JP2827055B2 - Polymer - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to high molecular weight lactic acid and / or lactic acid.
Or a polymer comprising a calcium salt of a polymer or copolymer of glycolic acid, particularly a polymer useful as a medical polymer material such as a bioabsorbable prosthetic material.

[0002]

2. Description of the Related Art Materials such as plates, screws, pins, nails, wires, and the like are used for osteosynthesis as prosthetic materials used in orthopedic surgery and the like. Materials used for these materials include metal materials such as stainless steel, titanium alloy, and cobalt-chromium alloy.

[0003] However, although the mechanical strength of these materials is sufficient, since the materials have a higher rigidity than hard tissues such as bones, stress concentrates on the joints of the materials, and deformation and deformation of the bone during bone repair. Fractures or fatigue deterioration of materials occur. Also,
Since the material is non-degradable, it is necessary to remove the material by re-operation after the injury is completely repaired so as not to hinder the self-healing of the bone. Further, the interaction between the material and the living body may cause problems such as durability, biocompatibility, and carcinogenicity of the treatment section.

Accordingly, in recent years, the use of polymers such as lactic acid and glycolic acid which are degradable in vivo has been studied as a raw material which does not require reoperation, and is used as a bioabsorbable suture in clinical practice. Have been. In addition, for osteosynthesis, it is known that polymers of lactic acid have been studied in beagle dogs as fracture bonding materials such as plates and screws.
(J. Oral. Surgery, 30, 344 (1972)). However, when a lactic acid polymer is used as a bonding material, it is melted and molded, which causes a problem of a reduction in molecular weight due to thermal decomposition. Therefore, a method of extracting and removing residual monomers, oligomers, and the like in the polymer acting as a catalyst for thermal decomposition of the lactic acid polymer from the lactic acid polymer (Biomaterials, 8, 31)
1 (1987)), or a method of molding a lactic acid polymer by a wet method using a solvent (Gogolew
Ski, P. et al., J. Appli. Polym. Sci. 28, 1045 (1983)), but have not yet achieved sufficient effects of preventing thermal degradation.

In order to apply the lactic acid polymer to various medical materials, various methods for modifying the lactic acid polymer are known. For example, JP-A-52-5711 discloses a low molecular weight lactic acid polymer and an alkali metal such as sodium carbonate as a modification method aimed at lowering the melting point of a lactic acid polymer base upon mixing a drug such as a drug. A method for reacting a salt is disclosed.
Japanese Patent Application Laid-Open No. 53-83381 discloses that a suture made of a polymer such as lactic acid and a polymer such as lactic acid and calcium are used to improve the knotting property and lubricity of a surgical suture. A method for coating a fatty acid salt mixture is disclosed. However, even if these methods are used, there is no effect in improving the prevention of thermal degradation of the lactic acid polymer, and a medical polymer material using a lactic acid polymer as a prosthetic material, which has excellent heat resistance during molding, is not available. At present, it has not been obtained yet.

[0006]

SUMMARY OF THE INVENTION In order to solve the above-mentioned problems, the present inventors have made a material which is highly safe and has excellent biocompatibility, and has less thermal decomposition and thermal degradation during melt molding. As a result of intensive studies to obtain materials, the present invention has been completed.

[0007]

That is, the present invention provides a compound having a molecular weight of 10
A polymer comprising a calcium salt of a polymer or copolymer of lactic acid and / or glycolic acid of 000 or more, wherein the equivalent ratio of calcium to the polymer or copolymer of lactic acid and / or glycolic acid is 0.1 to 4.0. Range of polymers.

[0008]

Hereinafter, the present invention will be described in more detail. The calcium salt of a polymer or copolymer of lactic acid and / or glycolic acid of the present invention can be obtained by reacting a polymer or copolymer of lactic acid and / or glycolic acid with a calcium salt. The lactic acid and / or glycolic acid polymer or copolymer to be used may be any polymer or copolymer as long as it is produced by a general method. For example, a polymer or copolymer can be obtained by directly dehydrating and polycondensing lactic acid and glycolic acid under reduced pressure (Yuhara et al.,
Engineering, 68 (5), 983 (1965)). In addition, lactic acid, glycolic acid is distilled under reduced pressure in the presence of a catalyst such as zinc oxide, lactide,
After obtaining glycolide, they can also be produced by carrying out a polymerization reaction in the presence of a catalyst such as tetraphenyltin or stannic chloride (Kulkarni, j. Biomed. Mater.Res., 5, 169).
(1971)). Further, the lactic acid monomer used in these cases may be any of D-form, L-form and DL-form.

