JPH0733433B2 - New polymer - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to a bioabsorbable pharmaceutical preparation.
The present invention relates to a copolymer of lactic acid and glycolic acid useful as a base (hereinafter sometimes referred to as the copolymer of the present invention).

[0002]

BACKGROUND OF THE INVENTION In recent years, degradable polymers have attracted considerable attention as easily degradable polymers for mitigating plastic pollution and as polymers for bioabsorbable pharmaceutical preparations.

As one for the above-mentioned purpose, Japanese Patent Laid-Open No.
56-45920 discloses a method of polymerizing lactic acid and glycolic acid in the presence of a strongly acidic ion exchange resin, according to which the weight average molecular weight is about 6,000 to 35,00.
It is said that a polymer having substantially no polymerization catalyst of 0 is obtained.

However, the polymer produced by the above-mentioned method has a large molecular weight dispersity of about 3 or more as determined by gel permeation chromatography, and therefore, when used,
Since factors such as solubility and other aspects are complicated and there are many problems in control, it is not preferable when used as a polymer for bioabsorbable pharmaceutical preparations. Moreover, in this method, the strongly acidic ion-exchange resin used as the polymerization catalyst is deteriorated by heat during the heat polycondensation reaction and is dissolved in the obtained polymer, which appears as coloring of the polymer. Furthermore, it is difficult to remove such color from once colored polymers and practically impossible to completely remove it. It goes without saying that such coloring not only lowers the commercial value but is also in an unfavorable state because it is caused by impurities.

[0005]

SUMMARY OF THE INVENTION In view of the above situation, the inventors of the present invention have conducted earnest studies on a production method of a copolymer of lactic acid and glycolic acid, which is effective and does not have the above-mentioned drawbacks. By subjecting these low molecular weight polymers or copolymers to polycondensation reaction by heating under reduced pressure without a catalyst, the weight average molecular weight is about 5,000 or more and 30,000 or more .
It was found that a colorless or almost white copolymer having a dispersity by gel permeation chromatography as small as 0 or less and a dispersity by the gel permeation chromatography method as small as about 1.5 to 2 and containing no polymerization catalyst at all can be obtained. As a result of further research based on this, the present invention has been completed.

[0006]

The present invention has a weight average molecular weight of about 5,000 or more 3
Lactic acid / glycolic acid consisting of about 50-95% by weight lactic acid and about 50-5% by weight glycolic acid having a dispersity determined by gel permeation chromatography of about 1.5 to 2 at a level of 0,000 or less and containing no catalyst. Is a copolymer.

[0007]

Further, the present invention has a weight average molecular weight of about 5,0
It is from 00 to 30,000 and contains no catalyst, and the dispersity determined by gel permeation chromatography is about 1.
5 to 2, a lactic acid / glycolic acid polymer consisting of about 50 to 95% by weight of lactic acid and about 50 to 5% by weight of glycolic acid.
A bioabsorbable base for a pharmaceutical preparation, comprising a polymer .

In producing the copolymer of the present invention, an aqueous solution of lactic acid having various concentrations is usually arbitrarily selected as the lactic acid used as a raw material. From the viewpoint of workability, the higher the lactic acid concentration is, the better. % Or more is desirable. Needless to say, it is better to use lactic acid itself rather than the aqueous solution if available. Also, as glycolic acid,
Usually, crystals are used as they are, but they can be used as an aqueous solution. When solid lactic acid and glycolic acid such as crystals are used, a solvent that dissolves them may be used if necessary. Examples of the solvent include water, methanol, ethanol, acetone and the like.

Lactic acid and glycolic acid used as raw materials for producing the copolymer of the present invention include low molecular weight polymers of lactic acid, low molecular weight polymers of glycolic acid, and low molecular weight copolymers of lactic acid and glycolic acid. It may be a polymer.

Examples of the low molecular weight polymer include lactic acid oligomers (eg, dimers, trimers, etc.) and glycolic acid oligomers (eg, dimers, trimers, etc.).

