CA1236641A - Copolymer of lactic acid and glycolic acid and method for producing same - Google Patents
Copolymer of lactic acid and glycolic acid and method for producing sameInfo
- Publication number
- CA1236641A CA1236641A CA000486283A CA486283A CA1236641A CA 1236641 A CA1236641 A CA 1236641A CA 000486283 A CA000486283 A CA 000486283A CA 486283 A CA486283 A CA 486283A CA 1236641 A CA1236641 A CA 1236641A
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- CA
- Canada
- Prior art keywords
- copolymer
- weight
- lactic acid
- glycolic acid
- hours
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
Abstract
Abstract of the Disclosure A copolymer of lactic acid and glycolic acid which has a weight-average molecular weight of not less than about 5000 and a dispersity of about 1.5 to 2 is advantageously used as a biode-gradable polymer for medical preparation. According to the invent-ion there is provided a method for producing a copolymer of lactic acid and glycolic acid, the copolymer having a weight-average molecular weight of not less than about 5,000 and a dispersity of about 1.5 to 2, which comprises subjecting lactic acid and glycolic acid or a low molecular polymer or copolymer thereof to a poly-condensation reaction under heating and reduced pressure in the absence of a catalyst.
Description
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The present invention relates to a copolymer of lactic acid and glycolic acid, and a method for producing the copolymer in the absence of a catalyst.
In recent years, degradable polymers have attracted a good deal of attention, for example, as readily degradable polymers serving to mitigate environmental pollution and also as bodyguard-able polymers for medical use.
A method for producing a copolymer of lactic acid and glycolic acid, is disclosed in U.S. Patent Jo. 4,273,920. In said U.S. Patent, it is stated thatacopolymer substantially free of polymerization catalyst is obtained by reacting lactic acid with glycolic acid in the presence of a readily removable strong acid ion-exchange resin, and removing the resin therefrom.
However, the copolymers produced by the above-described method all exhibit a dispersi-ty in molecular weight as high as nearly 3 or more, and in use, give great complexity in factors involving volubility and other aspects, thus preventing major problems in controlling such factors. Therefore, they cannot be said to be very favorable, when they are used, for example, as a biodegradable polymer for medical use. In addition, this method allows the strong acid ion-exehange resin being used as a polymerization catalyst to deteriorate due to heat during a polyp condensation reaction under heating and to get dissolved in the resulting copolymer, thereby contributing to the development of coloration of the eopolymer. Furthermore, it is difficult to eliminate such coloration, and it is practically impossible to . Ye , . .
~3~6~
remove such coloration completely, and the coloration shows that the catalyst, i.e. the strong acid ion-exchange resin, cannot be completely removed. Such coloration not only diminishes value as an article of commerce but also is undesirable by virtue of its impurities.
In view of such circumstances, the present inventors conducted repeatedly intensive research on the method for ; producing a copolymer of lactic acid and glycolic acid, which is effective and substantially free from the above-mentioned disk advantages, and have found that the desired copolymer of lactic acid and glycolic acid is obtained by a polycondensation of these ; compounds in the absence of a catalyst. The present inventors conducted further research and have completed the present invent lion.
The present invention is directed to:
(1) A copolymer of lactic acid and glycolic acid, which has a weight-average molecular weight of about 5,000 to 30,000 and a dispersity of about 1.5 to 2, and
The present invention relates to a copolymer of lactic acid and glycolic acid, and a method for producing the copolymer in the absence of a catalyst.
In recent years, degradable polymers have attracted a good deal of attention, for example, as readily degradable polymers serving to mitigate environmental pollution and also as bodyguard-able polymers for medical use.
A method for producing a copolymer of lactic acid and glycolic acid, is disclosed in U.S. Patent Jo. 4,273,920. In said U.S. Patent, it is stated thatacopolymer substantially free of polymerization catalyst is obtained by reacting lactic acid with glycolic acid in the presence of a readily removable strong acid ion-exchange resin, and removing the resin therefrom.
However, the copolymers produced by the above-described method all exhibit a dispersi-ty in molecular weight as high as nearly 3 or more, and in use, give great complexity in factors involving volubility and other aspects, thus preventing major problems in controlling such factors. Therefore, they cannot be said to be very favorable, when they are used, for example, as a biodegradable polymer for medical use. In addition, this method allows the strong acid ion-exehange resin being used as a polymerization catalyst to deteriorate due to heat during a polyp condensation reaction under heating and to get dissolved in the resulting copolymer, thereby contributing to the development of coloration of the eopolymer. Furthermore, it is difficult to eliminate such coloration, and it is practically impossible to . Ye , . .
~3~6~
remove such coloration completely, and the coloration shows that the catalyst, i.e. the strong acid ion-exchange resin, cannot be completely removed. Such coloration not only diminishes value as an article of commerce but also is undesirable by virtue of its impurities.
In view of such circumstances, the present inventors conducted repeatedly intensive research on the method for ; producing a copolymer of lactic acid and glycolic acid, which is effective and substantially free from the above-mentioned disk advantages, and have found that the desired copolymer of lactic acid and glycolic acid is obtained by a polycondensation of these ; compounds in the absence of a catalyst. The present inventors conducted further research and have completed the present invent lion.
