JPS61111326A - Novel polymer and its production - Google Patents

Abstract

PURPOSE:To obtain the titled colorless or substantially white polymer having a high MW and a small dispersion and containing no polymerization catalyst, by polycondensing lactic acid and/or glycolic acid in the presence of an inorganic solid acid catalyst. CONSTITUTION:Lactic acid and/or glycolic acid which are selected according to the purpose of use are polycondensed at 100-150 deg.C and a pressure of 350-30mmHg for at least 2hr in the absence of any catalyst to obtain a low- molecular (co)polymer of a MW of 2,000-4,000. Lactic acid and/or glycolic acid selected according to the purpose from among lactic acid (a highly concentrated aqueous solution), glycolic acid (an aqueous solution) and said (co)polymer are polyconensed at 150-250 deg.C and a pressure of 30-1mmHg for at least 10hr in the presence of 0.5-30wt% inorganic solid acid catalyst (e.g., acid clay) in, optionally, solvent (e.g., water) to obtain a (co)polymer of lactic acid and/or glycolic acid of a weight-average MW >=about 5,000 and a dispersion of about 1.5-2.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a polymer of lactic acid, a polymer of glycolic acid, or a copolymer of lactic acid and glycolic acid (hereinafter collectively referred to as polylactic acids), and a method for producing the same. .

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

For the purpose mentioned above, Japanese Patent Application Laid-Open No. 56-459
No. 20 discloses a method of polymerizing lactic acid and glycolic acid in the presence of a strongly acidic ion exchange resin, and according to the method, the am average molecular weight is about s, ooo to 35.
It is said that a polymer substantially free of polymerization catalyst can be obtained.

However, the polymer produced by the above method has a large molecular weight dispersity of around 3 or more, and when used,
Factors related to solubility and other aspects are complicated, and there are many problems in control, so this method is not very desirable when used as a polymer for bioabsorbable pharmaceutical preparations.Moreover, this method The strongly ugly ion exchange resin used as a polymerization catalyst is degraded by heat during the heated polycondensation reaction, and dissolved into the resulting polymer, which appears as coloration of the polymer. Yet again. It is difficult to remove such coloring from a polymer once it has been colored, and it is practically impossible to completely remove it.Such coloring not only reduces commercial value, but is also caused by impurities. Needless to say, this is an unfavorable situation.

In view of this situation, the present inventors have conducted intensive research on a production method for polylactic acids that is effective and does not have the drawbacks mentioned above. By carrying out a condensation reaction, the weight average molecular weight is as large as about 5,000 or more, and the degree of dispersion is about 1.5 to
It was discovered that colorless to almost white polylactic acids having a small size of 2 and containing no or substantially no polymerization catalyst can be obtained. Based on this, further research was conducted, and the present invention was completed. completed.

The present invention consists of (1) lactic acid and/or glycolic acid, has a weight average molecular weight of about 5,000 or more, and has a dispersity of about 1.5 to
(2) A polymer of lactic acid or glycolic acid or a copolymer thereof, and (2) Polycondensation of lactic acid and/or glycolic acid to produce a high molecular weight polymer. It is characterized by the use of This is a method for producing a polymer of lactic acid or glycolic acid or a copolymer thereof.

In the method for producing polylactic acids of the present invention, lactic acid aqueous solutions of various concentrations are usually arbitrarily selected as the lactic acid used as a raw material, but from the viewpoint of workability, the higher the lactic acid concentration, the better;
It goes without saying that 85% or more is desirable, and if available, it is better to use lactic acid rather than an aqueous solution.

In addition, as for glycolic acid, crystalline ones are usually used as they are, but there is no problem even if they are used as an aqueous solution.When using lactic acid and glycolic acid in solid forms such as crystals, if necessary, A solvent that dissolves water may be used. Examples of the solvent include water and methanol.

Examples include ethanol and acetone.

In the method for producing polylactic acids of the present invention, low-molecular polymers thereof may be used as lactic acid and/or glycolic acid used as raw materials.

