JPH043763B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a method for producing polylactide, polyglycolide, or a copolycondensate thereof obtained by a dehydration polycondensation reaction of lactic acid or glycolic acid, and is particularly useful as a sustained-release polymer. The object of the present invention is to provide high molecular weight polylactide, polyglycolide, or copolycondensates thereof. Polylactide, polyglycolide, or their copolycondensates are used as sustained-release polymers for biodegradable medical materials such as sutures, agricultural chemical compositions for soil treatment such as herbicides and soil fungicides, and base materials for microcapsules. In recent years, it has been used in many ways. In the case of agricultural chemical compositions, this sustained-release polymer must have a suitably high molecular weight to release the drug component over a long period of time. In addition, when used as a medical material, it is necessary for the polymer material to maintain the necessary strength until it fuses with the living body, and then be quickly decomposed and absorbed. is required. (Prior art) A generally known method for obtaining high molecular weight polylactide, polyglycolide, etc. is to produce lactide or glycolide from lactic acid or glycolic acid, and then ring-opening polymerize it to produce polylactide or polyglycolide. However, although this method allows the production of lactide and glycolide, it requires a great deal of labor and expense and is not economical. Another method is to directly obtain polylactide or polyglycolide from lactic acid or glycolic acid, but while this method is a simple polycondensation method, it does not yield a high molecular weight polycondensate. (Problems to be Solved by the Invention) Therefore, the present inventors investigated a direct polycondensation method from lactic acid and glycolic acid in order to obtain an inexpensive polycondensation product with a high molecular weight. The direct polycondensation reaction of lactic acid and glycolic acid is a sequential reaction similar to the esterification reaction between a dibasic acid and a polyhydric alcohol, and the molecular weight increases with the reaction time. However, this reaction is an equilibrium reaction and its equilibrium constant is extremely small, so a catalyst is required to increase the molecular weight. Generally, metal salts, metal oxides, etc. are used as this type of catalyst, but in the case of oxyacids such as lactic acid and glycolic acid, even if ester bonds are formed in the polycondensation reaction, they also have a decomposition effect on the polymer. Therefore, it has been difficult to obtain a high molecular weight polycondensation product due to this effect. (Means for Solving the Problems) Based on these findings, the present inventors developed a direct dehydration polycondensation method for lactic acid and glycolic acid in order to obtain high molecular weight polylactide, polyglycolide, or copolycondensates thereof. We have conducted extensive research into methods for further increasing the molecular weight of polycondensates obtained from The present invention has been completed based on the discovery that it is easy to further increase the molecular weight of the polycondensate by adding an amine compound or adding an amine compound to the polycondensate. That is, the present invention involves reacting low molecular weight polylactide, polyglycolide, or a copolycondensate thereof with an acid salt compound selected from a dichloride compound or thionyl chloride, and then melt polycondensing it under reduced pressure or introducing nitrogen gas. The present invention relates to a method for producing high molecular weight polylactide, polyglycolide, or a copolycondensate thereof, which comprises performing a reaction or reacting with the acid chloride, adding an amine compound, and performing a polycondensation reaction. (Function) The monomer used in the present invention is lactic acid or glycolic acid, and lactic acid may be either D-type or L-type, or racemic. There is no particular limitation on the concentration of these when carrying out the reaction, but if the concentration at the start of the polycondensation reaction is low, the amount of volatilization of oligomers etc. generated at the beginning of the reaction will increase, and the yield will decrease. When the monomer concentration is low, it is desirable to concentrate it appropriately before use. The polycondensation reaction is carried out by adding lactic acid, glycolic acid, or a mixture of lactic acid and glycolic acid to a temperature of 150 to 250 m Do this while heating to ℃. After the start of the reaction, the molecular weight of the polycondensate increases gradually, and the number average molecular weight of the polycondensate ranges from 1000 to 6000 within 1 to 10 hours after the start of the reaction. The molecular weight of the low molecular