JPH08196616A - Manufacture for in vivo degradation absorbable surgical material - Google Patents

Abstract

PURPOSE: To provide an in vivo degradation absorbable surgical material which is tough and excellent in hydrolysis-resistance, by melt-molding and drawing a polylactic acid polymer having a specific range of high viscosity average molecular weight under a specific adjusted temperature condition. CONSTITUTION: A polylactic acid polymer having viscosity average molecular weight of 300,000 to 600,000 is used as a raw material, and is melt-molded in a temperature range of 220 deg.C or less which is more than the melting point of the polylactic acid polymer and at which molecular weight reduction is suppressed in a minimum extent, and drawing is performed under a temperature range of 60∼180 deg.C at which molecular weight of the polymer is not further reduced. The obtained drawn molding has the same degree as bone or a little higher than that on compressive bending strength and a compressive bending elastic modulus, that is, toughness and excellent hydrolysis- resistance, and also is an in vivo degradation absorbable surgical material, by which strength keeping characteristics in vivo is improved, and the surgical material is degraded and absorbed gradually after passing a period necessary for adhesion of fracture of a bone or the like, thereby a bad influence of remaining as a foreign body in vivo can be excluded.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel in vivo living body made of polylactic acid or a lactic acid-glycolic acid copolymer (both are abbreviated as polylactic acid-based polymers hereinafter) and having excellent hydrolysis resistance. TECHNICAL FIELD The present invention relates to a novel method for producing a surgical material of a resorbable stretch-formed product. Furthermore, the novel method for producing a surgical material of the present invention has a viscosity average molecular weight of 30 as a starting material.
10,000 to 600,000 polylactic acid-based polymers are used and melt-molded in a temperature range of not less than the melting point of the polylactic acid-based polymer and 220 ° C. or less for minimizing the decrease in the molecular weight of the polymer, and then further polymerizing the polymer. It is characterized in that stretching is carried out under the temperature condition of 60 to 180 ° C. in a specific range that does not cause a decrease in molecular weight.

More specifically, the surgical material of the stretch-molded product obtained by the method of the present invention has a compressive bending strength and a compressive bending elastic modulus which are as high as those of bone and are slightly high, that is, toughness and excellent hydrolysis resistance. And a biodegradable and absorbable material,
The strength retention property in the body is greatly improved, and the property is maintained during the period required for fusion such as bone fracture, but after that period, it is gradually decomposed and absorbed, and as a foreign substance for a long time in the body. It has an effect that various adverse effects caused by the presence of the can be eliminated.

[0003]

2. Description of the Related Art In orthopedic surgery and oral surgery, high-strength osteosynthesis plates and screws are used to reduce fractures. Such artificial materials for osteosynthesis function only until the fracture heals, and after the healing, it is necessary to remove the bone as early as possible to prevent weakening of the bone. At present, most of the osteosynthesis plates and the like which are widely used clinically are made of metal, and recently, those made of ceramics have also appeared. However, these have problems such as deterioration of bone due to too high elastic modulus of the material itself, and biological damage due to elution of metal ions.

[0004] Therefore, if a material having a modulus of elasticity that is about the same as or slightly higher than that of bone and is biodegradable and absorbable is used for bone joining, not only is reoperation for pulling out unnecessary, but also It should be possible to exclude various adverse effects caused by the long-term presence of a foreign body in the living body. Under such circumstances, development of an osteosynthesis material using polylactic acid or a lactic acid-glycolic acid copolymer which is a biodegradable and absorbable material has been actively promoted. For example, Makromol Chem. Suppl. Vol.
5, p30-41 (1981), M.Vert; F.Chabot et al. Synthesized polylactic acid or lactic acid-glycolic acid copolymer as an osteosynthesis plate, and made 100% of polylactic acid a compressive bending elastic modulus. Reports a low value of 3.4 GPa (340 kg / mm ² ).

Also, in the 9th USA Biomaterials Society Abstracts, No. 6, p47. (1983), DC Tunc reports a polylactic acid bone-bonding plate having a compressive bending elastic modulus of 510 kg / mm ² . Further, JP-A-59-97654 discloses a method for synthesizing a polylactic acid or a lactic acid-glycolic acid copolymer which can be used as an absorbable bone fixing device. The material listed as the material is the polymerization product itself, and the tensile strength of this polylactic acid is a low value of about 580 kg / cm ² , and the molding process of this material is not explained at all, and its strength No attempt has been made to raise the bone to human bones.

[0006] Recently, Biomaterials, Vol.8, p42 (1987)
In P. Tormala et al. Reported an osteosynthesis plate composed of a glycolic acid-lactic acid copolymer composite reinforced with glycolic acid-lactic acid copolymer fibers, and its compressive bending strength was 265 MPa (26. It is as high as 5 kg / mm ² ), but the strength deterioration due to in vitro hydrolysis is extremely rapid, and the strength disappears in about 1 month. Also, JWLeenslag,
AJPennings et al. Reported that polylactic acid having a viscosity average molecular weight of about 1,000,000 was synthesized, and the compression bending elastic modulus of the bone bonding plate of the high molecular weight polylactic acid was 5 GPa (500 kg / mm ² ).

In "Artificial Organs" Vol.16, No.3 (1987), Nakamura et al. Reported that polylactic acid contains a small amount (5 to 20% by weight) of hydroxyapatite (HA), which is an inorganic substance, and heat. It is reported that after compression-molding into a plate shape, it was stretched to obtain a cylindrical pin, but this was only for HA.
Stretching in the presence of a polylactic acid-based polymer as in the present invention is not suggested at all. As described above, many studies have been reported to improve the mechanical properties such as the compressive bending strength of the conventional polylactic acid-based osteosynthesis material so as to approach those of the bone, and various methods have been tried, but still in clinical practice. A biodegradable and absorbable material which has been sufficiently used and has satisfactory compressive bending strength and the like and is gradually decomposed and absorbed after healing has not been developed.