In addition, when obtaining copolymers, these low-molecular copolymers
, polymers may be used.

Examples of compounds containing low molecules in 1 include lactic acid oligomers (eg, dimers, trimers, etc.) and glycolic acid oligomers (eg, dimers, trimers, etc.).

Examples of the low-molecular polymer or copolymer include those obtained by polycondensing lactic acid and/or glycolic acid in the absence of a catalyst.

The reaction temperature and reaction time when producing the low-molecular compound or low-molecular copolymer are, for example, 100 to 10 hours, e.g., 105°C/350-■H, to 150"Q/30mm. ) Water can be removed by heating under reduced pressure for 5 to 6 hours while gradually increasing the temperature and degree of vacuum to Ig. A copolymer can be easily obtained.

In addition, the low molecular weight polymer or low molecular weight copolymer may include y
! 4. It may be obtained by polycondensation using a known method using a catalyst, such as the method described in 1 or Kagaku Zasshi Vol. 88, pp. 983-98B (1985); and glycolic acid are reacted at 202° C. for 6 hours using a pyrocatalyst under a pressure of 1≦5. Further, as the known method, 1, for example, US Patent No. 2.3
The method described in Publication No. 82.511.

That is, a method may be mentioned in which milk and glycolic acid are reacted at a temperature of 200° C. for 2 hours, followed by lowering the pressure and continuing heating for a period of time.

The polylactic acids according to the present invention are a polymer of lactic acid alone, a polymer of glycolic acid accompanied by glycolic acid, or an arbitrary ratio of lactic acid and glycolic acid, preferably 50 to 95 tons of lactic acid. % and glycolic acid about 50-5%,
More preferably about 80 to 95% lactic acid and about 40 to 5% by weight of glycol, still more preferably 60 to 8% by weight of lactic acid.
It consists of a copolymer of lactic acid and glycolic acid with 1% of glycol and 40 to 15% of glycol. Particularly preferred ratios in the copolymer of lactic acid and glycolic acid include about 75±2 mole percent milk and about 25±2 mole percent glycol.

Examples of the inorganic solid acid catalyst used in the present invention include II* clay, activated clay, bentonite, kaolin, talc, aluminum silicate, magnesium silicate, alumina boria, and silicate. These can be used alone or in a mixture of two or more, and either can be used as is, or if necessary, in order to remove metal ions, etc., for example, about 5
It is used after washing with ~20% hydrochloric acid.

The amount of inorganic solid acid catalyst used in the present invention is based on m; a of lactic acid and/or glycolic acid.

Usually 0.5N 30% W/W, preferably about 1-20%
Approximately W/r is used in one to several times. The catalyst may be added to the reaction system during the reaction.

The reaction temperature in the polycondensation reaction of the present invention is typically 150 to 250°C, preferably about 150 to 200°C.
℃ is preferably carried out under reduced pressure, for example, the reduced pressure is usually 30 to 1 mmHg, preferably about 10 to 1 msHg.
For example, the reaction time is usually about 10 hours or more,
Preferably about 10 to 150 hours, more preferably about 10
~100 hours.

When lactic acid and/or glycolic acid is used as a raw material, primary reaction conditions are preferred6.For example,
100N 150℃/350~30msHg for 2 hours Amount E1 Usually about 2~1O hours 1 For example, 105"C
/ 350ms) After removing moisture by heating under reduced pressure for 5 to 6 hours while gradually increasing the temperature and degree of vacuum from Ig to 150℃ and 730mmHg,
b) Allow for a dehydration polycondensation reaction.

Also, the reaction conditions when using the low-molecular polymers or copolymers mentioned above as raw materials are as follows.

The following are preferred, ie, 1, for example, up to about 150 to 150 b) dehydration ff1m.

