JPH111443A - New polymer and medicine using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new copolymer capable of being mainly utilized as a base material for preparing pharmaceutical preparations, because the copolymer is produced by polycondensation reaction without using a polymerization catalyst and thereby never contains the polymerization catalyst, and to obtain a medicine containing the copolymer. SOLUTION: This lactic acid-glycolic acid copolymer is useful as a polymer for biologically absorbable pharmaceutical preparations, has a weight-average mol.wt. of 5,000-30,000, never contains a catalyst, has a dispersion degree of about 1.5-2 determined by gel permeation chromatography, and comprises about 50-95 wt.% of lactic acid and about 50-5 wt.% of glycolic acid. The copolymer can advantageously be utilized, e.g. for embedded type or microcapsule type sustained release preparations containing steroid hormones, peptide hormones, anticancer agents, etc., or for embolism medicines comprising particles containing anticancer agents.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

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

For the purpose described above, Japanese Patent Application 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 35,000.
It is stated that a polymer substantially free of a polymerization catalyst can be obtained.

However, the polymer produced by the above method has a large molecular weight dispersity determined by gel permeation chromatography of about 3 or more.
Factors are complicated in solubility and other aspects, and there are many problems in control. Therefore, it is not very preferable when used as a polymer for a bioabsorbable pharmaceutical preparation. Moreover, in this method, the strongly acidic ion exchange resin used as the polymerization catalyst is degraded by heat during the heat polycondensation reaction, and is dissolved in the obtained polymer, which appears as a coloration of the polymer. Furthermore, it is difficult to remove such coloration from the once colored polymer, and it is practically impossible to completely remove it. Such coloring not only lowers the commercial value but also is not preferable because it is caused by impurities.

[0005]

SUMMARY OF THE INVENTION In view of the above circumstances, the present inventors have conducted intensive studies on a method for producing a copolymer of lactic acid and glycolic acid which is effective and free from the above-mentioned disadvantages. By subjecting the low molecular weight polymer or copolymer to a polycondensation reaction in which the polymer or copolymer is heated under reduced pressure without a catalyst, the weight-average molecular weight is as large as about 5,000 to 30,000 and the dispersity by gel permeation chromatography is about
The present inventors have found that a colorless to almost white copolymer which is as small as 1.5 to 2 and does not contain any polymerization catalyst can be obtained. As a result of further studies based on this, the present invention has been completed.

[0006]

The present invention comprises the following constitutions (1) to (8). (1) About 50 to 95% by weight of lactic acid and about 50 to 5% of lactic acid having a weight average molecular weight of about 5,000 to 30,000, containing no catalyst, and having a dispersity of about 1.5 to 2 determined by gel permeation chromatography. Lactic acid / glycolic acid copolymer consisting of% by weight.

(2) Weight average molecular weight of about 5,000 to 30,000
In the following, no catalyst was contained, the degree of dispersion determined by gel permeation chromatography was about 1.5 to 2, and lactic acid was about 50 to 95
Lactic acid consisting of 50% by weight and about 50 to 5% by weight of glycolic acid
A base for a bioabsorbable pharmaceutical preparation, comprising a glycolic acid copolymer.

(3) Weight average molecular weight of about 5,000 to 30,000
Below, the catalyst and its heat degradation products are not included at all, and the degree of dispersion determined by gel permeation chromatography is about 1.
About 50-95% by weight of lactic acid and about 5
A lactic acid / glycolic acid copolymer comprising 0 to 5% by weight.

(4) Weight average molecular weight of about 5,000 to 30,000
Below, the catalyst and its heat degradation products are not included at all, and the degree of dispersion determined by gel permeation chromatography is about 1.
5-2, lactic acid about 50-95% by weight and glycolic acid about 50-
A base for a bioabsorbable pharmaceutical preparation, comprising 5% by weight of a lactic acid / glycolic acid copolymer.

(5) Weight average molecular weight of about 5,000 to 30,000
Below, the catalyst and its heat degradation products are not included at all, and the degree of dispersion determined by gel permeation chromatography is about 1.
About 50-95% by weight of lactic acid and about 5
A colorless to almost white lactic acid / glycolic acid copolymer comprising 0 to 5% by weight.

(6) Weight average molecular weight of about 5,000 to 30,000
Below, the catalyst and its heat degradation products are not included at all, and the degree of dispersion determined by gel permeation chromatography is about 1.
5-2, lactic acid about 50-95% by weight and glycolic acid about 50-
A base for a bioabsorbable pharmaceutical preparation, comprising 5% by weight of a colorless to almost white lactic acid / glycolic acid copolymer.