Examples of the low molecular weight polymer or low molecular weight copolymer include those obtained by polycondensing lactic acid and / or glycolic acid in the absence of a catalyst.
The reaction temperature and reaction time for producing the low molecular weight polymer or low molecular weight copolymer are 100 to 150 ° C / 350 to 30 mmHg for 2 hours or more, usually about 2 to 10 hours, for example, 105 ° C / 3.
Water may be removed by heating reaction under reduced pressure for 5 to 6 hours while gradually increasing the temperature and the degree of reduced pressure from 50 mmHg to 150 ° C./30 mmHg. In this way, the molecular weight is about 2,
000 to 4,000 low molecular weight polymers or low molecular weight copolymers can be easily obtained.

The low molecular weight polymer or low molecular weight copolymer may be obtained by polycondensation by a known method without catalyst. The known method is, for example, the method described in Industrial Chemistry, Vol. 68, pages 983-986 (1965), that is, lactic acid and glycolic acid under normal pressure without a catalyst.
A method of reacting at 202 ° C. for 6 hours can be mentioned. As the known method, for example, the method described in U.S. Pat.No. 2,362,511, that is, lactic acid and glycolic acid are used.
A method of reacting at a temperature of 200 ° C. for 2 hours and then continuing heating under reduced pressure for 1/2 hour can also be mentioned.

The copolymer of the present invention has a ratio of lactic acid and glycolic acid of about 50 to 95% by weight of lactic acid and about 50% of glycolic acid.
-5% by weight, preferably about 60-95% lactic acid and about 40-5% glycolic acid, more preferably about 60-85 lactic acid.
% And about 40-15% by weight glycolic acid. A particularly preferable ratio of lactic acid to glycolic acid is about lactic acid.
75 ± 2 mol% and about 25 ± 2 mol% glycolic acid.

The heating temperature in the polycondensation reaction for producing the copolymer of the present invention is, for example, usually about 150 to 250 ° C, preferably about 150 to 200 ° C. The reduced pressure is, for example, usually about 30 to 1 mmHg, preferably about 10 to 1 mmHg. The reaction time is, for example, about 10 hours or longer, preferably about 10 to 150 hours, more preferably about 10 to 100 hours.

The following reaction conditions are preferable when lactic acid and glycolic acid are used as raw materials. For example, 100 to 150 ° C / 350 to 30 mmHg for 2 hours or more, usually about 2 to 10 hours, for example, 105 ° C / 350 mmHg to 150 ° C / 3
5-6 while gradually increasing the temperature and the degree of vacuum to 0 mmHg
After removing water by heating reaction under reduced pressure for 10 hours at 150-200 ° C / 10-1mmHg for 10 hours or more (usually 100
The dehydration polycondensation reaction is sufficient.

The following reaction conditions are preferable when the above-mentioned low molecular weight polymer or copolymer is used as a raw material. That is, for example, 150 to 200 ° C / 10 to 1
The dehydration polycondensation reaction may be performed for 10 hours or longer (usually about 100 hours) at mmHg.

After completion of the reaction, the reaction solution is simply filtered while hot, or the polymer is added to an appropriate solvent such as methylene chloride, dichloroethane, chloroform or acetone (the same amount to about 10 times as much as the polymer is used). By removing the dust by dissolving and filtering, the former, that is, the reaction solution is filtered as it is, and the latter, that is, when the reaction solution is dissolved in the solvent and filtered, the solvent used is concentrated and distilled off. The desired high molecular weight copolymer can be easily obtained. Also,
If necessary, the filtered reaction solution may be separated directly by a conventional method such as pouring the concentrated filtrate into a large amount of a precipitating agent directly when a solvent is used, or reprecipitation if necessary. And the like. Hereinafter, the present invention will be described in more detail with reference to experimental examples and examples.

[0019]

【Example】

Experimental example 1. Mixing 160 g (1.5 mol) of 85% lactic acid aqueous solution and 38 g (0.5 mol) of glycolic acid, 100 to 1 under a nitrogen stream.
After stepwise heating under reduced pressure at 50 ° C./350 to 30 mmHg for 6 hours to remove distilled water, dehydration condensation reaction was carried out at 175 ° C./6 to 5 mmHg for 72 hours.

