KR840001675B1 - Polymerization proces - Google Patents

Abstract

Lactic acid-glycolic acid copolymer contg. 60-95 wt. % of lactic acid and 40-5 wt. % of glycolic acid, and having an intrinsic viscosity in chloroform of 0.08-0.030, a mean mol.wt. of 6000-35000 and being essentially free from polymerization catalyst is new. The polymn. is effected using an easily eliminated strong acid ion exchange resin as catalyst, at 100-250 deg.C for 3-1772hr. The copolymers pref. those contg. 70-80 wt.% of lactic acid and 30-20wt.% of glycolic acid and having an intrinsic viscosity of 0.10-0.25. Used as matries for prolonged release of medicaments. The copolymer is completely biodegradable within the animal and leaves no toxic residues.

Description

Method of Preparation of Copolymer

The present invention relates to a process for polymerizing glycolic acid and lactic acid to produce copolymers having an average molecular weight of about 6000 to 35000.

Polymers and copolymers are widely used in many fields. The widespread use of polymers is due to the unique physical properties exhibited by the various polymers. By varying the method of producing the same monomer, the polymerization catalyst, the amount of monomer used, and the related factors, many different kinds of polymers having various physical properties can be produced.

The prior art teaches polymers and copolymers of lactic acid and glycolic acid. In US Pat. Nos. 3,739,773, 3,736,646 and 3,875,937, Schmitt et al. Have illustrated and described general lactic and glycolic acid copolymers as well as general polymers and copolymers.

As pointed out by yolles in US Pat. No. 3,887,699, much attention has been paid to the possibility of sustained release of the drug in vivo by incorporating the drug into the polymer. However, many problems are involved in using polymers and copolymers to release drugs in vivo. For example, US patent

It is known from numerous references that this obtained by the use of copolymers consisting of glycolic acid and lactic acid is a component that is produced in normal metabolic pathways and is therefore nontoxic and harmless when exposed to human or animal tissue. . However, one of the drawbacks associated with the copolymers of the prior art is the presence of polymerization catalysts such as polyvalent metal oxides or metal halides. As the copolymer-drug matrix is degraded in vivo, a certain amount of such toxic polymerization catalyst remains in the animal tissue, which is not degraded in vivo.

Moreover, the catalyst used to promote the polymerization leads to degradation of the polymer if the contact is continued. Therefore, polymers containing a polymerization catalyst as impurities are subject to unexpected decomposition.

The present invention also relates to copol so that the prepared copolymer can be used as a drug carrier.

The present invention relates to a method for polymerizing lactic acid and glycolic acid by direct condensation and to copolymers prepared by such a method. In particular, the present invention contains about 60 to 95% by weight of lactic acid and about 40 to 5% by weight of glycolic acid and has an intrinsic viscosity of about 0.08 to 0.30, an average molecular weight of about 6000 to 35000, and almost no polymerization catalyst in chloroform. A copolymer derived from lactic acid and glycolic acid polymerization is provided. Intrinsic viscosity is measured by adding 0.50 g of copolymer in 100 ml of chloroform at 25 ° C.

This method is characterized by the polymerization of lactic acid and glycolic acid with an average molecular weight of about 6000 to 35000, an intrinsic viscosity of about 0.08 to 0.30 in chloroform, polymerization of about 60 to 95% by weight of lactic acid and about 40 to 5% by weight of glycolic acid. In the method for producing a copolymer derived from the above, it is characterized in that the resin is removed after being carried out in the presence of a strong acid ion exchange resin which can easily remove the polymerization of lactic acid and glycolic acid.

According to the method according to the invention, the preferred copolymers produced are derived from about 60 to 90% by weight lactic acid and about 40 to 10% by weight glycolic acid.

Copolymers of the present invention ideally have a viscosity of about 0.10 to 0.25 and an average molecular weight of about 15000 to 30000. Particularly preferred copolymers are copolymers derived from about 0.10 to 0.25 intrinsic viscosity and from about 70 to 80 weight percent lactic acid and about 30 to 20 weight percent glycolic acid.

According to the method of the present invention, condensation is carried out by reacting with lactic acid in the presence of a strong acid ion exchange resin which can easily remove glycolic acid. Preferred catalysts are those in the form of beads or similar solid compositions which are easy to remove by filtration or the like. Preferred catalysts include gel-type commercial resins such as Amberlite IR-118 (H) and Dow X HCR-W (life: Dow X 50 W) and macroreticular resins such as Amberlyst 15 and Dow X MSC-1. .