After the reaction is completed, the reaction solution is simply subjected to heat treatment, or the polymer is dissolved in an appropriate solvent such as methylene chloride, dichloroethane, chloroform, acetone, etc. (use the same amount to 10 times the amount of the polymer). If the solid acid catalyst used is removed by passing it through a
(can be easily removed by suction filtration using paper, etc.), in the former case, when the reaction liquid is filtered as it is, it is by itself, and in the latter case, when the reaction liquid is dissolved in a solvent and filtered, the solvent used can be removed. By concentrating and distilling off, the desired high molecular weight polymilk # can be easily obtained. If necessary, the filtered reaction solution may be separated directly, or if a solvent is used, the concentrated solution may be separated by a conventional method such as pouring into a large amount of precipitant, or if necessary. If the ion exchange resin is used as a catalyst, the coloring cannot be easily removed even if such operations are repeated.

According to the present invention, high molecular weight polylactic acids having a weight average molecular weight of about s, ooo or more (preferably about 5.CIQO to 3o, ooo) can be obtained, and the obtained polymer has a dispersity of about 1.00. It is as small as 5 to 2, and almost no coloration is observed in appearance, and it contains no or substantially no polymerization catalyst.

According to the present invention, its production can be easily carried out industrially. Furthermore, since the polymerization catalyst used does not dissolve in either polylactic acids or solvents, it can be completely removed from the product. Therefore, it is possible to easily obtain a high molecular weight polymer with a small dispersity of about 1.5 to 2, with substantially no polymerization catalyst mixed into the obtained polymer, and with almost no coloring of the polymer. I can do it.

Since the method of the present invention uses an inorganic solid acid catalyst, it has the advantage that the reaction time can be shortened compared to when the reaction is carried out without a catalyst. That is, the method of the present invention allows a polymer or copolymer of the same molecular weight to be obtained in a shorter reaction time than in the case of no catalyst.

The polymer or copolymer of the present invention can be mainly used as a pharmaceutical formulation base.For example, it can be used as an implantable or microcapsule sustained-release preparation containing steroid hormones, peptide hormones, or anticancer drugs. Alternatively, fine particles containing an anticancer agent can be produced and used advantageously as an embolism treatment agent.

The present invention will be explained in further detail by giving experimental examples and examples below.

Experimental example 1. (Lactic acid homopolymerization) 85% lactic acid aqueous solution 180g (As lactic acid!, 5■o
6.8g of inorganic solid acid catalyst was added to 1) under a nitrogen stream for 100~! Distillate wood was removed by stepwise heating under reduced pressure for 6 hours at 50"C/350-30am) Ill. After that, 6.8g of solid acid catalyst was added, and the mixture was heated at 175°C/6-5am) for 72 hours. Dehydration was caused by a condensation reaction.

Reaction time and attainment f in lactic acid polymer production according to this magazine
The relationship between fi weight and average molecular weight is shown in Table 1.

For comparison, Table 1 also shows the results obtained when DOWEX 50W (manufactured by Dow Chemical Company (USA), registered trademark), which is a commercially available strongly acidic ion exchange resin, was used as a single polymerization catalyst.

In addition, in this specification, the weight average molecular weight and dispersity (dispersity! weight average molecular weight / number average molecular weight) are measured by the gel permeation clobutythphy method using standard polystyrene with known molecular members, I asked for it.

In the table, catalyst addition M(1) is the initial amount of catalyst added.

Catalyst addition amount (2) is 175℃ 76~5 layer s after moisture removal
) Represents the amount of catalyst added at the start of the polycondensation reaction with Ig, and the reaction time is! 75° C./6 to 5 layers (■) It represents that in Ig, and the value in parentheses under the molecular light in the table represents the degree of dispersion.

As is clear from Table 1, according to the present invention, the polymerization catalyst can be easily dissolved, and the average molecular weight of g11 is approximately s, oo.
It is possible to obtain a high molecular weight polylactic acid having a molecular weight of more than It was clearly promoted by the addition of catalyst.