[0008]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned problems, and mechanical properties such as compressive bending strength and compressive bending elastic modulus of a conventionally known polylactic acid-based bone cement and its hydrolysis resistance. Provided is a method for producing a surgical material of a biodegradable and absorbable stretched polylactic acid-based biodegradation product that has high compressive bending strength and compressive bending elastic modulus that greatly exceed degradability and is excellent in hydrolysis resistance. The purpose is to do.

[0009]

As a result of various studies on the above-mentioned problems, the inventors of the present invention melt-molded and stretched a polylactic acid-based polymer having a high viscosity-average molecular weight in a specific range under specific controlled temperature conditions. By doing so, it was found that the compression bending strength and the compression bending elastic modulus of the surgical material of the stretched molded article can be made to be about the same as or slightly higher than that of bone, and the present invention has been completed. That is, the present invention has a viscosity average molecular weight of 30.
10,000 to 600,000 polylactic acid or lactic acid-glycolic acid copolymer is melt-molded under a temperature condition of the melting point or more and 220 ° C. or less, and further stretched under a temperature condition of 60 to 180 ° C. This is a method for producing a biodegradable and absorbable surgical material that is tough and has excellent hydrolysis resistance.

Hereinafter, the present invention will be described specifically. A method for producing a surgical material of a polylactic acid-based biodegradable and absorbable stretch molded product according to the present invention will be described below. The polylactic acid-based polymer as a starting material, particularly polylactic acid, is, for example, a lactide which is a cyclic dimer of lactic acid from an optically active L- or D-form lactic acid according to a conventional method (CE Lowe, US Pat. No. 2,668,162). Is obtained by synthesizing the above compound and then subjecting the lactide to ring-opening polymerization. This polylactic acid needs to have at least a viscosity average molecular weight of 300,000 or more in consideration of a decrease in molecular weight during melt molding. The higher the molecular weight, the higher the compression bending strength and the compression bending elastic modulus in surgery. Suitable for obtaining materials. However, if the molecular weight is too high, high temperature and high pressure are required during melt molding, especially extrusion molding, resulting in a large decrease in molecular weight, and as a result, the molecular weight after melt molding falls below 200,000. Therefore, it becomes difficult to obtain the intended surgical material having high compressive bending strength and high compressive bending elastic modulus. Therefore, the viscosity average molecular weight of the raw material polylactic acid is 300,000 to 60.
It is desirable that the molecular weight is about 10,000, preferably about 400,000 to 500,000.

In the present invention, a lactic acid-glycolic acid copolymer is also used as a starting material in place of the above polylactic acid. This copolymer has a viscosity average molecular weight similar to that of polylactic acid, and is preferably one having a large lactic acid content ratio. Among them, the weight ratio of lactic acid to glycolic acid is 99: 1 to 75: 2.
Those in the range of 5 are preferably used. When the amount of glycolic acid is in a small amount within the above range, the resulting surgical material has excellent hydrolysis resistance. Therefore, even if the glycolic acid is immersed in physiological saline at 37 ° C. for 3 months (necessary for fusion of bone fracture) Almost no deterioration in strength such as compressive bending strength and compressive bending elastic modulus occurs, which is equivalent to the situation of being implanted in the body for 3 months. However, when glycolic acid increases beyond the above range, hydrolysis resistance This is because there is an inconvenience in that the strength deteriorates and the strength deteriorates at an early stage.

The surgical material obtained by the method of the present invention uses a polylactic acid-based polymer having a high viscosity average molecular weight within the above-mentioned specific range as a starting material, and melts this into a predetermined shape such as a rod or a band (plate). It can be obtained by molding, for example, extrusion molding, press molding, and then uniaxially stretching in the major axis direction. Among the melt moldings, extrusion molding is particularly preferable because it has high productivity, and in this case, an ordinary extruder can be used. The conditions for melt molding (for example, extrusion molding) need to be in the temperature range from the melting point of the polylactic acid-based polymer to 220 ° C. In this case, if the melt molding temperature is lower than the melting point of the polylactic acid-based polymer, melt molding becomes difficult, and conversely, if it exceeds 220 ° C., the molecular weight of the polylactic acid-based polymer decreases remarkably, and the viscosity average molecular weight after melt-molding becomes a predetermined value. This is because it is below 200,000.

In order to minimize the decrease in the molecular weight of the polylactic acid polymer during melt molding, it is important to perform melt molding at a temperature slightly higher than the melting point of the raw polylactic acid polymer. Therefore, when the raw material polylactic acid-based polymer having a viscosity average molecular weight of about 400,000 to 500,000 is used, it is desirable to perform melt molding under a temperature condition of 200 ° C. or lower. Similarly, the pressure conditions for melt extrusion molding are set at the minimum extrusion pressure that can be extruded according to the viscosity (viscosity average molecular weight) of the molten polylactic acid-based polymer in order to minimize the decrease in molecular weight of the raw material polylactic acid-based polymer. It is desirable to do.

Therefore, when the viscosity average molecular weight of the raw material polylactic acid-based polymer is up to 600,000, 260 kg / cm ²
In the following, when the molecular weight is about 400,000 to 500,000, 170 to
An extrusion pressure of about 210 kg / cm ² is suitable. Before melt molding, it is preferable that the raw material polylactic acid-based polymer pellets be dried by heating under reduced pressure to sufficiently remove water. Since the molded product obtained by melt molding has a viscosity average molecular weight of 200,000 or more,
It has considerable compressive bending strength and compressive bending elastic modulus, but it is still below the target value (comparable to bone).

