JP3054451B2 - Hydrolysable resin composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a hydrolyzable resin composition having improved flexibility, which is mainly used as a medical material.

[0002]

2. Description of the Related Art In recent years, in the medical field, hydrolyzable (bioabsorbable) materials have been used which are decomposed and absorbed after performing functions in a living body for a certain period of time.

[0003] Bioabsorbable materials include hydrolysable resins such as polylactic acid, polyglycolic acid, polydioxanone, trimethylene carbonate polymer, polycaprolactone and copolymers thereof, poly-3-hydroxybutyrate, poly-3-hydroxybutyrate and the like. Enzymatically decomposable resins such as hydroxyvalerate, chitin and chitosan have been proposed.

Among them, polylactic acid, polyglycolic acid and glycolic acid-lactic acid copolymer are easily hydrolyzed in vivo, and the decomposition products are finally metabolized to carbon dioxide and water. It is an interesting bioabsorbable material that is excreted outside the body. Polyglycolic acid has already been put into practical use as a bioabsorbable surgical suture, and glycolic acid-lactic acid copolymer has been put into practical use as a matrix for a sustained-release drug matrix.

[0005] Recently, it has been particularly desired to provide a film material having hydrolyzability. For example, JP-A-60-238
3 No. is processed biodegradable absorbent polymer into a film, be used as therapeutic materials for diseases with antiadhesive material or adhesion BIOLOGICAL organization each other is disclosed. Polylactic acid, glycolic acid-lactic acid copolymer and lactic acid-ε-caprolactone copolymer are disclosed as biodegradable and absorbable polymers used in the invention described in this publication.

However, these polymers can form films having high strength, but all have high hardness.
It has a rough feel and is unsuitable as a medical material applied to a living body, particularly to soft tissue.

[0007] According to the present inventors' knowledge, the film to be applied to the soft tissue in an organism is necessary that at least a tensile tangent modulus is 100 kgf / mm ² or less, preferably 50 kgf / m m ² or more Below, more preferably a soft film of 10 kgf / mm ² or less.

In response to this requirement, for example, a homopolymer of L-lactic acid (solution intrinsic viscosity at 25 ° C. in chloroform =
The tensile tangent modulus of the film consisting of 2.2 is about 180 kgf / mm ² , and 50 mol% of DL-lactic acid
Tangent modulus of a film composed of a copolymer of glycerol and glycolic acid 50 mol% (solution intrinsic viscosity in chloroform at 25 ° C. = 0.5) is about 120 kgf
/ Mm ² .

However, the publication (JP-A-60-23)
No. 83) does not disclose a flexible film suitable for use in vivo, particularly for soft tissue, and a method for producing the same.

[0010] The PCT International Application WO90 / 0 1 521 JP, polylactic acid (degree of polymerization 150 or more, 20000 or less), lactide, plasticized by lactic acid oligomer, lactide oligomer and a plasticizer selected from a mixture thereof It is disclosed that the resin composition is biodegraded in a natural environment. More specifically, the preferred amount of the plasticizer is 5 to 40% by weight when it is a lactide monomer, and 2 to 60% by weight when it is lactic acid, a lactic acid oligomer or a lactide oligomer. Strength of 300 to 20000 psi (0.2 to 14.1 k
gf / mm ² ), elongation 50-1000%, tensile tangent modulus 20000-250,000 psi (14.
1 to 175.8 kgf / mm ² ).

When the present inventors conducted additional tests, the tensile tangent modulus of the resin composition was 10% even when the plasticizer was added at 15% by weight to the product obtained by the polymerization reaction.
It is difficult to reduce the weight to kgf / mm ² or less. When the above plasticizer is added in an amount of 15% by weight or more to further improve flexibility, the plasticizer is deposited on the surface of the film made of the resin composition to be stiff, and the strength is extremely reduced. It loses film-forming ability and is unsuitable for application as a medical material, for example, to soft tissue in a living body. The cause is presumed to be that the resin composition disclosed in the publication contains polylactic acid as a main component and is relatively rich in crystallinity, so that it is difficult to be plasticized.

[0012] Further, the resin composition disclosed in the publication includes:
Its main use is to replace general-purpose resins such as polystyrene. Specifically, since the film is a decomposable packaging film or the like, it is intended that the decomposition rate is relatively low.