Lactic acid is condensed with glycolic acid according to the process of the present invention by a process for preparing copolymers derived from about 60-95 weight percent lactic acid and about 40-5 weight percent glycolic acid. The polymerization process is carried out by condensing lactic acid and glycolic acid in the presence of a strong acid ion exchange resin catalyst which is convenient to remove by standard methods such as filtration. The catalyst can be prepared by polymerizing a crosslinker or a similar reagent such as divinyl benzene with styrene. These resin polymers react with sulfuric acid, phosphoric acid, tetrafluoroboric acid, paratoluenesulfonic acid and related acids

According to the present invention a strong acid ion exchange resin is added to the mixture of lactic acid and glycolic acid. Generally, the polymerization is carried out in the absence of a reaction solvent. However, if desired, a reaction solvent such as N (N-dimethylformamide, dimethyl sulfoxide, etc. may be used.The amount of strong acid ion exchange resin used in the condensation process is not a problem in the process. The amount is sufficient to effectively initiate and maintain the polymerization process, such an effective amount is typically from about 0.1 to 20% by weight relative to the total amount of glycolic acid and lactic acid in the reaction mixture.

The mixture of mixed strong acid ion exchange resins, glycolic acid and lactic acid is heated to a temperature of about 100 to 250 ° C. Ideally, the reaction is carried out in such a way that the water produced during the polymerization reaction is simply removed by distillation or the like. If necessary, the reaction vessel can be vacuumed to facilitate the removal of water. Typically, the resulting lactide and glycolide are removed by such vacuum distillation. The polymerization reaction is completed by heating continuously and removing by-product water from the reaction mixture. Reaction is about

Separation and purification of the resulting copolymers is carried out in a conventional manner. Strong acid ion exchange resins can be removed substantially from the copolymer product by simply filtering the molten reaction mixture (eg, through 20 to about 50 mesh metal bodies). Alternatively, the reaction mixture can be cooled to room temperature and the copolymer can be dissolved in an organic solvent in which the ion exchange resin is insoluble. Such organic solvents are chloroform, dichloromethane, benzene, xylene and the like. The copolymer dissolved in the organic solvent is subjected to conventional filtration to remove the insoluble strong acid ion exchange resin. For example, when the organic solvent is evaporated and removed from the filtrate under reduced pressure, the desired copolymer of the present invention containing almost no polymerization catalyst is obtained.

If necessary, the copolymer can be dissolved again in a suitable solvent and filtered again to remove all remaining traces of ion exchange resin.

Copolymers of the invention prepared according to the novel methods described above are identified according to conventional methods commonly used for identification of polymers and copolymers. The relative composition of the copolymers is determined by quantum nuclear magnetic resonance spectroscopy. The relative ratio of total glycolic acid units to total lactic acid units is measured by measuring the ratio of methylene quantum resulting from glycolic acid units to methine quantum resulting from lactic acid units.

The intrinsic viscosity of the copolymer of the present invention is measured by a standard method using a ubbelohde viscometer. Analytical copolymers are dissolved at a concentration of 0.50 g per 100 ml of chloroform. The intrinsic viscosity (ηinh) used here is defined by the following equation.

Where ln is the natural logarithm, c is the concentration of the solution (g / 100mL), and ηrel is the relative viscosity defined by the following equation:

Where t ₀ is the outflow time of the pure solvent (chloroform here) and t is the outflow time of the emulsion containing the copolymer.

Lactic acid and copolymers derived from lactic acid and glycolic acid prepared according to the process of the invention as described above are particularly suitable for the preparation of a medicament which continuously and uniformly releases the active substance in vivo. Such agents are particularly useful for the treatment and prevention of diseases occurring in animals that have not been treated daily by conventional methods.

The copolymer of the present invention has special physical properties that are controlled and uniformly degraded into non-toxic and easily metabolized substances when in contact with animal tissues and body fluids. For example, in order for the drug to be released from the copolymer, the copolymer must have a pH that can dissolve in the conditions used in body tissues and other areas that are contacted by injection (eg, in the stomach of ruminants). Thus, the copolymer is soluble at pH about 5.0 to 7.3. Furthermore, the copolymer of the present invention is produced by the novel method of the present invention, in which the polymerization catalyst can be almost completely removed, so that no body tissue toxic foreign matter is absorbed. In addition, since it has the ability to uniformly receive in vivo degradation partially measured according to the relative ratio of lactic acid and glycolic acid present, it is necessary to measure in advance the time required for in vivo degradation.

1 is the intrinsic viscosity and all copolymers are 80% by weight lactic acid and 20% by weight glycolic acid.

2 is the dissolution rate measured by averaging 3 tests.

As described above, the copolymers according to the present invention can be used in the formulation of various drugs for controlled release of drugs in vivo. The drug which can be incorporated in the formulation containing the copolymer of the present invention can be used as long as it is a drug useful for the treatment or prevention of mammals including humans and animals. In particular, the copolymer of the present invention is useful for the preparation of a sustained release agent for treating livestock, which is raised for edible purposes such as cattle and pigs.

