JP3141088B2 - Method for producing biodegradable and absorbable surgical materials - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] TECHNICAL FIELD The present invention relates to polylactic acid or lactic acid.
-Glycolic acid copolymer (hereinafter referred to as polylactic acid-based poly
Tough, excellent hydrolysis resistance
New biodegradable and absorbable stretch-formed surgical material
It relates to a new manufacturing method. Further, the surgical material of the present invention
The new production method has a viscosity average molecular weight of 300,000-
Using 600,000 polylactic acid-based polymers, the polylactic acid-based polymer
Above the melting point of the polymer, minimal decrease in molecular weight of the polymer
Melt molding at a temperature range of 220 ° C or less to suppress
A specific range of 6 which does not cause a further decrease in the molecular weight of the polymer.
Characterized in that stretching is performed under a temperature condition of 0 to 180 ° C.
You. More particularly, it is obtained by the process according to the invention.
The stretch-formed surgical material is compressed at a pressure similar to or slightly higher than that of bone.
Flexural strength and compressive flexural modulus, that is, toughness and excellent heat resistance
It is water-degradable and biodegradable and absorbable.
Significantly improved strength retention properties in the body and further fractures
While maintaining its strength during the period necessary for fusion of
After the period elapses, it is gradually decomposed and absorbed and becomes a long
Adverse effects caused by the presence in the body during
It has the characteristic that it can be excluded. [0003] 2. Description of the Related Art In orthopedic surgery and oral surgery, fractures
Of high-strength osteosynthesis plates and screws for reduction
I have. Such artificial materials for osteosynthesis can heal fractures
Function only for a period of time before healing to prevent bone weakening
It is necessary to pull out as soon as possible. Currently clinical
Most osteosynthesis plates, etc., which are widely used, are made of metal
In recent years, ceramics have also appeared. I
However, these materials alter the bone because the elasticity of the material itself is too high.
Quality or damage to the body due to elution of metal ions
There's a problem. [0004] Therefore, it has the same or slightly higher elastic modulus as bone.
And a material that is biodegradable and absorbable for osteosynthesis
Then, only the re-operation for pulling out becomes unnecessary.
And the presence of foreign substances in the body for a long time
It should be possible to rule out the various adverse effects that occur. Such a thing
From the circumstances, polylactic acid or lactic acid is a biodegradable and absorbable material
-Active development of osteosynthesis using glycolic acid copolymer
It is being advanced. For example, Makromol Chem.Suppl.Vol.
5, pp. 30-41 (1981), M. Vert, F. Chabot et al.
Polylactic acid or lactic acid-glycolic acid copolymer
Synthesized, 100% polylactic acid with compression bending elastic modulus
3.4 GPa (340 kg / mm^Two)
Tells. [0005] The 9th USA Biomaterials Society
Shoshushu, No. 6, p47. (1983) shows that D.C.
But510kg / mm^Two Polylactic acid bone joint play value
Report. Also, Japanese Unexamined Patent Publication No. 59-97654
According to the report, polymilk that can be used as a resorbable bone fixation device
A method for synthesizing an acid or lactic acid-glycolic acid copolymer is disclosed.
However, in this case, it is mentioned as the bone fixing material.
What is present is the polymerization product itself, and the tensile strength of this polylactic acid
The degree is about 580kg / cm^Two And low value, and this
There is no explanation about the forming of the material.
No attempt has been made to increase the strength to that of a human bone. More recently, Biomaterials, Vol. 8, p42 (1987)
P. Tormala et al. Are glycolic acid-lactic acid copolymer fibers
Of glycolic acid-lactic acid copolymer reinforced by phenol
Have reported an osteosynthesis plate consisting of
Strength is 265MPa (26.5kg / mm^Two ) And high
However, the strength degradation accompanying in vitro hydrolysis is extremely fast,
The strength is gone in one month. Also, J.W.Leenslag,
A.J.Pennings and colleagues report that the viscosity average molecular weight is about 1 million.
