JP2000159865A - Production of bioabsorbable polyester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a bioabsorbable polymer having a molecular weight deviating little from the target and being controllable within a narrow range by feeding the main starting material containing a cyclic ester compound, a catalyst, and an initiator into a reaction system, removing water from the system, and effecting the ring opening polymerization. SOLUTION: The main starting material containing a cyclic ester compound, 0.001-0.05 wt.%, based on the cyclic ester compound, catalyst, and 0.01-10 wt.%, on the same basis, initiator is fed into a reaction system, and the reaction system is deaerated for 30 min to 1 h at a reaction system temperature controlled at 10-70 deg.C so that the moisture content in the system may be controlled to 0.10-0.20 wt.% based on the entire weight of the fed cyclic ester compound. Next, the reaction mixture is subjected to ring opening polymerization at 180-240 deg.C for 2-24 h to obtain a bioabsorbable polyester having a weight-average molecular weight of 5,000-100,000, desirably, 5,000-20,000 and an intrinsic viscosity having a value of 0.1-1.0 dl/g, desirably, 0.1-0.5 dl/g and controlled in a narrow range of y±0.005 (wherein y is the target intrinsic viscosity).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a bioabsorbable polyester. More specifically, the present invention relates to a method for producing a bioabsorbable polyester whose molecular weight is controlled within a target range and which is suitable for a medical field such as a carrier of a sustained-release drug and a molding material.

[0002]

2. Description of the Related Art Polyhydroxycarboxylic acids such as polyglycolic acid, polylactic acid, polycaprolactone, polydioxanone, poly (trimethylene carbonate), and copolymers thereof are metabolized and excreted by hydrolysis or enzymatic degradation in vivo. Therefore, it is attracting attention as a bioabsorbable polyester. Various methods are known for synthesizing a cyclic ester compound as a raw material of these polyesters, and generally, a method of dehydrating and ring-closing a hydroxycarboxylic acid corresponding to a target cyclic ester compound is used. I have. Among them, polylactic acid, polyglycolic acid, or lactic acid-glycolic acid copolymer produced by ring-opening polymerization of lactide, glycolide or a mixture thereof is used in the medical field such as a base for a sustained-release drug and a molding material. Used for

[0003] When used in the medical field, it is required to design a polyester material which is properly controlled in strength and degradability. The factors involved in the strength and degradability considered in designing the polyester include the type and ratio of the cyclic ester compound used, the type and content of the catalyst used, the type of the initiator used and The content thereof, the composition and molecular weight of the polyester obtained by polymerization, the content of the cyclic ester compound present in the polyester, the chain (randomness / blocking property) of the cyclic ester compound in the polyester, and the like are listed.

In any case, a material having strength and decomposability in accordance with the intended use is desired. The strength is maintained at a certain level for a predetermined period of time and then decomposes quickly. Techniques for producing polyesters with controlled molecular weight or intrinsic viscosity are required.

[0005] US Pat. No. 5,041,529 discloses that in the presence of stannous chloride as a catalyst and an alcohol having no reactive group other than an alcoholic hydroxyl group as an initiator,
A method for producing polyglycolic acid by polymerizing glycolide is disclosed. This method is characterized by adjusting the viscosity of the resulting polyester, that is, the molecular weight, by adjusting the amount of the initiator. However, the adjustment method is such that if a large amount of the initiator is used, a polyester having a low molecular weight is obtained, and if a small amount of the initiator is used, a polyester having a high molecular weight is obtained, and the desired molecular weight range cannot be strictly controlled. .

Japanese Patent Application Laid-Open No. 60-144325 discloses a polyglycolic acid prepared from glycolide having a melting point of 81 ° C. or higher and an APHA value of 150 ° C. or lower of a solution heated and melted at 200 ° C. for 3 minutes. A manufacturing method is described. Japanese Patent Application Laid-Open No. 1-146924 discloses a method for producing polylactic acid by polymerizing lactide having a free acid content of 1 meq / kg or less. However, the melting point is 81 ° C. or more and the APHA value is 1
Glycolide of 50 or less, or 1 meq / kg
The lactides having the following free acid contents were each subjected to ring-opening polymerization, and production of polyglycolic acid or polylactic acid was attempted. However, in any of the above methods, the molecular weight of the obtained polyester still varied, and it was desired. The molecular weight range could not be tightly controlled.

