JPS5996123A - Production of high-molecular weight polylactide - Google Patents

Abstract

PURPOSE:To produce a high-MW (MW>=4,000) polylactide without employing any catalyst, by directly condensing lactic acid by dehydration under a specified condition. CONSTITUTION:Lactic acid (any of L-, D- and racemate) is condensed by dehydration in the absence of any catalyst in an inert gas atmosphere. Lactic acid is placed in a reaction vessel and heated slowly to effect the condensation under a stream of an inert gas (e.g., N2). Then, the reaction temperature is raised slowly and the pressure is lowered slowly and the reaction is brought to completion under a final condition including a temperature of 220-260 deg.C and a pressure of below 10mm.Hg to obtain a polylactide of a MW>=4,000. This polylactide is useful for use in medical materials.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing high molecular weight polylactide useful as a medical material and the like.

Lactic acid is widely distributed in nature and is harmless to animals, plants, and humans. Its polymer (polylactide) is relatively easily hydrolyzed in the presence of water, and is also hydrolyzed and absorbed in living organisms. For this reason, it is attracting attention as a synthetic polymer material for medical use.

Lactic acid has a hydroxyl group and a carboxyl group in its molecule, so it can undergo polycondensation, but the conventional dehydration condensation method has the disadvantage that only oligomers with a molecular weight of less than 4000 and a low degree of polymerization can be obtained (C , H, Haste
Author: “Lactic Ac1d” P-226, Ver.
7ag Chemie, 1971). Therefore, in order to obtain a high molecular weight polylactide with a molecular weight of 4,000 or more, lactic acid is not simply dehydrated and condensed, but lactic acid is dehydrated and condensed to form a lactic acid oligomer, and the dough is prepared using alumina trioxide, thymonium trifluoride, antimony trifluoride, % depolymerization in the presence of a catalyst such as tin tetrachloride to form a cyclic diester of lactic acid (lactide), followed by an open LJtitj reaction by adding a catalyst such as tin octylate, diethylzinc, boron trifluoride, etc. The method is widely and generally adopted (for example,
88).

However, this method is difficult to operate and the product contains metals such as zinc and tin that are of concern for toxicity, so it cannot be said to be suitable as a medical material. Therefore, there is a strong demand for a method for producing polylactide simply and easily, and without containing any impurities harmful to the human body.

The present inventors, in order to obtain a high molecular weight polylactide,
As a result of various studies on the polycondensation reaction of lactic acid, it was discovered that if the reaction conditions were specified, a polylactide with a molecular weight of 40,001 u could be obtained by directly dehydrating and condensing lactic acid without using any catalyst, which led to the present invention. Ta.

That is, in the present invention, lactic acid is heated in an inert gas atmosphere in the absence of a catalyst, and the pressure is lowered to cause polycondensation, and finally the polycondensation is carried out at a temperature of 220 to 260°C and a pressure of 10 or less. The present invention relates to a method for producing a high molecular weight polylactide, which comprises completing the condensation to obtain a polylactide having a molecular weight of at least 4,000.

According to the production method of the present invention, polylactide is produced in the absence of a catalyst, so there is no concern about toxicity as it does not contain any impurities derived from the catalyst, and it can be used in vivo as a medical detergent. It is extremely advantageous in that it is not only suitable for use, but also that the production method is extremely simple and high molecular weight polylactide can be easily obtained. This is unexpected in light of the knowledge of the above-mentioned C, I large HAlten that high molecular weight polylactide cannot be obtained by dehydration condensation, which has been conventionally carried out.

Next, a comparison of the method of the present invention and the conventional method (Japanese Patent Publication No. 14688/1988) for producing polylactide is as follows.

The lactic acid used in the present invention is L-lactic acid.

D-lactic acid, racemic form, and L-lactic acid.

The polycondensation reaction of lactic acid is carried out by heating lactic acid in an inert gas atmosphere such as nitrogen or argon in the absence of a catalyst, raising the temperature continuously or gradually, and lowering the pressure continuously or stepwise. polycondensation with distillation of condensed water,
Final temperature 220-260℃, pressure 10 mm I%
When the polycondensation reaction is higher than 10 tran Hg under the following conditions, the molecular weight of the polylactide produced is 40 tran Hg.
Keep it below 00. On the other hand, the final condensation temperature is 260℃
If the polylactide exceeds 50%, the polylactide produced not only becomes dark brown, but also thermal depolymerization becomes dominant, and its molecular weight decreases to 4.
It will be less than 000.

According to the production method of the present invention, polylactide having a molecular weight of 4,000 or more, particularly a molecular weight in the range of 4,000 to 20,000, can be easily obtained. The glass transition temperature of polylactides with molecular weights in this range is 20-45°C, and therefore, when they are used in the body, they become light-flexible at body temperature and do not damage surrounding living tissues, which is preferred. Conceivable.

Generally, the hydrolysis rate of polylactide largely depends on its molecular weight, and the higher the molecular weight, the longer the time required for hydrolysis. Therefore, as a sustained-release drug, the molecular weight should not be too high, from 4000 to 2.
Polylactides having a molecular weight on the order of 0,000 are often effective.

The same is expected for slow-acting pesticides. Naturally, high-molecular-weight polylactide is essential when high mechanical strength is required, such as surgical sutures and orthopedic bone prosthetic materials, but polylactide with moderate strength, such as cartilage, is essential. When a high decomposition rate is required, a polylactide having a molecular weight similar to that of the present invention is considered to be extremely effective.

Ma Hereinafter, the present invention will be explained in more detail by way of examples.

Example 1 A third flask of a 500i equipped with a condenser, a thermometer, a stirrer and a nitrogen gas introduction carrier was charged with commercially available D%L.
- Lactic acid (85 to 92 weight water valuable) 500.9 was charged and dehydrated at 180°C for 4 hours while blowing nitrogen gas, and then gradually heated to 2° arm Hy with a vacuum pump.
The pressure was reduced at t, and the dehydration reaction was further carried out for 2 hours.
Met. 1. The glass transition temperature was measured by DSC and was 22°C. ). After that, the temperature was further gradually raised and the pressure was gradually lowered, and the reaction was finally carried out for 8 hours at a temperature of 260 °C and a pressure of -2 mmI (y. 260 °C,
Table 1 shows the relationship between the reaction time after the reaction time was adjusted to 2 mmHy, the molecular weight of the obtained polylactide, and the glass transition temperature.

Table 1 Example 2 Using commercially available L-lactic acid (90% aqueous solution) as a starting material, a polycondensation reaction was carried out under the same conditions as in Example 1, resulting in a pale yellow product with a molecular weight of 18,000 and a glass transition temperature of 42°C. of polylactide was obtained.

Comparative Example 1゜Example 10 Under the polycondensation conditions, the final pressure was kept constant at 2 wn Hy and only the final temperature was raised to 280°C. Despite the effort to increase the molecular weight,
Thermal depolymerization of the polymer became predominant, and lactide, a cyclic diester of lactic acid, was produced significantly. The product also had a dark brown color and a molecular weight of less than 4,000.

Comparative Example 2゜Example 10 Under the polycondensation conditions, only the final temperature was kept constant at 260°C, and the final pressure was 20 mm H,! When the reaction was carried out at a temperature of 9, the molecular weight remained at 4 even if the reaction time was increased.
,000 or more, and when the reaction time was increased to 8 to 10 hours, the product turned dark brown.

Comparative Example 3 Reaction temperature (180°C) and pressure (20mmIi
) is left as it is, and when a condensation reaction is carried out by adding an IM amount of anotymone trioxide catalyst to the lactic acid monomer, rough maid is generated violently even at a relatively low pressure of 20 tan Hgi and a reaction temperature of 180°C. I've been doing it.

Patent applicant: Showa Kobunshi Co., Ltd. Representative Patent Attorney Sei Kikuchi

Claims (1)

[Claims] heating lactic acid in an inert gas atmosphere in the absence of a catalyst;
Polycondensation is carried out by lowering the pressure, and finally the temperature is 220~2
A method for producing a high molecular weight polylactide, which comprises completing the polycondensation reaction under conditions of 60° C. and a pressure of 10 mx Hy or less to obtain a polylactide having a molecular weight of at least 4000.