Synthesizes lactic acid and plays the role of high-molecular-weight polylactic acid in osteosynthesis
The compressive bending elastic modulus is 5 GPa (500 kg / mm^Two )
Is reported. [0007] Also, "Artificial Organs" Vol.16, No.3 (1987)
Reported that Nakamura et al.
Apatite (HA)ToContains a small amount (5-20% by weight)
Formed into a plate by thermocompression molding, then stretched and columnar
It is reported that he got a pin, but this is just HA
Stretching in the presence ofPolylactic acid polymer aloneof
There is no indication of the possibility of stretching. like this
In addition, conventional machines such as the compression bending strength of
Research to improve the mechanical properties and approach that of bone
Many reports have been made and various methods have been tried, but still
Satisfactory compression bending strength, etc., used sufficiently on the floor
And gradually decomposed and absorbed after healing
No material has been developed. [0008] SUMMARY OF THE INVENTION The present invention has been made in consideration of the above-mentioned problems.
In view of the above, conventionally known polylactic acid-based osteosynthesis
Mechanical properties such as compression bending strength and compression bending elastic modulus
High compressive bending strength that greatly exceeds both hydrolytic properties
Polyamide with excellent compression bending modulus and excellent hydrolysis resistance
Lactic acid based biodegradable and absorbable stretch molded surgical material
It aims to provide a manufacturing method. [0009] Means for Solving the Problems The present inventors have solved the above problems.
As a result of various studies, it has a high viscosity average molecular weight in a specific range.
Polylactic acid-based polymer under specific adjusted temperature conditions
By melt-forming and stretching, the outside of the stretch-formed product is
Compressive bending strength and compressive bending modulus of dental materials are comparable to bone
Completed the present invention, finding that it could be slightly higher
I came to. That is, the present invention:   Viscosity average molecular weight
300,000 to 600,000 polylactic acid or lactic acid-glycolic acid copolymer
Melt the coalesced under the temperature condition between its melting point and 220 ° C
Molded, and further stretched under a temperature condition of 60 to 180 ° C.
Surgical for biodegradable and absorbable tough and excellent hydrolysis resistance
Provide a method of manufacturing the material. Also,The above melt molded
Another characteristic is that the subsequent viscosity average molecular weight is 200,000 or more.
I do. Also,The above stretching is performed uniaxially in a heat medium
The point is also characteristic. Here, in the present invention, "water-resistant
"Excellent decomposability" means that it takes about three months for bone fusion.
Maintains the necessary strength and is gradually decomposed and absorbed after bone fusion
Hydrolytic properties that do not remain as foreign substances in the body for a long time. Hereinafter, the present invention will be described specifically. The present invention
Of polylactic acid-based biodegradable and absorbable stretched products
The method for producing the material for use is described below.materialPoly milk that is
Acid-based polymers, especially polylactic acid, for example, have optical activity
From L- or D-form lactic acid in a conventional manner (C.E.
No. 2,668,162), in the form of a cyclic dimer of lactic acid.
After synthesizing a lactide, the lactide is subjected to ring-opening polymerization.
It is obtained by doing. This polylactic acid
Considering the decrease in molecular weight during melt molding, at least the viscosity
The average molecular weight must be 300,000 or more
The higher the molecular weight, the higher the compression bending strength and compression
ElasticityHavingSuitable for obtaining surgical materials. Only
However, if the molecular weight is too high, melt molding, especially extrusion
High molecular weight is required due to high temperature and pressure required during molding
As a result, the molecular weight after melt molding falls below 200,000.
Because it will turn around,Even if this is stretchedTarget high
Compression bending strength, high compression bending modulusHavingSurgical materials
Is difficult to obtain. Therefore,materialPolylactic acid
Has a viscosity average molecular weight of about 300,000 to 600,000, preferably 4
Desirably, the molecular weight is about 0 to 500,000. In the present invention,materialAs above poly milk
A lactic acid-glycolic acid copolymer is also used in place of the acid.
This copolymer has the same viscosity average molecular weight as polylactic acid.
Have a higher lactic acid content, especially
When the weight ratio of lactic acid to glycolic acid is 99: 1 to 75:25
Those in the range are preferably used. Glycolic acid
If the amount is small and within the above range, the surgical material obtained is excellent.
