JPH04249527A - Polymer - Google Patents

Abstract

PURPOSE:To prevent the mol.wt. decrease on thermal melting of a polymer or copolymer of lactic acid and/or glycolic acid. CONSTITUTION:A polymer or copolymer having a mol.wt. of 10,000 or higher and prepd. from lactic acid and/or glycolic acid is reacted with a calcium salt of a higher fatty acid, etc., to give a calcium salt of the polymer or copolymer contg. calcium in an equivalent ratio to calcium contained in the polymer or copolymer before the reaction of 0.1-4.0. The prepd. polymer salt causes little decrease in mol.wt. on thermal melting during molding and is used as prosthetic material in organism, etc.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to high molecular weight lactic acid and/or
The present invention also relates to a polymer comprising a calcium salt of a polymer or copolymer of glycolic acid, which is particularly useful as a medical polymer material such as a bioabsorbable prosthetic material.

0002

2. Description of the Related Art Plates, screws, pins, nails, wires, and other materials are used as prosthetic materials used in orthopedic surgery and the like for bone joining. In addition, the materials used for these materials generally include metal materials such as stainless steel, titanium alloy, and cobalt-chromium alloy.

However, although these materials have sufficient mechanical strength, their stiffness is higher than that of hard tissues such as bones, so stress is concentrated at the joints of the materials, causing bone deformation and deformation during bone repair. This may result in fractures or fatigue deterioration of the material. In addition, since the material is non-degradable, it is necessary to remove the material by repeat surgery after the damaged area has completely healed so as not to inhibit the self-repair of the bone. Furthermore, the interaction between the material and the living body may cause problems such as durability of the treated area, biocompatibility, carcinogenicity, etc.

Therefore, in recent years, the use of biodegradable polymers such as lactic acid and glycolic acid has been studied as materials that do not require reoperation, and in clinical practice, they have been used as bioabsorbable sutures. has been done. In addition, for osteosynthesis, it is known that lactic acid polymers are being studied for use in beagle dogs as fracture-synthesis materials for plates, screws, etc. (J. Oral. Surgery, 30, 344 (1999).
72)). However, when a lactic acid polymer is used as a bonding material, since it is melted and molded, a problem arises in that the molecular weight decreases due to thermal decomposition. Therefore, for this purpose, there is a method for extracting and removing residual monomers, oligomers, etc. in the polymer that acts as a thermal decomposition catalyst for the lactic acid polymer (Biomaterials, 8, 311).
1987)), or to prevent thermal deterioration.
Method of molding lactic acid polymer by wet method using solvent (G
Ogolewski, P. et al., J. Appli. Pol
ym. Sci. 28, 1045 (1983)), but a sufficient effect of preventing thermal deterioration has not yet been achieved.

Furthermore, various methods for modifying lactic acid polymers are known in order to apply them to various medical materials. For example, JP-A-52-5711 describes a method for modifying a lactic acid polymer base with a low molecular weight lactic acid polymer and an alkali metal such as sodium carbonate as a modification method for lowering the melting point of a lactic acid polymer base when mixing drugs such as pharmaceuticals. A method of reacting salts is disclosed. In addition, Japanese Patent Application Laid-Open No. 53-83381 discloses that a polymer such as lactic acid and calcium etc. are added to a suture thread made of a polymer such as lactic acid in order to improve the ligation properties and lubricity of surgical suture thread. A method of coating a fatty acid salt mixture is disclosed. However, even if these methods are used, they are not effective in improving the prevention of thermal deterioration of lactic acid polymers, and medical polymer materials made from lactic acid polymers that have excellent heat resistance during molding and are used as prosthetic materials are not available. The current situation is that this has not been achieved yet.

[0006]

[Problems to be Solved by the Invention] In order to solve the above-mentioned problems, the present inventors have developed a material that is highly safe and has excellent biocompatibility, and has little thermal decomposition and thermal deterioration during melt molding. As a result of extensive research in order to obtain materials, the present invention has been completed.

