JPH0822898B2 - Manufacturing method of pullulan copolymer - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel pullulan copolymer.

Here, pullulan has a repeating unit of maltotriose having an α (1 → 4) glycoside bond, and α (1
→ 6) A linear polysaccharide formed by polycondensation with glycoside bonds.

<Prior Art> The inventor of the present invention pays attention to the fact that the pullulan is industrially produced at a low cost by a fermentation method, and that the molecular weight thereof is appropriate, and therefore, the inventors are keen on developing a functional polymer material. As a result of our efforts, we succeeded in developing a new polymer material with pullulan as the skeleton.

<Means for Solving Problems> The pullulan copolymer of the present invention is obtained by reacting pullulan with an unsaturated acid to introduce a carbon double bond, and reacting a polymerizable olefin compound with the pullulan ester. It is a thing.

<Effects of the Invention> Here, by using a polymerizable olefin compound having various functional groups, functional polymers having various functions can be obtained. Since this pullulan copolymer has pullulan as a skeleton and has a large hydrophilicity,
As a biocompatible material, for example, a dental material, a contact lens, an intraocular lens, an artificial bone, an artificial blood vessel, or the like, or a film formed into an ultrapermea, or an electron beam resist or the like. Is promising.

<Detailed Description of Configuration of the Invention> The pullulan copolymer of the present invention will be described in detail below. The pullulan copolymer is obtained through the following two steps.

I. Adjustment of pullulan ester First, pullulan ester is prepared by reacting pullulan with an unsaturated acid (which may be an anhydride) and a saturated acid (which may be an anhydride) in the presence of an acid catalyst or under basic conditions. To get Here, the unsaturated acid is represented by the formula R ¹⁰ COOH in which R ¹⁰ is an unsaturated hydrocarbon group having a double bond and having 2 to 16 carbon atoms, and the saturated acid is represented by the formula R ¹¹ COOH. It is assumed that R ¹¹ is an alkyl group having 1 to 14 carbon atoms.

The generated pullulan ester is represented by the following formula (1).

[C ₆ H ₇ O ₂ (OH) _3-ab (OX) _a (OY) _b ] _m H ₂ O (1) where X; -C (= O) R ¹ (R ¹ is unsaturated An unsaturated hydrocarbon group having 2 to 16 carbon atoms which is derived from an acid and has a double bond) Y; -C (= O) R ² (R ² is an alkyl group having 1 to 14 carbon atoms) m; An integer of 5 or more II. Preparation of pullulan copolymer The pullulan ester obtained in the above step I is reacted with a polymerizable olefin compound to obtain a pullulan copolymer, which may be prepared in a good solvent for both, for example, acetone. Alternatively, the direct pullulan ester may be dissolved or dispersed in the polymerizable olefin compound.

Here, the above-mentioned olefin compound refers to a compound which can form the repeating unit within a bundle in the following formula (2) during polymerization.

C (R ³ ) R ⁴ -C (R ⁵ ) R ⁶ _n (2) wherein R ³ , R ⁴ and R ^{5 in the} formula are selected from hydrogen or a methyl group.

^{R 6; -C (= 0)} OR 7, -C (= 0) CN, -ON, acyloxy group, phenyl group, a pyridine group, a tolyl group, a pyrrolidone group, a lower alkyl group substituted pyrrolidone group n; the 20-300000 Integer R ⁷ is an alkyl group having 1 to 12 carbon atoms, a cyclohexyl group, a hydroxylalkyl group having 1 to 4 carbon atoms,
C1-C8 aminoalkyl group, C1-C8 dialkylaminoalkyl group, glycidyl group, tetrahydrofuran group, C1-C4 alkyl group-substituted tetrahydrofuran group, benzyl group, polymerization number 2-11 polyethylene oxide Group and imino group are shown.