Typical drugs suitable for use in the treatment of animals as sustained-release agents using the copolymers of the present invention include antibiotics such as known penicillins, cephalosporins, tetracyclines and streptomycin A and streptomycin B, oreomycin, tyrosine and analogs. to be.

Other drugs that are well suited for formulation with the copolymers of the present invention that are released for extended periods of time are drugs that are used to enhance feed efficiency in animals such as meat calves. Typically these drugs are administered primarily as feed additives. Since the effective and effective dosage of the effective drug depends on the diet of the animal, it is difficult to administer by overdose and underdose. Moreover, while grazing livestock animals cannot be treated with feed additives, preparations containing suitable drugs dispersed through the copolymer of the present invention can be administered in the form of large pills (animal) which remain on the ruminant's well. Therefore, the effective amount of the drug may be controlled over several weeks or months. Typical feed efficiency enhancers and growth promoters that can be formulated using the copolymers of the present invention are monensin, lasaroside, apramycin, naracin, salinomycin and the like.

Other sustained release drugs that can be formulated using the copolymers of the present invention include natural and synthetic hormones and related drugs that act as modulators. Such drugs are estrogens, androgens, progestogens, corticosteroids and anabolic hormones.

The copolymer of the present invention can be used to formulate an effective drug for oral or parenteral administration.

For example, a copolymer derived from 30% by weight glycolic acid and 70% by weight lactic acid and having an intrinsic viscosity of 0.13 can be dissolved in a suitable organic solvent such as dichloromethane. Sufficient amount of antimicrobial agent such as tyrosine was added to the copolymer solution and the organic solvent was evaporated to obtain a homogeneous mixture composed of 30% by weight of the active drug and 70% by weight of the copolymer.

As described above, the effective drug can be formulated into a convenient oral dosage form using the copolymer of the present invention. Feed efficiency enhancers such as monesin, for example, disperse well through the copolymer matrix. The mixture is shaped into large pills and adjusted for oral administration to fattening calves. Such formulations may be transferred to the rumen on the calf to allow the calf to release the feed efficiency enhancer for a period of time. These formulations allow the younger calf to graze through the entire feeding season, producing more useful meat than ever before.

As pointed out above, the use of strong acid ion exchange resins can remove virtually completely (95% or more) the polymerization catalyst from the copolymer formed. This gives many advantages over the prior art because copolymers with greatly enhanced stability can be produced by completely removing the catalyst. It is well known that catalysts catalyze decomposition as well as polymerization. Thus, polymers prepared by standard methods using indelible catalysts, such as ferric sulfate, are somewhat unstable and degrade the formulation containing the active agent, as well as the short shelf life of the formulation. Unlike this

The following examples are intended to illustrate the polymerization process and products of the present invention in more detail.

Example 1

To a three-necked round bottom flask equipped with a cooler and a thermometer, 864.0 g of lactic acid, 201.0 g of glycolic acid, and 12.0 g of Dowex HCR-W2-H ion exchange resin are added, followed by heating the mixture to 130 ° C. for 3 hours while stirring. . At this time, 400 mg of water is distilled and collected. Stirring and heating are continued after the resulting water has been removed and the pressure is gradually reduced under vacuum for 3 hours. The temperature of the reaction mixture is then raised to 150 ° C. at a final pressure of 5 Torr. 12.0 g of Dowex HCR-W2-H catalyst is added again and heated at 5.0 Torr to 170 ° C. for 24 hours and then at 5.0 Torr to 185 ° C. for 48 hours. The molten reaction mixture was filtered to almost eliminate the ion exchange polymerization catalyst and then the filtrate was cooled to room temperature to yield 700 g of copolymer (80% lactic acid-20% glycolic acid). Analysis of the copolymer by quantum nuclear magnetic resonance spectroscopy revealed that it was composed of 76 wt% lactic acid units.

The viscosity of the copolymer is measured using a Uberod viscometer in chloroform with an outflow time of 51 seconds at 25 ° C.

The copolymer is dissolved in chloroform at a concentration of 0.50 g per 100 ml of solvent. The intrinsic viscosity of the copolymer is measured according to the following equation.

T = solution outflow time

ηrel = relative viscosity ηinh = unique viscosity

t ₀ = flow time of solvent (CHCl ₃ ) c = concentration (g / 100mL)

Intrinsic viscosity of the prepared copolymer was measured to 0.19dl / g.

