JP2001151878A - METHOD FOR PRODUCING POLY(p-DIOXANONE), POLY(p-DIOXANONE) MONOFILAMENT AND METHOD FOR PRODUCING THE SAME - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a poly(p-dioxanone) excellent in hydrolytic resistance, monofilament of the polymer obtained by the above method and a method for producing the above monofilament. SOLUTION: This method for producing poly(p-dioxanone) comprises carrying out ring-opening polymerization in the presence of a catalyst and an initiator and is characterized by adding 0.002 to 0.005 mol% stannous dioctanoate, which yields white crystals at 0 deg.C, and 0.01 to 0.1 mol% initiator to p-dioxanone, initiating ring-opening polymerization of the p-dioxanone with stirring at 85 to 105 deg.C, stopping the stirring at the time when the load of stirring has increased by 10 to 60% based on the initial load and lowering the polymerization temperature to 65 to 85 deg.C to conduct solid-phase polymerization.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a method for producing poly (p-dioxanone), a poly (p-dioxanone) monofilament, and a method for producing the same. Specifically, poly (p-dioxanone) monofilament which has a high retention of mechanical properties and is suitably used as a surgical suture, a method for producing the same, and poly (p-dioxanone) which can be suitably used as a raw material of the monofilament And a method for producing the same.

[Prior art]

[0003] At present, commercially available poly (p-dioxanone) monofilaments include PDS manufactured by Ethicon, USA.
II (trade name), which is known to exhibit very good hydrolysis resistance. On the other hand, as other chemically synthesized monofilament sutures, monocryl (trade name, manufactured by Ethicon), maxon (trade name, manufactured by ACC), biocin (trade name, manufactured by US Surgical Co., Ltd.) and the like are known. I have. The latter monofilaments hydrolyze faster than PDSII, are not effective in retaining longer hydrolysis resistance, and are used only for short-term applications. When longer hydrolyzability is required, it is necessary to use polycaprolactone monofilament or the like. However, heat resistance is actually insufficient and hydrolyzability is too slow.

[0004] In recent years, with the advance of medical treatment, the elderly are aging. However, since he is old, healing and recovery take a long time, and the strength of conventional degradable monofilament sutures decreases before the wound is repaired. I have. As monofilament sutures, safer ones that are less likely to be hydrolyzed have been desired.

[0005] Dotty et al. Disclose poly (p-dioxanone).
Manufactures bioabsorbable monofilaments.
(For example, Japanese Patent Publication No. 60-36785, USP-
4,052,988). Also, Japanese Patent Application Laid-Open No. 10-3167
No. 45 discloses a method for producing high molecular weight poly (p-dioxanone) having a narrow molecular weight distribution (Mw / Mn). For the former monofilament composed of poly (p-dioxanone), a suture having a solution viscosity of a tetrachloroethane solution of at least 0.5 dl / g or more is described by controlling the molecular weight by the amount of the organometallic catalyst and the monomer purity. ing. However, the higher the molecular weight, the greater the amount of catalyst contained, and even if the used catalyst is removed, it is not a good method from the viewpoint of safety. Similarly, the molecular weight of the latter poly (p-dioxanone) is controlled by the amount of tin dioctanoate, which is far from the catalyst amount intended by the present inventors. Further, even if the used catalyst is removed, it cannot be said that it is a good method in terms of safety.

On the other hand, JP-A-8-52205 discloses that
A process for producing poly (p-dioxanone) having a high solution viscosity and a surgical monofilament having a solution viscosity of 2.3 to 8.0 dl / g in hexafluoroisopropanol solvent are disclosed. The publication further discloses a one-stage polymerization using a reactor suitable for a polymer having a high viscosity,
Alternatively, it is described that poly (p-dioxanone) can be produced by two-stage polymerization in which a low-molecular-weight prepolymer is polymerized in a two-stage solid state. It is described that the content of the reaction tank was discharged to a curing tray when the viscosity of the polymer reached 100 to 500 cp after the polymerization was started. The polymers produced in this way are certainly of high molecular weight (intrinsic viscosity: 2.64 dl)
/ G), it is intended to improve the hydrolysis resistance to some extent by increasing the molecular weight. However, there is no specific description showing the hydrolysis resistance of the filament, and it merely shows the effect of having a high molecular weight in an injection molded article. Further, there is no description about deterioration of the polymer due to shearing caused by stirring during polymerization, and it is considered that the combined use of liquid phase stirring polymerization and solid phase polymerization is rather for improving the efficiency of liquid transfer.