weight polylactide, polyglycolide, or copolycondensate thereof used in the present invention is usually within this range, and there is no particular problem in using one with a molecular weight exceeding 6,000. It is difficult to obtain a substance within this range by direct dehydration polycondensation method, and it is economically undesirable to use a substance exceeding this range. Moreover, when the molecular weight is less than 1000, it becomes extremely difficult to obtain the high molecular weight polycondensate of the present invention. The number average molecular weight of the polycondensate, which increases sequentially during the polycondensation reaction, is determined by sampling the reaction solution at regular intervals and measuring the molecular weight using the following method. <Molecular weight measurement method> Approximately 1 g of the reaction solution is heated and dissolved in 20 ml of benzyl alcohol, and after cooling, it is titrated with a 0.025N potassium hydroxide solution in benzyl alcohol using phenolphthalein as an indicator. Titration is performed under a nitrogen atmosphere while introducing N ₂ gas to remove interference such as carbon dioxide in the air. The molecular weight of the polycondensate is determined from the titration value using the following formula. n=W/0.025x10 ^-3 f(S-B) where W: Weight of polycondensation (g) f: Factor of 0.025N potassium hydroxide solution S: 〃 Titration amount (sample) (ml) B: 〃 Titration amount (Blank) (ml) n: Number average molecular weight of the polycondensate In this method, the molecular weight is calculated from this value by quantifying the amount of carboxyl groups at the end groups of the polycondensate. The term "molecular weight" refers to the number average molecular weight. The polylactide, polyglycolide, or copolycondensate thereof obtained in this way is added to an organic solvent for 5 to 50 minutes.
Dissolve at a concentration of 60% by weight. The organic solvent may be any solvent as long as it dissolves the polycondensate, but benzene, chlorobenzene, toluene, xylene, tetrahydrofuran, dioxane, etc. are commonly used. Next, in the present invention, an acid chloride is added to this polycondensate solution to activate the polycondensate terminal group by converting it into acid chloride. Examples of the acid chloride used in the present invention include thionyl chloride, or dichloride compounds such as oxalyl chloride, succinyl chloride, and terephthaloyl dichloride. In addition, when using acid chlorides other than these, for example, monochloride compounds such as acetyl chloride, propionyl chloride, benzoyl chloride, etc., it is possible to convert the terminal group into acid chloride, but it is possible to convert the terminal group into acid chloride. I can't. The acid chloride is used in an amount of 0.25 to 2 moles based on the amount of carboxyl groups at the end of the molecular chain of the polycondensate. That is, if it is less than 0.25 mol, the high molecular weight of the present invention cannot be achieved, and if it exceeds 2 mol, even if it is possible to achieve a high molecular weight, the polycondensate contains too much of the acid chloride, resulting in This is more undesirable than inducing deterioration of the high molecular weight polycondensate obtained and lowering the molecular weight. Incidentally, the amount of carboxyl group at the molecular chain end of the above-mentioned polycondensate is calculated by the following formula from the number average molecular weight of the polycondensate calculated by the above-mentioned molecular weight measuring method. X = 1/Mn where X: Carboxyl group weight of polycondensate (mol/g) n: Number average molecular weight of polycondensate The reaction after addition of acid chloride is 0.5 at a temperature of 20 to 100°C.
Perform under stirring for ~10 hours. The relationship between temperature and time at this time is generally contradictory, with 8 hours at 20℃ and 4 hours at 60℃.
At 100℃, it takes 1 hour. The polycondensate obtained by the reaction with the acid chloride is then subjected to a melt polycondensation reaction under reduced pressure or nitrogen gas introduction, or by adding an amine compound to the polycondensate of the present invention. Obtain a condensate. That is, by performing such a reaction, the hydrochloric acid generated due to the esterification reaction between polycondensate molecular chains can be removed from the reaction system, or the hydrochloric acid can be reacted with an amine compound, thereby causing polycondensation. It becomes possible to increase the molecular weight of the body. The choice of whether to perform the melt condensation reaction under the introduction of nitrogen gas or to perform the addition reaction with an amine compound is as follows:
The choice may be made depending on the purpose of the copolycondensate, etc., and if high temperature reaction is not preferred, the latter is preferred.
