JPS62209146A - Porous base material - Google Patents

Abstract

PURPOSE:To obtain a porous base material readily controllable in the pore size, outstanding in strength and slow-release characteristics, by reaction between polylactide, polyglycolide or copolycondensate therefrom and aluminum alcoholate. CONSTITUTION:(A) A solution prepared by dissolving, in an organic solvent (e.g. chloroform), polylactide, polyglycolide or copolycondensate therefrom with a number-average molecular weight 300-200,000 derived from direct dehydration polycondensation of, e.g. lactic acid and/or glycolic acid, under reduced pressure, with a polymer concentration 0.5-40wt% is incorporated with, while stirring, (B) a second solution prepared by dissolving, in an organic solvent, an aluminum alcoholate such as aluminum isopropoxide, with a concentration up to 10wt% to carry out reaction. Following completion of the reaction, the resulting gelled product is dried under reduced pressure, thus obtaining the objective porous base material. The pore size can be regulated by controlling the molecular weight and/or concentration of the polymer in the component A.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to a porous base material, and in particular to a porous base material that provides excellent sustained release properties of a drug when the base material is impregnated with a drug. Regarding the 91 construction method.

Polycondensates of FL acid, glycolic acid, etc., ie, polylactide and polyglycolide, are biodegradable polymers that have recently been applied to medical implant materials such as suture threads, 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, gradual release of drugs from the base within a certain period of time. Release control is an issue.

As a new development, in recent years, the sustained release of polylactide, etc.
That is, making it porous is being considered.

(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, and after this solvent is evaporated at a constant rate, the sodium oxalate is dissolved in ethanol. A known method is to extract (Panni
ngs et al., C.

11oid, polyIl, Sci,, engineering, 477
(1983)) However, with this method, it is very difficult to control the evaporation rate of the solvent, making it impossible to obtain a polymer with the desired pore size.Also, added salts such as sodium oxalate remain in the polymer, and are harmful to biological systems. Usage is restricted.

Separately, a method is known in which low molecular weight polylactide is reacted with chlorides or carbonates of chromium, aluminum, etc. at a high temperature of about 260 to 280°C, and the resin is left with IR. This process takes an extremely long time, accelerates the decomposition of polylactide, and leaves multiple layers of decomposition products in the reaction product.

And since this material is low molecular weight and has low strength,
It cannot normally be used as a porous base.

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) In order to solve the above-mentioned problems, the present inventors have developed a porous base material that allows easy control of the pore diameter.

In addition, we have conducted extensive research into methods for obtaining porous bases made of polylactide, polyglycolide, etc., which have excellent strength and sustained release properties as bases.

(Means for solving It!I 111 points) As a result of various studies, the present inventors found that polylactide, polyglycolide, or their copolycondensates, and aluminum alcoholates such as aluminum isopropoester The reaction is carried out in an organic solvent or after the melt-mixing reaction.
We have discovered that polylactide, polyglycolide, or their copolycondensates can be made porous to a desired pore size by swelling them in a solvent, and that this reaction can be carried out in a short time at a temperature around room temperature. 1) It has now become possible to create a porous base that avoids the initial decrease in polymer molecular weight and has excellent sustained release properties and strength properties, leading to the completion of the present invention.

That is, the present invention relates to a porous base material formed by reacting polylactide, polyglycolide, or a copolycondensate thereof with aluminum alcoholate.

(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 directly dehydrating and polycondensing lactic acid and glycolic acid under reduced pressure. (Yubara et al., Wangka, L2(6), 955 (196
4)) 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 subjected to a polymerization reaction in the presence of a catalyst such as tetraphenyltin or stannous chloride. It can also be manufactured by (Kul
karni, J., Biomed, Mater, Res.
, J, 169 (1971)) Furthermore, the lactic acid monomer used in these cases may be any one of D monomer, L monomer, and DL monomer.

In the present invention, the polylactide, polyglycolide, or copolycondensate thereof obtained in this manner usually has a number average molecular weight of 300 to 200,000.

Next, regarding the aluminum alcoholate used in the present invention, aluminum isopropoxide, aluminum methoxide, aluminum ethoxide, aluminum-n-butoxide, phenyl methoxide, phenylethoxide, etc. can be used as the aluminum alcoholate. .

Furthermore, when aluminum salts other than aluminum alcoholate are used, the reaction of the present invention does not occur, or even if the reaction occurs, no porous body is formed, and therefore the porous body of the present invention cannot be obtained.