[0007] JP-A-07-233246 discloses a method for producing a polyester by adding a hydroxyl group compound to a reaction system and subjecting the cyclic ester compound to ring-opening polymerization to produce a polyester having an amount of free carboxylic acid contained in the cyclic ester compound. Describes a method for producing a polyester, characterized in that the amount of a hydroxyl group compound to be added to a reaction system is determined on the basis of the above formula. In this method, the molecular weight is controlled by adjusting the amount of the hydroxyl compound added to the reaction system according to the amount of the free carboxylic acid contained in the cyclic ester compound. As a result of studying details by the present inventors, a cyclic ester compound,
The catalyst and the solvent used to dissolve the catalyst are initially added, and after the desolvation and dehydration operations are performed, the hydroxyl compound to be adjusted is added, so that the water present in the hydroxyl compound is brought into the reaction system as it is. In addition, since a variation in the amount of water in the reaction system occurs, if more strict control of the molecular weight is required, a problem may be caused, and it cannot be said that the method is necessarily satisfactory.

When the bioabsorbable polyester is used as a base material of a sustained-release drug, for example, if the purpose is to use the bioabsorbable polyester for a short period of time such as one week to one month, the intrinsic viscosity (η value)
However, since the sustained release characteristics change due to the difference in molecular weight within a small range such as 0.10, 0.12, 0.14, and 0.16, for example, 0.10 and 0.11, or 0.20 and 0 A polyester production technique in which the intrinsic viscosity (η value) such as 0.21 is strictly controlled in a narrow range is required.

[0009]

SUMMARY OF THE INVENTION In view of the above problems, it is an object of the present invention to provide a base material for a sustained-release drug having a small deviation from a target value and a controlled molecular weight (intrinsic viscosity) in a narrow range. It is an object of the present invention to provide a method for producing a bioabsorbable polyester suitable as a medical material such as the above.

[0010]

In view of the above situation, the present inventors have conducted intensive studies on a production technique for controlling the intrinsic viscosity (η value) strictly and within a narrow range. Was charged into the reaction system, and after controlling the amount of water in the reaction system to a specific range by performing a dehydration operation, it was found that the above problem could be solved by initiating ring-opening polymerization of the cyclic ester compound. Was completed.

That is, the present invention relates to a method for producing a bioabsorbable polyester by ring-opening polymerization of a cyclic ester compound, wherein a main raw material containing a cyclic ester compound, a catalyst and an initiator is charged into a reaction system, and dehydration is carried out. By performing the operation, the amount of water in the reaction system is 0.10 to the total amount of the cyclic ester compound.
A method for producing a bioabsorbable polyester, comprising starting ring-opening polymerization after controlling the amount to be in the range of 0.20% by weight. As a preferred embodiment of the present invention, there is a method in which the dehydration operation is performed at a temperature of 10 to 70 ° C. and a pressure of 5 to 20 mmHg for 30 minutes to 1 hour.

The bioabsorbable polyester produced according to the present invention has an intrinsic viscosity, which is an index of molecular weight, having a target value (η).
In contrast, the molecular weight is controlled within the range of η ± 0.005, and the deviation from the target value is extremely small. Therefore, the present invention is extremely useful as a method for producing a bioabsorbable polyester used in the medical field such as a base material for a sustained release drug and a molding material.

The intrinsic viscosity of the bioabsorbable polyester and the water content of the reaction system in the present invention are values measured by the methods described in Examples described later.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. The present invention relates to a method for adding a material such as a cyclic ester compound, a catalyst and an initiator to a reaction system, and then performing a dehydration operation to control the water content in the reaction system to a specific range. How to get started.

Examples of the cyclic ester compound to which the present invention is directed include glycolide, lactide (D-form, L-form,
DL-form, meso-form), ε-caprolactone, p-dioxanone, trimethylene carbonate and the like.
Among these cyclic ester compounds, glycolide and lactide are preferred. Glycolide and lactide are cyclic dimers of the hydroxycarboxylic acids prepared by dehydrating polycondensation of glycolic acid or lactic acid, followed by thermal decomposition. Lactide includes D-lactide which is a cyclic dimer of D-lactic acid, L-lactide which is a cyclic dimer of L-lactic acid, cyclic dimerized meso-lactide of D-lactic acid and L-lactic acid, and D-lactide. And DL-lactide, which is a racemic mixture of L-lactide and L-lactide. In the present invention, any of these lactides can be used as a raw material.

The bioabsorbable polyester produced by ring-opening polymerization of the above cyclic ester compound includes poly (lactide), poly (glycolide), poly (caprolactone), poly (trimethylene carbonate), poly (dioxanone) and the like. And copolymers of poly (lactide-co-caprolactone), poly (glycolide-co-caprolactone), poly (lactide-co-caprolactone), and the like. In addition, a copolymer of each of the above-mentioned cyclic ester compounds may also be used. When the bioabsorbable polyester is poly (lactide-co-glycolide),
The composition ratio is preferably 55 to 100% by weight of lactide and 45 to 0% by weight of glycolide. In the case of poly (glycolide-co-caprolactone), the composition ratio is 1 to 99% by weight of glycolide and 99% by weight of caprolactone.
To 1% by weight. Further, in the case of poly (lactide-co-caprolactone), the composition ratio of lactide is 1 to 99% by weight and caprolactone is 99 to 1% by weight. In addition, a combination of other cyclic ester compounds is also possible. For example, in the case of a two-component system, one component has a composition ratio of 1 to 99% by weight, and the other component has a composition ratio of 99 to 1% by weight. .