[0007]

[Means for Solving the Problems] That is, the present invention has a molecular weight of 1
00,000 or more, the equivalent ratio of calcium to the polymer or copolymer of lactic acid and/or glycolic acid is 0.00,000 or more. 1 to 4.0.

[0008]

[Operation] The present invention will be explained in more detail below. 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. Further, the lactic acid and/or glycolic acid polymer or copolymer used may be any polymer or copolymer as long as it is produced by a common method. For example, a polymer or copolymer can be obtained by direct dehydration polycondensation of lactic acid or glycolic acid under reduced pressure (Yubara et al.
Koka, 68(5), 983 (1965)). In addition, by distilling lactic acid and glycolic acid under reduced pressure in the presence of a catalyst such as zinc oxide to obtain lactide and glycolide, these are subjected to a polymerization reaction in the presence of a catalyst such as tetraphenyltin or stannic chloride. can also be produced (Kulkarni,
j. Biomed. Mater. Res. ,5,169
(1971)). Furthermore, the lactic acid monomer used in these cases may be any of the D-form, L-form, and DL-form.

In the present invention, the molecular weight of the lactic acid and/or glycolic acid polymer thus obtained is 100,000.
Use 0 or more. In this case, if the molecular weight of these polymers is less than 100,000, even if the reaction with the calcium salt described below is carried out, there will be almost no effect on preventing thermal deterioration of the polymer.

Regarding calcium salts, it is most preferable to use calcium salts of higher fatty acids, such as pelargonic acid, 2-ethylhexanoic acid, lauric acid, palmitic acid,
Any calcium salt such as stearic acid or oleic acid can be used, but calcium stearate is most preferably used from the viewpoint of reactivity. In addition, other calcium salts such as calcium lactate,
If calcium propionate, calcium chloride, etc. are used, or other salts such as magnesium stearate are used, the effects of the present invention cannot be obtained at all.

Regarding 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 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 generally in the range of 1 to 20% by weight.

[0012] Next, a calcium salt is dissolved in the same solvent and added to the above polymer solution to carry out a reaction. Regarding the amount of calcium salt used, it is used so 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 weight of the polymer or copolymer of lactic acid and/or glycolic acid is based on the number (average) of carboxyl groups at the end of the polymer chain. Furthermore, if the ratio of both used exceeds the above range and the equivalent weight of both is less than 0.1, the heat resistance of the polymer of the present invention will hardly be improved; The use of calcium salts is
During melt molding of the polymer, unreacted calcium salts are thermally decomposed, and the generated acid accelerates thermal deterioration of the polymer, making it impossible to obtain the excellent heat resistant polymer of the present invention in either case. The concentration of calcium salt dissolved in an organic solvent is approximately 0.1
-1% by weight.

[0013] In the reaction between the polymer or copolymer and calcium salt, solutions of both are mixed and the reaction is accelerated by
This is usually carried out by heating from room temperature to a temperature around the boiling point of the solvent used. As the reaction progresses, the solution changes from cloudy to transparent, and the viscosity of the solution increases. Although the reaction time varies depending on the type, molecular weight, concentration, etc. of the raw materials used, it cannot be stated unconditionally, but it is approximately 2 hours.

After completion of the reaction, the product is placed in an organic solvent such as methanol, ethanol, hexane, etc., the polymer is precipitated in the solvent, and the liberated higher fatty acids are removed. By drying this precipitated polymer using a suitable drying means such as vacuum drying, it is possible to obtain a polymer having excellent heat resistance during melt molding according to the present invention.