[0013] The resin composition of the present invention is a polymer, oligomer and monomer mainly composed of lactic acid units, and is hydrolyzed and disappears in a natural environment in about six months to one year.

On the other hand, the hydrolyzability required for a material used for biomedical treatment varies depending on the site in the body where the material is used and the method of use.

For example, polylactic acid used for bone grafting plates and the like is hydrolyzed in six months to one year, and polyglycolic acid used for surgical sutures is hydrolyzed in about one month, and is released. It is said that a lactic acid-glycolic acid copolymer used as a base for a sex drug is hydrolyzed in several weeks.

In order to increase the rate of hydrolysis of the resin composition disclosed in the above publication, a method of lowering the degree of polymerization (molecular weight) of the polymer in the composition may be considered. However, in that case, the strength of the composition is reduced, and it is impossible to increase the hydrolyzability to such an extent that the composition is hydrolyzed in a few weeks only by adjusting the degree of polymerization.

[0017] Therefore, for this reason, the resin composition disclosed in this publication has a drawback that it cannot be applied to uses that require a high rate of hydrolysis in vivo.

[0018]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above problems and to provide a hydrolyzable resin composition which is useful as a medical material having high flexibility and a high rate of decomposition in a living body. It is in.

[0019]

The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a glycolic acid-lactic acid copolymer having a specific copolymer composition is used as a raw material for a monomer or oligomer. The present invention has been found that the resin composition is plasticized and exhibits flexibility, and that the obtained resin composition has good hydrolyzability.

[0020] ie, the present invention is repetitive structure 20 to 80 mol percent glycolic acid molecule, lactic acid units 80-2
0 mol% consists of glycolic acid - lactic acid copolymer 1 00 parts by weight, glycolic acid oligomer (polymerization degree 30),
Lactic acid oligomer (degree of polymerization 1 to 30), glycolic acid-lactic acid co-oligomer (degree of polymerization 2 to 30), 8 to 20 parts by weight of one or more low molecular weight substances selected from the group consisting of glycolide and lactide And a hydrolyzable resin composition having an improved flexibility and a tensile tangent modulus of 1 to 100 kgf / mm ² .

Hereinafter, the present invention will be described in detail.

The copolymer having 20 to 80 mol% of a glycolic acid unit and 80 to 20 mol% of a lactic acid unit as a molecular repeating structure, which is a main component of the resin composition of the present invention, is composed of glycolic acid and lactic acid. Can be obtained by dehydration polycondensation, but is preferably synthesized by ring-opening copolymerization of glycolide and lactide.

Glycolide and lactide are cyclic dimers that are easily prepared by the dehydration polycondensation reaction of glycolic acid and lactic acid, respectively, and the subsequent pyrolysis reaction.

Lactide includes D-lactide which is a cyclic dimer of D-lactic acid, L-lactide which is a cyclic dimer of L-lactic acid, meso-lactide in which D-lactic acid and L-lactic acid are cyclically dimerized, And DL-lactide, which is a racemic mixture of D-lactide and L-lactide. In the present invention, any lactide can be used.

In the present invention, in addition to glycolide or lactide used as a monomer, polymerization can be carried out using other lactones in combination.

Other lactones that can be used in combination include, for example, β-propiolactone, β-butyrolactone,
-Valerolactone, δ-valerolactone, ε-caprolactone, p-dioxanone, 3-methyl-1,4-dioxane-2,5-dione and the like. When these lactones are used, the amount added is preferably 20 mol% or less based on the total amount of glycolide and lactide as the main raw materials.

In order to copolymerize glycolide and lactide to obtain a high molecular weight copolymer in a short time, it is preferable to use a catalyst. As such a polymerization catalyst, various catalysts having a catalytic effect on this polymerization reaction can be used. For example, compounds containing mainly polyvalent metals such as stannous octoate, tin tetrachloride, zinc chloride, titanium tetrachloride, iron chloride, boron trifluoride ether complex, aluminum chloride, antimony trifluoride, and lead oxide. In particular, a tin compound or a zinc compound is preferably used. Of the tin compounds, stannous octoate is particularly preferred. The use amount of these catalysts is not particularly limited, but is usually 0.001 to 0.5% by weight based on the monomers.