Experimental example 2. (Lactic acid/glycolic acid co-composition) 85% lactic acid aqueous solution 180 g (1.5 mol) and glycolic acid 38
g (0,5o1) and add 1 liter of inorganic solid to this.
Add 8.7g of
Distilled water was removed by heating under reduced pressure at 7350°C to 30mm Hg for 6 hours, and solid acid catalyst 8.78 was added to the next page, and heated at 175°C 76 to 5 mmHl.
A dehydration condensation reaction was carried out for 72 hours.

The relationship between the reaction time and the uniform molecular damage achieved in the production of a copolymer of lactic acid and glycolic acid by Honbo is shown in i&2.

For comparison, Table 2 also shows the results when a strongly acidic ion exchange resin (Dowex 50W) was used as the single polymerization catalyst.

In Table 2, the amount of catalyst added (1) is the initial amount of catalyst added, and the amount of catalyst added (2) is 175℃/6-5 mmH after moisture removal.
The amount of catalyst added at the start of the polycondensation reaction at 100 g is shown, and the reaction time is that at 175 ° C / 6 ~ 5 + zHg. In addition, the values in parentheses under the molecular weight reached in the table are the dispersion. represents degree.

As is clear from Table 2, according to the present invention, polymerization catalysts having a weight average molecular weight of about 5,000, with almost no dissolved polymerization catalyst, can easily be used.
A high molecular weight lactic acid glycolic acid copolymer with a molecular weight of
A small molecular weight dispersity of 2 or less can be obtained in all cases. Furthermore, the reaction rate of the monopolymerization reaction was clearly promoted by the addition of the catalyst.

The copolymer composition of lactic acid and glycolic acid was analyzed by nuclear magnetic resonance spectroscopy using the copolymer of the present invention as a solution in deuterated chloroform, and the results were shown to the FC engineer. (Lactic acid nigericolic acid) Mol% (fE amount%) Example 1 In a four-necked flask equipped with a thermometer, a condenser, and a nitrogen inlet tube, 180 g of an 85% lactic acid aqueous solution and acidic -± 13
．． 8. was added, and the internal temperature and pressure were adjusted to 105℃ and 350mmH1 to 150℃ and 30a* under a nitrogen flow, respectively.
While gradually increasing the temperature and degree of vacuum until Hg,
.

Distilled water was removed by heating under reduced pressure for 6 hours. Subsequently, the internal pressure was set to 3 Mug, and the reaction solution was heated at an internal temperature of 175°C for 50 hours, then cooled to room temperature, 400 ml of methylene chloride was added, and after stirring and dissolving, the acid clay was filtered (Toyo Roshi Fk), 131) and the filtrate was concentrated to dryness to obtain 100 g of an almost white polymer. The weight average molecular weight and dispersity of this polymer are 22 and 22, respectively.
000 and 1.75.

Regarding the residual catalyst in the obtained copolymer, the copolymer was placed on a platinum Petri dish and subjected to a sodium carbonate melting treatment, and then the aluminone method and molybdenum blue method were applied to aluminum and silicon, respectively. As a result of colorimetric determination, none were detected, and no catalyst was observed.

Example 2゜Aluminum silicate as catalyst 2? , 2. Except using
All Example 1. The reaction was carried out in the same manner as 92. to produce an almost colorless polymer. I got it. The weight average molecular weight and dispersity of this polymer were 21.900 and 1.70, respectively.

The same result was obtained even when kaolin or talc was used as the catalyst. Regarding the residual catalyst in the obtained copolymer, see Example 1. As a result of detecting the remaining catalyst in the same manner as above, no catalyst was detected.

Example 3゜Example 1. Similarly, 85% lactic acid aqueous solution 180. , charged 6.8 g of activated clay instead of acid clay, and after removing distilled water, heated the reaction at an internal pressure of 5 m+*Hg and an internal temperature of 1.
After 86 hours at 85° C., 80 g of an almost white polymer was obtained. The weight average molecular weight and dispersity of this polymer were 29.80O and 1.85, respectively. ·still,
Regarding the residual catalyst in the obtained copolymer, see Example 1.
．． As a result of detecting the remaining catalyst in the same manner as above, no catalyst was detected.