[0015]

[Examples] The present invention will be further explained below with reference to Examples, but the present invention is not limited thereto. Further, in the examples of the present invention, all percentages indicate weight percentages unless otherwise specified. (Example 1) Polymer of L-lactic acid (molecular weight 30 x 104)
Chloroform (reagent manufactured by Kanto Kagaku Co., Ltd.) was added to 2 g of the solution to make a total amount of 100 g, and the mixture was heated to 35° C. to dissolve the polymer. Next, a predetermined amount of a 0.1% chloroform dispersion of calcium stearate (reagent manufactured by Kanto Kagaku Co., Ltd.) was added to this polymer solution, and the solution was heated to about 50° C. to perform a reaction. At this time, the polymer solution changed from cloudy to transparent as the reaction progressed, and the viscosity of the solution gradually increased. After reacting for about 1 hour, add chloroform in the same amount as the amount of evaporated solvent to the reaction solution, and then add this to methanol (reagent manufactured by Kanto Kagaku Co., Ltd.) under stirring to precipitate the polymer after the reaction. Ta. Next, the precipitated polymer was washed with methanol and filtered, and then the precipitated product was dried under reduced pressure at about 70° C. for 2 days to obtain the polymer of the present invention. Further, the same treatment was carried out while changing the equivalent ratio of calcium stearate to the L-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 thermal deterioration test was conducted on the polymer when the polymer was heat-melted and molded. The test method was to apply 0.5 g of the polymer to
In order to keep the heat conduction efficiency of the polymer constant, it was immersed in 7 g of liquid paraffin (reagent manufactured by Kanto Kagaku Co., Ltd.), and melted and heated at a temperature of 200° C. for 1 hour. After heating, the liquid paraffin attached to the polymer was dissolved in n-hexane (
The polymer was washed with a reagent manufactured by Kanto Kagaku Co., Ltd., and dried under reduced pressure at 50°C. Measurement of the intrinsic viscosity of the polymer after melting and heating in this way (Eling et al., Polymer, 23
, 1587 ((1982)), and the molecular weight of the polymer was determined from this result. The results are shown in Table 1.

[0017]

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

0018
] (Example 2) Copolymer of L-lactic acid and glycolic acid (L-lactic acid and glycolic acid)
- Methylene chloride was added to 20 g of lactic acid (80% content, molecular weight 15 x 104) to make a total amount of 200 g, and this was heated at 25
The copolymer was dissolved by heating to . This copolymer solution was then added with an equivalent ratio of calcium to copolymer of 1.0.
76 g of a 0.1% methylene chloride dispersion of calcium stearate was added so that the reaction was carried out by heating the solution to about 30°C. After reacting for about 1 hour, methylene chloride in an amount equal to the amount of the evaporated solvent was added to the reaction solution, and this 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 then the precipitated product was dried under reduced pressure at about 70° C. for 2 days to obtain the polymer of the present invention.

For comparison, the same reaction was carried out using sodium stearate and magnesium stearate (reagent manufactured by Kanto Kagaku Co., Ltd.) in place of the above-mentioned calcium stearate to obtain a polymer. Using the thus obtained polymers of the present invention and the polymers obtained for comparison, a thermal deterioration test during hot melt molding of the polymers was conducted in the same manner as in Example 1, and the results are shown in Table 2. Ta.

[0020]

[Table 2]

(Example 3) Polymer of L-lactic acid (molecular weight 9
The method of the present invention was carried out in the same manner as in Example 1, using calcium 2-ethylhexanoate as the calcium salt, and using it so that the equivalent ratio of the calcium salt to the L-lactic acid polymer was 1.0. A polymer was 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 explained above, the polymer of the present invention has extremely low thermal decomposition and thermal deterioration during melt molding processing, and is particularly useful as a bioabsorbable prosthetic material, for example, as a pin by melt molding. It is useful as a medical polymer material such as rods, plates, etc. Furthermore, the polymer of the present invention may be combined with water-soluble inorganic salt powder, water-soluble polymer, etc., or bioactive hydroxyapatite powder, etc., for the purpose of promoting biodegradation. They can also be used in combination. Furthermore, the polymer of the present invention can be treated by adding anticancer agents, local anesthetics, antibiotics, etc.
It is a biodegradable medical material that is extremely useful in the medical field.

Claims (1)

[Claims] Claim 1: A polymer consisting of 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 calcium salt of the polymer or copolymer of lactic acid and/or glycolic acid is A polymer having an equivalent ratio of from 0.1 to 4.0.