The present invention is directed to:
(1) A copolymer of lactic acid and glycolic acid, which has a weight-average molecular weight of about 5,000 to 30,000 and a dispersity of about 1.5 to 2, and
(2) A method for producing a copolymer of lactic acid and glycolic acid, the copolymer having a weight-average molecular weight of not less than about 5,000 and a dispersity of about 1.5 to 2, which comprises subjecting lactic acid and glycolic acid or a low molecular polymer or copolymer thereof to a polycondensation reaction under heating and reduced pressure in the absence of a catalyst.
,,, -: - .
.
aye In the method of the present invention, lactic acid and glycolic acid are employed, as the starting materials, in the form of crystals, powders or granules as such, or in the form of an aqueous solution. The concentration of the solution is arbiter-rile selected, preferably as high as possible, and more preferably not lower than 85% (w/w).
The low molecular polymer of lactic acid or glycolic acid, may be an oligomer (e.g. diver, triter, etc.) of lactic acid, or glycolic acid Such a low molecular polymer or copolymer starting mater-tat of lactic acid and glycolic acid, may be produced by subjecting lactic acid and/or glycolic acid to a polycondensation reaction in the absence of a catalyst at, for example, about 100 to 150C/350 to 30 mm~lgfor more than about 2 hours, normally about 2 to 10 hours, more preferably while increasing the temperature and reduce in the pressure stops from about 105C/350 mug to 150C/30 mml~g or about 5 to 6 hours, to remove water. In this process, a low molecular polymer or copolymer of molecular weight of about 2000 to 4000 is obtained Furthermore, as the low molecular copolymers, there are mentioned ones which are obtainable by the process described in Cage Kagaku Zasshi (Journal of the Chemical Society of Japan), vol. 68, pp.983-986 (1965), i.e. lactic acid and glycolic acid is reacted in a normal atmospheric pressure and in the absence of a catalyst at 202C for 6 hours, or U.S. Patent No. 2,362,511, i.e.
lactic acid and glycolic acid is reacted at a temperature of 200C
Jo , ~2~3,6Ç~
holding the mixture at that temperature for a period of about 2 hours and subsequently continuing the heating for another period of about 1/2 hour under vacuum.
The ratio of lactic acid to glycolic acid in the present copolymer is preferably about 50 to 95 weight % of lactic acid and 50 to 5 weight % of glycolic acid, preferably about 60 to 95 weight % of lactic acid and about 40 to 5 weight % of glycolic acid, more preferably about 60 to 85 weight % of lactic acid and about 40 to 15 weight % of glycolic acid. The ratio is more preferably about 75+2 mole % of lactic acid and about 25+2 mole %
of glycolic acid.
A solvent may be employed, especially when the starting material is in crystal, powder or granule form. Such solvents are for example water, methanol, ethanol and acetone.
The present me trod is carried out under heating and reduced pressure in the absence of a catalyst. The heating is carried out by heating the reaction system at about 150 to 250C, preferably about 150 to 200C. The reduced pressure is normally about 30 to 1 It, preferably about 10 to 1 Meg The reaction time of the present polycondensation reaction is normally not less than about 10 hours, preferably about 10 -to 150 hours, more preferably about 10 to 100 hours.
When lactic acid and glycolic acid are employed as starting materials, the following conditions are preferred:
Heating under reduced pressure at about 100 to 150C/350 to 30 mmHg for not less than about 2 hours, normally about 2 to 10 hours, for example, for about 5 to 6 hours while increasing the tempera-., 3L'~3Ç;~
lure and the degree of reduced pressure stops to about 105C/
350 mmHg to 150C/30 mmHg, to remove water, followed by a dodder-lion polycondensation reaction at about 150 to clue to l mmHg for not less than about lo hours, and normally, up to about lo hours may be adequate.
When a low molecular polymer or copolymer is employed as starting material, preferred reaction conditions are as follows:
A dehydration polycondensation reaction is carried out at about 150 to clue to 1 mmHg for not less than lo hours, and normally up to about lo hours may be adequate.
After termination of the reaction, the objective Capella men is readily obtained by removing dust. Hot filtration of the reaction solution or filtration after dissolution of the copolymer in a suitable solvent such as ethylene chloride, dichloroethane, chloroform acetone in an amount of about equal to about 10-times that of the copolymer, is su~fientO No subsequent treatment is required, either in the former case in which the reaction solution is filtered as such and the solvent is concentrated or distilled off, or in the latter case in which the reaction solution is filtered after being dissolved in a solvent. If desired, a conventional separation may be used, for example, by pouring the filtered reaction solution, either directly or in the form of a concentrated filtrate where a solvent is used, into a large amount of a precipitant. If required, further purification may be carried out by reprecipitation, etc.
The present invention provides a copolymer consisting of -~L~3~,6~
lactic acid and glycolic acid units having a weight-average molecular weight of not less than about 5,000 preferably about 5,000 to 30,000, and the resulting copolymer has a dispersity of about 1.5 to 2.
As the copolymer obtained by the present method has a low degree of dispersity, and the distribution of the molecular weight of the copolymer is not wide.