Therefore, in the present invention, the above melt-molded product is further uniaxially stretched in the longitudinal direction (extrusion direction) in a heat medium such as liquid paraffin or oil to orient the polymer molecules to achieve compressive bending strength and compression. The bending elastic modulus is improved.
This uniaxial stretching needs to be performed under the temperature condition of 60 to 180 ° C. If the stretching temperature is lower than 60 ° C., the molecular orientation due to stretching becomes insufficient because the glass transition point of the polylactic acid-based material is too close, and conversely, if the temperature is higher than 180 ° C., the molecular weight of the material decreases. Also, it becomes difficult to satisfactorily improve the compressive bending strength and the compressive bending elastic modulus by stretching. The preferable temperature condition varies depending on the molecular weight of the polylactic acid-based material after melt molding, but if the molecular weight is about 200,000 to 250,000, it is around 100 ° C.

It is desirable that the draw ratio is 2 times or more. If the stretching ratio is less than 2, the molecular orientation becomes insufficient, and it becomes difficult to satisfactorily improve the compressive bending strength and the compressive bending elastic modulus. Heretofore, it has not been possible to obtain a surgical material, particularly a bone-bonding material, which has a high compressive bending strength, a compressive bending elastic modulus comparable to bone and excellent hydrolysis resistance, using a polylactic acid type material alone. However, as described above, in the novel surgical material obtained by the method of the present invention, a raw material polylactic acid-based polymer having a high viscosity average molecular weight in a specific range of about 300,000 to 600,000 is selected and the melt molding temperature is selected. A certain range of conditions (above its melting point,
220 ° C. or less), it is possible to minimize the decrease in the molecular weight of the polylactic acid-based polymer during melt molding, and the glass transition of the polylactic acid-based material having a viscosity average molecular weight of 200,000 or more after melt molding is performed. Stretch molding with high strength and excellent hydrolysis resistance for the first time by uniaxially stretching at a temperature from around the point (60 ° C) to around the melting point (180 ° C), preferably at a temperature near the glass transition point (about 100 ° C). It has technical significance in that it can provide a surgical material for a product.

The novel surgical material obtained by the method of the present invention is a stretched molded article of a biodegradable and absorbable material composed of a polylactic acid type polymer, and its compressive bending strength is 1.6 × 10. ³ kg / cm ² or more, a compression flexural modulus 5.0 × 10 ² kg / mm ² or more, surgical material viscosity average molecular weight after the melt molding is 200,000 or more, which is excellent in toughness and resistance to hydrolysis Becomes This surgical material is then cut to size and finally machined into various sizes and shapes of osteosynthesis plates, pins, screws, screws, etc. in areas such as orthopedic surgery, oral surgery, thoracic surgery, etc. It can be used clinically.

Since the novel surgical material obtained by the method of the present invention is composed of only polylactic acid-based polymer, it has a very good biodegradability and absorbability, and is similar to the conventional metallic or ceramic surgical materials. There is almost no fear of adverse effects in the living body. More specifically, the novel surgical material obtained by the method of the present invention has a compressive bending strength and a compressive bending elastic modulus that are comparable to or slightly higher than those of bone, and fixes a site such as a fracture during surgical treatment. Even if it gradually decomposes as the bone regenerates, it retains its strength up to about three months after the fracture is repaired. After that, the bone is regenerated and the strength is maintained as a whole, although the decomposition progresses and the strength decreases. It is done.

Furthermore, in the novel surgical material obtained by the method of the present invention, the decrease in the molecular weight during melt molding is minimized to maintain the viscosity average molecular weight after melt molding at 200,000 or more, and further the molecular weight is increased by stretching. Because of the orientation and crystal orientation, its compressive bending strength is 1.6 × 10 ³ kg / cm
² or more, compressive bending elastic modulus is 5.0 × 10 ² kg / mm ²
In addition to the above, high compressive bending strength and high compressive bending elastic modulus, which could not be reached by conventional polylactic acid-based surgical materials, are shown. Further, hydrolysis resistance is improved, and the material is immersed in physiological saline at 37 ° C for about 3 months. Even if it is (corresponding to the situation of being implanted in a living body for 3 months, which is considered necessary for healing a bone fracture), there is an effect that almost no strength deterioration occurs.

The novel surgical material obtained by the method of the present invention must have a viscosity average molecular weight of 200,000 or more after melt molding. With such a viscosity average molecular weight value,
At the time of implantation, it gives a compressive bending strength and an initial compressive bending elastic modulus that are slightly higher than those of bone, and even if the bone cement is implanted in a living body for 3 months, which is considered necessary for fusion, It can be held so as not to reduce the compressive bending elastic modulus. Further, when the viscosity average molecular weight after melt molding is lower than 200,000, the initial compressive bending strength and compressive bending elastic modulus are below the target values (values equal to or higher than those of bone), and the bone cement decomposes quickly. Therefore, it cannot be used as a surgical material, and cannot be put to practical use in terms of both strength and hydrolysis resistance.

[0021]

EXAMPLES The present invention will be described in detail by way of examples, which do not limit the scope of the present invention. The compressive bending strength and the compressive bending elastic modulus shown in the examples are JIS K-7203.
It was measured based on. (Example 1) Polylactic acid pellets having an initial viscosity average molecular weight of 440,000 were dried under reduced pressure at 120 to 140 ° C for a whole day and night, and the dried pellets were put into an extruder and dried under reduced pressure for about 20 minutes.
After standing for a minute, the mixture was melt-extruded into a square rod or a round rod under the temperature conditions shown in Table 1 below. When the viscosity-average molecular weight of the obtained square bar or round bar-shaped molded product was measured, it was 220,000 as shown in Table 1 below.

The viscosity equation in this case is:

## EQU1 ## [η] = 5.45 × 10 ⁻⁴ M _v ^0.73 (chloroform 25 ° C.) was used. Next, this molded product was uniaxially stretched in the long axis direction to 100% in liquid paraffin at 100 ° C. and cut to obtain a test piece (dimensions: width 10 mm × thickness 5 mm × length 80 m).
m) was prepared. When the compression bending strength and the compression bending elastic modulus of the obtained test piece were measured, the compression bending strength was 1,720 kg / cm ² and the compression bending elastic modulus was 610 kg / mm ² , as shown in Table 1 below. .

Further, the test piece was dipped in a physiological saline solution at 37 ° C. for 3 months, and then the compressive bending strength and the compressive bending elastic modulus of the test piece were measured. The bending strength was 1,700 kg / cm ² and the compressive bending elastic modulus was 600 kg / mm ² , with almost no deterioration in strength.

Example 2 The initial viscosity average molecular weight is 42.
A test piece was prepared in the same manner as in Example 1 except that polylactic acid pellets were used. The test piece was subjected to compression bending strength, compression bending elastic modulus, and melt extrusion after initial immersion for 3 months. The viscosity average molecular weight was measured. The results are shown in Table 1 below.

Example 3 The initial viscosity average molecular weight is 40.
A test piece was prepared in the same manner as in Example 1 except that a lactic acid-glycolic acid copolymer (lactic acid: glycolic acid = 90: 10) was used, and the test piece was compressed at the initial stage and after immersion for 3 months. Bending strength, compressive bending elastic modulus, and viscosity average molecular weight after melt extrusion molding were measured. The results are shown in Table 1 below.

(Examples 4 to 5) The stretching temperature was 70
2 in the same manner as in Example 1 except that the temperature was changed to 0 ° C and 170 ° C.
Various kinds of test pieces were prepared, and the compression bending strength, the compression bending elastic modulus, and the viscosity average molecular weight after melt extrusion molding of the test pieces were measured at the initial stage and after immersion for 3 months. The results are also shown in Table 1 below.

Comparative Examples 1 and 2 Example 1 was repeated, except that polylactic acid having initial viscosity average molecular weights of 700,000 and 280,000 was used, and the temperature conditions for melt extrusion were changed to the temperatures shown in Table 1 below. Two types of test pieces were prepared in the same manner as in, and the compression bending strength, the compression bending elastic modulus, and the viscosity average molecular weight after melt extrusion molding of the test pieces were measured at the initial stage and after immersion for 3 months. The results are also shown in Table 1 below.

[0028]

[Table 1]

From Table 1 above, the biodegradable and absorbable stretch-molded surgical materials of the present invention obtained in Examples 1 to 5 all had a viscosity average molecular weight of 200,000 or more after melt molding. Compressive bending strength is 1.6 × 10 ³ kg / cm ²
As described above, it has excellent strength with a compressive bending elastic modulus of 5.0 × 10 ² kg / mm ² or more.
It can be seen that it has a high hydrolysis resistance with almost no strength deterioration even after soaking for a month. On the other hand, the material of Comparative Example 1 had a high molecular weight of 700,000, but the temperature and pressure of melt extrusion were high, so the molecular weight after molding was less than 200,000, and the uniaxial Even when stretched, as a result, the compressive bending strength and compressive bending elastic modulus are below the target values,
It can be seen that satisfactory strength cannot be obtained. In addition, Comparative Example 2
Since the molecular weight is lower than 300,000, even if the temperature and pressure of melt extrusion molding are lowered to suppress the decrease in molecular weight as much as possible, the molecular weight after molding is far below 200,000, and therefore uniaxially stretched, It can be seen that satisfactory strength cannot be obtained.

[0030]

As is clear from the above description and the results of the examples, the method of the present invention uses (a) a polylactic acid-based polymer having a high viscosity average molecular weight in a specific range as a starting material, and (b) Melt molding in a specific temperature range that minimizes the decrease in the molecular weight of the polymer, and (c) a specific adjusted condition that stretching is performed under a specific temperature condition that does not cause a further decrease in the molecular weight of the polymer. Since a surgical material for stretch-molded polylactic acid-based biodegradable and absorbable material was manufactured with

It is possible to obtain a surgical material having high compressive bending strength and compressive bending elastic modulus, which is not obtained by the conventional polylactic acid-based surgical material, and is also excellent in hydrolysis resistance. In the field of oral surgery or thoracic surgery, it can be suitably used as a bone-bonding plate, screw, pin or screw. Further, the production method of the present invention can be easily and highly efficiently carried out without preparing any special device, since it only adds the step of stretching to the step of melt molding which is generally used in the field of resin molding.
In addition, continuous processes are possible if necessary, and there is an effect that mass productivity and workability are excellent.

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[Procedure amendment]

[Submission date] October 23, 1995

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Detailed explanation of the invention

[Correction method] Change

[Correction content]

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel in-vivo body made of polylactic acid or a lactic acid-glycolic acid copolymer (both are abbreviated as polylactic acid-based polymers hereinafter), which is tough and has excellent hydrolysis resistance. TECHNICAL FIELD The present invention relates to a novel method for producing a surgical material of a resorbable stretch-formed product. Furthermore, the novel method for producing a surgical material of the present invention has a viscosity average molecular weight of 300,000 to 300,000 as a raw material.
600,000 polylactic acid-based polymers are used and melt-molded in a temperature range of not less than the melting point of the polylactic acid-based polymer and 220 ° C. or less to minimize the decrease of the molecular weight of the polymer, and then further decrease the molecular weight of the polymer. 6 of the specific range that does not invite
It is characterized in that stretching is performed under a temperature condition of 0 to 180 ° C.