Specific examples of the polymerizable olefin compound include alkyl esters of α, β-unsaturated acids such as acrylic acid and methacrylic acid, lower alkyl group-substituted cyclohexyl esters such as cyclohexyl ester, 2-hydroxyethyl ester, and 2-hydroxypropyl. Ester, 2-hydroxybutyl ester; acrylamide, methacrylamide, acryl or methacryl-dimethylamide, benzyl ester, C1-8 aminoalkyl ester of the above α, β-unsaturated acid, C1-8 dialkylamino Alkyl ester, glycidyl ester,
Nitrile groups of α, β-unsaturated acids such as polyethylene glycol monoesters, tetrahydrofurfuryl ester, acrylonitrile, methacrylonitrile; vinyl alcohol, methyl vinyl alcohol, dimethyl vinyl alcohol; vinyl acetate, vinyl propionate, vinyl butyrate As such, alkyl alcohols having 1 to 3 carbon atoms of vinyl alcohol and the above methyl-substituted vinyl alcohol; styrene; methylstyrene; vinyltoluene; vinylpyridine; vinylpyrrolidone; Also, as the polymerization initiator, azobisinbutyl nitrile (AIBN), benzoyl peroxide (BP
O), usual radical initiators such as t-butyl hydroperoxide are used.

Further, the initiator is usually used in an amount of about 0.1 to 5% by weight based on the total amount, although it depends on the reaction conditions.

The pullulan copolymer thus obtained is insoluble in most organic solvents such as acetone, dioxane, chloroform and dimethylformamide at a temperature of 40 ° C., and is hard, and sometimes has a Rockwell hardness of 150 on the M scale.

Further, the pullulan copolymer of the present invention is produced by the bulk polymerization method.
Polymerized in a suitable mold, its shape can be changed in any way. Further, since the ratio of the polymers of the formulas (1) and (2) can be appropriately selected, the ratio can be changed according to the application. As described above, the pullulan copolymer of the present invention is considered to be very promising for artificial organ materials such as contact lenses, intraocular lenses, artificial blood vessels, artificial bones, artificial corneas, and denture bases.

To describe the application to contact lenses in particular, as a hard contact lens material, mainly a methacrylic acid alkyl ester is desirable as a polymerizing monomer, and in that case, the polymer units of the formulas (1) and (2) are used. It is considered appropriate that the ratio (weight) is (1) / (2) = 1-40. In the bulk polymerization method, the solubility of the methacrylic acid ester of pullulan ester is considered to be important, but in the case of a mixed ester of pullulan such as acetic acid, methacrylic acid, acrylic acid, the acetic acid content is 10% to 40%, and other The saturated acid content is preferably 5 to 20%. A contact lens obtained by cutting, polishing and beveling the plate-shaped or rod-shaped bulk polymer thus obtained is promising.

When comparing conventional polymethylmethacrylate and contact lenses made of, for example, pullulan-methylmethacrylate copolymer, the ones that cannot be worn due to hyperemia with the conventional polymethylmethacrylate, the pullulan-methylmethacrylate copolymer When the combined contact lens was worn, the wearer could wear it without difficulty for 8 hours. Further, this feeling of wearing became better as the wetness increased, and for example, those surface-treated with alcoholic alkaline became more wet, and the feeling of wearing became better.

In addition, when the pullulan ester is copolymerized with a hydroxyalkyl methacrylate such as 2-hydroxyethyl methacrylate (HEMA), a hydrogel having a high water absorption is produced. For example, pullulan-HEMA copolymer (with pullulan
A rod-shaped lump polymer with a ratio of 1: 5) with HEMA is cut, polished and beveled, and heated in boiling water for 10 minutes to obtain a soft contact lens having good mechanical properties such as tensile strength and elasticity.

Moreover, these hydrogels are promising as carriers for pharmaceuticals.

<Example> Example 1 Acetic anhydride 130 g, methacrylic acid 370 g, acrylic acid 100 g, potassium acetate 20 g, hydroquinone 16 g, dimethylformamide
500 g of the mixture was heated with stirring at 118 ° C for 10 minutes.