Furthermore, in the present method, as no catalyst is used, the product is produced by polycondensation reaction in the absence of a catalyst, and is substantially free of coloration.
The copolymer obtained by the present method can be utilized as a base for drug preparation. For example, the copolymer can be advantageously utilized by incorporating steroid hormones, peptize hormones or anti-tumor agents, etc. into it for embedded or micro capsule type controlled release preparations or by preparing fine particles containing an anti-tumor agent to process into a therapeutic agent for embolization.
The Experiment Examples and Examples are described below to illustrate the present invention in more detail.
Experiment Example 1 After 160 g (1~5 molt of a 85% aqueous solution of lactic acid and 38 g (0.5 molt of glycolic acid were mixed and heated under reduced pressure and under a nitrogen gas stream under the stops varying conditions of 100 to 150C/350 to 30 mmHg for 6 hours to remove the resulting water, the mixture was subjected to a dehydration polycondensation reaction at 175C/5 mmHg for 72 ~3Ç~64~
hours.
Shown in Table 1 is the relationship between reaction time and weiyht-average molecular weight attained in the production of copolymer of lactic acid and glycolic acid and its dispersity in accordance with the present process.
Also shown in Table 1 for the purpose of comparison are the results obtained with Dixie (a cross-linked polystyrene resin, Dow Chemical Co., U.S.A.), a strongly acidic ion-exchange resin being commercially available, which was used as a polymerize-lion catalyst.
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:.
aye Table 1:
Comparison between the present p osseous and process utilizing ion exchange resin in terms of molecular weight attained and its dispersity _ .
The present method Control example (Dower 50 used as a catalyst) Reaction We gut average Dispersity We ght-aVerag~ DispersitY
12 Horace 1.70 24 " 9,600 1.68 9,100 2.43 36 " 13,500 1.71 11,400 2.63 48 " 15,800 1.~6 14,900 2.80 " 18,000 OWE 17,~00 2.81 72 " _ _20,700 1.66 20,200 2.80 Appearance Dark brown of the White polymer* _ (The color deepens with time) Note: *; Each of the copolymers obtained after the respective reaction time was dissolved in ethylene chloride of the volume four times that of the copolymer, and the solution was filtered and then concentrated to distill off the solvent; the resulting copolymers were tested in accordance with JIG K8004-2 (namely, about 3 g of the test specimen is taken and examined on a sheet of white paper).
The weight-average molecular weight and dispersity dispersity = whatever molecular weight) in the number-average molecular weight present specification were measured by gel permeation chromatography utilizing the standard polystyrene with the known molecular weight.
As is clear from Table 1, the present invention : can permit readily the production of high-molecular-weight lactic acid~glycolic acid copolymers having a weight-average molecular weight of not less than about S,000, ... . . .
3L;~3~
whereby the resulting copolymers exhibit that colored appearance is hardly observed and show a dispersity of not more than 2.
Furthermore, analysis of nuclear magnetic resonance spectrometer on the resulting copolymer obtained in the above in a CDC13 solution indicates the following composition of lactic acid and glycolic acid.
.
lo Copolymer ratio of the present copolymer , Copolymer ratio mow %
Reaction time (weight %) lactic acid glycolic acid _ _ 1512 hours (79 3) (20 7) 24 hours 75.5 24.5 . (79.3) (20.7) ___ , 36 hours 75 25 2048 hours 75 5 24 5 _ _ _.(79.3) (20.7) .
60 hours 76 24 . (79.7) (20.3) 72 hours 75.5 24.5 ` (79.3) I(20.7) :
:
., .
I
Example 1 Weighed in a four-necked flask fitted with a thermometer, condenser and inlet tube for nitrogen gas were 191 g of a 85~ aqueous solution of lactic acid and 17.5 g of glycolic acid, and heating under reduced pressure was carried out, under a stream of nitrogen gas, at the internal temperature and internal pressure of 105C and 350 mmHg to 150C and 30 mmHg over the period of 6 hours to remove the resulting water. Successively, heating was conducted under reduced pressure of 3 mmHg at the internal temperature of 175C for 72 hours. The reaction solution was cooled to room temperature to give 140 g of an almost colorless bulk copolymer as a copolymer of lactic acid and glycolic acid. The copolymer showed a weight-average molecular weight of 22,000, a dispersity of 1.70 and a composition of lactic acid and glycolic acid of 89 mow %: 11 mow % (90.9 weight %: 9.1 weight %).
Experiment Example 2 To 191 g of a 85% aqueous solution of lactic acid and 17.5 g of glycolic acid was added 6.8 g of Dower WOW, and in the manner of Example 1, heating under reduced pressure was conducted, under a stream of nitrogen gas, at the internal temperature and internal pressure of 105C and 350 mmHg to 150C and 30 mmHg, respectively, over the period of 6 hours to remove the resulting water.
Furthermore, 6.8 g of Dower WOW was additionally added, and heating was carried out under reduced pressure of 3 mmHg at the internal temperature of 175C for 72 hours.
; The reaction solution was filtered hot to remove the .
.
.
