JPH0428020B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a porous base, and more particularly to a method for producing a porous base that imparts excellent sustained release characteristics of a drug when the base is impregnated with a drug. Polymers such as lactic acid and glycolic acid, ie, polylactide and polyglycolide, are biodegradable polymers that have recently been applied to medical implant materials such as sutures, artificial tracheas, and artificial blood vessels. On the other hand, it is also being applied as a sustained release base for drugs such as physiologically active substances and agricultural chemicals. Desired properties for these materials include not only biocompatibility and biodegradability, but also
For materials impregnated with drugs, etc., sustained release control, in which the drug is released from the base within a certain period of time, is an issue. As a new development, in recent years, sustained release of polylactide and the like, that is, making it porous, has been studied. (Prior art) Conventionally, as a method of making polylactide porous, polylactide and sodium oxalate are dissolved in a specific mixed solvent such as chloroform-ethanol,
A known method is to evaporate the solvent at a constant rate and then extract sodium oxalate with ethanol. (Pennings et al., Colloid.
Polym. Sci., 261 , 477 (1983)) However, with this method, it is very difficult to control the evaporation rate of the solvent, and a polymer with the desired pore size cannot be obtained. Furthermore, added salts such as sodium oxalate remain in the polymer, which limits its use in biological systems. Separately, low molecular weight polylactide and chromium,
Approximately 260 to 280 chlorides and carbonates of aluminum, etc.
A method of producing resin by reacting at a high temperature of °C is known, but this method requires an extremely long time for the reaction, accelerates the decomposition of polylactide, and leaves a large amount of decomposed products in the reaction product. Since this material has a low molecular weight and low strength, it cannot normally be used as a porous base material. Another known method is to dissolve alkaline earth metal salts or aluminum salts of higher fatty acids, polylactide, etc. in a solvent, coat the fibers with the solution, and modify the fiber surface. (Japanese Patent Application Laid-open No. 53-83381) However, this method is aimed at modifying higher fatty acid salts that are normally used for modifying fibers.
Since polylactide containing a large amount of higher fatty acids and having a high molecular weight is used, the reaction as in the present invention does not occur and a porous body cannot be formed, and polylactide is simply mixed in a small amount. This is completely different from the porous body of the present invention. As described above, as a porous base made of polylactide, polyglycolide, etc., no method has yet been found to obtain a base having excellent sustained release properties, base strength, etc. (Problems to be Solved by the Invention) Therefore, in order to solve the above-mentioned problems, the present inventors developed polylactide, which is a porous base material whose pore diameter can be easily controlled, and which has excellent strength and sustained release properties as a base material. We also conducted intensive research on methods for obtaining porous bases made of polyglycolide. (Means for Solving the Problems) As a result of various studies, the present inventors found that polylactide, polyglycolide, or a copolycondensate thereof in an organic solvent and aluminum stearate having 8 carbon atoms, etc. By reacting the above higher fatty acids with aluminum salts, polylactide, polyglycolide, or their copolycondensates can be made porous to a desired pore size, and this reaction can be carried out in a short time at a temperature around room temperature. As a result, the initial decrease in polymer molecular weight was avoided,
It has become possible to obtain a porous base that is excellent in both sustained release properties and strength properties, thus completing the present invention. That is, in the present invention, the number average molecular weight is
500 to 15,000 polylactide, polyglycolide, or a copolycondensate thereof and an aluminum salt of a higher fatty acid having 8 or more carbon atoms, the amount of aluminum salt is in the range of 3 to 20% by weight based on the amount of the polymer. It relates to a porous base obtained by adding and reacting as described above. (Function) As raw materials for producing the porous base of the present invention, polylactide, polyglycolide, or their copolycondensates may be any polylactide, polyglycolide, or copolycondensate thereof, as long as they are produced by a general method. It may be. For example, polylactide and polyglycolide can be obtained by direct dehydration polycondensation of lactic acid and glycolic acid under reduced pressure. (Yubara et al., Koka. 67 (6),
956 (1964)) In addition, lactic acid and glycolic acid are condensed in the presence of a catalyst such as zinc oxide to obtain lactide and glycolide, which are then polymerized in the presence of a catalyst such as tetraphenyltin or stannous chloride. It can also be produced by conducting a reaction. (Kulkarni, J. Biomed. Mater.
Res., 5 , 169 (1971)) Furthermore, the lactic acid monomer used in these cases may be of the D-form, L-form, or DL-form. In the present invention, the number average molecular weight of polylactide or polyglycolide obtained in this way is 500 to 500.
Use the 1500 one. That is, if a polymer having a molecular weight outside this range is used, the porous base of the present invention cannot be obtained. If the molecular weight deviates from this range and is less than 500, the pore size of the base material becomes too large and the strength of the base material decreases, and conversely, if it exceeds 15,000, the combination of the polymer and aluminum salt described below As the reactivity decreases, the pore size of the base material becomes too small, making it difficult to obtain the porous base material of the present invention. Therefore, this molecular weight range of the polylactide, polyglycolide, or copolycondensate thereof used is particularly important in the present invention. Next, regarding the organic solvent used in the present invention, any organic solvent may be used as long as it dissolves the polylactide, polyglycolide, or copolycondensate thereof, such as chloroform, carbon tetrachloride,