Further, in the present invention, an organic solvent is used, and any organic solvent may be used as long as it dissolves the polylactide, polyglycolide, or copolycondensate thereof, including chloroform, carbon tetrachloride, etc. , benzene, toluene, dioxane, alcohols such as isopropanol, butanol, acetone, etc. can be used.

The method for producing the porous base of the present invention using these raw materials is as follows.

First, when polylactide, polyglycolide, or a copolycondensate thereof is dissolved in the above-mentioned organic solvent, the a degree of the polymer varies depending on its molecular weight, the desired pore size of the base material, etc., but is approximately 0. It is used in a range of 5 to 40%.

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. In other words, the higher the polymer concentration or the larger the molecular weight used, the smaller the base pore diameter.
Conversely, the lower the polymer concentration or the lower the molecular weight used, the larger the pore size of the base material.

Further, if the polymer concentration at this time deviates from the range of 0.5 to 40% by weight and is less than 0.5% by weight.

Not only does the reaction take an extremely long time, but the pore size of the base material becomes too large and the strength of the base material decreases, which is undesirable.On the other hand, if the amount exceeds 40%, the reaction between the polymer and aluminum alcoholate described below The porous base material becomes localized and the pore size of the base material becomes too small, making it difficult to obtain the porous base material of the present invention.

Next, the aluminum alcoholate listed above is similarly dissolved or suspended in an organic solvent.

In this case, these aluminum alcoholates are dissolved or dispersed and suspended in an amount of up to about 10% by weight.

Polylactide, polyglycolide dissolved in Ia0 solvent,
In the reaction of a copolycondensate thereof and the aluminum alcoholate, first, a solution of the polymer is placed in a reaction vessel, and then a solution of the aluminum alcoholate is added while stirring.

In this case, there is no particular limitation on the order of addition, and the aluminum alcoholate may be added first, or the polymer and alcoholate may be added simultaneously.

Furthermore, the amount added at this time varies depending on the concentration and molecular weight of the polylactide, polyglycolide, or their co-fL polycondensate used in the reaction, but is generally based on the A I /C0OH molar ratio (however, AI is derived from the aluminum alcoholate). ^
l, and C00) I is polylactide, polyglycolide,
or the reactive COOH of a polycondensate derived from a copolycondensate thereof) is 0.2 or more.

That is, if it is less than 0.2, the strength of the product decreases significantly, making it difficult to obtain the porous base of the present invention.

In addition, the reactivity C00H of the polylactide, polyglycolide, or a polycondensate derived from their co-Yil condensate
JI is determined by the following method.

<C0OH quantification method> Approximately 1 g of polylactide, polyglycolide, or their copolycondensates was heated and dissolved in 20 ml of benzyl alcohol, and after cooling, phenolphthalein was used as an indicator.
．． The zero titration, in which titration is performed with a benzyl alcohol solution of 025N potassium hydroxide, is carried out under a nitrogen atmosphere while introducing N2 gas in order to remove interference such as carbon dioxide in the air.

The reactivity C00H of the polycondensate is determined from the titration value using the following formula.

0.025 x 10-” f(S-B)X=
(mol/g) However, gL Amount of condensate ffi (g) f: 0.025)l 7 actors of potassium hydroxide solution S: Titration amount (71 l) B:
Titration amount (79 rank)

As the reaction progresses, the reaction solution turns into a gel, but the reaction usually ends within 2 hours from the start of the reaction.

After the reaction is completed, the porous base of the present invention can be prepared by subjecting the resulting gel to a solvent precipitation treatment with a solvent such as methanol, ethanol, or ether, and drying, or by directly drying the gel under reduced pressure. You can get it.

Alternatively, polylactide, polyglycolide, or a copolycondensate thereof and aluminum alcoholate may be melt-mixed at a temperature of 90 to 230°C, and then swelled in the above-mentioned organic solvent. A porous base of the invention can be obtained.

The base of the present invention obtained in this way is porous,
It has excellent strength properties as a base, and since the base is mainly polylactide, polyglycolide, or their copolycondensates, the sustained release properties are significantly increased due to the synergistic effect with the sustained release properties of the base itself. , has the excellent sustained release properties that A should have as a sustained release base.

Therefore, the product of the present invention is suitable not only for use as a matrix for drugs, as an implant material t1, but also for bacterial cells, microorganism retention agents, carriers as microcapsules, soil conditioners, disintegrating agricultural films, fruit quality improvers, gaseous Separation permeable membranes, fragrances, etc.
It can be used for a wide range of purposes.

(Examples) Specific examples will be described below, but the present invention is not limited thereto.

It should be noted that all percentages are by weight unless otherwise specified.