More specifically, the surgical material of the stretch-molded product obtained by the method of the present invention has a compressive bending strength and a compressive bending elastic modulus which are as high as or slightly higher than those of bone, that is, toughness and excellent hydrolysis resistance. It becomes a material that has the property of being biodegradable and absorbable in vivo, the strength retention properties in vivo are greatly improved, and it retains its strength during the period required for fusion such as bone fracture, but after that period It has a characteristic that various adverse effects caused by being gradually decomposed and absorbed and existing as a foreign substance in the living body for a long time can be excluded.

[0003]

2. Description of the Related Art In orthopedic surgery and oral surgery, high-strength osteosynthesis plates and screws are used to reduce fractures. Such artificial materials for osteosynthesis function only until the fracture heals, and after the healing, it is necessary to remove the bone as early as possible to prevent weakening of the bone. At present, most of the osteosynthesis plates and the like which are widely used clinically are made of metal, and recently, those made of ceramics have also appeared. However, these have problems such as deterioration of bone due to too high elastic modulus of the material itself, and biological damage due to elution of metal ions.

[0004] Therefore, if a material having a modulus of elasticity that is about the same as or slightly higher than that of bone and is biodegradable and absorbable is used for bone joining, not only is reoperation for pulling out unnecessary, but also It should be possible to exclude various adverse effects caused by the long-term presence of a foreign body in the living body. Under such circumstances, development of an osteosynthesis material using polylactic acid or a lactic acid-glycolic acid copolymer which is a biodegradable and absorbable material has been actively promoted. For example, Makromol Che
m. Suppl. Vol. 5, p30-41 (198
1), M. Vert, F.F. Chabot et al. Synthesized polylactic acid and lactic acid-glycolic acid copolymer as an osteosynthesis plate, and reported a low compression flexural modulus of 3.4 GPa (340 kg / mm ² ) for 100% polylactic acid. There is.

Also, the 9th USA Biomaterials Society Abstracts, No.6. p47. (1983). C. T
unc compression flexural modulus is reported polylactic acid osteosynthesis plates with a value of 510kg / mm ^2. Further, JP-A-59-97654 discloses a method for synthesizing a polylactic acid or a lactic acid-glycolic acid copolymer which can be used as an absorbable bone fixing device. The material listed as the material is the polymerization product itself, and the tensile strength of this polylactic acid is a low value of about 580 kg / cm ² , and the molding process of this material is not explained at all. No attempt has been made to raise the bone to human bones.

[0006] Recently, Biomaterials, V
ol. 8, p42 (1987), P. Tormal
a et al. reported an osteosynthesis plate composed of a glycolic acid-lactic acid copolymer composite reinforced with a glycolic acid-lactic acid copolymer fiber, and the compressive bending strength thereof was 265M.
High as Pa (26.5 kg / mm ² ), but in vitro
The deterioration of strength due to ro hydrolysis is extremely rapid, and the strength is lost in about one month. Also, J. W. Leensla
g, A. J. Pennings et al. Synthesized polylactic acid having a viscosity average molecular weight of about 1 million, and the compression bending elastic modulus of the high molecular weight polylactic acid osteosynthesis plate was 5 GPa (500).
It is reported to be a value of kg / mm ² ).

In addition, "artificial organ" Vol. 16, No.
3 (1987), the Nakamura et al., Polylactic acid which is an inorganic substance hydroxyapatite (HA) a small amount (5-20
After molding on weight%) plate shape by are contained thermal compression molding, although reported to give a cylindrical pin extends, which is merely drawn in the presence of HA, polylactic
It does not suggest the possibility of stretching the acid-based polymer alone . As described above, many studies have been reported to improve the mechanical properties such as the compressive bending strength of the conventional polylactic acid-based osteosynthesis material so as to approach those of the bone, and various methods have been tried, but still in clinical practice. A biodegradable and absorbable material which has been sufficiently used and has satisfactory compressive bending strength and the like and is gradually decomposed and absorbed after healing has not been developed.

[0008]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned problems, and mechanical properties such as compressive bending strength and compressive bending elastic modulus of a conventionally known polylactic acid-based bone cement and its hydrolysis resistance. Disclosed is a method for producing a surgical material for a polylactic acid-based biodegradable and absorbable stretched molded article, which has a high compressive bending strength and a compressive bending elastic modulus, both of which greatly exceed the degradability and is excellent in hydrolysis resistance. The purpose is to

[0009]

As a result of various studies on the above-mentioned problems, the inventors of the present invention melt-molded and stretched a polylactic acid-based polymer having a high viscosity-average molecular weight in a specific range under specific controlled temperature conditions. By doing so, it was found that the compression bending strength and the compression bending elastic modulus of the surgical material of the stretched molded article can be made to be about the same as or slightly higher than that of bone, and the present invention has been completed. That is, the present invention has a viscosity average molecular weight of 30.
10,000 to 600,000 polylactic acid or lactic acid-glycolic acid copolymer is melt-molded under a temperature condition of the melting point or more and 220 ° C. or less, and further stretched under a temperature condition of 60 to 180 ° C. It is a method of producing a biodegradable and absorbable surgical material that is tough and has excellent hydrolysis resistance. Here, in the present invention
“Excellent hydrolysis resistance” means that 3 is necessary for bone fusion.
Hold the required strength for about a month, and gradually
Water that is desorbed and does not remain in the body as a foreign substance for a long time
Says the solution.