Moreover, if the residual amine compound is undesirable, the former may be selected. Regarding the method of performing the melt polycondensation reaction, after removing the organic solvent by heating appropriately under reduced pressure or nitrogen gas introduction, the melt condensation reaction is performed for 1 to 10 hours by heating to 150 to 250°C. In this manner, the high molecular weight polycondensate of the present invention can be obtained. On the other hand, the high molecular weight polycondensate of the present invention can also be obtained by adding an amine compound to the polycondensate solution after the reaction with the acid chloride and causing a polycondensation reaction. As a method, first, as an amine compound, trimethylamine, triethylamine, tripropylamine, tributylamine, pyridine, etc. are used,
It is added in a proportion ranging from 0.5 to 2 moles based on the amount of carboxyl groups at the molecular chain ends of the polycondensate before acid chloride treatment. At a reaction temperature of 30 to 100℃, 1
By reacting for up to 8 hours, the high molecular weight polycondensate of the present invention can be obtained. The molecular weight of the high molecular weight polylactide, polyglycolide, or copolycondensate thereof of the present invention obtained in this way is high, and the molecular weight of the polycondensate obtained by the ordinary direct dehydration polycondensation method is about
4,000 and about 7,000 in a system with a catalyst added such as a tin compound, but according to the method of the present invention, this molecular weight can be increased to about 40,000. Therefore, since the product of the present invention has a high molecular weight, the decomposability of the polycondensate is extremely low, and when this polycondensate is molded, it has excellent properties such as high strength. Therefore, as sustained release bases, for example, bioabsorbable materials, drug sustained release matrices such as pharmaceuticals, agricultural chemicals, etc.
It has a wide range of uses, including not only microcapsule bases and soil conditioners, but also disintegrating agricultural films, surfactants, fruit quality improvers, gas separation permeable membranes, etc. Furthermore, the product of the present invention has a decomposition property that cannot be obtained by the conventional direct dehydration polycondensation method, in that the degradability is extremely low up to a certain period of time, and then the decomposition progresses rapidly. When applied to drugs, it has the advantage that the polycondensate base decomposes quickly after drug release. (Example) Examples of the present invention will be described below,
The present invention is not limited to these. It should be noted that all percentages are by weight unless otherwise specified. Example 1 500 equipped with stirrer, thermometer and condenser
Pour 400 g of 90% L-lactic acid into a three-neck flask, and add L-lactic acid under stirring at a temperature of 85°C and a reduced pressure of 100 mmHg.
Lactic acid was concentrated. After about 45 g of water had flowed out, the temperature and degree of vacuum were gradually increased, and the reaction was carried out at 200° C. and 15 mmHg for 12 hours. The number average molecular weight of the polycondensate obtained at this time is
It was 3100. ( _{Polycondensate} sample 1) 90% L-lactic acid 90%
Add 60.8 g of glycolic acid and 300 g of _N2 gas.
While blowing into the solution at a flow rate of ml/min, the temperature is increased.
The temperature was raised to 205℃. The reaction was carried out for 10 hours while maintaining this temperature. The number average molecular weight of the polycondensate obtained at this time was 3200
It was hot. (Polycondensate sample 2) 500 equipped with stirrer, thermometer, and condenser
Pour 400g of 90% DL-lactic acid into a 3-neck flask and DL at a temperature of 90℃ and a reduced pressure of 100mmHg with stirring.