In the present invention, the catalyst used for the polymerization of the bioabsorbable polyester includes tin dichloride, tin tetrachloride, stannous fluoride, stannous acetate, stannous stearate, stannous octoate. , Stannous oxide, stannic oxide and other tin salts. Further, antimony trifluoride, lead oxide, lead stearate, titanium tetrachloride, boron trifluoride, diethylaluminum chloride, triethylamine, tributylamine and the like can be mentioned. Among these, FDA is preferred as a non-toxic stabilizer.
(US Food and Drug Administration) approved stannous octoate. The amount of these catalysts used is in the range of 0.001 to 0.05% by weight based on the total amount of the cyclic ester compound. If the amount is less than 0.001% by weight, the polymerization reaction is slow, and it is difficult to increase the degree of polymerization until the target molecular weight is reached.
If it exceeds 0.05% by weight, the polymerization proceeds rapidly, and the heat generated by the polymerization raises the reaction temperature, making it difficult to control the temperature. If the temperature rises sharply, the molecular weight may decrease due to depolymerization of the polyester, making it difficult to obtain a polyester having a desired molecular weight.

The initiator used in the present invention is used for controlling the molecular weight. Examples of the type include methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, amyl alcohol, octyl alcohol, lauryl alcohol, stearyl alcohol and the like. Aliphatic alcohols, phenol, benzoic acid, acetaminophen, methyl salicylate, aromatic alcohols such as benzyl alcohol, ethylene glycol, propylene glycol 1,4-butanediol, diethylene glycol, glycerin, pentaerythritol, sorbitol, etc. Polyhydric alcohols, and further, hydroxycarboxylic acids such as lactic acid and glycolic acid can be mentioned. The amount of these initiators used is 0.01 to
It is in the range of 10% by weight. The amount of initiator used is selected according to the target molecular weight (intrinsic viscosity). If it is less than 0.01% by weight, the molecular weight of the polyester becomes too high, the melt viscosity becomes high, and it becomes difficult to mold the molding material or the sustained-release drug as a base material. On the other hand, if it exceeds 10% by weight, the molecular weight of the polyester does not increase, and it does not have a sufficient sustained release function as a molding material or a base material for a sustained release drug.

In the method for producing a bioabsorbable polyester according to the present invention, after the above-mentioned raw materials are charged into a polymerization reaction system, a dehydration operation is performed to reduce the amount of water in the reaction system, and then ring-opening polymerization is carried out. It is characteristic to start. The dehydration operation is performed so that the water content in the reaction system is in the range of 0.10 to 0.20% by weight based on the total amount of the charged cyclic ester compound. As a preferable method for controlling the water content in the reaction system to the above range, a method of performing depressurization and deaeration at a pressure of 5 to 20 mmHg for 30 minutes to 1 hour while adjusting the temperature of the reaction system to 10 to 70 ° C. .

If the temperature of the dehydration operation is lower than 10 ° C., it takes too long to remove water. When the temperature exceeds 70 ° C., linear oligomers are generated by the reaction between the cyclic ester compound and water, and the molecular weight varies. In addition, the dehydration operation is 30
If it is less than minutes, it is difficult to remove water to a target value. Temperature and pressure conditions exceeding one hour are not industrial. Further, the lower the pressure of the dehydrating operation, the more the water can be removed in a short time. However, the above range is preferable in consideration of the energy consumption, the capacity of the pressure reducing device, and the like. Further, the total amount of water accompanying the cyclic ester compound, the catalyst, the initiator, and the like present in the reaction system, with respect to the total amount of the cyclic ester compound,
If the amount is less than 0.10% by weight, the influence of the amount of the initiator is greatly involved, and it is difficult to control the molecular weight within a desired range. If the amount exceeds 0.20% by weight, the influence of the amount of water in the reaction system is greatly involved, and the molecular weight of the obtained polyester varies more than the control range, which is not preferable.

After controlling the water content in the reaction system to the above range,
The temperature of the reaction system is raised to initiate ring-opening polymerization of the cyclic ester compound. When starting ring-opening polymerization, 140
℃, 180 ℃ stepwise, finally 180 ~ 24
The polymerization reaction is performed at 0 ° C. for 2 to 24 hours.