As a method for producing a monofilament, JP-A-3-206143, US Pat. No. 5,294,395,
And production methods disclosed in US Pat. No. 5,451,461 and the like. Specifically, the stretching of the undrawn yarn performed after the spinning is performed by exposing the monofilament surface layer to heat at a temperature equal to or higher than the melting point to form a monofilament having a two-layer structure in which the outer and central portions have different crystal structures. This is generally called a zone stretching method, and is characterized in that the surface is slightly melted to impart softness, while maintaining high crystallinity at the center and maintaining hydrolyzability. However, in this method, since thermal decomposition is partially caused, it is necessary to use a high molecular weight poly (p-dioxanone) as a raw material. In addition, it is hard to say that it is excellent in terms of economics, such as the complexity of the process and the need for special equipment. Further, it is conceivable that the hydrolysis resistance is sacrificed. Considering the above reasons, it can be seen that it is necessary to produce a high molecular weight polymer in order to perform zone stretching.

[0008]

DISCLOSURE OF THE INVENTION In view of the above, an object of the present invention is to provide a poly (p-dioxanone) filament, such as PDSII, which has superior hydrolysis resistance and is safer than poly (p-dioxanone) filaments. An object of the present invention is to provide a monofilament of (p-dioxanone) and a method for producing the same, and a method for producing poly (p-dioxanone) useful as a raw material thereof.

[0009]

The present inventors have conducted intensive studies and, surprisingly, surprisingly found that stannous dioctanoate, which was conventionally believed to be a liquid, was purified by distillation or the like, and thus was reduced in temperature. Using the purified high-purity stannous dioctanoate as a polymerization catalyst, a liquid-phase ring-opening polymerization of p-dioxanone is started, and the polymerization proceeds to form a solid. When the viscosity (stirring load) increases by a specific value or more, the stirring is stopped, the polymerization temperature is lowered, and the method is switched to solid-state polymerization, which is obtained as compared with the case of using unpurified stannous dioctanoate. Despite having the same molecular weight of poly (p-dioxanone), the filaments obtained by spinning the same have been found to be excellent in hydrolysis resistance, and have reached the present invention.

That is, the first invention of the present invention relates to a method for producing poly (p-dioxanone) by ring-opening polymerization of p-dioxanone in the presence of a catalyst and an initiator, wherein 0 ° C. Of 0.001 to 0.005 mol% of stannous dioctanoate and 0.01 to 0.1 mol% of an initiator which form white crystals in the above, and a liquid phase of p-dioxanone is stirred at 85 to 105 ° C. Ring opening polymerization is started, stirring is stopped when the stirring load increases by 10 to 100% with respect to the initial load, and the polymerization temperature is lowered to 65 to 85 ° C. to perform solid phase polymerization. Poly (p-
Dioxanone).

In a preferred embodiment of the first invention, after the solid phase polymerization is completed, an unreacted p-dioxanone is removed by bubbling an inert gas at a temperature of 60 to 80 ° C. and a pressure of 10 mmHg or less, and the content thereof is reduced to 0. The above-mentioned production method in which the conversion is controlled to 5% by weight or less, and the above-mentioned production method in which the polymerization reaction is continued until the conversion to poly (p-dioxanone) reaches 95% by weight or more. In any of the production methods, as a raw material, a p-
It is preferred to use dioxanone. In particular, in addition to the above-mentioned characteristics, stannous dioctanoate having a melting point of −3 ° C. or more is used. Further, a commercially available product is purified by distillation to obtain 0.25 to 0.3 mmHg, and a top temperature of 180 to 20.
It is preferable to use a distillate under the condition of 0 ° C. Further, it is preferable to stop stirring when the stirring load increases by 20 to 80% with respect to the initial load. The intrinsic viscosity of the poly (p-dioxanone) produced by the above method can be changed by adjusting the amount of the initiator, and specifically, at 25 ° C., 1.8 to 2.5 dl / g. It is. In addition, the melting point of tin dioctanoate in the present invention can be measured by a method described in Examples described later.

According to a second aspect of the present invention, poly (p-dioxanone) is produced by the above method, and then (1) 125
A spinning step of melt-spinning the obtained poly (p-dioxanone) at） 165 ° C., (2) a stretching step of stretching at 60-110 ° C. at a stretching ratio of 3-8, (3) 6.
80-90% relaxation at 0-110 ° C.
(4) A method for producing a poly (p-dioxanone) monofilament, comprising a step of performing a heat treatment at 80 to 100 ° C. for 1 to 24 hours. The diameter of the drawn monofilament produced in this way is between 4 and 40 mils.

A third invention of the present invention is a poly (p-dioxanone) monofilament produced according to the second invention, which has a single knot tensile strength of at least 30,000 p.
poly (p-dioxanone) monofilament having a tensile strength retention of 58% or more after immersion in physiological saline at 37 ° C. for 4 weeks. The monofilament according to the present invention is suitably used as a surgical suture.