In the polymerization, a known chain-enhancing agent can be used. Alcohols such as lauryl alcohol, hydroxy acids such as lactic acid and glycolic acid, and the like are preferably used as the chain extender. A polymer can be obtained in a short time because the polymerization rate is increased by the coexistence of the chain-enhancing agent, and the molecular weight of the polymer can be adjusted by adjusting the amount of the chain-enhancing agent. The usual addition amount is 0.001 to 0.5% by weight based on the monomer.

A solvent may or may not be used for the copolymerization reaction, but bulk polymerization in a molten state is preferred.

The polymerization temperature may be, in principle, a temperature higher than the melting point of glycolide and lactide as monomers in the case of melt bulk polymerization, and lower than the melting point in the case of solution polymerization using a solvent such as chloroform or dichloroethane. Polymerization is possible at the following temperature. The polymerization temperature usually preferably performed in the case of the melt bulk polymerization is in the range of 120 to 250 ° C. 2
If the temperature exceeds 50 ° C. , decomposition of the produced polymer occurs, which is not preferable.

The molecular weight of these copolymers is not particularly limited. However, when used as a medical material requiring strength, for example, a material for preventing adhesion between living tissues or a material for treating a disease caused by adhesion, 10,000 to 10,000 is used. About one million is preferred. However, when used as a material that does not require strength, such as a sustained-release drug substrate, the molecular weight may be about several hundreds to about 10,000. If it exceeds one million, the processability is lowered and the operability of the polymerization reaction is lowered due to an increase in the melt viscosity.

The glycolic acid-lactic acid copolymer, which is the main component of the decomposable resin composition of the present invention, has 20 to 80 mol% of a glycolic acid unit and 80 to 20 mol% of a lactic acid unit as a molecular repeating structure. However, it is preferable that the glycolic acid unit is 30 to 70 mol% and the lactic acid unit is 70%.
３０30 mol%. If the amount of glycolic acid units is at most 20 mol%, or at least 80 mol%, the plasticizing effect of the low molecular weight substance will be small, which is not preferable. It is presumed that the plasticization effect decreases because the crystallinity of the obtained copolymer increases.

The composition of the copolymer can be controlled by the charged composition of the monomers glycolide and lactide. For example, when a copolymer having a repeating molecular structure of 50 mol% of glycolic acid units and 50% of lactic acid units is obtained, the amounts of glycolide and lactide used as raw materials are 40 to 50 mol% and 50 to 60 mol%, respectively. Mol%
Should be within the range.

The resin composition of the present invention comprises the above copolymer, a glycolic acid oligomer (polymerization degree 1 to 30), a lactic acid oligomer (polymerization degree 1 to 30), and a glycolic acid-lactic acid co-oligomer (polymerization degree 2 to 30). , Glycolide, and lactide with one or more low molecular weight substances.

The above oligomer can be easily prepared by subjecting lactic acid and / or glycolic acid to heat dehydration condensation. Usually, oligomers obtained by this method,
The degree of polymerization of the co-oligomer is about 1 to 30. It can also be prepared by heating glycolide or lactide in the presence of water, glycolic acid or lactic acid.

The copolymer is effectively plasticized by the mixture of the above low molecular weight substances and preferably further heating, and the resulting resin composition has flexibility. The amount of the low molecular weight substance is 3 to 40 parts by weight, preferably 8 to 20 parts by weight based on 100 parts by weight of the copolymer. If it is less than 3 parts by weight, it is difficult to obtain sufficient flexibility, and if it is more than 40 parts by weight, it becomes too soft to be formed into a film or the like.

The method of mixing and plasticizing the above copolymer and a low molecular weight substance includes a method of performing a copolymerization reaction of glycolide and lactide and stopping the reaction while leaving unreacted glycolide and lactide. After completion of the copolymerization reaction of glycolide and lactide, there is a method in which a predetermined amount of the low molecular weight substance is mixed, preferably heated. Further, the above methods may be used in combination.

In the method (1), unreacted glycolide and lactide are mixed microscopically with the copolymer, and a good plasticizing effect is exhibited. The monomers (glycolide and lactide) are converted to 120-120 in the presence of a catalyst, optionally in the presence of a chain extender.
After heating to a temperature range of 250 ° C. to start the copolymerization reaction, the reaction is stopped when a desired conversion is reached.