Hereinafter, the present invention will be described specifically. A method for producing a surgical material of a polylactic acid-based biodegradable and absorbable stretch molded product according to the present invention will be described below. The polylactic acid-based polymer as a raw material , particularly polylactic acid, is prepared from, for example, L-form or D-form lactic acid having optical activity according to a conventional method (CE Lowe, US Pat. No. 2,668,162). It is obtained by synthesizing a lactide which is a cyclic dimer and then subjecting the lactide to ring-opening polymerization.
This polylactic acid needs to have at least a viscosity average molecular weight of 300,000 or more in consideration of a decrease in molecular weight at the time of melt molding. The higher the molecular weight, the higher the compression bending strength and the compression bending elastic modulus . Suitable for obtaining surgical material. However, if the molecular weight is too high, high temperature and high pressure are required during melt molding, especially extrusion molding, resulting in a large decrease in molecular weight, and as a result, the molecular weight after melt molding falls below 200,000. Therefore, even if it is stretched, it has the desired high compressive bending strength and high compressive bending elastic modulus .
It is difficult to obtain a suitable surgical material. Therefore, the raw material
Poly viscosity average molecular weight of lactic acid from 300000 to 600000 about is, preferably it is desirable that the molecular weight of 40-50 250,000.

In the present invention, a lactic acid-glycolic acid copolymer is also used as a raw material instead of the above polylactic acid.
This copolymer has a viscosity average molecular weight similar to that of polylactic acid, and is preferably one having a large lactic acid content. Among them, the weight ratio of lactic acid to glycolic acid is in the range of 99: 1 to 75:25. Some are preferably used. When the amount of glycolic acid is in a small amount within the above range, the resulting surgical material has excellent hydrolysis resistance. Therefore, even if the glycolic acid is immersed in physiological saline at 37 ° C. for 3 months (necessary for fusion of bone fracture) Almost no deterioration in strength such as compressive bending strength and compressive bending elastic modulus occurs, which is equivalent to the situation of being implanted in the body for 3 months. However, when glycolic acid increases beyond the above range, hydrolysis resistance This is because there is an inconvenience in that the strength deteriorates and the strength deteriorates at an early stage.

The surgical material obtained by the method of the present invention is made of a polylactic acid polymer having a high viscosity average molecular weight within the above-mentioned specific range as a raw material, and is melt-molded into a predetermined shape such as a rod or a strip (plate). For example, it can be obtained by extrusion molding, press molding, and then uniaxially stretching in the major axis direction. Among the melt moldings, extrusion molding is particularly preferable because it has high productivity, and in this case, an ordinary extruder can be used. The conditions for melt molding (for example, extrusion molding) are the melting point of the polylactic acid-based polymer or higher,
The temperature range needs to be 220 ° C. or less. In this case, if the melt molding temperature is lower than the melting point of the polylactic acid-based polymer, the melt molding becomes difficult, and conversely, if it exceeds 220 ° C., the molecular weight of the polylactic acid-based polymer is remarkably decreased, and the viscosity average molecular weight after the melt-molding is 20 %. Because it is less than 10,000 .

In order to minimize the decrease in the molecular weight of the polylactic acid polymer during melt molding, it is important to perform melt molding at a temperature slightly higher than the melting point of the raw polylactic acid polymer. Therefore, when the raw material polylactic acid-based polymer having a viscosity average molecular weight of about 400,000 to 500,000 is used, it is desirable to perform melt molding under a temperature condition of 200 ° C. or lower. Similarly, the pressure conditions for melt extrusion molding are set at the minimum extrusion pressure that can be extruded according to the viscosity (viscosity average molecular weight) of the molten polylactic acid-based polymer in order to minimize the decrease in molecular weight of the raw material polylactic acid-based polymer. It is desirable to do.

Therefore, when the viscosity average molecular weight of the raw material polylactic acid-based polymer is up to 600,000, 260 kg / cm ²
In the following, when the molecular weight is about 400,000 to 500,000, 170 to
An extrusion pressure of about 210 kg / cm ² is suitable. Before melt molding, it is preferable that the raw material polylactic acid-based polymer pellets be dried by heating under reduced pressure to sufficiently remove water. Since the viscosity average molecular weight of the molded product obtained by melt molding is maintained at 200,000 or more, it has considerable compressive bending strength and compressive bending elastic modulus, but it is still the target value (comparable to bone). Does not reach

Therefore, in the present invention, the above melt-molded product is further uniaxially stretched in the longitudinal direction (extrusion direction) in a heat medium such as liquid paraffin or oil to orient the polymer molecules to achieve compressive bending strength and compression. The bending elastic modulus is improved.
This uniaxial stretching needs to be performed under the temperature condition of 60 to 180 ° C. If the stretching temperature is lower than 60 ° C., the molecular orientation due to stretching becomes insufficient because it is too close to the glass transition point of the melt-molded product , and conversely, if the temperature is higher than 180 ° C. , the molecular weight of the molded product decreases. Also, it becomes difficult to satisfactorily improve the compressive bending strength and the compressive bending elastic modulus by stretching. The preferable temperature condition varies depending on the molecular weight of the molded product after melt molding, but if the molecular weight is about 200,000 to 250,000, it is around 100 ° C.

Further, the draw ratio is 2 times or more .
It is desirable that the range is suitable for surgical materials . If the stretching ratio is less than 2, the molecular orientation becomes insufficient, and it becomes difficult to satisfactorily improve the compressive bending strength and the compressive bending elastic modulus. Heretofore, it has not been possible to obtain a surgical material having a high compressive bending strength, a compressive bending elastic modulus which is comparable to that of bone and excellent hydrolysis resistance, particularly a material for osteosynthesis, by using a polylactic acid type polymer alone. Therefore, as mentioned above, the novel surgical material obtained by the method of the present invention is
Since a raw material polylactic acid-based polymer having a high viscosity average molecular weight in a specific range of about 10,000 to 600,000 was selected and the melt molding temperature condition was set to a specific range (above the melting point and below 220 ° C.), polylactic acid during melt molding was selected. The viscosity average molecular weight after molding is set to 200,000 or more by minimizing the decrease in the molecular weight of the base polymer.
This melt-molded product is uniaxially stretched at a temperature near the glass transition point (60 ° C.) to the melting point (180 ° C.), preferably around 100 ° C. , so that it has high strength and excellent hydrolysis resistance for the first time. obtaining a surgical material stretched molded product was
It has technical significance in that it can be done .