The poly (p-dioxanone) monofilaments according to the present invention hydrolyze more slowly than known hydrolyzable polyester filaments, for example PDSII.
That is, even when subjected to a hydrolysis treatment in a physiological saline solution, the retention rate such as the single knot tensile strength is high, and the hydrolysis resistance is excellent. Therefore, it is an extremely useful material that can be used as a surgical suture having a long healing period.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. First, a method for producing poly (p-dioxanone) will be described. In the method for producing poly (p-dioxanone) according to the present invention, when performing ring-opening polymerization of p-dioxanone in the presence of a catalyst and an initiator, 0 ° C.
Using stannous dioctanoate, which produces white crystals, starts liquid-phase ring-opening polymerization with stirring at a specific temperature, captures the increase in viscosity of the reaction system with a stirring load, and increases the stirring load by a specific value or more. In this method, the stirring is stopped to eliminate mechanical shearing of the reaction system, and the polymerization temperature is lowered to carry out solid-state ring-opening polymerization.

In the present invention, stannous dioctanoate is used as a catalyst. Stannous dioctanoate is approved by the US FDA as a food additive. The stannous dioctanoate used in the present invention produces white crystals at 0 ° C. Preferably, it has a melting point of -3 ° C or higher. These catalysts can be obtained by subjecting a commercially available product to distillation purification and the like. As a commercially available product, Nippon Kagaku Sangyo Co., Ltd., trade name: Nikka Octin Tin 28%, may be mentioned. The product is a pale yellow liquid at a temperature of 0 ° C. By purifying this commercial product by distillation and collecting the distillate at a pressure of 0.25 to 0.3 mmHg and a top temperature of 180 to 200 ° C, a catalyst having a purity suitable for the purpose of the present invention can be obtained. When the above commercial product is distilled under the above conditions, the recovery of the distillate is about 80% by weight. At the time of distillation purification, distillate having an overhead temperature of less than 180 ° C. is removed as an initial fraction, and
Those exceeding 00 ° C are removed as bottoms. Stannous dioctanoate purified by distillation is a colorless and viscous liquid at room temperature, and is a white crystal at 0 ° C under a nitrogen atmosphere, and has a melting point of -3 ° C. Further, ¹ H-NMR and I
According to the results of the R measurement, most of the first distillate was a free carboxylic acid. The use amount of the catalyst is preferably in the range of 0.002 to 0.005 mol% based on the charged amount of p-dioxanone.

Examples of the initiator include the following.
Examples include aliphatic alcohols, glycols, hydroxycarboxylic acids, and phenols. Specifically, aliphatic saturated alcohols such as methanol, ethanol, propanol, butanol, amyl alcohol, caprylic alcohol, and lauryl alcohol; alicyclic alcohols such as cyclopentanol and cyclohexanol; glycols such as diethylene glycol; And hydroxycarboxylic acids such as glycolic acid, and phenols such as aminophenol and acetaminophen. Of these, lauryl alcohol is preferably used. The amount of the initiator used is preferably in the range of 0.01 to 0.1 mol% based on the amount of p-dioxanone to be described later.

The p-dioxanone (monomer) used in the present invention may be distilled or purified by distillation, but preferably has low water content. The allowable range of water is desirably 150 ppm or less. When the water content exceeds 150 ppm, the production of a polymer using water as an initiator becomes dominant, and a large amount of poly (p-dioxanone) having a high hydrolysis rate tends to be produced.

In the present invention, a dye may be added to the polymerization system. The time of addition is preferably at the start of polymerization. Dyes that can be used include D, which is regulated by US CFR21.
& C, Green-No. 6 (CAS number: 128-8)
0-3) and D & C, Violet-No. 2 (C
AS number: 81-48-1). The amount of the dye to be used is 0.1% based on the charged amount of the monomer.
Preferably, the range is less than 21% by weight and the latter less than 0.3% by weight. More preferably, the former is less than 0.15% by weight and the latter is less than 0.25% by weight. At the same viscosity, a large amount of addition is less susceptible to shearing due to stirring during polymerization, but increases the reaction time and the stirring duration. On the other hand, if the amount is small, it is susceptible to shearing and does not have a good effect on hydrolysis resistance.

In the present invention, a polymer and a filament having excellent hydrolysis resistance can be produced without adding a dye. That is, the object of the present invention is achieved by controlling the stirring load and performing the liquid phase reaction at a high temperature and the solid phase reaction at a low temperature using the purified catalyst as described above.

In the polymerization reaction, ring-opening polymerization of p-dioxanone is carried out in the presence of the catalyst and the initiator and, if necessary, with the addition of a dye. Ring-opening polymerization is carried out under stirring with 8
The reaction is started in the liquid phase at 5 to 105C, preferably 90 to 100C. The polymerization reaction proceeds, and as the production of the polymer proceeds, the viscosity of the reaction system increases. In the present invention, this increase in viscosity is captured by an increase in the stirring load.

Using a 300 ml reactor (inner diameter: 87 mm, depth: 170 mm), the liquid depth of the reaction solution was 90%, and the ratio of the length (L) of the stirring blade to the inner diameter (D) of the reactor, L /
D: The stirring load will be described using an example in which a stirring blade of 0.6 to 0.7 is used. Stirring is started at a stirring load of 0.006 V (maximum load of the stirrer: 5 V, torque at that time: 10 kgf · cm) at the start of the reaction, and when the stirring load exceeds, for example, 0.008 V, a point at which viscosity is generated That is, it is defined as the time when the stirring load increases. The load increase at this time is 0.002 V, which means that the load has increased by 33% compared to the initial load. The polymerization temperature at this time is 8
5 to 105 ° C. Preferably it is in the range of 90 to 100 ° C.