Table 1 shows the relationship between the reaction time and the achieved weight average molecular weight in the production of the copolymer of lactic acid and glycolic acid by this method.

For comparison, Table 1 also shows the results when a commercially available strong acid ion-exchange resin Dowex 50W [Dow Chemical Company (USA), registered trademark] is used as a polymerization catalyst. .

[0022]

[Table 1] *: The copolymer obtained at each reaction time is dissolved in 4 volumes of methylene chloride, filtered and concentrated to remove the solvent,
The obtained copolymer was tested according to JIS K8004-2 (that is, about 3 g of a sample was taken with a watch glass and examined on a white paper).

The weight average molecular weight and the degree of dispersion (weight average molecular weight / number average molecular weight) in the table were determined by gel permeation chromatography using standard polystyrene of known molecular weight.

As is clear from Table 1, according to the production method of the present invention, a high molecular weight lactic acid / glycolic acid copolymer having a weight average molecular weight of about 5,000 or more can be easily obtained, and the obtained copolymer is obtained. Coloring is not observed in the polymer, and a polymer having a small molecular weight dispersity of 2 or less is obtained.

The copolymer composition of lactic acid and glycolic acid obtained by analyzing the copolymer of the present invention obtained above in a deuterated chloroform solution by nuclear magnetic resonance spectrum is shown in Table 2.

[0026]

[Table 2]

Example 1. In a four-necked flask equipped with a thermometer, a condenser, and a nitrogen introduction tube, take 191 g of 85% lactic acid aqueous solution and 17.5 g of glycolic acid. Distilled water was removed by heating under reduced pressure over time. Subsequently, the degree of vacuum was set to 3 mmHg, and heating was performed at an internal temperature of 175 ° C. for 72 hours. The reaction solution was cooled to room temperature and 140 g of an almost colorless bulk polymer as a copolymer of lactic acid and glycolic acid.
Got The weight average molecular weight and dispersity of the copolymer are 22,0
It was 00 and 1.70. The weight average molecular weight and the dispersity were determined by the gel permeation gel chromatography method (hereinafter the same). Further, the obtained copolymer was analyzed by nuclear magnetic resonance spectrum as a heavy chloroform solution, and the composition of lactic acid and glycolic acid in the copolymer was 89 mol%: 11 mol% (90.9 wt%: 9.1 wt% )Met.

Comparative Example 1. To 191 g of 85% aqueous lactic acid solution and 17.5 g of glycolic acid, 6.8 g of Dowex 50W (crosslinked polystyrene resin), which is a commercially available strong acidic ion exchange resin, was added, and a nitrogen stream was prepared in the same manner as in Example 1. The inner temperature and the inner pressure were reduced from 105 ° C. and 350 mmHg to 150 ° C. and 30 mmHg, respectively, under reduced pressure heating for 6 hours to remove distilled water. Furthermore, 6.8g of Dowex 50W is added to reduce the pressure to 3mmHg,
Heating was performed at an internal temperature of 175 ° C for 72 hours. The reaction solution was filtered while hot to remove Dowex 50W, and the filtrate was cooled to room temperature to obtain a bulk polymer having a weight average molecular weight of 23,700 and a dispersity of 2.88.
Although 31 g was obtained, the polymer was colored brown. The composition of lactic acid and glycolic acid in the obtained copolymer was 88.5.
It was mol%: 11.5 mol% (90.5 wt%: 9.5 wt%).

Example 2. In the same polymerization apparatus as in Example 1, 85
% Aqueous lactic acid solution (106 g) and glycolic acid (76 g) are used, and the internal temperature and internal pressure are respectively from 105 ℃ and 350mmHg under nitrogen stream.
Distilled water was removed by heating under reduced pressure to 150 ° C. and 30 mmHg for 3 hours. Continue to reduce the pressure to 3 mmHg and set the internal temperature to 18
Heated at 0 ° C. for 36 hours. The reaction solution was cooled to room temperature to obtain 124 g of an almost colorless bulk polymer as a copolymer of lactic acid and glycolic acid. The weight average molecular weight and dispersity of the copolymer were 15,300 and 1.73. As a result of nuclear magnetic resonance spectrum analysis of the obtained copolymer as a deuterated chloroform solution, the composition of lactic acid and glycolic acid in the copolymer was 50.5 mol%: 49.5 mol% (55.9 wt%: 44.1
% By weight).