After cooling, 20 g of pullulan (equivalent to 10 g of pullulan) having an average molecular weight of MW60000, which has been previously treated with a saturated potassium acetate solution, is dissolved in the mixed solution. Then, while stirring well, 118 ℃
After heating for 30 minutes at 30 ° C., the reaction mixture is cooled and then poured into three times the amount of water to separate the white product.

Next, the procedure of dissolving this in acetone and pouring it into water to obtain a precipitate was repeated 3 times and dried under reduced pressure to obtain 6 g of white powder pullulan ester.

This product is soluble in acetone, chloroform, dimethylformamide, methylmethacrylate, etc.
Swelling in toluene, insoluble in water, methanol, formamide, acetic acid content 31%, methacrylic acid content 10%, acrylic acid content 8%.

5 g of this pullulan ester is dissolved in 15 g of methyl methacrylate, 0.1 g of azobisisobutyronitrile is added, and this solution is charged into a glass tube having a diameter of 15 mm, sufficiently deaerated, and sealed to start polymerization.

After the polymerization temperature was 40 ° C. and the polymerization time was 24 hours, the mixture was heated for 3 hours in an air bath at 100 ° C.

After cooling, the rod-shaped polymer was removed from the glass tube and annealed in an air bath at 80 ° C. for 24 hours to obtain 19 g of a lump polymer.

This product was almost insoluble in acetone, chloroform, formamide, etc., organic solvents, methanol and water. The softening point was 165 ° C (ASTM-D1525) and the Rockwell hardness (M scale) was 100 (ASTM-D785).

FIG. 1 is an IR spectrum of this copolymer. When looking at this spectrum, absorption at 1635 cm ^-1 due to> C = C <is not seen. In addition, since it does not dissolve in organic solvents, water, etc., it can be confirmed as a copolymer. Pullulan copolymer
1 g was sufficiently dispersed in 40 ml of 72% H ₂ SO _{4 and} treated at 30 ° C. for 2 hours, and then poured into 1.5 l of pure water and boiled for 40 minutes to obtain a polymerized polymethyl methacrylate ( PM
MA) was isolated. Next, PMMA was dissolved in acetone, filtered through a filter, and then precipitated in methanol for purification.
Then, dissolve in acetone and obtain the intrinsic viscosity at 25 ° C.
The molecular weight Mw was calculated from the formula: 0.96 × 10 ⁻⁴ Mw ^0.67 . As a result, the molecular weight Mw of the isolated PMMA was 520,000.

Example 2 A mixed solution of 410 g of methacrylic acid, 135 g of acetic anhydride, 20 g of potassium acetate, 500 g of dimethylformamide and 1 g of hydroquinone was heated at 115 ° C. for 12 minutes while stirring.

Next, 20 g of the saturated potassium acetate-treated pullulan (corresponding to 10 g of pullulan) used in Example 1 was added to the above mixture, heated at 118 ° C. for 30 minutes with stirring, cooled, and then the reaction solution was poured into 3 times the volume of water to carry out the operation. The same procedure as in Example 1 was carried out to obtain a white powdery product.
14g was obtained. Acetic acid content 31.2%, Methacrylic acid content 18.0%
Is.

This product was insoluble in water and methanol, and soluble in acetone and dioxane.

5 g of this mixed ester of acetic acid and methacrylic acid of pullulan was mixed with 30 g of methyl methacrylate, 0.1 g of azobisisobutylnitrile was added, and thereafter polymerized in a glass tube in the same manner as in Example 1 to obtain 34 g of a rod-shaped lump polymer. Obtained. This product was insoluble in water and methanol, and insoluble in acetone, dioxane and chloroform. The Rockwell hardness (M scale) was 100, and the Bicatt softening point was 165 ° C. Polymerized polymethylmethacrylate (PMMA) isolated and purified by the same procedure as in Example 1 was dissolved in acetone to obtain an intrinsic viscosity at 25 ° C., and a molecular weight was ^{calculated from} the formula of “η” = 0.96 × 10 ⁻⁴ Mw ^0.67.
As a result of calculating Mw, the molecular weight Mw of the isolated PMMA was 620,000.