The weight average molecular weight of the bioabsorbable polyester produced according to the present invention is from 5,000 to 100,000.
0, preferably 5,000 to 20,000
It is. When the weight-average molecular weight is in the above range, when used as a molding material or a base for a sustained-release drug, it has appropriate mechanical strength and biodegradability, and functions as a base for a sustained-release drug. Fully demonstrate. When the molecular weight is expressed by intrinsic viscosity, it is in the range of 0.1 to 1.0 dl / g, and preferably in the range of 0.1 to 0.5 dl / g.
In the present invention, when controlling the molecular weight (intrinsic viscosity) of the bioabsorbable polyester, first, a target molecular weight (intrinsic viscosity) is determined from the above range, and the amount of the initiator to be used is adjusted from the above range. After selection and then controlling the amount of water in the reaction system by the above method, ring-opening polymerization is started. By producing a bioabsorbable polyester according to this method, the target intrinsic viscosity (η) is
A bioabsorbable polyester controlled to a narrow range of η ± 0.005 can be produced.

[0023]

The present invention will be described below in further detail with reference to examples. In addition, the intrinsic viscosity of the bioabsorbable polyester shown in the Example and the water content in the reaction system were measured by the following methods. (1) Intrinsic viscosity (dl / g) Polyester is dissolved in chloroform and the concentration is 0.5 g.
/ Dl after preparing a chloroform solution of 25 ± 0.0
At 5 ° C., the falling time of the solvent and the solution is measured using an Ubbelohde viscometer, and the intrinsic viscosity (η) is calculated from the following equation. η = [ln (T / T _o )] / C where T: falling time of solution (seconds), T _o : falling time of solvent chloroform (seconds), C: solution concentration (g / dl). (2) Moisture in the reaction system (% by weight) It is measured according to the Karl Fischer titration method (b) coulometric titration method specified in JIS K-0068. As a solvent, 2-methoxyethanol was used instead of methanol. As the apparatus, a Hiranuma trace moisture measuring apparatus, type: AQ-6 was used. When the reaction solution was used as a sample, 2 ml was collected from the reactor using a syringe. In the case of a cyclic ester, 2 g of a solid was used as a sample.

Example 1 A target intrinsic viscosity was set to 0.100 (control range 0.100).
± 0.005), and the DL-
Lactide (hereinafter abbreviated as LTD) 1160.0 g (water content 50 ppm), glycolide (hereinafter abbreviated as GLD) 84
0.0 g (water content: 60 ppm), and the catalyst was added in an amount of 0.4% by weight to the total amount of the cyclic ester compound.
g / 10 g of tin octoate / toluene (water content 100
ppm) solution and 80.0 g of a 90% by weight aqueous DL-lactic acid solution (8.0 g of water content) so that the initiator is 4.0% by weight based on the total amount of the cyclic ester compound.
After the charging, desolvation and dehydration operations were performed at an internal temperature of 20 ° C. and 6 mmHg for 60 minutes. The amount of detoluene obtained at this time was 5.2 g, and the amount of dehydration was 5.1 g. Thereafter, when the water content of the reaction system at the time when the cyclic ester compound was dissolved was measured at 140 ° C. under a nitrogen stream, 0.150% by weight based on the total amount of the cyclic ester compound (water content 3.
0 g). Furthermore, the temperature was raised to 180 ° C and 215 ° C,
Polymerization was performed at 215 ° C. for 2 hours. The intrinsic viscosity of the obtained polyester was η = 0.102, which was within the control range.

Example 2 The target intrinsic viscosity was set to 0.100 (control range 0.100).
± 0.005) and LTD in a 5L stainless steel reactor.
1160.0 g (water content: 50 ppm), GLD840.
0 g (water content 60 ppm), 0.4 g / 10 g tin octoate / toluene (water content 100 ppm) solution.
2 g, initiator based on the total amount of cyclic ester compound
After loading 80.0 g (water content: 8.0 g) of a 90 wt% aqueous solution of DL-lactic acid so as to be 0 wt%, a desolvation / dehydration operation was performed for 60 minutes at an internal temperature of 20 ° C. and 15 mmHg. went. The amount of detoluene obtained at this time was 5.2 g,
The amount of dehydration was 4.1 g. Then, under nitrogen stream, 14
When the water content of the cyclic ester compound at the time of dissolution was measured at 0 ° C., it was 0.200% by weight (water content 4.0 g) based on the total amount of the cyclic ester compound. Further, at 180 ° C., 21
The temperature was raised to 5 ° C, and polymerization was performed at 215 ° C for 2 hours. The intrinsic viscosity of the obtained polyester was η = 0.096, which was within the control range.

