoconductivity, so that as PDLLA decomposes,
Since the HA particles are continuously surfaced and osteoblasts can easily penetrate into the implant material, the bone defect can be repaired very quickly.

[0048]

[Table 2]

[0049]

EFFECT OF THE INVENTION The amorphous biodegradable and absorbable implant material of the present invention is dense and has improved strength, and has little strength anisotropy, so that it is hard to be broken by a force from any direction. Because of its high toughness, it does not crack or chip even when subjected to an impact force, and has a remarkable effect such as absorption and disappearance in a relatively short period of time in a living body because of rapid hydrolysis. It is preferably applied to a part where toughness is required rather than rigidity or strength.

 ──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Masayuki Ejiri 2-3-3 Azuchicho, Chuo-ku, Osaka-shi F-Term in Takiron Co., Ltd. 4C081 AB04 AC03 BA16 BB07 BB08 CA171 CC01 CC08 CF012 CF032 CF062 DA01 DA11 DC13 EA03

Claims (6)

[Claims] 1. A biodegradable and absorbable implant material comprising an amorphous molded body having a crystallinity of less than 5% and comprising a dense molded body having a density higher than that before molding. 2. The biodegradable and absorbable implant material according to claim 1, wherein the amorphous molded body is forged. 3. The amorphous molded article according to claim 1 or 2, wherein the amorphous molded article is formed from a copolymer of L-lactic acid and D-lactic acid or a copolymer of L-lactide and D-lactide. Biodegradable and absorbable implant material. 4. The method according to claim 1, wherein the copolymer is a random copolymer.
The biodegradable and absorbable implant material according to claim 3, wherein the proportion of lactic acid or L-lactide is 20 to 80 mol%. 5. The biodegradable and absorbable implant material according to claim 1, wherein the amorphous molded body is formed of an amorphous homopolymer of poly-L-lactic acid or poly-D-lactic acid. . 6. The implant material according to claim 1, further comprising a bioceramic powder.