Allah Dower WOW, and the filtrate was cooled to room temperature to give 131 g of a bulk copolymer with a welght-average molecular weight of 23,700 and a dispersity of 2.88, which was brown color-Ed The resulting copolymer showed a composition of lactic acid and glycolic acid of 88.5 mow % : 11.5 mow % (90.5 weight % : 9.5 weight %).
Example 2 Placed in the same polymerization apparatus as used in Example 1 were 106 g of a 85% aqueous solution of lactic acid and 76 g of glycolic acid, and heating under reduced pressure was car-fled out, under a stream of nitrogen gas, at the internal tempera-lure and internal pressure of 105C and 350 mmHg to 150C and 30 mmHg, stops, over the period of 3 hours and then the no-sult~gwater was removed. Successively, heating was conducted under reduced pressure of 3 jig at the internal temperature of 180C for 36 hours, and the reaction solution was cooled to room temperature to give 124 g of an almost colorless bulk polymer as a copolymer from lactic acid and glycolic acid. The copolymer show-Ed a weight -average molecular weight of 15,300, a dispersity of 1.73, and a composition of lactic acid and glycolic acid of 50.5 mow % : 49.5 mow % (55.9 weight % : 44.1 weight %).
Example 3 146 g of a 93% aqueous solution of lactic acid and 38 g of glycolic acid was used, a heating reaction was conducted at the temperature of 202C for 6 hours, whereby a copolymer with a weight-average molecular weight of 2,700 and a composition of iffy tactic acid and glycolic acid of 75 mow % : 25 mow % was obtained.
Weighed in the same polymerization apparatus as used in Example 1 was 100 g of this copolymer, and heating was carried out under reduced pressure of 5 mmHg at the internal temperature of 175C
for 70 hours, and the reaction solution was cooled to room temperature to give 92 g of an almost colorless bulk copolymer with a weight-average molecular weight of 17,700 and a dispersity of 1.85. The resulting copolymer showed a composition of lactic acid and glycolic acid of 75.S mow % : 24.5 mow % (79.3 weight % : 20.7 lo weight %).
sample 4 Placed in the same polymerization apparatus as used in Example 1 were 97 g of lactic acid diver (Lactic acid lactate) and 54 g of glycolic acid diver (Glycologlycoli.c acid), and heating was carried out under reduced pressure of 5 mug at internal temperature of 180C for 48 hours. The reaction solution was cooled to room temperature to give 105 g of an almost colorless bulk copolymer with a weight-average molecular weight of 18,300 and a dispersity of 1.76. The copolymer showed a composition of lactic acid and glycolic acid of 60 mow % : 40 mow % (65.1 weight % : 34.9 weight %).
Example 5 After 3337 g (33 molt of a 89 % aqueous solution of lactic acid and 836 g (11 molt of glycolic acid were mixed and heated under reduced pressure and under a nitrogen gas stream under the stops varying conditions of 100 to 150C/350 to 30 mmHg I, 3Çi6-~
for 6 hours to remove the resulting water, the mixture was subject-Ed to a dehydration polycondensation reaction at 175C/5 mmHg for 50 hours. The reaction solution was cooled to room temperature to give 2400 g of an almost colorless bulk eopolymer with a weight-average molecular weight of 14400 and a dispersity of 1.66, The copolymer showed a composition of lactic acid and glyeolie acid of 75 mow %: 25 mow % (78.8 weight %: 21.2 weight %).
- ha -` ..-
,,, -: - .
.
aye In the method of the present invention, lactic acid and glycolic acid are employed, as the starting materials, in the form of crystals, powders or granules as such, or in the form of an aqueous solution. The concentration of the solution is arbiter-rile selected, preferably as high as possible, and more preferably not lower than 85% (w/w).
The low molecular polymer of lactic acid or glycolic acid, may be an oligomer (e.g. diver, triter, etc.) of lactic acid, or glycolic acid Such a low molecular polymer or copolymer starting mater-tat of lactic acid and glycolic acid, may be produced by subjecting lactic acid and/or glycolic acid to a polycondensation reaction in the absence of a catalyst at, for example, about 100 to 150C/350 to 30 mm~lgfor more than about 2 hours, normally about 2 to 10 hours, more preferably while increasing the temperature and reduce in the pressure stops from about 105C/350 mug to 150C/30 mml~g or about 5 to 6 hours, to remove water. In this process, a low molecular polymer or copolymer of molecular weight of about 2000 to 4000 is obtained Furthermore, as the low molecular copolymers, there are mentioned ones which are obtainable by the process described in Cage Kagaku Zasshi (Journal of the Chemical Society of Japan), vol. 68, pp.983-986 (1965), i.e. lactic acid and glycolic acid is reacted in a normal atmospheric pressure and in the absence of a catalyst at 202C for 6 hours, or U.S. Patent No. 2,362,511, i.e.
lactic acid and glycolic acid is reacted at a temperature of 200C
Jo , ~2~3,6Ç~
holding the mixture at that temperature for a period of about 2 hours and subsequently continuing the heating for another period of about 1/2 hour under vacuum.
The ratio of lactic acid to glycolic acid in the present copolymer is preferably about 50 to 95 weight % of lactic acid and 50 to 5 weight % of glycolic acid, preferably about 60 to 95 weight % of lactic acid and about 40 to 5 weight % of glycolic acid, more preferably about 60 to 85 weight % of lactic acid and about 40 to 15 weight % of glycolic acid. The ratio is more preferably about 75+2 mole % of lactic acid and about 25+2 mole %
of glycolic acid.