Comparative Example 1 The target intrinsic viscosity was set to 0.100 (control range 0.100).
± 0.005) and LTD in a 5L stainless steel reactor.
1160.0 g (water content: 50 ppm), GLD840.
0 g (water content 60 ppm), 0.4 g / 10 g tin octoate / toluene (water content 100 ppm) solution.
2 g, 80.0 g of a 90 wt% DL-lactic acid aqueous solution (water content: 8.0 g) was charged, and then the internal temperature was 20 ° C. and 3 mmHg.
For 60 minutes. The amount of detoluene obtained at this time was 5.2 g, and the amount of dehydration was 7.8 g. Thereafter, the water content of the reaction system when the cyclic ester compound was dissolved at 140 ° C. under a nitrogen stream was 0.015% by weight (0.3 g water content) based on the total amount of the cyclic ester compound. Further, at 180 ° C, 2
The temperature was raised to 15 ° C, and polymerization was performed at 215 ° C for 2 hours. The intrinsic viscosity of the obtained polyester was η = 0.111, which was out of the control range.

Comparative Example 2 The target intrinsic viscosity was set to 0.100 (control range 0.100).
± 0.005) and LTD in a 5L stainless steel reactor.
1160.0 g (water content: 50 ppm), GLD840.
0 g (water content 60 ppm), 0.4 g / 10 g tin octoate / toluene (water content 100 ppm) solution.
2 g, 80.0 g of a 90 wt% DL-lactic acid aqueous solution (water content: 8.0 g) was charged, and then the internal temperature was 20 ° C. and 25 mmH.
g, a solvent removal / dehydration operation was performed for 60 minutes. The amount of detoluene obtained at this time was 5.2 g, and the amount of dehydration was 1.9 g.
Met. Thereafter, the water content of the reaction system at the time when the cyclic ester compound was dissolved at 140 ° C. under a nitrogen stream was measured to be 0.310 with respect to the total amount of the cyclic ester compound.
% By weight (water content: 6.2 g). In addition, 180 ° C,
The temperature was raised to 215 ° C, and polymerization was performed at 215 ° C for 2 hours.
The intrinsic viscosity of the obtained polyester was η = 0.090, which was out of the control range.

Example 3 The target intrinsic viscosity was set to 0.100 (control range 0.100).
± 0.005) and LTD in a 5L stainless steel reactor.
1160.0 g (water content: 50 ppm), GLD840.
0 g (water content 60 ppm), 0.4 g / 10 g tin octoate / toluene (water content 100 ppm) solution.
2 g, 80.0 g of a 90% by weight aqueous solution of DL-lactic acid (water content: 8.0 g) was charged, and then the internal temperature was 20 ° C. and 6 mmHg.
For 30 minutes. At this time, the amount of detoluene obtained was 5.2 g, and the amount of dehydration was 4.2 g. Thereafter, the water content of the reaction system when the cyclic ester compound was dissolved at 140 ° C. in a nitrogen stream was 0.195% by weight (water content: 3.9 g) with respect to the total amount of the cyclic ester compound. Further, at 180 ° C, 2
The temperature was raised to 15 ° C, and polymerization was performed at 215 ° C for 2 hours. The intrinsic viscosity of the obtained polyester was η = 0.098, which was within the control range.

Comparative Example 3 The target intrinsic viscosity was set to 0.100 (control range 0.100).
± 0.005) and LTD in a 5L stainless steel reactor.
1160.0 g (water content: 50 ppm), GLD840.
0 g (water content 60 ppm), 0.4 g / 10 g tin octoate / toluene (water content 100 ppm) solution.
2 g, 80.0 g of a 90% by weight aqueous solution of DL-lactic acid (water content: 8.0 g) was charged, and then the internal temperature was 20 ° C. and 6 mmHg.
For 10 minutes. The amount of toluene removed at this time was 5.2 g, and the amount of dehydration was 2.0 g. Thereafter, the water content of the reaction system when the cyclic ester compound was dissolved at 140 ° C. under a nitrogen stream was 0.305% by weight (water content 6.1 g) with respect to the total amount of the cyclic ester compound. Further, at 180 ° C, 2
The temperature was raised to 15 ° C, and polymerization was performed at 215 ° C for 2 hours. The intrinsic viscosity of the obtained polyester was η = 0.092, which was out of the control range.

Comparative Example 4 The target intrinsic viscosity was set to 0.100 (control range 0.100).
± 0.005) and LTD in a 5L stainless steel reactor.
1160.0 g (water content: 50 ppm), GLD840.
0 g (water content 60 ppm), 0.4 g / 10 g tin octoate / toluene (water content 100 ppm) solution.
After charging 2 g of a 90 wt% DL-lactic acid aqueous solution (80.0 g, water content: 8.0 g), an internal temperature of 20 ° C. and 6 mmH
g, a solvent removal / dehydration operation was performed for 120 minutes. The amount of toluene removed at this time was 5.2 g, and the amount of dehydration was 7.9.
g. Thereafter, when the water content of the reaction system at the time when the cyclic ester compound was dissolved at 140 ° C. under a nitrogen stream was measured, it was 0.01 to the total amount of the cyclic ester compound.
It was 0% by weight (water content: 0.2 g). In addition, 180
The temperature was raised to 215 ° C, and polymerization was performed at 215 ° C for 2 hours. The intrinsic viscosity of the obtained polyester is η = 0.11.
2, which is outside the control range.

Example 4 The target intrinsic viscosity was set to 0.100 (control range 0.100).
± 0.005) and LTD in a 5L stainless steel reactor.
1160.0 g (water content: 50 ppm), GLD840.
0 g (water content 60 ppm), 0.4 g / 10 g tin octoate / toluene (water content 100 ppm) solution.
2 g, 80.0 g of a 90% by weight aqueous solution of DL-lactic acid (water content: 8.0 g) was charged, and then an internal temperature of 40 ° C. and 6 mmH
g, a solvent removal / dehydration operation was performed for 60 minutes. The amount of toluene removed at this time was 5.2 g, and the amount of dehydration was 6.1 g.
Met. Thereafter, the water content of the reaction system at the time when the cyclic ester compound was dissolved at 140 ° C. under a nitrogen stream was measured to be 0.100 with respect to the total amount of the cyclic ester compound.
% By weight (water content: 2.0 g). In addition, 180 ° C,
The temperature was raised to 215 ° C, and polymerization was performed at 215 ° C for 2 hours.
The intrinsic viscosity of the obtained polyester was η = 0.104, which was within the control range.

Comparative Example 5 The target intrinsic viscosity was set to 0.100 (control range 0.100).
± 0.005) and LTD in a 5L stainless steel reactor.
1160.0 g (water content: 50 ppm), GLD840.
0 g (water content 60 ppm), 0.4 g / 10 g tin octoate / toluene (water content 100 ppm) solution.
2 g, 80.0 g of a 90 wt% DL-lactic acid aqueous solution (water content: 8.0 g) was charged, and then the internal temperature was 80 ° C. and 6 mmHg.
For 60 minutes. The amount of toluene removed at this time was 5.2 g, and the amount of dehydration was 7.6 g. Thereafter, the water content of the reaction system at the time when the cyclic ester compound was dissolved at 140 ° C. under a nitrogen stream was 0.025% by weight (water content 0.5 g) with respect to the total amount of the cyclic ester compound. Further, at 180 ° C, 2
The temperature was raised to 15 ° C, and polymerization was performed at 215 ° C for 2 hours. The intrinsic viscosity of the obtained polyester was η = 0.108, which was out of the control range.

Example 5 A target intrinsic viscosity was set to 0.250 (control range: 0.250
± 0.005) and LTD in a 5L stainless steel reactor.
1560.0 g (water content: 50 ppm), GLD440.
0 g (water content 60 ppm), 0.4 g / 10 g tin octoate / toluene (water content 100 ppm) solution.
After charging 2 g, 50.0 g of 90% by weight DL-lactic acid aqueous solution (water content: 5.0 g), the internal temperature is 20 ° C., 6 mmHg.
For 60 minutes. The amount of toluene removed at this time was 5.2 g, and the amount of dehydration was 3.0 g. Thereafter, the water content of the reaction system when the cyclic ester compound was dissolved at 140 ° C. under a nitrogen stream was 0.105% by weight (2.1 g water content) based on the total amount of the cyclic ester compound. Further, at 180 ° C, 2
The temperature was raised to 15 ° C, and polymerization was performed at 215 ° C for 2 hours. The intrinsic viscosity of the obtained polyester was η = 0.252, which was within the control range.

Example 6 The target intrinsic viscosity was set to 0.250 (control range η = 0.
250 ± 0.005) and 5L stainless steel reactor
LTD 1560.0 g (water content 50 ppm), GLD4
5.2 g of a 40.0 g (water content: 60 ppm), 0.4 g / 10 g tin octanoate / toluene (water content: 100 ppm) solution, 50.0 g of a 90 wt% DL-lactic acid aqueous solution
(Water content: 5.0 g), the internal temperature was 20 ° C,
The solvent removal / dehydration operation was performed at 5 mmHg for 60 minutes. At this time, the amount of detoluene obtained was 5.2 g, and the amount of dehydration was 2.6 g. Thereafter, the water content of the reaction system when the cyclic ester compound was dissolved at 140 ° C. in a nitrogen stream was 0.125% by weight (water content: 2.5 g) based on the total amount of the cyclic ester compound. Furthermore,
The temperature was raised to 180 ° C and 215 ° C, and polymerization was performed at 215 ° C for 2 hours. The intrinsic viscosity of the obtained polyester is η =
0.248, which was within the control range.