The novel surgical material obtained by the method of the present invention is a stretched molded article of a biodegradable and absorbable material composed of a polylactic acid type polymer, and its compressive bending strength is 1.6 × 10. ³ kg / cm ² or more, compressive bending elastic modulus of 5.0 × 10 ² kg / mm ² or more, viscosity average molecular weight of 200,000 or more after melt molding, tough and excellent in hydrolysis resistance Becomes This surgical material is then cut to the appropriate size and finally machined into osteosynthesis plates, pins, screws, screws, etc. of various sizes and shapes for orthopedic surgery, oral surgery, thoracic surgery, plastic surgery. It can be used clinically in such areas.

Since the novel surgical material obtained by the method of the present invention is composed of only polylactic acid-based polymer, it has a very good biodegradability and absorbability, and is similar to the conventional metallic or ceramic surgical materials. There is almost no fear of adverse effects in the living body. More specifically, the novel surgical material obtained by the method of the present invention has a compressive bending strength and a compressive bending elastic modulus that are comparable to or slightly higher than those of bone, and fixes a site such as a fracture during surgical treatment. Even if it gradually decomposes as the bone regenerates, it retains its strength up to about three months after the fracture is repaired. After that, the bone is regenerated and the strength is maintained as a whole, although the decomposition progresses and the strength decreases. It is done.

Further, according to the method of the present invention, the decrease in molecular weight during melt molding is minimized, the viscosity average molecular weight after melt molding is kept at 200,000 or more, and further molecular orientation and crystal orientation are given by stretching to obtain The obtained surgical material has a compressive bending strength of 1.6 × 10 ³ kg / cm ² or more and a compressive bending elastic modulus of 5.0 × 10 ² kg / mm ² or more. It shows high compressive bending strength, high compressive bending elastic modulus that could not be reached, and also improved hydrolysis resistance. Even when immersed in physiological saline at 37 ° C for about 3 months (it is considered necessary for fusion of fractures. It corresponds to the situation of being implanted in a living body for 3 months), and there is an effect that the strength is hardly reduced .

In the method of the present invention, it is important that the viscosity average molecular weight after melt molding is 200,000 or more. Surgery obtained by stretching a molded product having such a viscosity average molecular weight
The material for use gives an initial compressive bending strength and an initial compressive bending elastic modulus that are similar to or slightly higher than those of bones at the time of implantation, and even if the bone cement is considered to be necessary for fusion for 3 months, it can be implanted in a living body. It can be maintained so as not to reduce the compressive bending strength and the compressive bending elastic modulus. Further, if the viscosity average molecular weight after melt molding is lower than 200,000, the initial compressive bending strength and compressive bending elastic modulus are below the target values (values equal to or higher than those of bone) even if they are stretched , The decomposition of the bonding material becomes too fast to use, and it cannot be put to practical use as a surgical material in terms of both strength and hydrolysis resistance.

In the present invention, the viscosity average content after melt molding is
Although it is desirable that the child quantity is 200,000 or more,
The upper limit cannot be uniquely determined. That is, the raw material
Desirable viscosity average molecular weight of polylactic acid type polymer is 300,000
Since it is ~ 600,000, it will not exceed 600,000, but it will be used
Raw material Polylactic acid-based polymer molecular weight, copolymerization ratio, molding
There is a wide range of melt molding conditions such as temperature and extrusion pressure.
In addition, depending on the above molecular weight, copolymerization ratio and molding conditions, the molecular weight is low.
Since the degree below will change, the upper limit can be set uniquely.
I can't come.

The novel surgical material obtained by the present invention has a compressive bending strength of 1.6 × 10 ³ kg.
/ Cm ² or more, the compression bending elastic modulus is 5.0 × 10 ² kg /
Although it is set to be mm ² or more, the upper limit cannot be uniquely determined. That is, the lower limit of the strength characteristics of these surgical materials is derived from stretching a molded product having a viscosity average molecular weight value of 200,000 after melt molding, and therefore,
The upper limit is based on stretching of the molded product having the upper limit of the viscosity average molecular weight after melt molding, which is determined by the upper limit (600,000) of the viscosity average molecular weight of the raw material polylactic acid-based polymer. Molecular weight of copolymer, copolymerization ratio,
Melt molding condition, upon which there is a considerable width stretch ratio, and these by compression flexural strength thereof, the compression flexural modulus turn into strange
Therefore, the upper limit cannot be set uniquely.

[0023]

EXAMPLES The present invention will be described in detail by way of examples, which do not limit the scope of the present invention. The compressive bending strength and the compressive bending elastic modulus shown in the examples are JIS K-7203.
It was measured based on. (Example 1) Polylactic acid pellets having an initial viscosity average molecular weight of 440,000 were dried under reduced pressure at 120 to 140 ° C for a whole day and night, and the dried pellets were put into an extruder and dried under reduced pressure for about 20 minutes.
After standing for a minute, the mixture was melt-extruded into a square rod or a round rod under the temperature conditions shown in Table 1 below. When the viscosity-average molecular weight of the obtained square bar or round bar-shaped molded product was measured, it was 220,000 as shown in Table 1 below.

The viscosity formula in this case is:

[Equation 1] Was used. Next, this molded product was uniaxially stretched in the long axis direction to 100% in liquid paraffin at 100 ° C. and cut to obtain a test piece (dimensions: width 10 mm × thickness 5 mm × length 80 m).
m) was produced. When the compression bending strength and the compression bending elastic modulus of the obtained test piece were measured, as shown in Table 1 below, the compression bending strength was 1,720 kg / cm ² and the compression bending elastic modulus was 610 kg / mm ² . .