In the present invention, the ring-opening polymerization is started, and the stirring is stopped after the viscosity is generated and the stirring load increases to a specific value.
At the same time, the polymerization temperature is lowered to switch to solid-state polymerization. The target of the degree of increase in the stirring load when switching to solid phase polymerization is:
This is the point in time when the amount increased by 10 to 100% with respect to the initial stirring load. Preferably, it is at the point when the increase is 20 to 80%. The polymerization temperature of the solid-state polymerization is 65 to 85 ° C. Preferably it is in the range of 70 to 80 ° C.

The polymerization reaction is preferably continued until the conversion of the monomer reaches 95% by weight or more. The polymerization time varies depending on the temperature, the amount of the catalyst, and the amount of the initiator. Usually, the reaction time of the liquid phase reaction under stirring is preferably about 2 to 24 hours. More preferably, it is about 6 to 12 hours. During this time, the workability is greatly improved by incorporating a control system that automatically detects the increase in the stirring load due to the occurrence of viscosity, automatically stops stirring, and automatically switches to solid state polymerization. Can be. The polymerization time of the solid phase polymerization is preferably about 3 to 6 days. If the number of days is longer, the efficiency is lower than the workability and the economical viewpoint, and if it is less than 3 days, the desired conversion may not be attained. The poly (p-dioxanone) polymer is spun to obtain desired properties. It becomes difficult to obtain a monofilament having the same. The heating medium is not limited, and may be an oil bath or a dryer. However, a dryer is preferable in consideration of an efficient method.

The poly (p-dioxanone) produced by the above method has an intrinsic viscosity of 1.8 to 2.0 at 25 ° C.
5 dl / g. Preferably about 1.9 to 2.4 dl /
g. If it is less than 1.8 dl / g, the melt viscosity at the time of molding becomes low, and it becomes difficult to obtain a filament having a good shape. On the other hand, if it exceeds 2.5 dl / g, the melt viscosity becomes too high during molding, and it becomes difficult to obtain good moldability. In addition, it is necessary to increase the temperature during spinning, so that good hydrolysis resistance cannot be maintained.

As for the purity of the catalyst, the molar ratio of the monomer to the initiator (hereinafter referred to as M /
Even if I is the same value, poly (p-dioxanone) having a high intrinsic viscosity, that is, a high molecular weight can be obtained (comparison between Examples 1 and 2 and Comparative Example 1 or Comparative Examples 4 and 2). And comparison). Furthermore, the filament obtained by spinning poly (p-dioxanone) obtained using the purified catalyst has an intrinsic viscosity of poly (p-dioxanone) as compared with a case where a commercially available product is used without purification. Even if the same, hydrolysis resistance is excellent. Regarding the stirring load control, when the M / I is the same and the distillation purified catalyst is used, the stirring is stopped when the stirring load increases by a predetermined value, and the polymerization temperature is reduced to a predetermined value. The lower the polymerization, the higher the poly (p-dioxanone) having a high intrinsic viscosity is obtained (Examples 1 to 5).
3 and Comparative Examples 3 and 4).

Regarding the effect of the addition of the dye, when the M / I value was set to the same condition without controlling the stirring load, the difference in the intrinsic viscosity of the obtained poly (p-dioxanone) was as follows. Almost no (see Comparative Examples 3 and 4). A plasticizing effect such as gelation prevention by the addition of the dye is observed.

In the present invention, the control of the molecular weight is uniquely determined by the addition amount of the initiator and the like. Here, the initiator and the like mean water and an initiator. The M / I value obtained by dividing the total number of moles of the monomer by the number of moles of the initiator or the like is used as the index. After measuring the water content of the monomer, the amount of the initiator to be added is determined from a previously prepared calibration curve. Next, a method for producing a poly (p-dioxanone) monofilament using the poly (p-dioxanone) produced by the above method will be described. Before spinning the filament, the monomer contained in the polymer is removed, and the polymer is dried. Poly (p-dioxanone) is preferably one from which impurities are removed as much as possible. That is, it is preferable to minimize the amount of substances that promote hydrolysis, such as moisture and monomers. The content of the monomer in the poly (p-dioxanone) is 0.5% by weight or less, more preferably 0.1% by weight or less.
% Is desirable.