A solvent may be employed, especially when the starting material is in crystal, powder or granule form. Such solvents are for example water, methanol, ethanol and acetone.
The present me trod is carried out under heating and reduced pressure in the absence of a catalyst. The heating is carried out by heating the reaction system at about 150 to 250C, preferably about 150 to 200C. The reduced pressure is normally about 30 to 1 It, preferably about 10 to 1 Meg The reaction time of the present polycondensation reaction is normally not less than about 10 hours, preferably about 10 -to 150 hours, more preferably about 10 to 100 hours.
When lactic acid and glycolic acid are employed as starting materials, the following conditions are preferred:
Heating under reduced pressure at about 100 to 150C/350 to 30 mmHg for not less than about 2 hours, normally about 2 to 10 hours, for example, for about 5 to 6 hours while increasing the tempera-., 3L'~3Ç;~
lure and the degree of reduced pressure stops to about 105C/
350 mmHg to 150C/30 mmHg, to remove water, followed by a dodder-lion polycondensation reaction at about 150 to clue to l mmHg for not less than about lo hours, and normally, up to about lo hours may be adequate.
When a low molecular polymer or copolymer is employed as starting material, preferred reaction conditions are as follows:
A dehydration polycondensation reaction is carried out at about 150 to clue to 1 mmHg for not less than lo hours, and normally up to about lo hours may be adequate.
After termination of the reaction, the objective Capella men is readily obtained by removing dust. Hot filtration of the reaction solution or filtration after dissolution of the copolymer in a suitable solvent such as ethylene chloride, dichloroethane, chloroform acetone in an amount of about equal to about 10-times that of the copolymer, is su~fientO No subsequent treatment is required, either in the former case in which the reaction solution is filtered as such and the solvent is concentrated or distilled off, or in the latter case in which the reaction solution is filtered after being dissolved in a solvent. If desired, a conventional separation may be used, for example, by pouring the filtered reaction solution, either directly or in the form of a concentrated filtrate where a solvent is used, into a large amount of a precipitant. If required, further purification may be carried out by reprecipitation, etc.
The present invention provides a copolymer consisting of -~L~3~,6~
lactic acid and glycolic acid units having a weight-average molecular weight of not less than about 5,000 preferably about 5,000 to 30,000, and the resulting copolymer has a dispersity of about 1.5 to 2.
As the copolymer obtained by the present method has a low degree of dispersity, and the distribution of the molecular weight of the copolymer is not wide.
Furthermore, in the present method, as no catalyst is used, the product is produced by polycondensation reaction in the absence of a catalyst, and is substantially free of coloration.
The copolymer obtained by the present method can be utilized as a base for drug preparation. For example, the copolymer can be advantageously utilized by incorporating steroid hormones, peptize hormones or anti-tumor agents, etc. into it for embedded or micro capsule type controlled release preparations or by preparing fine particles containing an anti-tumor agent to process into a therapeutic agent for embolization.
The Experiment Examples and Examples are described below to illustrate the present invention in more detail.
Experiment Example 1 After 160 g (1~5 molt of a 85% aqueous solution of lactic acid and 38 g (0.5 molt of glycolic acid were mixed and heated under reduced pressure and under a nitrogen gas stream under the stops varying conditions of 100 to 150C/350 to 30 mmHg for 6 hours to remove the resulting water, the mixture was subjected to a dehydration polycondensation reaction at 175C/5 mmHg for 72 ~3Ç~64~
hours.
Shown in Table 1 is the relationship between reaction time and weiyht-average molecular weight attained in the production of copolymer of lactic acid and glycolic acid and its dispersity in accordance with the present process.
Also shown in Table 1 for the purpose of comparison are the results obtained with Dixie (a cross-linked polystyrene resin, Dow Chemical Co., U.S.A.), a strongly acidic ion-exchange resin being commercially available, which was used as a polymerize-lion catalyst.
- pa -* Trade mark ,.
:.
aye Table 1:
Comparison between the present p osseous and process utilizing ion exchange resin in terms of molecular weight attained and its dispersity _ .
The present method Control example (Dower 50 used as a catalyst) Reaction We gut average Dispersity We ght-aVerag~ DispersitY
12 Horace 1.70 24 " 9,600 1.68 9,100 2.43 36 " 13,500 1.71 11,400 2.63 48 " 15,800 1.~6 14,900 2.80 " 18,000 OWE 17,~00 2.81 72 " _ _20,700 1.66 20,200 2.80 Appearance Dark brown of the White polymer* _ (The color deepens with time) Note: *; Each of the copolymers obtained after the respective reaction time was dissolved in ethylene chloride of the volume four times that of the copolymer, and the solution was filtered and then concentrated to distill off the solvent; the resulting copolymers were tested in accordance with JIG K8004-2 (namely, about 3 g of the test specimen is taken and examined on a sheet of white paper).
The weight-average molecular weight and dispersity dispersity = whatever molecular weight) in the number-average molecular weight present specification were measured by gel permeation chromatography utilizing the standard polystyrene with the known molecular weight.