Further, the test piece was dipped in a physiological saline solution at 37 ° C. for 3 months, and the compressive bending strength and the compressive bending elastic modulus of the test piece were measured. The bending strength was 1,700 kg / cm ² and the compressive bending elastic modulus was 600 kg / mm ² , and almost no strength deterioration was observed.

Example 2 The initial viscosity average molecular weight is 42.
A test piece was prepared in the same manner as in Example 1 except that polylactic acid pellets were used. The test piece was subjected to compression bending strength, compression bending elastic modulus, and melt extrusion after initial immersion for 3 months. The viscosity average molecular weight was measured. The results are shown in Table 1 below.

Example 3 The initial viscosity average molecular weight is 40.
A test piece was prepared in the same manner as in Example 1 except that a lactic acid-glycolic acid copolymer (lactic acid: glycolic acid = 90: 10) was used, and the test piece was compressed at the initial stage and after immersion for 3 months. Bending strength, compressive bending elastic modulus, and viscosity average molecular weight after melt extrusion molding were measured. The results are shown in Table 1 below.

(Examples 4 to 5) Stretching temperature was 70
2 in the same manner as in Example 1 except that the temperature was changed to 0 ° C and 170 ° C.
Various kinds of test pieces were prepared, and the compression bending strength, the compression bending elastic modulus, and the viscosity average molecular weight after melt extrusion molding of the test pieces were measured at the initial stage and after immersion for 3 months. The results are also shown in Table 1 below.

Example 6 Initial viscosity average molecular weight is 49
Tens of thousands of polylactic acid pellets and melt extrusion temperature
The conditions were changed to the temperatures shown in Table 1 below, and the stretching temperature was set to 105.
Same as Example 1 except that the temperature was changed to ° C and the film was stretched 2.5 times.
To prepare a test piece, and the initial and three months of this test piece
Compressive bending strength after immersion, compressive bending elastic modulus and melt extrusion
The viscosity average molecular weight after molding was measured. The results are shown in the table below
1 is also shown.

Comparative Examples 1 and 2 Example 1 was repeated except that polylactic acid having an initial viscosity average molecular weight of 700,000 and 280,000 was used, and the temperature conditions for melt extrusion were changed to the temperatures shown in Table 1 below. Two types of test pieces were prepared in the same manner as in, and the compression bending strength, the compression bending elastic modulus, and the viscosity average molecular weight after melt extrusion molding of the test pieces were measured at the initial stage and after immersion for 3 months. The results are also shown in Table 1 below.

[0031]

[Table 1] From Table 1 above, the viscosity average content after melt molding of Examples 1 to 6
The amount of each of these is 200,000 or more, and the biodegradable and absorbable surgical material obtained by stretching the material has a compressive bending strength of 1.6 ×.
10 ³ kg / cm ² or more, compressive bending elastic modulus 5.0 × 1
It has excellent strength of 0 ² kg / mm ² or more, and also has high hydrolysis resistance that does not cause strength deterioration even when immersed in physiological saline for 3 months. In contrast, the material of Comparative Example 1, to the molecular weight with extremely high polylactic 700,000, the temperature and pressure of the melt extrusion
If it is not high, extrusion is not possible, the molecular weight after molding is less than 200,000, and even if it is uniaxially stretched, as a result, the compressive bending strength and the compressive bending elastic modulus are below the target values, and satisfactory strength may not be obtained. I understand. Moreover, since the molecular weight of Comparative Example 2 is lower than 300,000, the molecular weight after molding is far below 200,000 even if the temperature and pressure of the melt extrusion molding are lowered to suppress the decrease of the molecular weight as much as possible, and therefore uniaxial It can be seen that satisfactory strength cannot be obtained even by stretching.

[0032]

As is apparent from the above description and the results of the examples, the method of the present invention uses (a) a polylactic acid-based polymer having a high viscosity average molecular weight in a specific range as a raw material , and Under certain adjusted conditions, such as melt molding in a specific temperature range that minimizes the decrease in the molecular weight of the polymer, and (c) stretching is performed under the specific temperature conditions that do not cause a further decrease in the molecular weight of the polymer. Since we produced a surgical material for polylactic acid-based biodegradable and absorbable stretched molded products,

It is possible to obtain a surgical material having a high compressive bending strength and a compressive bending elastic modulus, which are not obtained with conventional polylactic acid-based surgical materials, and also excellent in hydrolysis resistance. In the field of oral surgery or thoracic surgery, it can be suitably used as a bone-bonding plate, screw, pin or screw. Further, the production method of the present invention can be easily and highly efficiently carried out without preparing any special device, since it only adds the step of stretching to the step of melt molding which is generally used in the field of resin molding.
In addition, continuous processes are possible if necessary, and there is an effect that mass productivity and workability are excellent.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Gen Roh, 1 43-43 Higashikujo Minami Matsunoki-cho, Minami-ku, Kyoto (72) Inventor Kaoru Tsuta 2-30 Azuchi-cho, Higashi-ku, Osaka City Takiron Co., Ltd. (72 ) Inventor Hidekazu Banya 2-30 Azuchi-cho, Higashi-ku, Osaka Takiron Co., Ltd.

Claims (1)

[Claims] Polylactic acid or lactic acid having a viscosity average molecular weight of 300,000 to 600,000
A tough and excellent hydrolysis resistant raw material characterized in that the glycolic acid copolymer is melt-molded under the temperature condition of the melting point or more and 220 ° C. or less and further stretched under the temperature condition of 60 to 180 ° C. A method for producing a biodegradable and absorbable surgical material.