As a method for removing the monomer, the following methods can be mentioned, but there is no problem as long as the heating container can be aerated to heat the filled container under reduced pressure. A method in which poly (p-dioxanone) is packed in a packed tower column in which the surface of a vessel is heated, and stripping is performed by using heated dry nitrogen or the like from the bottom of the column under reduced pressure. A method in which stripping is carried out while aerating dried nitrogen with a rotary conical dryer heated on the surface of a container under reduced pressure suction. If the scale is small,
Method is effective and convenient. In the case of a scale of 5 kg or more, it is effective to use the above method. By these methods, poly (p-dioxanone) from which monomers have been removed can be obtained. The heating temperature is in the range of 60 to 80C. More preferably, it is in the range of 60 to 70 ° C. The flow rate of the inert gas such as nitrogen depends on the evacuation capacity of the vacuum pump and the size of the container. However, if the flow rate is too large, the degree of vacuum does not increase and the initial target cannot be achieved. Preferably, it is performed at a flow rate of 0.5 liter / min or less. More preferably, 0.3 liter / min. It is desirable to carry out in about. The pressure during decompression and suction is 10 mmHg
The following is preferred. The poly (p-dioxanone) thus obtained from which monomers have been removed can be preferably used as a spinning raw material.

The monofilament according to the present invention is produced by spinning the above-mentioned poly (p-dioxanone) and then drawing it. For spinning, a known spinning method can be adopted. The same applies to stretching.
When producing a monofilament by melt spinning, the spinning temperature is preferably from 125 to 165 ° C. 125
If the temperature is lower than ℃, the melt viscosity of poly (p-dioxanone) is too high, and spinning is difficult. When the temperature exceeds 165 ° C., poly (p-dioxanone) is decomposed, and the strength of the obtained monofilament decreases. It is also possible to prepare a solution of poly (p-dioxanone) and spin the solution.
In that case, a solvent such as tetrachloroethane can be used as the solvent. In this case, spinning is performed at a temperature equal to or lower than the boiling point of the solvent. The solution concentration is usually preferably from 10 to 30% by weight. However, the melt spinning method of the former is preferred from the economic point of view.

An undrawn yarn is produced by spinning, and the obtained undrawn yarn is drawn to obtain a linear tensile strength of 50,0.
A monofilament having a strength of 00 psi or more is obtained. Preferred stretching conditions are a stretching temperature of 60 to 110 ° C,
The stretching ratio is in the range of 3 to 8 times. The stretching method is preferably two-stage stretching. In this case, the stretching is performed such that the total stretching ratio of the one-stage stretching and the two-stage stretching is within the above range. If the stretching ratio is less than 3 times, sufficient tensile strength cannot be obtained. On the other hand, if it exceeds 8 times, a whitening phenomenon occurs at the time of stretching, so that sufficient strength cannot be obtained. Further, the monofilament may be broken during stretching, which is not preferable.

After the monofilament according to the present invention is drawn under the above conditions, it is heated at 60 to 110 ° C. at 80 to 90 ° C.
% Relaxed. Next, heat treatment is performed. The heat treatment temperature is
A temperature range from 80 ° C. to below the melting point of the poly (p-dioxanone) is preferred. Specifically, it is about 80 to 100 ° C. The processing time is preferably about 1 to 24 hours. Usually, for example, it is carried out under appropriate tension while being wound around a bobbin or the like. The monofilament obtained under the above conditions is subjected to a hydrolysis test. Monofilament with dye added
Compared with a monofilament (trade name: PDSII) manufactured by Ethicon having the same intrinsic viscosity, it clearly shows that the hydrolysis resistance is excellent.

The monofilament according to the present invention has a linear tensile strength of at least 50,000 psi, preferably at least 60,000 psi.
000 psi or more. One knot tensile strength is 30,
000 psi or more, preferably 40,000 psi or more. Young's modulus is 290,000 psi or less, preferably 220,000 psi or less. Elongation rate is 60%
Or less, preferably 40% or less. Also, the diameter of the monofilament is between 4 and 40 mils. When immersed in a physiological saline solution at 37 ° C., the retention rate of the single knot tensile strength after 4 weeks is 58% or more. A monofilament having such properties can be suitably used, for example, as a bioabsorbable surgical suture, particularly a wound healing surgical suture having a long healing period.

[0034]

EXAMPLES Hereinafter, the present invention will be described based on examples, but the present invention is not limited to these examples. The physical properties described in the examples were measured by the following methods.

1. Residual monomer amount (% by weight) After preparing a calibration curve of a monomer having a known concentration in advance, 0.3 g of the obtained copolymer was dissolved in 10 ml of hexafluoroisopropanol (hereinafter referred to as HFIP), and subjected to gas chromatography. [Hitachi, Ltd., 1
63-type gas chromatograph, capillary column: cp-si
l 5CB, 50mx 0.32mmφ, column temperature: 1
(70 ° C.) to quantify the residual monomer.

2. Intrinsic Viscosity (dl / g) After dissolving 0.025 g of the obtained copolymer in 25 ml of HFIP to prepare a 0.1 g / dl HFIP solution, the solution was heated at 25 ° C. using an Ubbelohde (1B type) viscometer. The solution viscosity is measured, and the intrinsic viscosity (η: dl / g) is calculated by the following equation (1) η = (lnt / to) / C (1) (where t is the falling time of the polymer solution [ s], t
o is the solvent drop time [s], C is the solution concentration [g / dl]
).