In the present invention, a polymer of lactic acid and / or glycolic acid thus obtained having a molecular weight of 100,000 or more is used. In this case, if the molecular weight of these polymers is less than 100,000, the effect of preventing the polymer from being thermally degraded will hardly be obtained even if the polymer is reacted with a calcium salt described below.

With respect to the calcium salt, the most preferred type of calcium salt to be used is a calcium salt of a higher fatty acid, such as pelargonic acid, 2-ethylhexanoic acid, lauric acid, palmitic acid, stearic acid. Any of calcium salts such as oleic acid and oleic acid can be used, but the use of calcium stearate is most preferred from the viewpoint of reactivity. Also,
Use of calcium salts other than these, for example, calcium lactate, calcium propionate, calcium chloride, and the like, or the use of other salt species such as magnesium stearate, will not provide any effect of the present invention.

As for the method for obtaining the polymer of the present invention using these raw materials, first, a polymer or copolymer of lactic acid and / or glycolic acid is dissolved in an organic solvent. Examples of the type of the organic solvent used include chloroform, dichloromethane, dioxane, toluene, hexafluoroisopropanol, trifluoroacetic acid, and benzyl alcohol. Further, the concentration of the above-mentioned polymer or copolymer is used so as to be generally in the range of 1 to 20% by weight.

In this solution, a calcium salt is dissolved in the same solvent, and the solution is added to the polymer solution to carry out a reaction. With respect to the amount of calcium salt used, the calcium salt is used such that the equivalent ratio of calcium to the polymer or copolymer of lactic acid and / or glycolic acid is in the range of 0.1 to 4.0.
In this case, the equivalent of the polymer or copolymer of lactic acid and / or glycolic acid is based on the number of carboxyl groups (average) at the terminal of the polymer chain. Further, when the use ratio of both deviates from the above range and the equivalent of both is less than 0.1, the heat resistance of the polymer of the present invention is hardly improved, and conversely, the use of excess calcium salt exceeding 4.0 The unreacted calcium salt is thermally decomposed during melt molding of the polymer, and the generated acid promotes thermal deterioration of the polymer. In any case, the polymer having excellent heat resistance of the present invention cannot be obtained. The concentration of calcium salt dissolved in organic solvents is generally 0.1-1% by weight
Range.

The reaction between the polymer or copolymer and the calcium salt is carried out by mixing the two solutions and accelerating the reaction.
Usually, the heating is carried out from normal temperature to a temperature of about the boiling point of the solvent used. As the reaction proceeds, the solution becomes clear from a cloudy state, and the viscosity of the solution increases. The reaction time varies depending on the type, molecular weight, concentration, etc. of the raw materials used, and cannot be unconditionally determined, but is generally about 2 hours.

After completion of the reaction, the product is put into an organic solvent such as methanol, ethanol, hexane, etc., and a polymer is precipitated in the solvent to remove free higher fatty acids. By drying the precipitated polymer using an appropriate drying means such as drying under reduced pressure, the polymer of the present invention having excellent heat resistance during melt molding can be obtained.

[0015]

The present invention will be further described below with reference to examples of the present invention, but the present invention is not limited to these examples. In Examples of the present invention, all percentages are by weight unless otherwise specified. (Example 1) Chloroform (a reagent manufactured by Kanto Chemical Co., Ltd.) was added to 2 g of a polymer (molecular weight: 30 × 10 ⁴ ) of L-lactic acid to make a total amount of 100 g, which was heated to 35 ° C. to dissolve the polymer. did. Next, add calcium stearate (Kanto Scientific
A predetermined amount of a 0.1% chloroform dispersion of Reagent Co., Ltd.) was added, and the solution was heated to about 50 ° C. to perform a reaction. At this time, the polymer solution changed from cloudy to a transparent state with the progress of the reaction, and the viscosity of the solution gradually increased. After reacting for about 1 hour,
The same amount of chloroform as the amount of the evaporated solvent was added to the reaction solution,
Then, this was added to methanol (a reagent manufactured by Kanto Chemical Co., Ltd.) with stirring to precipitate a polymer after the reaction. Next, the precipitated polymer was washed with methanol and filtered, and the precipitate was dried under reduced pressure at about 70 ° C. for 2 days to obtain a polymer of the present invention. In addition, the calcium stearate L
-The same treatment was carried out while changing the equivalent ratio to the lactic acid polymer to obtain polymers of the present invention having different calcium equivalent ratios.