- Concentrated lactic acid. After approximately 45 g of water had flowed out, 0.18 g of stannous chloride (Sncl _{2.2H 2} O) was added, and the temperature and degree of vacuum were gradually increased to carry out a reaction at 205° C. and 10 mmHg for 8 hours. The number average molecular weight of the polycondensate obtained at this time was 6000
It was hot. (Polycondensate sample 3) 100 g of the above polycondensate sample (carboxyl group weight at the end of one molecular chain: 3.23X10 ^-4 mol/g) was ground and placed in a 500 ml container equipped with a stirrer, thermometer, and condenser. The mixture was placed in a three-neck flask, 200 ml of benzene was added, and the polycondensate was dissolved with stirring. To this, thionyl chloride and various acid chlorides shown in Table 1 were added in predetermined amounts, and a reaction was carried out at 82°C for 4 hours. Then, after removing benzene at a reduced pressure of 100 mmHg, a reaction was carried out at 250° C. and a reduced pressure of 15 mmHg for 4 hours. The polycondensate after the reaction was dissolved in 200 ml of chloroform, and then precipitated into a large amount of methanol.
After further washing with methanol, it was vacuum dried at 30°C overnight. The number average molecular weight of the polycondensate thus obtained was measured and the results are shown in Table 1.

[Table] Example 2 100 g of the polycondensate sample 2 of Example 1 (carboxyl group amount at the end of the molecular chain: 3.13X10 ^-4 mol/g) was pulverized, and a stirrer, a thermometer, and a condenser were equipped.
Pour into a 500ml three-necked flask and add 200ml of toluene.
was added to dissolve the polycondensate under stirring. Add to this 4.8g (3.38X10 ^-2 mol) of oxalyl chloride.
was added, and the reaction was carried out at 78°C for 6 hours. Next, 4.0g of triethylamine
(3.96X10 ^-2 mol) was gradually dropped into the reaction system, and 83
The reaction was carried out at ℃ for 2 hours. The polycondensate after the reaction was precipitated in a large amount of methanol, washed with methanol, and then vacuum-dried at 30° C. for one day. The number average molecular weight of the polycondensate of the present invention thus obtained was 17,800. Example 3 80 g of the polycondensate sample 3 of Example 1 (carboxyl group amount at the end of the molecular chain: 1.29X10 ^-4 mol/g) was pulverized and placed in a container equipped with a stirrer, a thermometer, and a condenser.
Add 250ml of xylene to a 500ml three-necked flask.
was added to dissolve the polycondensate under stirring. Add to this succinyl chloride 3.0g (1.94X10 ^-2 mol)
was added, and the reaction was carried out at 85°C for 5 hours. Next, after removing xylene at a reduced pressure of 50 mmHg, a reaction was carried out at 203° C. and a reduced pressure of 8 mmHg for 5 hours. The polycondensate after the reaction was dissolved in 300 ml of chloroform, and then precipitated into a large amount of methanol.
After further washing with methanol, it was vacuum dried at 30°C overnight. The number average molecular weight of the polycondensate of the present invention thus obtained was 37,700. Reference Example 1 Using the polycondensates of the present invention and comparative example obtained in Example 1, hydrolysis of the polycondensates was investigated. The test method is to crush these polycondensates and
Put the 48mesh into a 50ml screw bottle.
1.00 g each was taken, 30 ml of water was added, the mixture was sealed, and the mixture was stored at a constant temperature of 37°C. After this was left to stand for a predetermined period, the dry weight of the polycondensate was measured, and the hydrolysis rate of the polycondensate was determined using the following formula. Y=(1.00-W)/1.00X100 where Y: Hydrolysis rate of polycondensate (%) W: Weight of polycondensate after drying (g) The results are shown in Table 2.

【table】

Claims (1)

[Claims] 1. After reacting a low molecular weight polylactide, polyglycolide, or a copolycondensate thereof with an acid chloride selected from a dichloride compound or thionyl chloride, a melt polycondensation reaction is performed under reduced pressure or under nitrogen gas introduction. Alternatively, a method for producing high molecular weight polylactide, polyglycolide, or a copolycondensate thereof, which comprises reacting with the acid chloride, adding an amine compound, and performing a polycondensation reaction.