3. Tensile strength and single knot tensile strength (kp
si) Using a tensile tester (manufactured by Orientec Co., Ltd., type; Tensilon RTA-100), use EUROPEAN PHARMACOPOEIA
According to the method specified in COMMISSION, chuck width 13
It is measured at 0 mm and a crosshead speed of 250 mm / min. In the single knot tensile strength, after forming a single knot on the filament, the filament is attached so that the knot is located at the center of the clamp, and this is used as a sample. The Young's modulus is calculated by the following equation from the gradient of the initial linear elastic region of the obtained stress-strain curve. The unit of the tensile strength and the Young's modulus obtained from the measurement is [kg / mm ² ], but indicates a value converted to [kpsi]. Young's modulus = (tan θ × L × C × S) / (H × A) In the above equation, θ: angle [degree] between the initial straight line of the stress-strain curve and the x-axis (strain axis), L: distance between chucks [Mm], C: chart speed [mm / min], S: y
Load (kg / mm) per axis (stress axis) scale,
H: Crosshead speed [mm / min], A: Initial cross-sectional area [mm ² ] of filament.

4. Retention rate of single knot tensile strength (%) Samples were placed in a physiological saline solution (solution prepared by dissolving 9.0 g of sodium chloride in distilled water to make a total volume of 1000 ml) at 37 ° C. , 28 days each, and the tensile strength is measured once by the method described in the preceding section, and the retention rate for the non-immersed sample is calculated.

5. Melting point of catalyst (° C.) 6.8 to 7.0 mg of a sample is weighed and packaged in an aluminum pan, and allowed to stand in a freezer at −5 ° C. for one day. DSC (RIG
The initial temperature of AKU Co., Ltd., model: DSC-8230) is set to -67 ° C, a sample is put in, and measurement is started. The temperature is measured from -67 to 100 ° C at a rate of 5 ° C / min.
The temperature at which the top of the melting peak appears is defined as the melting point. Note that Al ₂ O ₃ is used as a standard substance.

Preparation Example 1 <Distillation and Purification of Stannous Dioctanoate> A 100 equipped with a thermometer sack and a nitrogen-introduced capillary.
109 g of commercially available stannous dioctanoate (manufactured by Nippon Kagaku Sangyo Co., Ltd., trade name: Nikkaoctic tin 28%) was placed in a ml four-necked flask, and distillation was performed by simple distillation under reduced pressure. The degree of pressure reduction was 0.25 to 0.3 mmHg. The top temperature, the amount of distillate and its weight% are as follows. First fraction: 93-95 ° C., 9.5 g, 8.7% by weight, second
Distillate: 180-200 ° C, 88.2 g, 80.9% by weight, kettle residue: 7.0 g, 6.4% by weight. 0 ° C for the second fraction
Yielded white crystals. Further, as a result of measuring the melting point by the above method, the melting point was -3 ° C. Hereinafter, the second fraction is referred to as a purification catalyst.

EXAMPLE 1 298.2 g (2.921 mol) of p-dioxanone (hereinafter referred to as PDO) having a water content of 27.7 ppm after distillation was cut into a 300 ml reaction flask so as to prevent water from further entering the reaction flask. Under a nitrogen atmosphere, and purified catalyst 0.004 mol% (0.21 ml of a solution obtained by adding 0.6 g of purified catalyst to 2 ml of toluene for high performance liquid chromatography (manufactured by Wako Pure Chemical Industries, Ltd.)) and lauryl alcohol 0.068 Mol% (considering the number of moles of water, equivalent to M / I = 1200)
Was added. Reaction flask with stirrer (stirrer: EYEL
A, type: MAZELA Z-1310, maximum stirring load: 10 kgf · cm) at room temperature at 60 rpm
, And left for 60 minutes at a pressure of 1 mmHg or less. Then, after raising the temperature from room temperature to 60 ° C. under reduced pressure,
The vacuum was released. In a nitrogen atmosphere, while stirring at the same rotation speed, the temperature was further raised to 95 ° C., and the rotation speed of the stirring was 5
The polymerization was started by switching to rpm. Internal temperature from room temperature to 9
It took 2 hours to raise to 5 ° C. At this time, the load value at the initial stage of stirring of the recorder (model YR100, manufactured by Yokogawa Electric Corporation) was 0.1.
006 V (equivalent to 10 kgf · cm at 5 V). The upper limit of the load due to viscosity was set to 0.008 V (33% increase from the initial load), and the control was performed so that stirring was stopped when a load exceeding this value was generated. Further, a temperature controller (manufactured by Rikagaku Kogyo Co., Ltd., type: REX-P100)
The polymerization temperature was controlled by automatic control in which switching control was performed so as to replace the next set pattern when a stirring stop signal was generated. 9
The time when the temperature reached 5 ° C. was defined as the start of polymerization, and the stirring was stopped 4 hours after the start of polymerization. With stirring stopped,
Furthermore, solid-state polymerization was performed at 80 ° C. for 6 days to complete the polymerization.

