JPH0564982B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a method for producing a biodegradable porous material, and more specifically to a method for producing a biodegradable porous material that is characterized by decomposing and disappearing in a living body over a certain period of time. Regarding the manufacturing method. (Prior art) Medical prosthetic materials are required to have extremely minimal reactions in living tissue, and in recent years, biocompatible materials such as polylactic acid and polyglycolic acid have been used for medical applications. Many examples are given.
In addition, these materials such as polylactic acid and polyglycolic acid are degradable in vivo, so sutures,
It is used as a bio-implantable material in orthopedic prosthetics, etc. However, when this material is processed into various implant materials, it is still not perfect in terms of biological tissue reaction, and improvements in the shape and surface structure of the material are the main causes of this. .
Tissue growth on biomaterials is possible when the pore size of the material is 20 μm.
It is known that this occurs when the temperature exceeds, for example,
Bone cell growth requires material pore diameters of 100 to 250 μm. For this purpose, by considering making biomaterials porous,
Attempts have been made to reduce inflammation in the body. Conventionally, porous materials have been produced by dissolving a polymer such as lactic acid or glycolic acid in an organic solvent such as toluene, and then drying the solution. Furthermore, a freeze-drying method that is generally used as a means of making the material porous is known. In addition, polylactic acid is dissolved in chloroform, and sodium citrate etc. are dissolved in the chloroform.
A known method is to add an ethanol mixture, evaporate the solvent, crystallize it, and then extract and remove sodium citrate with ethanol. (A.J.
Pennings, Colloid.Polym.Sci., 261 , 477
(1983)) However, these methods only yield porous bodies with small pore diameters, and require heat treatment at high temperatures and for long periods of time to remove trace amounts of residual solvent, resulting in decomposition of the polymer. , causing contraction;
Further, trace amounts of organic solvents remaining may cause inflammation of living tissues, causing problems. In addition, according to the method of Pennings et al., although it is possible to adjust the pore size to some extent, the additives are not completely removed even though the additives are extracted for a long time with ethanol, and they cannot be completely removed by heating at high temperatures. , decomposition and shrinkage of the polymer occur in the same manner as above. Furthermore, JP-A-61-149160 discloses that a biodegradable sponge can be obtained by dissolving a polymer such as lactic acid in an organic solvent such as benzene and freeze-drying the solution. However, although it is possible to create porosity using this method, the pore size is small, on the order of several tens of microns, and it is not only unusable when the purpose is the growth of bone cells mentioned above, but also It is difficult to adjust the pore size accordingly. Therefore, even though it is known that the adhesion of living tissues is dependent on the pore size of the material, excellent porous materials that are biocompatible, harmless, and safe, and whose pores can be adjusted have not yet been found. The current situation is that this has not been done. (Problems to be Solved by the Invention) In order to solve the above-mentioned problems, the present inventors are able to arbitrarily adjust the pores of a material that is highly safe and has excellent biocompatibility. The present invention was completed as a result of extensive research in order to obtain a porous material with excellent biodegradability. (Means for Solving the Problems) That is, the present invention involves dissolving a polymer of lactic acid or a copolymer of lactic acid and glycolic acid in an organic solvent, and adding a polymer that is substantially inert to the organic solvent and The present invention relates to a method for producing a porous body, which comprises adding a water-soluble filler material, solidifying the same, removing the organic solvent, adding water thereto, and removing the filler material. (Function) The method for producing a porous body of the present invention will be described in further detail below. The polymer of lactic acid or the copolymer of lactic acid and glycolic acid used in the present invention is L-, D-, DL-
Even if it is polymerized using lactic acid or glycolic acid as a raw material, or L-, D-, DL-lactide,
It may be one obtained by polymerizing glycolide, and there are no particular limitations on the manufacturing method. Moreover, those having a molecular weight of approximately 5,000 to 200,000 are used. Glycolic acid or glycolide is preferably used as a copolymer with lactic acid or lactide in terms of in vivo degradability, and the composition ratio thereof is approximately 40 mol% or more as a lactic acid/glycolic acid molar ratio. . In the present invention, these polymers are first dissolved in an organic solvent. Types of organic solvents include dioxane, P
- Use xylene and benzene. The concentration of the polymer at this time varies depending on the type of polymer used, composition ratio, molecular weight, type of organic solvent used, etc., and cannot be particularly limited, but the amount of polymer relative to the organic solvent is approximately 0.8 to 30% by weight.
It dissolves within the range. The polymer dissolved in the solvent is then mixed with a filler material that is substantially inert to the organic solvent and soluble in water. As the filling material, water-soluble inorganic salts such as potassium chloride and sodium chloride, sugars such as sucrose, glucose, and D-mannite, proteins such as gelatin, and water-soluble synthetic polymers such as polyvinyl alcohol and polyacrylamide are used. However, in terms of safety and ease of processing, it is usually preferable to use sucrose. The present invention is characterized in that the desired pore size of the porous body can be adjusted by adjusting the particle size of the additive such as sucrose used at this time. In other words, when producing a porous body with a large pore size, it is sufficient to use additives with a large particle size, and when producing a porous body with a small pore size, it is sufficient to select an additive with a small particle size.The adjustment method is as follows. It's quite easy. Regarding the amount of additive used, the amount of additive used is approximately twice the weight of the amount of polymer and the amount of organic solvent in which it is dissolved. That is, this usage ratio is such that the organic solvent solution in which the polymer is dissolved sufficiently fills the voids in the additive particles, and if there is an excess or deficiency in both, a homogeneous porous body cannot be obtained. In addition, in the present invention, when using the biodegradable porous material, for example, as a bone prosthesis material, hydroxyapatite powder etc. may be added at the same time when adding and mixing the above-mentioned additives, and the hydroxyapatite component As a bone prosthetic material, it has extremely effective in-vivo properties due to its inclusion of and the porous nature of the material. After the filler material of the present invention is added and then solidified, the added organic solvent is removed. As a means of solidification, freezing is usually carried out at a temperature of 0 to 5°C. Further, as a means for removing the organic solvent, it is carried out at a low temperature after freezing or at room temperature under a reduced pressure of 1 to 25 mmHg. Note that if dioxane is used as the organic solvent at this time, this drying and removal operation only needs to be carried out moderately; dioxane, which is highly soluble in water, will be completely removed during the subsequent step of removing additives with water. removed. In this case, the porous material becomes like a nonwoven fabric,
This is effective when a cloth-like porous body is desired. After removing the organic solvent, water is added to this polymer containing additives such as sucrose to make it wet, and this process is repeated several times to extract and remove the additives. After extraction and removal of the additives, the wetted porous body is air-dried at room temperature to have a controlled pore size that does not contain the impurities of the present invention. A porous body excellent as a biodegradable material can be obtained. (Example) The present invention will be further explained below with reference to Examples, but the present invention is not limited thereto.
It should be noted that all percentages are by weight unless otherwise specified. Example 1 1,4-dioxane (reagent manufactured by Kanto Kagaku Co., Ltd.) was added to 1.0 g of a copolymer of L-lactic acid and glycolic acid (L-lactic acid 49 mol%, molecular weight 1.5 × 10 ⁴ ) to make 50 g. This was heated and dissolved. Next, after cooling this polymer liquid to room temperature, it was mixed with granulated sucrose (particle size approximately 0.5 mm)117
In addition to the stainless steel pot (20 x 20 cm) filled with g, add the homogeneous sugar and polymer solution to
Frozen at °C. After freezing, this was dried under reduced pressure at 1 mmHg for 2 hours.
After drying, it was immersed in water at 27°C to extract the sucrose. This extraction operation with water was repeated until no elution of sucrose from the porous material was observed by colorimetric method, and then the material was taken out and air-dried on filter paper to obtain the porous material of the present invention. The colorimetric method used for the determination of sucrose was based on the phenol-sulfuric acid method (Tozo Uriya et al., Biochemistry Experimental Methods I, p. 44, published by Gakkai Publishing Center (1969)). It was done quantitatively. Separately, instead of the above 1,4-dioxane,
A porous body of the present invention was similarly produced using P-xylene and benzene as organic solvents. Furthermore, for comparison, a comparative example product was produced in the same manner using chloroform as an organic solvent. The pore diameters of the products of the present invention and comparative examples were measured by electron microscopy, and the porosity was calculated from the apparent specific gravity and true specific gravity. These results are shown in Table 1.

[Table] Example 2 L-lactide polymer (molecular weight 2.8×10 ⁴ ) 1.3 g
1,4-dioxane was added to make 49 g, and this was dissolved by heating. Next, after cooling this polymer liquid to room temperature, it was mixed with 100% of granulated sucrose (particle size: approximately 0.5 mm).
A 100ml glass cylindrical container (5cmφ) filled with
x 7 cm), and the homogeneous sucrose and polymer solution was frozen at 0°C. After freezing, this was dried under reduced pressure at 2 mmHg for 3 hours.
After drying, it was immersed in water at 70°C to extract the sucrose. This extraction operation with water was repeated, and after the elution of sucrose from the porous body was no longer observed, it was then taken out and air-dried on filter paper to obtain the porous body of the present invention. Separately, in place of the above-mentioned sucrose, potassium chloride (reagent manufactured by Kanto Kagaku Co., Ltd.), polyvinyl alcohol (manufactured by Nippon Gosei Kagaku Kogyo Co., Ltd., trade name KH) can be used as additives.
-20) and gelatin (reagent manufactured by Kanto Kagaku Co., Ltd.), the porous body of the present invention was similarly produced. Furthermore, for comparison, a comparative example product was manufactured by performing the same operation without using this additive. The elution of additives during the extraction operation was confirmed by potassium chloride atomic absorption spectrophotometry, and polyvinyl alcohol and gelatin were measured by a total organic carbon meter. The pore diameters of the products of the present invention and comparative examples were measured by electron microscopy, and the porosity was calculated from the apparent specific gravity and true specific gravity. These results are shown in Table 2.