Benzene, toluene, dioxane, etc., alcohols such as isopropanol, butanol, and acetone can be used. In addition, aluminum salts of higher fatty acids having 8 or more carbon atoms include aluminum stearate, aluminum palmitate, aluminum laurate, aluminum myristate, aluminum octylate, aluminum oleate, sorbitan aluminum monooleate, and sorbitan aluminum monostearate. , aluminum cinnamate, aluminum 3-phenylpropionate, and the like. When aluminum salts other than these aluminum salts of higher fatty acids having 8 or more carbon atoms are used, the reaction of the present invention does not occur, or even if the reaction occurs, a porous body is not generated. can't get it. The method for producing the porous base of the present invention using these raw materials is as follows. First, polylactide, polyglycolide, or a copolycondensate thereof is dissolved in the above-mentioned organic solvent.
The concentration of these polymers at this time is their molecular weight,
It varies depending on the pore size of the desired base material, etc., but approximately 3
Use in the range of ~40% by weight. That is, by selecting the polymer molecular weight and polymer concentration at this time, the pore diameter of the porous base material can be freely adjusted in the present invention. The higher the polymer concentration or the higher the molecular weight used, the smaller the base pore size becomes. Conversely, the lower the polymer concentration or the lower the molecular weight used, the larger the base pore size becomes. Next, the above-mentioned aluminum salt of higher fatty acid having 8 or more carbon atoms is similarly dissolved or suspended in an organic solvent. In this case, the concentration of these aluminum salts is generally dissolved or suspended in a range of up to 50% by weight. The reaction between polylactide, polyglycolide, or their copolycondensates dissolved in an organic solvent and the aluminum salt is carried out by first placing the polymer solution in a reaction vessel, and then stirring the aluminum salt solution. Added. In this case, there is no particular limitation on the order of addition, and the aluminum salt may be added first or the polymer and the aluminum salt may be added simultaneously. Furthermore, the ratio of addition of both at this time varies depending on the molecular weight of polylactide, polyglycolide, or their copolycondensate used in the reaction, the type of aluminum salt of higher fatty acid having 8 or more carbon atoms, etc. The amount of aluminum salt is used in a range of 3 to 20% by weight based on the amount of polymer. That is, a base material outside this range will not become porous, and the porous base material of the present invention cannot be obtained. The temperature of the solution during the reaction may normally be room temperature, but it may be heated appropriately. As the reaction progresses, the reaction solution turns into a gel, but the reaction usually ends within about 2 hours from the start of the reaction. After the reaction is completed, the resulting gel is subjected to solvent precipitation treatment with a solvent such as methanol, ethanol, or ether.
The porous base of the present invention can be obtained by drying or by directly drying the gel-like material under reduced pressure. The base material of the present invention obtained in this way is porous and has excellent strength properties as a base material, and since the base material is mainly polylactide, polyglycolide, or a copolycondensate thereof, The sustained release property is significantly increased due to the synergistic effect with the sustained release property of the base itself, and it has excellent sustained release properties that a sustained release base should have. Therefore, the product of the present invention can be used not only as a matrix for drugs, as an implant material, but also as a holding agent for bacterial cells and microorganisms, a carrier as a microcapsule, a soil conditioner, a disintegrating agricultural film, a fruit quality improver,
It can be used in a wide range of applications, such as gas separation permeable membranes and fragrance agents. (Example) Examples of the present invention will be described below, but
The present invention is not limited to these. still,
All percentages are by weight unless otherwise specified. Example 1 Poly-L-lactide and aluminum monostearate having a number average molecular weight of 760 were respectively dissolved or dispersed in chloroform in the proportions shown in Table 1. This chloroform solution of poly-L-lactide was prepared using a thermometer, a stirrer, and a condenser.
The mixture was placed in a 300 ml separable flask, heated to 40°C, and a chloroform dispersion of aluminum monostearate was added while stirring. The reaction system gelled several minutes after the addition of aluminum monostearate, to which 40 g of chloroform was further added, stirring was stopped 12 minutes after the start, and the product was taken out from the flask. The reaction product was dried under reduced pressure at 40° C. and 7 mmHg to obtain the porous base material of the present invention. The porous state of the products was observed using a scanning electron microscope, and the results are shown in Table 1. Furthermore, the dioxane absorption amount was measured for the products of the present invention and comparative products obtained after reaction drying, and the degree of porosity of the base was determined. The results are shown in Table 1. <Measurement method of dioxane absorption amount> Put 2 g of the base sample into a 300 ml beaker,
200g of dioxane was added to this and immersed for 24 hours. After immersion, excess dioxane was removed, and the sample was air-dried for 1 hour on a filter paper.The weight of the sample was measured, and the amount of dioxane absorbed was calculated using the following formula. X= _W2 - _W1 / _W1 (g/g) However, X: Dioxane absorption amount (g/g) _W1 : Sample collection amount (g) _W2 : Sample weight after dioxane absorption (g)