The amounts of the copolymer and the residual monomer in the produced resin composition are quantified by gas chromatography analysis or thermogravimetric analysis, and reaction conditions and termination conditions for obtaining a desired composition ratio are set in advance.

For example, a composition containing a total of 20 parts by weight of glycolide and lactide with respect to 100 parts by weight of a copolymer having a repeating molecular structure of 50 mol% of glycolic acid units and 50 mol% of lactic acid units is obtained. In this case, a copolymerization reaction is carried out using 100 mol parts of glycolide and lactide as monomers, and when the conversion reaches 80% by weight, the reaction is stopped, and the obtained reaction product is heated and plasticized. Good.

In the method of (1), the copolymer obtained by the copolymerization reaction is dissolved in a solvent such as chloroform, or heated and melted to a temperature higher than the glass transition point, and a predetermined amount of a plasticizer (glycolic acid oligomer, lactic acid Oligomers, glycolic acid-lactic acid co-oligomers, glycolides, lactides) are added, mixed and plasticized. This method has an advantage that the amount of the plasticizer can be easily adjusted. When a solvent is used, the mixture is mixed with 50 to 50% when or after the solvent is evaporated or removed.
It is preferable to heat to about 150 ° C.

[0042] The, in International Application WO90-0 1 521 JP, a method of adding a plasticizer is admixed polylactic acid is disclosed, mixing 15% by weight or more plasticizers to polylactic acid in the process Then, especially when the composition is formed into a film, the plasticizer precipitates or crystallizes on the surface, which is not preferable. In contrast, in the case of the resin composition of the present invention,
Even if 15% by weight of the plasticizer is mixed, no precipitation of the plasticizer is observed.

The resin composition of the present invention has excellent flexibility and is used as a medical material, especially a hydrolyzable film material, for example, a biomedical material such as a temporary inter-organ membrane, an anti-adhesion membrane, and an artificial blood vessel. It is suitable as an application material.

The hydrolyzable medical material is required to have various hydrolyzabilities depending on the body part used, the method of use, and the like, due to the nature of the intended use. The resin composition of the present invention has a variety of hydrolyzable medical materials having a period from several weeks to one year until disappeared by hydrolysis by adjusting the copolymer composition and the molecular weight of the copolymer. Becomes It is also used as a base material for sustained release drugs.

[0045]

The method of the present invention will be specifically described below with reference to examples and comparative examples. In addition, each physical property evaluation in an Example was performed by the following method.

After stopping the polymerization reaction, the reaction product was dissolved in hexafluoroisopropanol (hereinafter referred to as HFIP) or methylene chloride to obtain a solution having a known concentration, and the amount of the remaining monomer was determined by gas chromatography.

[0047] The average molecular weight copolymer of the copolymer were dissolved in HFIP, a weight average molecular weight by gel permeation chromatography (GP C) (hereinafter, referred to as Mw) was measured.

Average degree of polymerization of oligomers The oligomers are dissolved in THF or chloroform,
The polymerization degree distribution was measured at C and calculated.

Tensile strength test The resin composition was dissolved in chloroform (concentration: 5% by weight).
It was cast on a Teflon flat dish. The film was slowly evaporated at room temperature, heated when the fluidity of the solution began to disappear, and dried under reduced pressure while keeping the solution at 80 ° C. for 3 hours to obtain a film. A film-like test piece having a width of 10 mm and a length of 50 mm was prepared, and measured using a tensile tester at a chuck width of 20 mm and a tensile speed of 50 mm / min.

Hydrolysis test A film-like test piece was prepared from the resin composition and
Immersed in a phosphate buffer solution (pH 7.3 ) for 2 weeks.
Hydrolysis was performed. The hydrolyzability was evaluated based on the reduction rate of the weight average molecular weight of the film before and after the hydrolysis.

Preparation Example 1 4.0 g of 87% lactic acid aqueous solution was added to 7.2 g of L-lactide put in a test tube, and heated at 100 ° C. Upon cooling, a viscous transparent liquid was obtained at room temperature. The average degree of polymerization was 2.9. Hereinafter, it is referred to as oligomer 1.

[0052] Preparation Example 2 3 liters of 90% in a glass reaction vessel DL- lactic acid aqueous solution were placed and 1100g and 70% glycidyl call acid aqueous solution 100 g, was heated with stirring. When the temperature reached 150 ° C., the pressure of the system was slowly reduced to 30 mmHg, and the reaction was carried out for 4 hours while removing water and volatile components. When the reaction product was cooled, about 860 g of lactic acid-glycolic acid co-oligomer was obtained. The average degree of polymerization was about 3.3. Hereinafter, it is referred to as oligomer 2.

Examples 1-4 In a glass polymerization tube, lactide (hereinafter referred to as LTD) was used as a monomer.
), And glycolide (hereinafter referred to as GLD), and stannous octoate as catalysts were charged in the amounts shown in [Table 1]. A degassing cock was attached to this polymerization tube, and after degassing and drying for several hours, the cock was closed and the polymerization tube was sealed while keeping the vacuum. The copolymerization reaction was carried out at a temperature shown in Table 1 for a predetermined time to obtain a resin composition as a reaction product. The Mw and residual monomer content of the copolymer in the resin composition after the polymerization reaction were measured, and the results are shown in [Table 1].

The obtained resin composition was dissolved in chloroform, and a plasticizer shown in Table 1 was added thereto. The film was cast as it was on a Teflon flat dish, and the solvent was evaporated at room temperature to form a film. Further decompression (3
The film was dried at 50 ° C. for 24 hours under mmHg), and it was confirmed by the measurement of the infrared absorption spectrum of the film that there was no solvent remaining in the film.

The results of the tensile test of the obtained film are shown in [Table 1]. Both films have good flexibility,
And it was rich in elongation.

In addition, all the films showed high hydrolyzability under an environment similar to that in a living body, and the molecular weight was reduced. The results are shown in [Table 2]. That is, these films are suitable for application as soft tissue or the like in a living body, for example, as a material for transplantation or a material for preventing adhesion.

Example 5 During the polymerization reaction in Example 1, during the reaction (14 hours)
A part of the reaction mixture was sampled from the reaction system. Table 1 shows the measurement results of the residual monomer amount. This resin composition was dissolved in chloroform and cast on a petri dish without adding a plasticizer to form a film. It has sufficient flexibility for application to soft tissue in vivo.

Comparative Examples 1 to 4 Films were prepared without adding a plasticizer to the reaction products obtained in the same manner as in Examples 1 to 4. The flexibility was clearly inferior to that with the addition of the plasticizer. This film is not suitable for application to soft tissue in a living body. The results are shown in [Table 1]. Comparative Examples 5 to 7 L-lactide (L-LTD) and DL-lactide (DL-lactide)
LTD) with a molar ratio of 9: 1 into a glass polymerization tube,
The copolymerization was carried out under the conditions shown in Table 1. A plasticizer shown in [Table 1] was added to the obtained reaction product and dissolved in chloroform to prepare a film in the same manner as in Example 1. The obtained film did not show satisfactory flexibility as a material used for soft tissue in vivo. The results are shown in [Table 1]. Further, the hydrolysis rate was low, and it was not suitable for applications requiring a high hydrolysis rate. The results are shown in [Table 2].

[0059]

[Table 1]

[0060]

[Table 2]

[0061]

According to the present invention, a hydrolyzable resin composition having good flexibility and hydrolyzability is provided.

Since the resin composition of the present invention has good flexibility and wide hydrolyzability, it can be applied to medical materials that require a high rate of hydrolysis in vivo.

For example, it can be suitably used as a temporary biological isolation material, an anti-adhesion material, a medical material such as an artificial blood vessel, a substrate for sustained-release medicine, and the like, and is extremely useful in industry.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References WO 90/1521 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C08G 63/06-63/08 C08L 67/04 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. 100 parts by weight of a glycolic acid-lactic acid copolymer having a repeating molecular structure of 20 to 80 mol% of a glycolic acid unit and 80 to 20 mol% of a lactic acid unit, and a glycolic acid oligomer (degree of polymerization 1 to 30) Lactic acid oligomer (degree of polymerization 1-30), glycolic acid-lactic acid co-oligomer (degree of polymerization 2-30), one or more low molecular weight substances selected from the group consisting of glycolide and lactide 8
Consists of a 20 parts by weight, hydrolyzable resin composition flexibility thereof tensile tangent modulus is 1~100kgf / mm ² is improved. 2. A biomedical material made from the hydrolyzable resin composition according to claim 1. 3. A base for sustained-release medicine made from the hydrolyzable resin composition according to claim 1.