As is clear from Table 1, the present invention : can permit readily the production of high-molecular-weight lactic acid~glycolic acid copolymers having a weight-average molecular weight of not less than about S,000, ... . . .
3L;~3~
whereby the resulting copolymers exhibit that colored appearance is hardly observed and show a dispersity of not more than 2.
Furthermore, analysis of nuclear magnetic resonance spectrometer on the resulting copolymer obtained in the above in a CDC13 solution indicates the following composition of lactic acid and glycolic acid.
.
lo Copolymer ratio of the present copolymer , Copolymer ratio mow %
Reaction time (weight %) lactic acid glycolic acid _ _ 1512 hours (79 3) (20 7) 24 hours 75.5 24.5 . (79.3) (20.7) ___ , 36 hours 75 25 2048 hours 75 5 24 5 _ _ _.(79.3) (20.7) .
60 hours 76 24 . (79.7) (20.3) 72 hours 75.5 24.5 ` (79.3) I(20.7) :
:
., .
I
Example 1 Weighed in a four-necked flask fitted with a thermometer, condenser and inlet tube for nitrogen gas were 191 g of a 85~ aqueous solution of lactic acid and 17.5 g of glycolic acid, and heating under reduced pressure was carried out, under a stream of nitrogen gas, at the internal temperature and internal pressure of 105C and 350 mmHg to 150C and 30 mmHg over the period of 6 hours to remove the resulting water. Successively, heating was conducted under reduced pressure of 3 mmHg at the internal temperature of 175C for 72 hours. The reaction solution was cooled to room temperature to give 140 g of an almost colorless bulk copolymer as a copolymer of lactic acid and glycolic acid. The copolymer showed a weight-average molecular weight of 22,000, a dispersity of 1.70 and a composition of lactic acid and glycolic acid of 89 mow %: 11 mow % (90.9 weight %: 9.1 weight %).
Experiment Example 2 To 191 g of a 85% aqueous solution of lactic acid and 17.5 g of glycolic acid was added 6.8 g of Dower WOW, and in the manner of Example 1, heating under reduced pressure was conducted, under a stream of nitrogen gas, at the internal temperature and internal pressure of 105C and 350 mmHg to 150C and 30 mmHg, respectively, over the period of 6 hours to remove the resulting water.
Furthermore, 6.8 g of Dower WOW was additionally added, and heating was carried out under reduced pressure of 3 mmHg at the internal temperature of 175C for 72 hours.
; The reaction solution was filtered hot to remove the .
.
.
Allah Dower WOW, and the filtrate was cooled to room temperature to give 131 g of a bulk copolymer with a welght-average molecular weight of 23,700 and a dispersity of 2.88, which was brown color-Ed The resulting copolymer showed a composition of lactic acid and glycolic acid of 88.5 mow % : 11.5 mow % (90.5 weight % : 9.5 weight %).
Example 2 Placed in the same polymerization apparatus as used in Example 1 were 106 g of a 85% aqueous solution of lactic acid and 76 g of glycolic acid, and heating under reduced pressure was car-fled out, under a stream of nitrogen gas, at the internal tempera-lure and internal pressure of 105C and 350 mmHg to 150C and 30 mmHg, stops, over the period of 3 hours and then the no-sult~gwater was removed. Successively, heating was conducted under reduced pressure of 3 jig at the internal temperature of 180C for 36 hours, and the reaction solution was cooled to room temperature to give 124 g of an almost colorless bulk polymer as a copolymer from lactic acid and glycolic acid. The copolymer show-Ed a weight -average molecular weight of 15,300, a dispersity of 1.73, and a composition of lactic acid and glycolic acid of 50.5 mow % : 49.5 mow % (55.9 weight % : 44.1 weight %).
Example 3 146 g of a 93% aqueous solution of lactic acid and 38 g of glycolic acid was used, a heating reaction was conducted at the temperature of 202C for 6 hours, whereby a copolymer with a weight-average molecular weight of 2,700 and a composition of iffy tactic acid and glycolic acid of 75 mow % : 25 mow % was obtained.
Weighed in the same polymerization apparatus as used in Example 1 was 100 g of this copolymer, and heating was carried out under reduced pressure of 5 mmHg at the internal temperature of 175C
for 70 hours, and the reaction solution was cooled to room temperature to give 92 g of an almost colorless bulk copolymer with a weight-average molecular weight of 17,700 and a dispersity of 1.85. The resulting copolymer showed a composition of lactic acid and glycolic acid of 75.S mow % : 24.5 mow % (79.3 weight % : 20.7 lo weight %).
sample 4 Placed in the same polymerization apparatus as used in Example 1 were 97 g of lactic acid diver (Lactic acid lactate) and 54 g of glycolic acid diver (Glycologlycoli.c acid), and heating was carried out under reduced pressure of 5 mug at internal temperature of 180C for 48 hours. The reaction solution was cooled to room temperature to give 105 g of an almost colorless bulk copolymer with a weight-average molecular weight of 18,300 and a dispersity of 1.76. The copolymer showed a composition of lactic acid and glycolic acid of 60 mow % : 40 mow % (65.1 weight % : 34.9 weight %).