Example 3 Using 146 g of a 93% aqueous lactic acid solution and 38 g of glycolic acid, a heating reaction was carried out at 202 ° C. for 6 hours to give a weight average molecular weight of 2,700 and a copolymer composition of lactic acid: glycolic acid = 75 mol%: 25 mol% To obtain a copolymer of Using 100 g of the copolymer thus obtained, 5 mmHg, 175
The reaction was carried out under reduced pressure and heating at 70 ° C. for 70 hours. The reaction solution was cooled to room temperature to obtain 92 g of an almost colorless block copolymer. The weight average molecular weight and dispersity of the copolymer are 17,700 and 1.85, respectively, and the copolymer composition of lactic acid and glycolic acid is
It was 75.5 mol%: 24.5 mol% (79.3 wt%: 20.7 wt%).

Example 4. In the same polymerization apparatus as in Example 1, 97 g of lactic acid dimer (lactic acid lactate) and 2 parts of glycolic acid were added.
54 g of a monomer (glycolic acid glycolate) was taken and directly subjected to a reduced pressure / heating reaction at 5 mmHg and 180 ° C. for 48 hours under a nitrogen stream. The reaction solution was cooled to room temperature to obtain 105 g of a substantially white block copolymer as a copolymer of lactic acid and glycolic acid. The weight average molecular weight and dispersity of the copolymer are
18,300 and 1.76, and the copolymer composition of lactic acid and glycolic acid was 60 mol%: 40 mol% (65.1 wt%: 34.9 wt%).

Example 5. In the same polymerization apparatus as in Example 1,
89% lactic acid aqueous solution 3337 g (33 mol) and glycolic acid 83
6 g (11 mol) was taken, and the internal temperature and internal pressure were heated under reduced pressure from 100 ° C. and 350 mmHg to 150 ° C. and 30 mmHg for 6 hours to remove the distilled water. Subsequently, the degree of vacuum was set to 5 mmHg, and heating was performed at an internal temperature of 175 ° C. for 50 hours. The reaction solution was cooled to room temperature to obtain 2400 g of an almost colorless bulk polymer as a copolymer of lactic acid and glycolic acid. The weight average molecular weight and dispersity of the copolymer are each 1
4,400 and 1.66, and the copolymer composition of lactic acid and glycolic acid was 75 mol%: 25 mol% (78.8 wt%: 21.2 wt%).

[0033]

The copolymer of the present invention has a weight average molecular weight of about
It has a high molecular weight of 5,000 to 30,000 and a small degree of dispersion by gel permeation chromatography of about 1.5 to 2. The copolymer of the present invention undergoes polycondensation without using any polymerization catalyst, so that the obtained copolymer does not contain any polymerization catalyst,
Therefore, almost no external coloration is observed.

The copolymer of the present invention can be mainly used as a pharmaceutical preparation base. For example, steroid hormones, peptide hormones, or carcinostatic agents, etc. are contained, and they can be advantageously used as implantable or microcapsule sustained-release preparations, or fine particles containing carcinostatic agents are prepared and embolization therapeutic agents.

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Claims (2)

[Claims] 1. A weight average molecular weight of about 5,000 or more 30,0.
Lactic acid consisting of about 50 to 95% by weight of lactic acid and about 50 to 5% by weight of glycolic acid having a dispersity determined by a gel permeation chromatography method of about 1.5 to 2 and containing no catalyst. Glycolic acid copolymer. 2. A weight average molecular weight of about 5,000 or more 30,0.
A gel permeation chromatograph of less than 00, containing no catalyst
The dispersity determined by the Fee method is about 1.5 to 2,
50-95 wt% and glycolic acid about 50-5 wt%
Lactic acid / glycolic acid
A base for bioabsorbable pharmaceutical preparations .