Thereafter, poly (p-dioxanone) was taken out of the reactor by quenching with liquid nitrogen and freeze-ground with a Morita-type mill (JC-2 type). It was dried at room temperature for 12 hours with a vacuum dryer to obtain 290 g of a pulverized product. Further, the demonomer operation was performed by the following method. 40 crushed products
In a 0 ml column, the column was heated and maintained at a temperature of 63 ° C. under a reduced pressure of 8 mmHg.
The demonomer operation was carried out at a flow rate of 00 ml / min for 36 hours. The content of unreacted monomer after the demonomerization is 0.1%.
It was less than 1% by weight. The intrinsic viscosity (η) of the obtained poly (p-dioxanone) was 2.31 [dl / g]. The amount of the obtained poly (p-dioxanone) is 280 g.
Met. The amount of polymer loss at the time of adhesion to the kettle, pulverization and post-treatment was 12.3 g, and the conversion to polymer was 98% by weight. The melting point of the polymer was 115 ° C.

Example 2 Charges of PDO, LAOH and purification catalyst, and PD
The same operation as in Example 1 was performed, except that the water content of O was changed as described in Table 1 (Table 1), to obtain poly (p-dioxanone). Reproducibility was confirmed.

Example 3 Charges of PDO, LAOH and purification catalyst, and PD
O was replaced with the one described in Table 1 (Table 1), and the dye [D & C Violet No. 2 (CASN
o81-48-1)] with respect to PDO in an amount of 0.13% by weight.
Except for the addition, the same operation as in Example 1 was performed to obtain poly (p-dioxanone).

Examples 4 to 6 Charges of PDO, LAOH and purified catalyst, and PD
The same operation as in Example 3 was carried out except that the water content of O was changed as shown in Table 1 (Table 1), to obtain poly (p-dioxanone).

Comparative Example 1 A commercially available stannous dioctanoate (manufactured by Nippon Chemical Industry Co., Ltd., trade name: Nikkaoctin tin 28%, hereinafter referred to as unpurified catalyst) was used, and the amount of PDO and LAOH charged was determined. And PDO
Of Example 1 was carried out except that the water content was changed as shown in Table 2 (Table 2) to obtain poly (p-dioxanone).

Comparative Example 2 Using an unpurified catalyst, the charged amounts of PDO and LAOH and the water content of PDO were changed as shown in Table 2 (Table 2), and stirring was carried out for 12 hours from the start of polymerization. Continuously, the same operation as in Example 1 was performed except that stirring was stopped (increase rate of stirring load: 3300%) to lower the polymerization temperature, to obtain poly (p-dioxanone).

Comparative Example 3 Charges of PDO, LAOH and Purified Catalyst, and PD
The water content of O was changed as described in Table 2 (Table 2), and the polymerization temperature and the stirring load were controlled (increase rate of the stirring load:
Poly (p-dioxanone) was obtained by performing the same operation as in Example 1 except that Comparative Example 2 was performed (3500%).

Comparative Example 4 PDO, LAOH, purification catalyst, and dye D & C Vio
let No. 2 (CAS No. 81-48-1) and the water content of PDO were changed as described in Table 2 (Table 2), and the polymerization temperature and stirring load were controlled (increase rate of stirring load: 2300). %) Was carried out in the same manner as in Comparative Example 2 to obtain poly (p-dioxanone). Table 1 (Table 1) shows the results of Examples 1 to 6, and Table 2 (Table 2) shows the results of Comparative Examples 1 to 4.

[0050]

[Table 1]

[0051]

[Table 2]

Example 7 The poly (p-dioxanone) obtained in Example 1 was spun at an extrusion temperature of 155 ° C. to produce a monofilament undrawn yarn. The extruder had a nozzle diameter of 1.0 mm. The obtained undrawn yarn is drawn at a drawing temperature of 90 ° C to a draw ratio of 4.0 times, and further at 110 ° C at a draw ratio of 1.5 times.
It was stretched twice. Further, the obtained drawn yarn is heated at 110 ° C. for 90 minutes.
After the% relaxation, heat treatment was performed at 90 ° C. for 6 hours.
The linear tensile strength, single knot tensile strength, elongation, and Young's modulus of the stretched monofilament after the heat treatment were measured, and Table 3 (Table 3,
4).

Examples 8 to 9 and Comparative Examples 5 to 8 The same spinning, stretching, relaxation, and the same procedures as in Example 1 were carried out except that the poly (p-dioxanone) described in Table 3 (Tables 3 and 4) was used. A heat treatment operation was performed. The results obtained are shown in Table 3 (Tables 3 and 4).