Example 2

In accordance with the method described in Example 1, 432 g of lactic acid and 101 g of glycolic acid were condensed in the presence of a total of 12.0 g of Amberlyst 15 ion exchange polymerization catalyst to obtain 350 g of copolymer (80% of lactic acid units and 20% of glycolic acid units). To obtain. Intrinsic Viscosity of Copolymer: 0.18dl / g

Example 3

According to the method of Example 1, 424.0 g of lactic acid 144.0 g of glycolic acid and 12.0 g of Dowex HCR-W2-H ion exchange polymerization catalyst were condensed. The molten reaction mixture is filtered and the catalyst is removed to yield 350 g of copolymer derived from 75 wt% lactic acid and 25 wt% glycolic acid. Intrinsic Viscosity of Copolymer: 0.19dl / g

Example 4

According to the method of Example 1, 1080 g of lactic acid is condensed with 252 g of glycolic acid in the presence of 30.0 g of Dowex HCR-W2-H ion exchange polymerization catalyst. The catalyst is removed to yield 750 g of copolymer. Quantum analysis showed that 79% of lactic acid units and 21% of glycolic acid units were contained.

Intrinsic Viscosity of Copolymer: 0.20dl / g

Example 5

According to the method of Example 1, 1080 g of lactic acid was condensed with 120 g of glycolic acid in the presence of a total of 15.0 g of Dowex HCR-W2-H ion exchange polymerization catalyst, followed by filtration and removal of the catalyst to remove 90% by weight of lactic acid and 10% by weight. 630 g of copolymer derived from glycolic acid of are obtained. Intrinsic Viscosity of Copolymer: 0.20dl / g

Example 6

500 g of copolymer consisting of 70% lactic acid unit and 30% glycolic acid unit by condensing 710 g of lactic acid with 190 g of glycolic acid in the presence of a total of 12.0 g of Dowex HCR-W2-H ion exchange polymerization catalyst according to the method of Example 1 To obtain. Intrinsic viscosity of copolymer: 0.12dl / g after 24 hours at 175 ℃

Example 7

According to the method of Example 1, 1080 g of lactic acid was condensed with 120 g of glycolic acid in the presence of a total of 30.0 g of Dowex HCR-W2-H ion exchange polymerization catalyst and filtered to remove the catalyst to thereby remove 89% by weight of lactic acid and 11% by weight of 750 g of copolymer derived from glycolic acid are obtained. Intrinsic Viscosity of Copolymer: 0.20dl / g

The copolymer obtained by the present invention is confirmed by gel permeation chromatography (high pressure liquid chromatography) and molecular weight measurement. Gel permeation chromatography separates the sample molecules according to the difference in the effective molecular size in the solution and is separated according to the pore size distributed in the packing material. This method uses the average molecular weight, average molecular weight, molecular weight distribution and

Several experiments have been performed on the copolymers of the present invention. In each experiment, a standard gel permeation chromatography column was used, and a commercially available μ star gel (μ Styragel) was used as a support. All samples and standards were dissolved in 80 parts of tetrahydrofuran and 20 parts of dichloromethane solution. The average molecular weight of the copolymer of the present invention was measured using a direct calibration curve method (eg, "Q-factor method") of the gel permeation chromatography column. Commercial polystyrene with Q factor 41.3 was used in the assay. The following table shows the molecular weight measurement by the standard gel permeation chromatography method as described above. A detailed description of this method is described by Slade in the following document (Slade in Poiymer Molecular Weights, Marcel Deckker, Inc., 1975).

In the following table, each column represents:

Section I: Relative proportions of lactic and glycolic acid units in the analyzed copolymer

Section II: Intrinsic viscosity of each polymer analyzed

Section III: Strong Acid Ion Exchange Resin Used in Preparation of the Analyzed Copolymers

Section IV: Weight average angstrom size measured by gel permeation chromatography residence time for each polymer

Section V: average molecular weight of various polymers prepared according to the process of the invention

The average molecular weight is obtained by multiplying the Q factor (41.3) of polyester by the weight of the average Angstrom size of each copolymer analyzed.

Section VI: Relevant Example No.

As shown in the table, the molecular weight of the preferred copolymers of the present invention is about 15,000 to 35,000, preferably about 15,000 to 30,000.

[table]

Average molecular weight

Claims (1)

Polymerization of lactic acid and glycolic acid, consisting of about 60 to about 95% by weight of lactic acid and about 40 to about 5% by weight of glycolic acid, intrinsic viscosity in chloroform of about 0.08 to 0.30 and average molecular weight of about 6,000 to A method for preparing a copolymer having about 35,000 and containing little polymerization catalyst, the method comprising: about 100 to about 100 hours for about 3 to 172 hours in the presence of a strong acid ion-exchange resin that can easily remove the polymerization of lactic acid and glycolic acid

To resin after which the resin is removed.