Example 5 After 3337 g (33 molt of a 89 % aqueous solution of lactic acid and 836 g (11 molt of glycolic acid were mixed and heated under reduced pressure and under a nitrogen gas stream under the stops varying conditions of 100 to 150C/350 to 30 mmHg I, 3Çi6-~
for 6 hours to remove the resulting water, the mixture was subject-Ed to a dehydration polycondensation reaction at 175C/5 mmHg for 50 hours. The reaction solution was cooled to room temperature to give 2400 g of an almost colorless bulk eopolymer with a weight-average molecular weight of 14400 and a dispersity of 1.66, The copolymer showed a composition of lactic acid and glyeolie acid of 75 mow %: 25 mow % (78.8 weight %: 21.2 weight %).
- ha -` ..-
Claims (18)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A copolymer of lactic acid and glycolic acid, which has a weight-average molecular weight of about 5,000 to 30,000 and a dispersity of about 1.5 to 2.
2. A copolymer according to Claim 1, wherein the copolymer ratio is about 50 to 95 weight % of lactic acid and about 50 to 5 weight % of glycolic acid.
3. A copolymer according Claim 1, wherein the copolymer ratio is about 60 to 95 weight % of lactic acid and about 40 to 5 weight % of glycolic acid.
4. A copolymer according to Claim 1, wherein the copolymer ratio is about 60 to 85 weight % of lactic acid and about 40 to 15 weight % of glycolic acid.
5. A copolymer according to Claim 1, wherein the copolymer ratio is about 75?2 mol % of lactic acid and about 25 ?2 mol % of glycolic acid.
6. A method for producing a copolymer of lactic acid and glycolic acid, the copolymer having a weight-average molecular weight of not less than about 5,000 and a dispersity of about 1.5 to 2, which comprises subjecting lactic acid and glycolic acid or a low molecular polymer of copolymer thereof to a polycondensation reaction under heating and reduced pressure in the absence of a catalyst.
7. A method according Claim 6, wherein the low molecular copolymer of lactic acid and glycolic acid is produced by sub-jecting lactic acid and glycolic acid to a condensation reaction in the absence of a catalyst and removing water, and the poly-condensation reaction is carried out for not less than about 10 hours.
8. A method according to Claim 6, wherein the weight-average molecular weight of the resulting copolymer is about 5,000 to 30,000.
9. A method according to Claim 6, wherein the copolymer ratio is about 50 to 95 weight % of lactic acid and about 50 to 5 weight % of glycolic acid.
10. A method according to Claim 6, wherein the copolymer ratio is about 60 to 85 weight % of lactic acid and about 40 to 5 weight % of glycolic acid.
11. A method according to Claim 6, wherein the copolymer ratio is about 60 to 85 weight % of lactic acid and about 40 to 15 weight % of glycolic acid.
12. A method according to Claim 6, wherein the copolymer ratio is about 75?2 mol % of lactic acid and about 25?2 mol % of glycolic acid.
13. A method according to claim 6, 7 or 8, wherein the polycondensation reaction is carried out at a temperature of about 150 to about 250°C and at a reduced pressure of about 30 to about 1 mmHg for not less than about 10 hours.
14. A method according to claim 9, 10 or 11, wherein the polycondensation reaction is carried out at a temperature of about 150 to about 250°C and at a reduced pressure of about 30 to about 1 mmHg for not less than about 10 hours.
15. A method according to claim 6, 7 or 8, wherein the polycondensation reaction is carried out at a temperature of about 150 to about 200°C at a reduced pressure of about 10 to about 1 mmHg for about 10 to about 100 hours.
16. A method according to claim 9, 10 or 11, wherein the polycondensation reaction is carried out at a temperature of about 150 to about 200°C at a reduced pressure of about 10 to about 1 mmHg for about 10 to about 100 hours.
17. A method according to claim 6, 8 or 9, wherein at first lactic acid, glycolic acid or a mixture thereof is heated starting from a temperature of about 105°C and a reduced pressure of about 350 mmHg for not less than two hours while increasing the temperature and decreasing the pressure to about 150°C
and 30 mmHg to remove water forming a low molecular weight polymer of the starting material and then heating the low molecular weight polymer at a temperature of about 150 to about 220°C and at a pressure of about 10 to about 1 mmHg for about 10 to about 100 hours.
and 30 mmHg to remove water forming a low molecular weight polymer of the starting material and then heating the low molecular weight polymer at a temperature of about 150 to about 220°C and at a pressure of about 10 to about 1 mmHg for about 10 to about 100 hours.