37 ° C saline solution
Immersion for 3 months (may be necessary for healing of fractures)
Almost compressed (corresponding to the situation of being implanted in the living body for 3 months)
No deterioration in strength such as bending strength and compression bending modulus
However, when glycolic acid increases beyond the above range,
The disadvantage is that the water-decomposability is reduced and the strength is deteriorated early.
This is because a combination occurs. Surgical material obtained by the method of the present invention
Is a polymer having a high viscosity average molecular weight within the above specified range.
Lactic acid based polymermaterialAnd put it in a rod or band
Melt molding into a predetermined shape such as extruded
After shape and press molding, it is further uniaxially stretched in the long axis direction
Obtained by: Among melt molding, especially extrusion molding
Shapes can be used favorably because of their high productivity.
Extruder can be used. Melt molding (eg extrusion
Molding) conditions are above the melting point of the polylactic acid-based polymer,
It is necessary to set the temperature range to 220 ° C. or lower. in this case
In addition, the melt molding temperature is lower than the melting point of the polylactic acid-based polymer
Melt molding becomes difficult.
The molecular weight of the lactic acid-based polymer decreases significantly, and
Has a viscosity average molecular weight of200,000Because it is below. [0013] Molecular weight of polylactic acid-based polymer during melt molding
In order to minimize the decline, the raw material
It is important to melt-mold at a temperature slightly higher than the melting point.
You. Accordingly, as a raw material polylactic acid-based polymer,
Use a material having a viscosity average molecular weight of about 400,000 to 500,000
If used, melt molding at a temperature of 200 ° C or less
Is desirable. Similarly, pressure conditions for melt extrusion
Minimizes decrease in molecular weight of raw material polylactic acid-based polymer
Therefore, the viscosity of the molten polylactic acid-based polymer (viscosity average
The minimum extrusion pressure that can be extruded according to the molecular weight)
Is desirable. Accordingly, the viscosity of the starting polylactic acid-based polymer is
When the average molecular weight is up to 600,000, 260 kg / cm^Two
Hereinafter, when the molecular weight is about 400,000 to 500,000,
210kg / cm^Two It is appropriate to set the extrusion pressure to about
You. Prior to melt molding, the raw material polylactic acid-based polymer
The pellets are dried in advance by heating under reduced pressure to sufficiently remove moisture.
It is preferable to keep it. Molded product obtained by melt molding
IsThatThe viscosity average molecular weight is kept above 200,000
With considerable compression bending strength and compression bending elastic modulus
However, it is still below the target value (comparable to bone). Therefore, in the present invention, the above-mentioned melt-molded product is renewed.
In the heat transfer medium such as liquid paraffin, oil, etc.
Uniaxially stretching the polymer molecules to orient the polymer molecules.
To improve the compression bending strength and compression bending elastic modulus.
This uniaxial stretching should be performed at a temperature of 60 to 180 ° C.
is necessary. When the stretching temperature is lower than 60 ° C
IsMelt moldingStretching due to too close to the glass transition point of
Insufficient molecular orientation, conversely, temperatures higher than 180 ° C
ThenMoldingMolecular weight decrease, and in all cases, stretching
Satisfactorily improved compression bending strength and compression bending modulus
It becomes difficult to make it. Preferred temperature conditions are melt molding
The molecular weight varies depending on the molecular weight of the subsequent molded product.
If it is about 200,000 to 250,000, it is around 100 ° C. The stretching ratio is 2 times or more.So
Range suitable for surgical materialsdesirable. Less than twice
At low stretch ratio, molecular orientation becomes insufficient and compression is satisfactory
It is difficult to improve flexural strength and compressive flexural modulus.
This is because that. Conventionally, polylactic acidpolymerUsed alone
High compression bending strength and compression bending elasticity comparable to bone
Materials with excellent hydrolysis resistance, especially bone grafts
No joint material was obtained. However, as mentioned above,
The novel surgical material obtained by the method of the invention comprises 30
High viscosity average molecular weight in a specific range of about
Select the raw material polylactic acid polymer to have and melt molding temperature
The conditions were in a specific range (above its melting point, below 220 ° C.)