Example I 300m with TJA meter, condenser and stirrer
A predetermined amount of aluminum alcoholate shown in Table 1 and 45 g of chloroform were placed in a 1-volume separable flask and stirred.

A solution obtained by dissolving 9.51 g of polyJ-L-lactide with a number average molecular weight i of 2590 in chloroform to make 75 g was added to the solution, and a reaction was carried out. (^l/C0OH molar ratio 1.0)
The reaction system gels within a few minutes after adding poly-lactide, but QJ's chloroform is further added to this and 3 minutes after the start.
Stirring was stopped at 0 minutes and the product was removed from the flask.

The reaction product was dried under reduced pressure at 30° C. and 5 mmHg to obtain a porous base of the present invention.

For comparison, aluminum salts other than aluminum alcoholate were reacted and dried under reduced pressure in the same manner as described above.

These were observed with a scanning electron microscope to examine the porous state of the product. The results are shown in Table 1.

Further, an electron-a micrograph of the porous group M of the present invention obtained using aluminum isopropoxide is shown in FIG.

Furthermore, the dioxane absorption amount was measured for the products of the present invention and comparative preparations obtained after drying, and the degree of porosity of the base was determined. M fruits are shown in Table 1.

Method for Measuring Absorption of Dioxane> 2 g of base sample f1 was placed in a 300 ml beaker, 200 g of dioxane was added thereto, and the mixture was immersed for 24 hours. After soaking i) and removing excess dioxane,
It was air-dried on a filter paper for 1 hour, its weight was measured, and the amount of dioxane absorbed was calculated using the following formula.

However, x Nidioxane absorption amount (g #) W,: Sample collection 1 (g) 112; Sample type after dioxane absorption Nk (g) Table 1 Example 2 Using the same reactor as Example 1, the second Two amounts of Bo II-DL-lactide and aluminum isopropoxide of each molecular weight shown in the table were dissolved in chloroform, and the reaction was carried out under stirring at 400 C. (Al/C0OH molar ratio 0
．． 5) The gelled product obtained after 1 hour of reaction was immersed in petroleum ether to remove chloroform and then dried at room temperature to obtain the porous base of the present invention.

The obtained porous base material was observed using a scanning electron microscope and the amount of dioxane absorbed was measured, and the results are shown in Table 2.

Example 3 In a 300 ml beaker equipped with a stirring loss, 0.6 g of aluminum isopropoxide and 50 sections of xylene were placed and stirred.

While continuing to stir, add 1°-glycolide with a number average molecular weight of 1300! 3.82 g of condensate (relily-free-bis-one-cut mole ratio 2.33) was added to 150 g of xylene.
After the reaction was completed, the resulting gelled product was dissolved in methanol and reacted for 1.7 hours.
i After removing crushed xylene, 40°C 3mmHg-C-
It was dried under reduced pressure to obtain a porous base of the present invention. ! As a result of electron microscopic observation of this base, it was found to be a dense porous body, and the amount of dioxane absorbed was 45 g/g.
Furthermore, the base had a strength that did not become brittle even when touched with a finger.

Implementation Ij44 Powder 4 obtained by pulverizing the porous base of the present invention obtained in Example 1 and comparative toner powder and dividing it into 250 to 420μ gourds.
．． 0.5g of butamben (p-7 minobenzoic acid n) in 5g
-7'f ester) developed in chloroform so that the amount was within the solvent absorption limit of each powder, and the entire amount of the solution was absorbed. This was dried in Drying 5 for 20°03 hours to volatilize and remove chloroform.

After absorbing this butaneben, 0.15 g of the base was immersed in 300 ml of phosphate buffer solution at 37°C, pH 7.4, and heated at 300 rpm.
While stirring at m, the amount of butaneben eluted into water was measured at predetermined intervals using an absorptiometer.

The results are shown in Table 3.

II3 table Procedural amendment I (method) 6J18, 1985 1.Display of the incident Patent Application No. 54334 of 1985.

2. Name of the invention Porous base 3. Relationship with the case of the person making the amendment Patent applicant 4. The amendment order was dated May 7, 1986. 5. Specification to be amended and drawings 6. Amendment Contents (1) Page 13 of the specification, lines 4 to 6: ``Aluminum isopropoxide is also shown in Figure 1.

'' is deleted in its entirety.

(2) Delete the entire text of the brief description of the drawing column in lines 1 to 4 of the same page ff1lQ.

(3) Delete Figure 1 of the drawings.

Claims (1)

[Claims] A porous base obtained by reacting polylactide, polyglycolide, or a copolycondensate thereof with aluminum alcoholate.