Using the thus obtained polymer of the present invention, a heat deterioration test was performed on the polymer when the polymer was heated and melt molded. In the test method, 0.5 g of the polymer was immersed in 7 g of liquid paraffin (a reagent manufactured by Kanto Chemical Co., Ltd.) in order to keep the heat transfer efficiency to the polymer constant. Melting heating was performed for hours. After heating, the liquid paraffin attached to the polymer was washed with n-hexane (a reagent manufactured by Kanto Chemical Co., Ltd.), and the polymer was dried at 50 ° C. under reduced pressure. The intrinsic viscosity of the polymer after melting and heating is measured (Eling
Polymer, 23 , 1587 ((1982)), and the molecular weight of the polymer was determined from the results. The results are shown in Table 1.

[0017]

[Table 1] Note) * 1 PLLA is an abbreviation for L-lactic acid polymer

Example 2 Methylene chloride was added to 20 g of a copolymer of L-lactic acid and glycolic acid (L-lactic acid content: 80%, molecular weight: 15 × 10 ⁴ ) to make the total amount 200 g. Heated to dissolve the copolymer. Next, 76 g of a 0.1% methylene chloride dispersion of calcium stearate was added to the copolymer solution so that the equivalent ratio of calcium to the copolymer was 1.0, and the solution was heated to about 30 ° C. to perform a reaction. Was. After the reaction was carried out for about 1 hour, the same amount of methylene chloride as the amount of the evaporated solvent was added to the reaction solution, which was then added to methanol with stirring to precipitate the polymer after the reaction.
Next, the precipitated polymer was washed with methanol and filtered, and the precipitate was dried under reduced pressure at about 70 ° C. for 2 days to obtain a polymer of the present invention.

For comparison, a reaction was carried out in the same manner using sodium stearate and magnesium stearate (reagents manufactured by Kanto Chemical Co., Ltd.) in place of the above calcium stearate to obtain a polymer. Using the thus obtained present invention and the polymer obtained for comparison, a heat deterioration test was performed on the polymer during heat melting and molding in the same manner as in Example 1, and the results are shown in Table 2. Was.

[0020]

[Table 2]

Example 3 L-lactic acid polymer (molecular weight 90 ×
10 ⁴ ) The polymer of the present invention was prepared in the same manner as in Example 1 by using calcium 2-ethylhexanoate as the calcium salt and using the calcium salt to the L-lactic acid polymer in an equivalent ratio of 1.0. Obtained. The obtained polymer was subjected to a thermal deterioration test in the same manner as in Example 1, and the results are shown in Table 3.

[0022]

[Table 3]

[0023]

As described above, the polymer of the present invention has extremely low thermal decomposition and thermal deterioration of the polymer during the melt molding process. , Rods, plates, etc. are useful as medical polymer materials. Further, the polymer of the present invention,
For the purpose of accelerating biodegradation, a water-soluble inorganic salt powder, a water-soluble polymer, or the like may be used in combination with the powder, or a powder of hydroxyapatite having bioactivity may be mixed and used. Furthermore, the polymer of the present invention becomes an extremely useful biodegradable medical material in the medical field by adding a carcinostatic agent, a local anesthetic, an antibiotic and the like.

Claims (1)

(57) [Claims] 1. A polymer comprising a calcium salt of a polymer or copolymer of lactic acid and / or glycolic acid having a molecular weight of 100,000 or more, wherein the equivalent of calcium to the polymer or copolymer of lactic acid and / or glycolic acid. Ratio 0.1 ~
Polymers in the range of 4.0.