Therefore, the molecular weight of the polylactic acid-based polymer during melt molding can be reduced.
MinimallySuppress the viscosity average molecular weight after molding to 200,000 or more
This melt molded product can beNear the glass transition point
(60 ° C) to a temperature around the melting point (180 ° C), preferably
100 ℃Before and afterHigh strength for the first time by uniaxial stretching
And stretch-formed surgical materials with excellent hydrolysis resistanceobtain
be able toIt has technical significance in this respect. [0017] A novel surgical device obtained by the method of the present invention.
The material is biodegradable and absorbable made of polylactic acid-based polymer
A stretched product of the material, the compression bending strength of which is
1.6 × 10^Three kg / cm^Two As mentioned above, the compression bending elastic modulus
5.0 × 10^Two kg / mm^Two Above, the viscosity flatness after melt molding
Has an average molecular weight of 200,000 or more, is tough and has excellent hydrolysis resistance
Surgical material. This surgical material is then applied
Cut to the right size and finally come in various sizes and shapes
Cutting into osteosynthesis plates, pins, screws, screws, etc.
And orthopedics, oral surgery, thoracic surgery,Plastic surgeryEtc.
Can be used clinically in the area. Novel surgical products obtained by the method of the present invention
Since the material consists only of polylactic acid-based polymer,
Decomposition and absorption are very good, and conventional metals or ceramics
Mind that has a negative effect in vivo like surgical materials
There are few arrangements. More particularly, it is obtained by the method of the invention.
New surgical material is used for compression music that is as high as or slightly higher than bone.
With high compression strength and compressive bending elastic modulus.
Fixes fractures, etc., and gradually decomposes as bone regenerates
However, strength is maintained until about 3 months when the fracture is repaired
After that, decomposition progresses and strength decreases, but bones are
It is produced to maintain strength as a whole. Moreover, the method of the present inventionBy, Melt molding
Viscosity reduction after melt molding with minimum molecular weight reduction
The molecular weight is maintained at 200,000 or more,
And crystal orientationWhen given, the resulting surgical material isIts compression
Bending strength is 1.6 × 10^Three kg / cm^Two Above, compression bending
The elastic modulus is 5.0 × 10^Two kg / mm^Two With the above,
High compression bending not achieved with lactate-based surgical materials
Shows strength, high compressive bending modulus and hydrolysis resistance
Immersion in physiological saline at 37 ° C for about 3 months
(Embedded in the living body for 3 months, which is considered necessary for the healing of fractures
), Almost strengthDeclineCan cause
There is no effect. The method of the present inventionThen, Average viscosity after melt molding
200,000 or more molecular weightIt is important to. like this
High viscosity average molecular weightSurgery obtained by stretching molded products with
MaterialInitial pressure at the time of implantation
Provides compression bending strength and initial compression bending elastic modulus, and further fusion
The osteosynthesis material was introduced into the living body for 3 months,
Compressive bending strength and compressive bending elastic modulus are reduced even when plant is used
Can be held so as not to cause. Also, the viscosity flatness after melt molding
If the average molecular weight is lower than 200,000,Even if this is stretchedAbove first
Compressive bending strength and compressive bending elastic modulus at target
), And the osteosynthesis material disassembles quickly.
Can no longer be used, and as a surgical material
In addition, it cannot be put to practical use in terms of both hydrolysis resistance. [0021]In the present invention, the average viscosity after melt molding
Although it is desirable that the amount of particles is 200,000 or more,
The upper limit cannot be set uniquely.That is, the raw material
Desirable viscosity average molecular weight of polylactic acid polymer is 300,000
It does not exceed 600,000 because it is ~ 600,000
Raw materials of polylactic acid-based polymer Molecular weight, copolymerization ratio, molding
There is considerable variation in melt molding conditions such as temperature and extrusion pressure
In addition, the molecular weight is low depending on the above molecular weight, copolymerization ratio and molding conditions.