[Table] Example 3 L-lactide polymer (molecular weight 7.2×10 ⁴ ) 2.0 g
1,4-dioxane was added to make 100 g, and this was dissolved by heating. Next, after cooling this polymer liquid to room temperature, the polymer liquid and granulated sucrose (particle size: approximately 0.5 mm) were mixed in the proportions shown in Table 3, and the mixture was homogenized and frozen at 0°C. I let it happen. After freezing, it was heated to 1mmHg under the conditions shown in Table 3.
After drying, the mixture was dried in water at 27°C to extract the sucrose. This extraction operation with water was repeated until no elution of sucrose from the porous material was observed by colorimetric assay, and then the material was taken out and dried under reduced pressure at 70°C for 2 hours to obtain the porous material of the present invention. Obtained. The porosity was calculated from the apparent specific gravity and true specific gravity, and the results are shown in Table 3.

[Table] Example 4 In Example 2, using the product of the present invention obtained using sucrose as an additive and the comparative product without using the additive, the porous material was tested in a rat. We looked at tissue reactivity. The porous bodies of the present invention and comparative examples were prepared with a thickness of 2 mm and a 5×
When cut into 5 mm square sheets and implanted subcutaneously in rats, foreign giant cells appeared in the comparative example product after 6 weeks, but no cell abnormalities were observed in the inventive product.

Claims (1)

[Claims] 1 Dissolving a polymer of lactic acid or a copolymer of lactic acid and glycolic acid in an organic solvent, adding thereto a filler substance that is substantially inert to the organic solvent and water-soluble, and then solidifying this. . A method for producing a porous body, which comprises removing the organic solvent and then adding water thereto to remove the filler material.