(7) Weight average molecular weight of about 5,000 to 30,000
In the following, about 50% of lactic acid containing no catalyst and having a dispersity of about 1.5 to 2 determined by gel permeation chromatography is used.
A medicament comprising as a base a lactic acid / glycolic acid copolymer consisting of about 95% by weight and about 50-5% by weight of glycolic acid.

(8) Weight average molecular weight of about 5,000 to 30,000
In the following, about 50% of lactic acid containing no catalyst and having a dispersity of about 1.5 to 2 determined by gel permeation chromatography is used.
~ 95% by weight and about 50-5% by weight of glycolic acid,
A medicament containing a colorless to almost white lactic acid / glycolic acid copolymer as a base.

In the production of the copolymer of the present invention, lactic acid used as a raw material is usually arbitrarily selected from various concentrations of lactic acid aqueous solution. From the viewpoint of workability, the higher the lactic acid concentration, the better. % Or more is desirable. Needless to say, it is better to use lactic acid itself instead of an 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 lactic acid and glycolic acid are used as solids such as crystals, a solvent that dissolves them may be used if necessary. Examples of the solvent include water, methanol, ethanol, acetone and the like.

In producing the copolymer of the present invention, lactic acid and glycolic acid used as raw materials include a low molecular weight polymer of lactic acid, a low molecular weight polymer of glycolic acid, and a low molecular weight copolymer 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
The water may be removed by performing a 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, a molecular weight of about 2,2
000-4,000 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 one obtained by polycondensation by a known method carried out without a catalyst. As the known method, for example, a method described in Kogaku Kagaku Zasshi, Vol. 68, pp. 983-986 (1965), that is, lactic acid and glycolic acid are reacted under normal pressure without a catalyst.
A method of reacting at 202 ° C. for 6 hours may be used. Further, as the known method, for example, a method described in U.S. Pat. No. 2,362,511, that is, lactic acid and glycolic acid
A method in which the reaction is carried out at a temperature of 200 ° C. for 2 hours, and then heating is continued under reduced pressure for 1/2 hour, may be mentioned.

In the copolymer of the present invention, the ratio of lactic acid and glycolic acid is about 50 to 95% by weight of lactic acid and about 50% by weight of glycolic acid.
-5% by weight, preferably about 60-95% by weight lactic acid and about 40-5% by weight glycolic acid, more preferably about 60-85% lactic acid.
% By weight and about 40 to 15% by weight of glycolic acid. A particularly preferred ratio of lactic acid to glycolic acid is about lactic acid.
75 ± 2 mol% and about 25 ± 2 mol% of 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 more, preferably about 10 to 150 hours, and more preferably about 10 to 100 hours.

When lactic acid and glycolic acid are used as starting materials, the following reaction conditions are preferred. For example, at 100 to 150 ° C./350 to 30 mmHg for 2 hours or more, usually about 2 to 10 hours, for example, from 105 ° C./350 mmHg to 150 ° C./3
5-6 while increasing the temperature and the degree of decompression gradually to 0 mmHg
After removing water by heating under reduced pressure for 10 hours, the temperature is reduced to 150-200 ° C / 10-1 mmHg for 10 hours or more (usually 100
Dehydration polycondensation reaction may be performed.

The reaction conditions when the above-mentioned low molecular weight polymer or copolymer is used as a starting material are preferably as follows. That is, for example, 150 to 200 ° C./10 to 1
The dehydration polycondensation reaction may be carried out at 10 mmHg or more (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 a suitable solvent such as methylene chloride, dichloroethane, chloroform, acetone or the like (using the same amount to about 10 times the amount of the polymer). By removing the dust by dissolving and filtering, etc., the former, ie, when the reaction solution is filtered as it is, by itself, and the latter, ie, when the reaction solution is dissolved and filtered, by concentrating and distilling the solvent used. The desired high molecular weight copolymer can be easily obtained. Also,
If necessary, the filtered reaction solution may be separated directly or, if a solvent is used, the concentrated filtrate may be separated by a conventional method such as pouring into a large amount of a precipitating agent. And the like. Hereinafter, the present invention will be described in more detail with reference to Experimental Examples and Examples.