Since the lower degree changes, the upper limit can be set uniquely.
I ca n’t come. [0022]Also, a novel surgical device obtained by the present invention
The material has a compressive bending strength of 1.6 × 10 ^Three kg
/ Cm ^Two As described above, the compression bending elastic modulus is 5.0 × 10 ^Two kg /
mm ^Two It is said that it is above, but the upper limit is determined uniquely
Cannot do.In other words, the strength characteristics of these surgical materials
Lower limit of the viscosity average molecular weight after melt molding is 200,000.
Derived from stretching the molded article, therefore,
The upper limit is the viscosity range of the specific range of the raw polylactic acid polymer.
Melt molding determined from the upper limit of the average molecular weight (600,000)
After stretching the molded product having the upper limit of the viscosity average molecular weight after
The molecular weight of the raw material polylactic acid-based polymer, copolymerization ratio,
There is considerable variation in melt molding conditions, stretch ratio, etc.
These change the compression bending strength and compression bending elastic modulus.
Therefore, it is not possible to set an upper limit uniquely. [0023] The present invention will be described in detail with reference to examples.
They do not limit the scope of the invention. Pressure shown in the examples
The compressive bending strength and compressive bending elastic modulus are JIS K-7203.
Is measured based on (Example 1) Pellets of polylactic acid with initial viscosity average molecular weight of 440,000
Dry under reduced pressure at 120-140 ° C all day and night.
The let was placed in an extruder and left under reduced pressure for about 20 minutes.
Then, it was melted into a square or round bar under the temperature conditions shown in Table 1 below.
It was melt extruded. Viscosity of the obtained square or round bar-shaped molded product
When the average molecular weight was measured, as shown in Table 1 below,
It was 20,000. The viscosity equation in this case is: (Equation 1) [Η] = 5.45 x 10^-FourM_v ^0.73(Chloroform 25 ° C) Was used. Next, the molded product is subjected to liquid paraffin at 100 ° C.
And stretched uniaxially twice in the machine direction in the
Test piece (Dimensions: width 10 mm x thickness 5 mm x length 80 m
m) was prepared. Compression bending strength and pressure of the obtained test piece
When the flexural modulus was measured, as shown in Table 1 below
Has a compressive bending strength of 1,720 kg / cm^Two , Compression bending
The elastic modulus is 610kg / mm^Two Met. Further, the test piece was placed in a physiological saline solution at 37 ° C.
Immersion for 3 months, then the compressive bending strength and
Table 1 below shows the results
Y, the compression bending strength is 1,700 kg / cm^Two , Compressed song
Elasticity is 600kg / mm^Two And strength deterioration is almost
I couldn't see it. (Example 2) Pellets of polylactic acid with initial viscosity average molecular weight of 420,000
A test piece was prepared in the same manner as in Example 1 except that the test piece was used.
Flexural strength and pressure after initial and 3 months immersion
Flexural modulus and viscosity average molecular weight after melt extrusion molding
It was measured. The results are shown in Table 1 below. (Embodiment 3) Lactic acid-glycolic acid having an initial viscosity average molecular weight of 400,000
After using the polymer (lactic acid: glycolic acid = 90: 10)
A test piece was prepared in the same manner as in Example 1 except for the test piece.
Bending strength after initial and 3 months immersion
And viscosity average molecular weight after melt extrusion.
Was. The results are shown in Table 1 below. (Examples 4 and 5) Except that the stretching temperature was changed to 70 ° C and 170 ° C respectively
Two types of test pieces were prepared in the same manner as in Example 1, and
Compressive bending strength and compressive music of specimens at initial stage and after immersion for 3 months
Measurement of viscosity average molecular weight after melt extrusion molding
did. The results are shown in Table 1 below. (Comparative Examples 1 and 2) Initial viscosity average molecular weights of 700,000 and 280,000 respectively
Table 1 below shows the temperature conditions for melt extrusion molding using lactic acid.