Comparative Examples 9 to 10 A commercially available suture, PDSII (trade name, manufactured by Ethicon Co., Ltd.)
Dye-containing product) was evaluated for physical properties in the same manner as in Example 1. The obtained results are shown in Table-3 (Tables 3 and 4).

Comparative Example 11 A commercially available suture, PDSII (trade name, manufactured by Ethicon Co., Ltd.)
(Clear product containing no dye) was evaluated for physical properties in the same manner as in Example 1. The obtained results are shown in Table-3 (Tables 3 and 4).

[0056]

[Table 3]

[0057]

[Table 4]

Comparison between Example 9 and Comparative Example 9 shows that the filaments of Example 9 have improved hydrolysis resistance even though the intrinsic viscosities of the filaments are almost the same, that is, the molecular weight of the polymer hardly changes. You can see that there is. In addition, comparing Examples 7 and 8 with Comparative Example 11, the filaments of Examples 7 and 8 show that the intrinsic viscosity of the filaments is almost the same. It can be seen that it has improved.

[0059]

The monofilament produced by spinning and drawing using the poly (p-dioxanone) obtained by the production method according to the present invention is more hydrolyzed than the existing poly (p-dioxanone) monofilament. It is an excellent suture for wound repair surgery with a slow and long healing period.
Therefore, poly (p-dioxanone) obtained by the production method of the present invention is a very useful material as a bioabsorbable surgical suture in the form of a monofilament.

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Claims (14)

[Claims] A process for producing poly (p-dioxanone) by ring-opening polymerization of p-dioxanone in the presence of a catalyst and an initiator. 1 tin 0.002-0.0
After adding 0.05 mol% and an initiator of 0.01 to 0.1 mol%, the liquid-phase ring-opening polymerization of p-dioxanone was started at 85 to 105 ° C with stirring, and the stirring load was 1% of the initial load.
A method for producing poly (p-dioxanone), wherein stirring is stopped at the point of time when the increase is from 0 to 100%, and the polymerization temperature is lowered to 65 to 85 ° C to carry out solid phase polymerization. 2. The method for producing poly (p-dioxanone) according to claim 1, wherein p-dioxanone having a water content of 150 ppm or less is used. 3. The method for producing poly (p-dioxanone) according to claim 1, wherein the melting point of stannous dioctanoate is -3 ° C. or higher. 4. Stannous dioctanoate is a commercially available product obtained by distillation and purification, 0.25 to 0.3 mmHg, tower temperature 180 to 180.degree.
The method for producing poly (p-dioxanone) according to claim 1, wherein the distillate is a distillate under the condition of 200 ° C. 5. The stirring is stopped when the stirring load increases by 20 to 80% with respect to the initial load.
A method for producing the described poly (p-dioxanone). 6. After completion of the solid phase polymerization, unreacted p-dioxanone is removed by passing an inert gas at a temperature of 60 to 80 ° C. and a pressure of 10 mmHg or less, and the content is reduced to 0.5% by weight.
The method for producing poly (p-dioxanone) according to claim 1, wherein the control is performed as follows. 7. The conversion to poly (p-dioxanone) is 9
2. The method for producing poly (p-dioxanone) according to claim 1, wherein the polymerization reaction is continued until the amount reaches 5% by weight or more. 8. The poly (p-dioxanone) having an intrinsic viscosity of 2
The method for producing poly (p-dioxanone) according to claim 1, wherein the viscosity is 1.8 to 2.5 dl / g at 5 ° C. 9. A method for producing a poly (p-dioxanone) monofilament, comprising producing the poly (p-dioxanone) by the method according to any one of claims 1 to 8,
Next, (1) a spinning step of melt-spinning the obtained poly (p-dioxanone) at 125 to 165 ° C,
(2) a stretching step of stretching at a stretching ratio of 3 to 8 at 60 to 110 ° C;
A method for producing a poly (p-dioxanone) monofilament, comprising: a step of relaxing by 90%; and (4) a step of performing a heat treatment at 80 to 100 ° C. for 1 to 24 hours. 10. The drawn monofilament has a diameter of 4 to 40.
10. The poly (p-) according to claim 9, which is a mill.
Dioxanone) monofilament production method. 11. A poly (p-dioxanone) monofilament obtained by the method of claim 9 having a single knot tensile strength of at least 30,000 psi (21.0 psi).
9 kg / mm ² ), after immersion in physiological saline at 37 ° C.
A poly (p-dioxanone) monofilament having a retention of the tensile strength after 58 weeks of 58% or more. 12. A poly (p-dioxanone) monofilament obtained by the method according to claim 10, wherein
The knot tensile strength is at least 30,000 psi (21.
A poly (p-dioxanone) monofilament having a tensile strength retention of 58% or more 4 weeks after immersion in a physiological saline solution at 37 ° C. at a rate of 09 kg / mm ² ). 13. The poly (p-dioxanone) monofilament according to claim 11, wherein the monofilament is a surgical suture. 14. The poly (p-dioxanone) monofilament according to claim 12, wherein the monofilament is a surgical suture.