[0024]

【Example】

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

Table 1 shows the relationship between the reaction time and the achieved weight average molecular weight in the production of a copolymer of lactic acid and glycolic acid according to the present method.

For comparison, Table 1 also shows the results obtained when Dowex 50W (a registered trademark of Dow Chemical Co., USA) was used as a polymerization catalyst. .

[0027]

[Table 1] *: The copolymer obtained at each reaction time was dissolved in 4 times the amount of methylene chloride, filtered, concentrated and the solvent was distilled off. The obtained copolymer was subjected to JIS K8004-2 ( That is, about 3 g of a sample was placed on a watch glass and examined on a white sheet of 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 having a known molecular weight.

As apparent 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. No coloring is observed in the polymer, and a polymer having a small molecular weight dispersity of 2 or less is obtained.

Table 2 shows the results of analyzing the copolymer composition of lactic acid and glycolic acid by nuclear magnetic resonance spectroscopy using the above-obtained copolymer of the present invention as a heavy chloroform solution.

[0031]

[Table 2]

Embodiment 1 In a four-necked flask equipped with a thermometer, a condenser, and a nitrogen inlet tube, 191 g of an 85% aqueous lactic acid solution and 17.5 g of glycolic acid are taken. Heating under reduced pressure was performed over time to remove distillate water. Subsequently, the pressure was reduced 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 as a copolymer of lactic acid and glycolic acid, 140 g of an almost colorless bulky polymer was obtained.
I got The weight average molecular weight and the degree of dispersion of the copolymer are 22,0
00 and 1.70. The weight average molecular weight and the degree of dispersion were determined by gel permeation gel chromatography (the same applies hereinafter). Further, the obtained copolymer was analyzed by a nuclear magnetic resonance spectrum as a deuterated chloroform solution. As a result, 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 an 85% aqueous lactic acid solution and 17.5 g of glycolic acid, 6.8 g of Dowex 50W (cross-linked polystyrene resin), which is a commercially available strongly acidic ion exchange resin, was added. Under the conditions, the internal temperature and the internal pressure were increased from 105 mm and 350 mmHg to 150 ° C and 30 mmHg, respectively, under reduced pressure for 6 hours to remove distillate water. Further, 6.8 g of Dowex 50W was added to reduce the degree of decompression to 3 mmHg.
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 1 having a weight average molecular weight of 23,700 and a dispersity of 2.88.
31 g were obtained, but the polymer was colored brown. Incidentally, the composition of lactic acid and glycolic acid in the obtained copolymer is 88.5
Mol%: 11.5 mol% (90.5 wt%: 9.5 wt%).

Embodiment 2 FIG. In the same polymerization apparatus as in Example 1, 85
A 106% aqueous solution of lactic acid and 76 g of glycolic acid were taken and the internal temperature and internal pressure were increased from 105 ° C and 350 mmHg, respectively, under a nitrogen stream.
The mixture was heated under reduced pressure to 150 ° C. and 30 mmHg for 3 hours to remove distillate water. Continue to reduce the pressure to 3 mmHg and set the internal temperature to 18 mmHg.
Heating was performed at 0 ° C. for 36 hours. The reaction solution was cooled to room temperature to obtain 124 g of a substantially colorless bulky polymer as a copolymer of lactic acid and glycolic acid. The weight average molecular weight and the degree of dispersion of the copolymer were 15,300 and 1.73. Further, the obtained copolymer was analyzed by a nuclear magnetic resonance spectrum as a heavy chloroform solution. As a result, the composition of lactic acid and glycolic acid in the copolymer was 50.5 mol%: 49.5 mol% (55.9 wt%: 44.1 mol%).
Wt%).

Example 3 A heating reaction was carried out at 202 ° C. for 6 hours using 146 g of a 93% aqueous lactic acid solution and 38 g of glycolic acid, with a weight average molecular weight of 2,700 and a copolymer composition lactic acid: glycolic acid = 75 mol%: 25 mol% Was obtained. Using 100 g of the copolymer thus obtained, 5 mmHg, 175
The reaction was performed 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 bulky 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
75.5 mol%: 24.5 mol% (79.3 wt%: 20.7 wt%).

Embodiment 4 FIG. In the same polymerization apparatus as in Example 1, 97 g of lactic acid dimer (lactic acid lactate) and glycolic acid 2
A monomer (glycolic acid glycolate) (54 g) was taken and subjected to a reduced pressure / heat reaction at 180 ° C. and 5 mmHg directly under a nitrogen stream for 48 hours. The reaction solution was cooled to room temperature to obtain 105 g of an almost white block copolymer as a copolymer of lactic acid and glycolic acid. The weight average molecular weight and the degree of dispersion of the copolymer are respectively
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%).