[Table] Example 2 300 equipped with magnetic stirrer and thermometer
In a ml beaker, add 17.4 g of poly-L-lactide of each molecular weight shown in Table 2 and 161 g of chloroform.
and stirred at 30°C to dissolve. A solution obtained by dispersing 2.6 g of aluminum distearate in chloroform to make 39 g was added thereto, and the mixture was reacted at 45° C. for 10 minutes. After the reaction, the gel product was immersed in petroleum ether to remove chloroform, and then heated at 40°C and 3 mmHg.
The porous base of the present invention was obtained by drying under reduced pressure. For comparison, polyamides with molecular weights of 350 and 25,000
A similar reaction was carried out with L-lactide to obtain a base. The obtained products of the present invention and comparative products were observed with a scanning electron microscope and the amount of dioxane absorbed was measured, and the results are shown in Table 2.

【table】

[Table] Example 3 500 equipped with stirrer, thermometer, and condenser
In a ml separable flask, add glycolide-L-
18 g of lactide copolycondensate (glycolide/L-lactide molar ratio 2.1, number average molecular weight 2000) and 350 g of benzene were added and dissolved by heating at 50°C. To this was added a solution in which a predetermined amount of aluminum salt of a higher fatty acid having 8 or more carbon atoms as shown in Table 3 was dispersed in 56 g of benzene, and a reaction was carried out at 60° C. for 20 minutes with stirring. After the reaction, remove the product from the flask and store at 30°C.
It was dried under reduced pressure at 3 mmHg to obtain a porous base of the present invention. For comparison, other aluminum salts than the aluminum salts of higher fatty acids having 8 or more carbon atoms were reacted and dried under reduced pressure in the same manner as described above. The porous state of these samples was observed using a scanning electron microscope, and the amount of dioxane absorbed was measured. The results are shown in Table 3.

[Table] Example 4 The porous base of the present invention obtained in Example 1 and the comparative example were crushed and sieved to a powder size of 250 to 420 μm.To 4.5 g of powder was added 0.5 g of butaneben (P-amino Benzoic acid n-butyl ester) was developed in chloroform so as to be within the solvent absorption limit of each powder, and the entire amount of the solution was absorbed. Place this in a dryer at 20℃
It was dried for 8 hours and the chloroform was removed by volatilization. After absorbing this butaneben, add 0.15g of the base to 300ml.
The sample was immersed in a phosphate buffer solution at 37°C and pH 7.4, and the amount of butaneben eluted was measured using an absorptiometer at predetermined intervals while stirring at 300 rpm. The results are shown in Table 4.

【table】

Claims (1)

[Claims] 1 Polylactide, polyglycolide, or a copolycondensate thereof having a number average molecular weight of 500 to 15,000 and an aluminum salt of a higher fatty acid having 8 or more carbon atoms are mixed in an organic solvent in an amount of aluminum salt relative to the amount of the polymer. A porous base material that is added and reacted in an amount ranging from 3 to 20% by weight.