Example 4 The reaction was carried out in the same manner as in Example 1, except that 180 g of 85% lactic acid aqueous solution, 38 g of glycolic acid and 17.4 g of activated clay were used, and an almost white copolymer 122 was obtained.
, g was obtained. The weight average molecular weight and dispersity of this copolymer were 20, 100 and 1.70, respectively. Furthermore, as a result of analyzing the obtained copolymer as a deuterated chloroform solution by nuclear magnetic resonance spectroscopy, what is the copolymer composition of lactic acid and glycolic acid? E1mo1%: 24mo1% (7L7
ilJi%: 20.331ft%)
=.

Regarding the residual catalyst in the obtained copolymer, see Example 1. As a result of detecting the remaining catalyst in the same manner as above, no catalyst was detected.

Example 5 191 g of 85% lactic acid aqueous solution, and 17 g of glycolic acid.
After charging 5 g and 8 g of acid clay and removing distilled water, the heating reaction was carried out at an internal pressure of 3 m) Ig and an internal temperature of 170°C.
After 6 hours, 130 g of an almost white copolymer was obtained. The weight average molecular weight and dispersity of this copolymer are each 2
11,100 and 1.73, and the copolymerization composition of lactic acid and glycolic acid is 88μ01%:11ma1% (
9G, 9% by weight: 8.1% by weight).

Similar reactions and results were obtained when aluminum silicate, bentonite, and kaolin were used as catalysts.

Regarding the residual catalyst in the obtained copolymer, 1
Example 1. As a result of detecting the remaining catalyst in the same manner as above, no catalyst was detected.

Example 6 Using 93% lactic acid aqueous solution 14B and glycolic acid 388, a heating reaction was carried out at 202°C for 6 hours to obtain a weight average molecular weight of 2,700 and a copolymer composition of lactic acid nigericolic acid +
*? 5molX: A 25mall copolymer was obtained.

Example 1. 100% of the obtained copolymer was added to the same polymerization apparatus as
g and acid clay log were taken, the internal pressure was set to 5 mdlg, the internal temperature was heated at 180°C for 50 hours, the 0 reaction solution was cooled to room temperature, and 500 d of methylene chloride was added.
After stirring and dissolving, the acid clay was removed by filtration (using Toyo Roshi Paper No. 131), and the IP solution was concentrated to dryness to obtain an almost white polymer.82. I got it. The weight average molecular weight and dispersity of this polymer were 23. TOO and 1.73,
Furthermore, what is the copolymerization composition of lactic acid and glycolic acid? 5mol
$: 25molX (78.8 weight 1%: 21.2
weight%).

Regarding the residual catalyst in the obtained copolymer, see Example 1. As a result of detecting the remaining catalyst in the same manner as above, no catalyst was detected.

Example G47゜The reaction was carried out in the same manner as in Example 6, except that 117 g of lactic acid dimer (lactic acid lactate), 117 g of glycolic acid dimer (glycolic acid glycolate), and 7.5 g of acid clay were used. An almost white copolymer 98 was obtained. The weight average molecular weight and dispersity of this copolymer are 21,000 and 1.75, respectively, and the copolymer composition of lactic acid and glycolic acid is 511.5 mol: 40.5
so1% (84, Bji amount%: 35.4% by weight) Tea ivy.

Regarding the residual catalyst in the obtained copolymer, see Example 1. As a result of detecting the remaining catalyst in the same manner as above, no catalyst was detected.

Patent applicant: Takeda Pharmaceutical Company Limited Wako Pure Chemical Industries, Ltd.

Claims (2)

[Claims] (1) Consists of lactic acid and/or glycolic acid, has a weight average molecular weight of about 5,000 or more, and a dispersity of about 1.5 to 2.
Polymers of lactic acid or glycolic acid or copolymers thereof. (2) A polymer of lactic acid or glycolic acid or a copolymer thereof, characterized in that an inorganic solid acid catalyst is used as a catalyst when manufacturing a high molecular weight polymer by polycondensing lactic acid and/or glycolic acid. manufacturing method.