Embodiment 5 FIG. In the same polymerization apparatus as in Example 1,
3337 g (33 mol) of 89% lactic acid aqueous solution and glycolic acid 83
6 g (11 mol) was taken and heated under reduced pressure from 350 mmHg to 150 ° C and 30 mmHg for 6 hours at 100 ° C and 350 mmHg in a nitrogen stream to remove distillate. Subsequently, the pressure was reduced 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 the degree of dispersion 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%).

[0038]

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 of about 1.5 to 2 by gel permeation chromatography. Since the copolymer of the present invention is polycondensed without using any polymerization catalyst, the obtained copolymer does not contain any polymerization catalyst,
Therefore, almost no external coloring is observed.

The copolymer of the present invention can be used mainly as a pharmaceutical preparation base. For example, a steroid hormone, a peptide hormone, an anticancer agent, or the like is contained therein, and it can be advantageously used as an implantable or microcapsule-type sustained-release preparation, or as a microparticle containing an anticancer agent, as an embolic therapeutic agent.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Toshio Watanabe 2--12-10 Kasumigas Kanto, Kawagoe-shi, Saitama

Claims (8)

[Claims] 1. Lactic acid having a weight average molecular weight of about 5,000 to 30,000, containing no catalyst, and having a dispersity of about 1.5 to 2, as determined by gel permeation chromatography, of about 50 to 95 lactic acid.
Lactic acid consisting of 50% by weight and about 50 to 5% by weight of glycolic acid
Glycolic acid copolymer. 2. A polymer having a weight average molecular weight of about 5,000 to 30,000, containing no catalyst, having a dispersity of about 1.5 to 2 determined by gel permeation chromatography, about 50 to 95% by weight of lactic acid and about 50 A base for a bioabsorbable pharmaceutical preparation, comprising a lactic acid / glycolic acid copolymer comprising up to 5% by weight. 3. A catalyst having a weight-average molecular weight of about 5,000 to 30,000, containing no catalyst or heat degradation products, and having a dispersity of about 1.5 to about 1.5 determined by gel permeation chromatography.
2, about 50-95% by weight of lactic acid and about 50-
Lactic acid / glycolic acid copolymer comprising 5% by weight. 4. A polymer having a weight-average molecular weight of about 5,000 to 30,000, containing no catalyst or heat degradation products, and having a dispersity of about 1.5 to about 1.5 determined by gel permeation chromatography.
2. A base for a bioabsorbable pharmaceutical preparation, comprising a lactic acid / glycolic acid copolymer comprising about 50 to 95% by weight of lactic acid and about 50 to 5% by weight of glycolic acid. 5. A catalyst having a weight-average molecular weight of about 5,000 to 30,000, containing no catalyst or heat degradation products, and having a dispersity of about 1.5 to about 1.5 determined by gel permeation chromatography.
2, about 50-95% by weight of lactic acid and about 50-
A colorless to almost white lactic acid / glycolic acid copolymer comprising 5% by weight. 6. A catalyst having a weight average molecular weight of about 5,000 to 30,000, containing no catalyst or heat degradation products, and having a dispersity of about 1.5 to about 1.5 determined by gel permeation chromatography.
2. A base for a bioabsorbable pharmaceutical preparation, comprising a colorless to almost white lactic acid / glycolic acid copolymer comprising about 50 to 95% by weight of lactic acid and about 50 to 5% by weight of glycolic acid. 7. Lactic acid having a weight average molecular weight of about 5,000 to 30,000, containing no catalyst, and having a dispersity of about 1.5 to 2, as determined by gel permeation chromatography, of about 50 to 95 lactic acid.
Lactic acid consisting of 50% by weight and about 50 to 5% by weight of glycolic acid
A medicament comprising a glycolic acid copolymer as a base. 8. Lactic acid having a weight average molecular weight of about 5,000 to 30,000, containing no catalyst, and having a dispersity of about 1.5 to 2, as determined by gel permeation chromatography, of about 50 to 95 lactic acid.
A colorless or almost white lactic acid / glycolic acid copolymer as a base, comprising about 50 to 5% by weight of glycolic acid and about 50 to 5% by weight of glycolic acid.