18. A method according to claim 10, 11 or 12, wherein at first lactic acid, glycolic acid or a mixture thereof is heated starting from a temperature of about 105°C and a reduced pressure of about 350 mmHg for not less than two hours while increasing the temperature and decreasing the pressure to about 150°C and 30 mmHg to remove water forming a low molecular weight polymer of the starting material and then heating the low molecular weight polymer at a temperature of about 150 to about 220°C and at a pressure of about 10 to about 1 mmHg for about 10 to about 100 hours.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59140356A JPH0678425B2 (en) | 1984-07-06 | 1984-07-06 | New polymer manufacturing method |
| JP140356/1984 | 1984-07-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1236641A true CA1236641A (en) | 1988-05-10 |
Family
ID=15266918
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000486283A Expired CA1236641A (en) | 1984-07-06 | 1985-06-28 | Copolymer of lactic acid and glycolic acid and method for producing same |
| CA000486142A Expired CA1256638A (en) | 1984-07-06 | 1985-06-28 | Polymer and its production |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000486142A Expired CA1256638A (en) | 1984-07-06 | 1985-06-28 | Polymer and its production |
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| Country | Link |
|---|---|
| US (2) | US4683288A (en) |
| EP (2) | EP0171907B2 (en) |
| AT (2) | ATE39936T1 (en) |
| BG (1) | BG61520B2 (en) |
| CA (2) | CA1236641A (en) |
| DE (2) | DE3567470D1 (en) |
| HK (1) | HK19592A (en) |
| SG (1) | SG108191G (en) |
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Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1995970A (en) * | 1931-04-04 | 1935-03-26 | Du Pont | Polymeric lactide resin |
| US2362511A (en) * | 1939-11-21 | 1944-11-14 | Du Pont | Modified glycolide resins |
| US2438208A (en) * | 1943-07-10 | 1948-03-23 | Us Agriculture | Continuous process of converting lactic acid to polylactic acid |
| US2683136A (en) * | 1950-10-25 | 1954-07-06 | Du Pont | Copolymers of hydroxyacetic acid with other alcohol acids |
| US2703316A (en) * | 1951-06-05 | 1955-03-01 | Du Pont | Polymers of high melting lactide |
| US2758987A (en) * | 1952-06-05 | 1956-08-14 | Du Pont | Optically active homopolymers containing but one antipodal species of an alpha-monohydroxy monocarboxylic acid |
| US3531561A (en) * | 1965-04-20 | 1970-09-29 | Ethicon Inc | Suture preparation |
| US3498957A (en) * | 1965-09-14 | 1970-03-03 | Ethicon Inc | Polymerization of cyclic carboxylic esters in the presense of a nonpolymerizable ester plasticizer |
| US3468853A (en) * | 1966-06-15 | 1969-09-23 | American Cyanamid Co | Process of polymerizing a glycolide |
| BE758156R (en) * | 1970-05-13 | 1971-04-28 | Ethicon Inc | ABSORBABLE SUTURE ELEMENT AND ITS |
| US3839297A (en) * | 1971-11-22 | 1974-10-01 | Ethicon Inc | Use of stannous octoate catalyst in the manufacture of l(-)lactide-glycolide copolymer sutures |
| US4137921A (en) * | 1977-06-24 | 1979-02-06 | Ethicon, Inc. | Addition copolymers of lactide and glycolide and method of preparation |
| US4273920A (en) * | 1979-09-12 | 1981-06-16 | Eli Lilly And Company | Polymerization process and product |
| IE52535B1 (en) * | 1981-02-16 | 1987-12-09 | Ici Plc | Continuous release pharmaceutical compositions |
-
1985
- 1985-06-28 CA CA000486283A patent/CA1236641A/en not_active Expired
- 1985-06-28 CA CA000486142A patent/CA1256638A/en not_active Expired
- 1985-07-03 EP EP85304733A patent/EP0171907B2/en not_active Expired - Lifetime
- 1985-07-03 US US06/751,671 patent/US4683288A/en not_active Expired - Lifetime
- 1985-07-03 AT AT85304734T patent/ATE39936T1/en not_active IP Right Cessation
- 1985-07-03 AT AT85304733T patent/ATE39935T1/en not_active IP Right Cessation
- 1985-07-03 EP EP85304734A patent/EP0172636B2/en not_active Expired - Lifetime
- 1985-07-03 DE DE8585304733T patent/DE3567470D1/en not_active Expired
- 1985-07-03 US US06/751,672 patent/US4677191A/en not_active Expired - Lifetime
- 1985-07-03 DE DE8585304734T patent/DE3567471D1/en not_active Expired
-
1991
- 1991-12-24 SG SG1081/91A patent/SG108191G/en unknown
-
1992
- 1992-03-12 HK HK195/92A patent/HK19592A/en not_active IP Right Cessation
-
1994
- 1994-02-11 BG BG98460A patent/BG61520B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0172636A1 (en) | 1986-02-26 |
| US4683288A (en) | 1987-07-28 |
| ATE39935T1 (en) | 1989-01-15 |
| ATE39936T1 (en) | 1989-01-15 |
| CA1256638A (en) | 1989-06-27 |
| EP0171907B2 (en) | 1994-08-10 |
| US4677191A (en) | 1987-06-30 |
| EP0171907B1 (en) | 1989-01-11 |
| EP0172636B2 (en) | 1992-11-11 |
| EP0171907A1 (en) | 1986-02-19 |
| BG61520B2 (en) | 1997-10-31 |
| DE3567471D1 (en) | 1989-02-16 |
| HK19592A (en) | 1992-03-20 |
| DE3567470D1 (en) | 1989-02-16 |
| EP0172636B1 (en) | 1989-01-11 |
| SG108191G (en) | 1992-06-12 |
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