Example 3 In Example 2, acrylic acid was used instead of methacrylic acid.
The esterification reaction was carried out under the same conditions except that 410 g was used to obtain 12 g of a white powdery product. The acetic acid content is 28.0% and the acrylic acid content is 14.6%.

This product was insoluble in water and methanol, and soluble in acetone and dioxane. Pullulan / acetic acid /
20 g of methyl methacrylate was copolymerized with 5 g of the acrylic acid mixed ester in the same manner as in Example 1 to obtain 24 g of a rod-shaped lump polymer.
I got

This product was insoluble in water, methanol, dioxane, and chloroform. The Rockwell hardness was 100 and the softening point at 165 ° C was 165 ° C. Polymerized polymethylmethacrylate (PMMA) isolated and purified by the same procedure as in Example 1 was dissolved in acetone to obtain an intrinsic viscosity at 25 ° C., and “η” = 0.96 ×
As a result of calculating the molecular weight Mw from the formula of 10 ⁻⁴ Mw ^0.67 , it was isolated.
The molecular weight Mw of PMMA was 580,000.

Example 4 A mixture of acrylic acid (400 g), acetic anhydride (130 g), potassium acetate (90 g), toluene (490 g) and hydroquinone (1 g) was stirred at 115 ° C.
Heated for minutes. Next, 20 g of the saturated potassium acetate-treated pullulan used in Example 1 (corresponding to 10 g of pullulan) is dissolved in the mixed solution.

After that, the mixture was reacted at 118 ° C for 35 minutes with thorough stirring, cooled, poured into water, and an ice block was added to the mixture, which was then added with a caustic soda solution.
The pH was adjusted to 5.0, the main component was collected, washed well with a large amount of water, taken out and dried under reduced pressure to obtain 11 g of a white powder product.

 The acetic acid content was 21% and the acrylic acid content was 10.9%.

This product is insoluble in water and methanol, and soluble in dioxane and chloroform.

60 g of 5 g of this acetic acid / acrylic acid mixed ester of pullulan
Dissolve in 0 ml dioxane, add 50 g of methyl methacrylate while introducing nitrogen gas, and add benzoyl peroxide 0.6.
Add g and react at reaction temperature 70 ℃ for 10 hours. After cooling, add the reaction mixture to 3
It is poured into a double amount of a methanol solution and the precipitate is collected. Then, it was dried under reduced pressure, the dried product was subjected to Soxhlet extraction with acetone, and the residue was again dried under reduced pressure to obtain 40 g of a white product.

This product was insoluble in water, methanol and formamide. Polymerized polymethylmethacrylate (PMMA) isolated and purified by the same procedure as in Example 1 was dissolved in acetone and the temperature was adjusted to 25 ° C.
Intrinsic viscosity was calculated with and the molecular weight Mw was calculated from the formula of “η” = 0.96 × 10 ⁻⁴ Mw ^0.67 . As a result, the molecular weight Mw of the isolated PMMA was 50.
It was good.

Example 5 Acetic acid / methacrylic acid of the pullulan obtained in Example 1
5 g of the acrylic acid mixed ester was dissolved in 50 g of 2-hydroxyethyl methacrylate, 0.25 g of azobisisobutyl nitrile was added as an initiator, and polymerization was carried out in the glass tube of Example 1. (Polymerization temperature is 50 ° C, polymerization time is 24 hours). After heating at 80 degrees for 2 hours, take out from the glass tube and anneal at 100 ° C for 4 hours in a dryer.
A molded article having hydrophilicity was obtained.