Comparative Example 6 The target intrinsic viscosity was set to 0.250 (control range 0.250).
± 0.005) and LTD in a 5L stainless steel reactor.
1560.0 g (water content: 50 ppm), GLD440.
0 g (water content 60 ppm), 0.4 g / 10 g tin octoate / toluene (water content 100 ppm) solution.
2 g, 50.0 g of a 90 wt% DL-lactic acid aqueous solution (water content: 5.0 g) was charged, and then the internal temperature was 20 ° C. and 3 mmHg.
For 60 minutes. At this time, the amount of detoluene obtained was 5.2 g, and the amount of dehydration was 4.6 g. Thereafter, the water content of the reaction system at the time when the cyclic ester compound was dissolved at 140 ° C. under a nitrogen stream was 0.025% by weight (water content 0.5 g) with respect to the total amount of the cyclic ester compound. Further, at 180 ° C, 2
The temperature was raised to 15 ° C, and polymerization was performed at 215 ° C for 2 hours. The intrinsic viscosity of the obtained polyester was η = 0.261, which was out of the control range.

Comparative Example 7 A target intrinsic viscosity was set to 0.250 (control range η = 0.2
50 ± 0.005), and the L
TD1560.0g (water content 50ppm), GLD44
5.2 g of a 0.0 g (water content of 60 ppm), 0.4 g / 10 g tin octanoate / toluene (water content of 100 ppm) solution, and 50.0 g of a 90 wt% aqueous solution of DL-lactic acid (containing 5.0 g of water content) After charging, internal temperature 20 ℃, 25m
The solvent removal / dehydration operation was performed at mHg for 60 minutes. The amount of detoluene obtained at this time was 5.2 g, and the amount of dehydration was 0.1 g.
2 g. Thereafter, when the water content of the reaction system at the time when the cyclic ester compound was dissolved at 140 ° C. under a nitrogen stream was measured, the water content was 0.2 to the total amount of the cyclic ester compound.
It was 45% by weight (water content: 4.9 g). In addition, 180
The temperature was raised to 215 ° C, and polymerization was performed at 215 ° C for 2 hours. The intrinsic viscosity of the obtained polyester is η = 0.24
2, which is outside the control range.

Example 7 The target intrinsic viscosity was set to 0.140 (control range η = 0.1
40 ± 0.005) and 5L stainless steel reactor
TD 2000.0 g (water content 50 ppm), 0.6 g /
10 g of tin octoate / toluene (water content 100 pp
m) 5.3 g of solution, 90% by weight DL-lactic acid aqueous solution 7
After charging 0.0 g (water content 7.0 g), the internal temperature 2
Desolvation and dehydration operations were performed at 0 ° C. and 6 mmHg for 60 minutes. The amount of detoluene obtained at this time was 5.3 g, and the amount of dehydration was 4.0 g. Then, under nitrogen stream, 140
When the water content of the reaction system at the time when the cyclic ester compound was dissolved was measured at 0 ° C., it was 0.155% by weight (water content: 3.1 g) based on the total amount of the cyclic ester compound. Further, the temperature was raised to 180 ° C. and 215 ° C., and polymerization was performed at 215 ° C. for 2 hours. The intrinsic viscosity of the obtained polyester is η
= 0.142, which was within the control range.

Example 8 The target intrinsic viscosity was set to 0.140 (control range: 0.140
± 0.005) and LTD in a 5L stainless steel reactor.
2000.0 g (water content 50 ppm), 0.6 g / 10
g of tin octoate / toluene (water content: 100 ppm)
5.3 g of a solution, 70.0% by weight DL-lactic acid aqueous solution 70.0%
g (water content: 7.0 g), the internal temperature was 20 ° C,
The solvent removal / dehydration operation was performed at 15 mmHg for 60 minutes. The amount of detoluene obtained at this time was 5.3 g, and the amount of dehydration was 3.1 g. Thereafter, the water content of the reaction system at the time when the cyclic ester compound was dissolved at 140 ° C. under a nitrogen gas flow was 0.20% by weight (water content 4.0 g) with respect to the total amount of the cyclic ester compound. Furthermore, 1
The temperature was raised to 80 ° C and 215 ° C, and polymerization was performed at 215 ° C for 2 hours. The intrinsic viscosity of the obtained polyester is η = 0.
138, which was within the control range.

Comparative Example 8 The target intrinsic viscosity was set to 0.140 (control range: 0.140
± 0.005) and LTD in a 5L stainless steel reactor.
2000.0 g (water content 50 ppm), 0.6 g / 10
g of tin octoate / toluene (water content: 100 ppm)
5.3 g of a solution, 70.0% by weight DL-lactic acid aqueous solution 70.0%
g (water content: 7.0 g), the internal temperature was 20 ° C,
The solvent removal / dehydration operation was performed at 3 mmHg for 60 minutes. The amount of detoluene obtained at this time was 5.3 g, and the amount of dehydration was 6.7 g. Thereafter, the water content of the reaction system when the cyclic ester compound was dissolved at 140 ° C. in a nitrogen stream was 0.02% by weight (0.4 g water content) based on the total amount of the cyclic ester compound. Furthermore, 1
The temperature was raised to 80 ° C and 215 ° C, and polymerization was performed at 215 ° C for 2 hours. The intrinsic viscosity of the obtained polyester is η = 0.
151, out of the control range.

Comparative Example 9 The target intrinsic viscosity was 0.140 (control range 0.140).
± 0.005) and LTD in a 5L stainless steel reactor.
2000.0 g (water content 50 ppm), 0.6 g / 10
g of tin octoate / toluene (water content: 100 ppm)
5.3 g of a solution, 70.0% by weight DL-lactic acid aqueous solution 70.0%
g (water content: 7.0 g), the internal temperature was 20 ° C,
The solvent removal / dehydration operation was performed at 25 mmHg for 60 minutes. At this time, the amount of detoluene obtained was 5.3 g, and the amount of dehydration was 1.2 g. Thereafter, the water content of the reaction system at the time when the cyclic ester compound was dissolved at 140 ° C. under a nitrogen stream was 0.295% by weight (water content: 5.9 g) with respect to the total amount of the cyclic ester compound. Furthermore,
The temperature was raised to 180 ° C and 215 ° C, and polymerization was performed at 215 ° C for 2 hours. The intrinsic viscosity of the obtained polyester is η =
0.129, which was out of the control range. Examples 1 to 8,
The results obtained in Comparative Examples 1 to 9 are shown in [Table 1] and [Table 2].

[0041]

[Table 1]

[0042]

[Table 2]

[0043]

According to the bioabsorbable polyester produced by the method of the present invention, the intrinsic viscosity, which is an index of the molecular weight, is controlled within the range of η ± 0.005 with respect to the target value (η),
It has a molecular weight with very little deviation from a target value. Therefore, the present invention is extremely useful as a method for producing a bioabsorbable polyester used in the medical field such as a base material for a sustained release drug and a molding material.

Continued on the front page (72) Inventor Hideyuki Akieda 2-1-1 Tangodori, Minami-ku, Nagoya-shi, Aichi Mitsui Chemicals Co., Ltd. (72) Inventor Yuzo Ono 2-1-1 Tangodori, Minami-ku, Nagoya-shi, Aichi Mitsui Chemicals Co., Ltd. In company

Claims (8)

[Claims] 1. A method for producing a bioabsorbable polyester by ring-opening polymerization of a cyclic ester compound, comprising charging a main material containing a cyclic ester compound, a catalyst and an initiator into a reaction system, and performing a dehydration operation. A method for producing a bioabsorbable polyester, comprising controlling the amount of water in a reaction system within a range of 0.10 to 0.20% by weight based on the total amount of a cyclic ester compound, and then starting ring-opening polymerization. 2. A temperature of 10 to 70 ° C. and a pressure of 5 to 20 mmH.
The method for producing a bioabsorbable polyester according to claim 1, wherein the dehydration operation is performed for 30 minutes to 1 hour under the condition of g. 3. The method for producing a bioabsorbable polyester according to claim 1, wherein the intrinsic viscosity of the bioabsorbable polyester is controlled within a range of η ± 0.005 with respect to a target value (η). 4. The bioabsorbable material according to claim 1, wherein the cyclic ester compound is at least one compound selected from glycolide, lactide, ε-caprolactone, p-dioxanone, and trimethylene carbonate. Polyester manufacturing method. 5. The method for producing a bioabsorbable polyester according to claim 1, wherein the cyclic ester compound is at least one compound selected from glycolide and lactide. 6. The method for producing a bioabsorbable polyester according to claim 1, wherein the amount of the catalyst used is 0.001 to 0.05% by weight based on the total amount of the cyclic ester compound. 7. The method for producing a bioabsorbable polyester according to claim 1, wherein the amount of the initiator used is 0.01 to 10% by weight based on the total amount of the cyclic ester compound. 8. The method for producing a bioabsorbable polyester according to claim 1, wherein the polymerization temperature is 180 to 240 ° C. and the polymerization time is 2 to 24 hours.