Two types in the same manner as in Example 1 except that the temperature was changed to the indicated temperature
And immersion of the specimen for the initial and three months
Compression bending strength, compression bending elastic modulus and melt extrusion
The subsequent viscosity average molecular weight was measured. The results are shown in Table 1 below.
Also shown. [0030] [Table 1] According to Table 1, Examples 1 to 5 are shown.After melt molding
Have a viscosity average molecular weight of 200,000 or more.
StretchedBiodegradable and absorbable surgicalmaterialIs the compression bending strength
The degree is 1.6 × 10^Three kg / cm^Two Above, the compression bending modulus
Is 5.0 × 10^Two kg / mm^Two With the above and excellent strength
And even when immersed in physiological saline for 3 months
It is known that it has high hydrolysis resistance without causing strength deterioration
You. In contrast, the material of Comparative Example 1 had a molecular weight of 700,000.
Due to the use of extremely high polylactic acid, the temperature of melt extrusion molding
Degree and pressureCan not be extruded unless, Molecule after molding
Even if the amount is less than 200,000 and the film is uniaxially stretched, the compression
Strength and compressive bending modulus are below target
It turns out that a degree cannot be obtained. Also, Comparative Example 2
Since the amount is lower than 300,000, the temperature and pressure of melt extrusion molding
Even if the molecular weight decrease is minimized by lowering the
Is far below 200,000, so even if it is uniaxially stretched,
It turns out that satisfactory strength cannot be obtained. [0032] As is apparent from the above description and the results of the examples.
Thus, the method of the present invention comprises:materialAs a specific range of high
Uses polylactic acid polymer with high viscosity average molecular weight
(B) specifying that the molecular weight reduction of the polymer is minimized.
(C) further molecules of the polymer
It is said that stretching is performed under specific temperature conditions that does not cause a decrease in amount
Under certain adjusted conditions, polylactic acid-based biodegradation
Since the surgical material of the stretch-formed product with good yield was manufactured, It cannot be obtained with conventional polylactic acid-based surgical materials.
High compression bending strength and compression bending elastic modulus, and
Surgical materials with excellent hydrolysis resistance.
In areas such as orthopedic, oral, or thoracic surgery
Plate, screw, pin or screw for osteosynthesis
It can be used very suitably. In addition, the present invention
The manufacturing method of melt molding is widely used in the field of resin molding.
Since it only adds a stretching process to
Can be performed easily and efficiently without preparing any equipment,
In addition, if necessary, continuous process is possible, mass production, work
It has the effect of being excellent in properties and the like.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Gen Jongle, 43-1, 43-1, Higashikujo Minamimatsunogicho, Minami-ku, Kyoto-shi (72) Inventor Kaoru 2--30 Azuchicho, Higashi-ku, Osaka, Japan 72) Inventor Hidekazu Yoya, 2-30, Azuchicho, Higashi-ku, Osaka, Japan, within Tagiron Co., Ltd. (56) References JP-A-1-198552 (JP, A) JP-A-59-97654 (JP, A) JP-A-61-181469 (JP, A) JP-A-61-259674 (JP, A) JP-A-61-36321 (JP, A) JP-A-61-293445 (JP, A) International publication 89/6143 (WO, A1) Artificial organ, Vol. 16, No. 3, (1987) pp. 1419-1422. (58) Field surveyed (Int. Cl. ⁷ , DB name) A61L 27/00

Claims (1)

(57) [Claims] Melt molding a polylactic acid or a lactic acid-glycolic acid copolymer having a viscosity average molecular weight of 300,000 to 600,000 under a temperature condition of a melting point or more and 220 ° C or less, and further stretching under a temperature condition of 60 to 180 ° C. A method for producing a biodegradable and absorbable surgical material having toughness and excellent hydrolysis resistance. 2. The viscosity average molecular weight after the above melt molding is 200,000 or more
2. The method according to claim 1, wherein
Surgical for biodegradable and absorbable tough and excellent hydrolysis resistance
The method of manufacturing the material. 3. The stretching is uniaxially stretching in a heat medium.
To, resistance to water at tough Patent described first or second term claims
Production of biodegradable and absorbable surgical materials with excellent degradability
Law.