The product had a Rockwell hardness (M scale) of 100, a Vicat softening point of 115 ° C., and a water absorption rate of 20%. Polymerized polyhydroxyoxymethacrylate (PHEMA), which was isolated and purified by the same procedure as in Example 1, was used as an effluent in 0.2 M Na ₂ SO ₄
The pore size of the porous glass is 3000A with 2 and 700
Sample injection condition 0.04g / dl, 200 using a high performance liquid chromatography column consisting of one 1400A and one 75 / 240A.
The chromatogram was obtained with mml and an outflow rate of 2 ml / min. The molecular weight Mw of the polymerized PHEMA was 730,000 from the calibration curve of the outflow amount by standard dextran and the molecular weight Mw.

Example 6 The rod-shaped lump polymer obtained in Example 1 is cut with a lathe at 2000 revolutions per minute, and uneven surface processing is performed at the same rotation speed to determine a constant curvature. Then, the lens was fitted into a pit plate of a lens polisher, and after polishing under the conditions of the upper part rotating 15 times per minute and the lower part rotating 200 times per minute, a bevel machine was used to obtain a contact lens. Next, this contact lens whose surface was made hydrophilic with an alcoholic alkali exhibited good hydrophilicity with a contact angle of 49 °.

Those who were not able to wear conventional poly (methylmethacrylate), left eye visual acuity 0.01 (1.0 × S-5.50), right eye visual acuity 0.01 (1.0 × S-5.50) as power −5.50, and wearable for 8 hours. It was. The visual acuity produced 1.0 in both eyes.

After wearing this contact lens for one year, the base curve and power were measured and no change was found. The contact lenses used were as follows.

 Base curve power size Left eye 740mm −5.50 8.8mm Right eye 740mm −5.50 8.8mm

[Brief description of drawings]

FIG. 1 is an infrared absorption spectrum diagram of the pullulan-methyl methacrylate copolymer of Example 1 of the present invention.

Claims (1)

[Claims] 1. The following (1) obtained by reacting pullulan with an unsaturated carboxylic acid having 3 to 17 carbon atoms (including anhydride) and a saturated carboxylic acid having 2 to 15 carbon atoms (including anhydride). In the pullulan ester represented by the formula, [C ₆ H ₇ O ₂ (OH) _3-ab・ (OX) _a (OY) _b ] m ・ H ₂ O (1) [wherein X represents 2 to 16 carbon atoms] Represents an unsaturated organic group, and Y is-
C (═O) R ² (R ² is a group selected from the group consisting of C _{1 to} C ₁₄ alkyl groups), a and b are positive numbers 0 <a + b ≦ 3, and m is 50,000 ≧ m ≧ An integer of 5] characterized by reacting an olefin compound represented by the following formula (2): [Wherein R ³ , R ⁴ and R ⁵ are each selected from a hydrogen atom or CH ₃ , and R ⁶ is (R ⁷ is a hydrogen atom, a C _{1 to} C ₁₂ alkyl group, a cyclohexyl group, a C _{1 to} C ₄ hydroxyalkyl group, a C _{1 to} C ₈ aminoalkyl group, and a C _{1 to} C ₈ dialkylaminoalkyl. group, a glycidyl group, tetrahydrofuran group, C ₁ -C ₄ lower alkyl substituted tetrahydrofuran group, and benzyl group _{(-CH 2 CH 2 -O-) yCH} 2 CH 2 OH group (y is 1 to 10 a positive number) , -N (R ⁸⁾ ₂ (alkyl group R ⁸ is a hydrogen atom or a C ₁ -C _4, the two R ⁸ may be the same or different)), (R ⁹ represents a group selected from the group consisting of C ₁ -C ₈ alkyl groups), phenyl group, pyridine group, tolyl group, and pyrrolidone group] Pullulan ester is obtained from pullulan and olefin monomer is radical-polymerized A method for producing a copolymer characterized by: