JP2021172684A - Method for producing polyether composition, and polyether composition - Google Patents

Abstract

To provide a method for producing a polyether composition which can afford a polyether composition having excellent mechanical properties while being a method for producing a polyether composition comprising a step of sterilization by radioactive rays.SOLUTION: Provided is a method for producing a polyether composition comprising a polyether (A) having a specific structure and a radical scavenger (RS). The method for producing a polyether composition comprises a sterilization step of sterilizing a non-sterile polyether composition by radioactive rays. The non-sterile polyether composition comprises the polyether (A) and the radical scavenger (RS). The radical scavenger (RS) is a specific compound. A weight ratio of the radical scavenger (RS) and the polyether (A) in the non-sterile polyether composition and a water content in the non-sterile polyether composition have specific values.SELECTED DRAWING: None

Description

The present invention relates to a method for producing a polyether composition and a polyether composition.

Conventionally, a technique of using a polyether having a branched structure as a gelled product such as hydrogel is known (Patent Document 1).
As described above, the gelled product of the polyether having a branched structure may be used as a material for medical use, biochemical use and the like, but at that time, the polyether needs to be sterilized. Sterilization is carried out by ethylene oxide gas sterilization, filtration sterilization, radiation sterilization, etc., but radiation sterilization is superior from the viewpoint of no toxic residue (ethylene oxide gas, etc.) after sterilization, cost, and validation.

Japanese Patent Application Laid-Open No. 2013-515791

However, when a polyether is sterilized by radiation, it is decomposed and denatured, and there is a problem that the mechanical properties are deteriorated.
For example, when a gelled product is prepared by using the above-mentioned conventional polyether that has been sterilized by radiation, the mechanical properties of the gel are lower than those in the case of using a polyether that is not sterilized by radiation. Collapse will occur in a short period of time.
When the above-mentioned disintegration occurs in a short period of time, if the gelled product contains the drug, the drug may be released all at once, resulting in a problem that the drug is administered at an unintended rate.
Further, when the gelled product is used as a sealant, there may be a problem that the gelled product is coagulated and broken and the sealant effect is lost.

Therefore, an object of the present invention is to provide a production method for producing a polyether composition having a step of sterilizing by radiation, which is excellent in mechanical properties.

［式（１）及び式（７）中、ＯＲ^１、Ｒ^２Ｏ、Ｒ^３Ｏ及びＲ^４Ｏはそれぞれ独立に炭素数２〜８のオキシアルキレン基であり、複数ある場合のＯＲ^１、Ｒ^２Ｏ、Ｒ^３Ｏ及びＲ^４Ｏは同一でも異なっていてもよく、ａ、ｂ、ｃ及びｄはそれぞれ独立に５０〜１２００の整数であり、式（１）中Ｘ^１〜Ｘ^４はそれぞれ独立に一般式（２）で表される置換基又は一般式（３）で表される置換基であり、式（７）中Ｘ^１〜Ｘ^４はそれぞれ独立に一般式（８）で表される置換基又は一般式（９）で表される置換基であり、ｍは１〜１０の整数である。］
［式（２）、式（３）、式（８）及び式（９）中、Ｒ^５は炭素数１〜１０のアルキレン基を表し；式（１）において式（２）又は（３）で表される置換基が複数個ある場合、及び、式（７）において式（８）又は（９）で表される置換基が複数個ある場合、それらの置換基におけるＲ^５は同一でも異なっていてもよい。］ The present inventors have arrived at the present invention as a result of diligent studies to solve the above problems.
That is, the present invention is a method for producing a polyether composition containing a polyether (A) represented by the general formula (1) and a radical scavenger (RS).
The method for producing a polyether composition comprises a sterilization step of sterilizing the pre-sterilization polyether composition by radiation.
The pre-sterilized polyether composition contains the polyether (A) and the radical scavenger (RS).
The water content in the pre-sterilized polyether composition is 0 to 30% by weight based on the weight of the pre-sterilized polyether composition.
The radical scavenger (RS) is derived from α-tocopherol, δ-tocopherol, trolox, a compound represented by the chemical formula (4), a compound represented by the chemical formula (5), and a compound represented by the chemical formula (6). At least one selected from the group
The weight ratio of the radical scavenger (RS) to the polyether (A) in the pre-sterilized polyether composition [radical scavenger (RS) / polyether (A)] is 0.00001 to 1.0. A method for producing a certain polyether composition;
A polyether composition containing a polyether (A) represented by the general formula (7) and a radical scavenger (RS).
The radical scavenger (RS) is derived from α-tocopherol, δ-tocopherol, trolox, a compound represented by the chemical formula (10), a compound represented by the chemical formula (11), and a compound represented by the chemical formula (12). At least one selected from the group
The weight ratio [radical scavenger (RS) / polyether (A)] of the radical scavenger (RS) to the polyether (A) in the polyether composition is 0.00001 to 1.0.
It is a radiation-sterilized polyether composition.

[In the formulas (1) and (7), OR ¹ , R ² O, R ³ O and R ⁴ O are independently oxyalkylene groups having 2 to 8 carbon atoms, and OR ¹ , R when there are a plurality of them. ² O, R ³ O and R ⁴ O may be the same or different, and a, b, c and d are independently integers of 50 to 1200, and X ^{1 to} X ⁴ in the equation (1) are respectively. independently is a substituent represented by the general formula (2) substituent or compound represented by general formula (3), represented in each formula (7) was X ¹ to X ⁴ are independently the general formula (8) It is a substituent or a substituent represented by the general formula (9), and m is an integer of 1 to 10. ]
[In the formula (2), the formula (3), the formula (8) and the formula (9), R ⁵ represents an alkylene group having 1 to 10 carbon atoms; in the formula (1), the formula (2) or (3) is used. when the substituent represented there is a plurality, and, when in the formula (7) there are a plurality of substituents represented by the formula (8) or (9), R ⁵ is either the same or different in their substituents You may. ]

The polyether composition obtained by the production method of the present invention has an effect of being excellent in mechanical properties even though it is a radiation-sterilized polyether.

The pre-sterilized polyether composition used in the method for producing a polyether composition of the present invention contains a polyether (A) and a radical scavenger (RS).
The "pre-sterilized polyether composition" in the method for producing a polyether composition of the present invention refers to the polyether (A) and the radical trapping agent (RS) before the sterilization step in the method for producing a polyether composition of the present invention. ) Is included.

The polyether (A) in the present invention is a polyether represented by the general formula (1).

^{OR 1} , R ² O, R ³ O, and R ⁴ O in the general formula (1) are independently oxyalkylene groups having 2 to 8 carbon atoms, and OR ¹ , R ² O, and R ³ O when there are a plurality of them. and R ^{4 O} may be different from each other in the same.

Examples of the oxyalkylene group having 2 to 8 carbon atoms include an oxyethylene group, a 1,2- or 1,3-oxypropylene group, 1,2-, 1,3-, 1,4- or 2,3-oxybutylene. Examples thereof include a group, an oxypentylene group, an oxyhexylene group and an oxyoctylene group.

As the oxyalkylene group having 2 to 8 carbon atoms, from the viewpoint of mechanical properties after radiation sterilization, the oxyethylene group alone and the oxyethylene group in combination with other oxyalkylene groups are preferable, and oxy is more preferable. The ethylene group alone and the oxyethylene group and the oxypropylene group are used in combination, and the oxyethylene group alone is particularly preferable.
When the oxyethylene group and the other oxyalkylene group are used in combination, the amount of the oxyethylene group is preferably 85 mol% or more based on the total number of moles of the oxyethylene group and the other oxyalkylene group.

When the oxyalkylene group is composed of two or more kinds of oxyalkylene groups, the bonding form of the polyoxyalkylene group may be a random form or a block form, but from the viewpoint of mechanical properties after radiation sterilization, it is a block copolymer. It is preferable to have.

A, b, c and d in the general formula (1) are independently integers of 50 to 1200.
If it is less than 50 or more than 1200, the mechanical properties after radiation sterilization deteriorate.
Further, from the viewpoint of mechanical physical properties after radiation sterilization, a, b, c and d are preferably 50 to 1100, and more preferably 50 to 700, respectively.
When the bonding type of the oxyalkylene group is a block type (including the case where one type of oxyalkylene group is used alone), a, b, c and d are each of a, b, c and d from the viewpoint of mechanical properties after radiation sterilization. It is preferably 50 to 1100, more preferably 50 to 1000, and particularly preferably 50 to 700.
When the bond type of the oxyalkylene group is a random type, a, b, c and d are preferably 50 to 1100 and 50 to 1000, respectively, from the viewpoint of mechanical properties after radiation sterilization. Is more preferable, and 50 to 650 is particularly preferable.

Regarding the bonding type of the oxyalkylene group, it can be determined whether it is a random type or a block type by assigning a signal derived from a dimer or a signal derived from a trimmer by a pyrolysis gas chromatography method.
The block format shows a characteristic signal different from the random format. For example, in the case of the two-component diblock format of monomer A and monomer B, the proportion of the signal derived from AA and the proportion of the signal derived from BB among the signals derived from dimer are higher than those of the random format, and are derived from AB. The proportion of signals is lower than in the random form.
In addition, among the signals derived from trimmers, the ratio of signals derived from AAA and the ratio of signals derived from BBB are higher than those of the random format, and the proportion of signals derived from other trimmers (ABB, etc.) is higher than that of the random format. Decrease.
The above ratio of the signal of the random type, in addition to the method of measuring a thermal decomposition gas chromatography method, by ^{1 H-NMR,} and calculates the ratio of each monomer constituting the random copolymer, Monte Carlo sheet Mühle Deployment It can also be derived by utilizing the law.

The measurement by the pyrolysis gas chromatography method and the measurement by ¹ H-NMR can be performed under the following conditions, for example.
<Example of measurement conditions by pyrolysis gas chromatography method>
Curie Point Pyrolyzer: JHP-3 type (manufactured by Nippon Analytical Industry Co., Ltd.)
Gas chromatograph: HP-5890A (manufactured by Hewlett-Packard)
Mass spectrometer: JMS-DX303 (manufactured by JEOL Ltd.)
Pyrolysis temperature: 445 ° C
< ¹ Example of measurement conditions by 1 H-NMR>
Solvent: Deuterated methanol Equipment: AVANCE300 (manufactured by Japan Bruker Co., Ltd.)
Frequency: 300MHz

X ¹ to X ⁴ in the general formula (1) is a substituent represented by a substituent or formula (3) represented independently by Formula (2).

^{R 5} in the general formulas (2) and (3) is an alkylene group having 1 to 10 carbon atoms, and a plurality of substituents represented by the general formula (2) or (3) are present in the general formula (1). in some cases, R ⁵ in the substituents may be the same or different.

Examples of the alkylene group having 1 to 10 carbon atoms include a methylene group, an ethylene group, a 1,3-propylene group, a 1-methylethylene group, a 1,4-butylene group, a 1-ethylethylene group, a 1-methylpropylene group and 2 -Methylpropylene group, 1,5-pentylene group, 1-methylbutylene group, 2-methylbutylene group, 1,1-dimethylpropylene group, 1,2-dimethylpropylene group, 1-ethylpropylene group, 2-ethylpropylene Examples thereof include a group, a 1,6-hexylene group, a 1,4-cyclohexylene group, a 1,8-octylene group, a 2-ethyloctylene group, a 1,9-nonylene group and a 1,10-decylene group.

Of the alkylene groups having 1 to 10 carbon atoms, a linear alkylene group having 1 to 10 carbon atoms is preferable from the viewpoint of mechanical properties after radiation sterilization, and a methylene group, an ethylene group, 1,3- It is a propylene group, a 1,5-pentylene group and a 1,6-hexylene group.

From the viewpoint of hydrolysis resistance, it is preferable X ¹ to X ⁴ is a substituent represented by the general formula (3).

In the general formula (1), m is an integer of 1 to 10.

The number average molecular weight (hereinafter abbreviated as Mn) of the polyether (A) represented by the general formula (1) is preferably 10,000 to 200,000, more preferably 10,000 to 10,000 from the viewpoint of mechanical properties after radiation sterilization. It is 180,000, particularly preferably 10,000 to 130,000.

The ratio (Mw / Mn) of the weight average molecular weight (hereinafter abbreviated as Mw) of the polyether (A) to Mn is the viewpoint of the pharmaceutical stability after modification to a physiologically active protein and an enzyme and the temporal stability of the drug efficacy. Therefore, it is preferably 1.20 or less, more preferably 1.15 or less, and particularly preferably 1.10 or less.
In order to reduce Mw / Mn to 1.20 or less, the oxygen concentration in the gas phase when ring-opening polymerization of alkylene oxide (ethylene oxide or the like) is carried out on the starting material (pentaerythritol or the like) is preferably 0.1% or less. The water content in each raw material is preferably 0.4% by weight or less, the reaction temperature is preferably 125 to 135 ° C., and the aging temperature is preferably 145 to 155 ° C.

The Mn, Mw and molecular weight distribution of the polyether (A) in the present invention is measured by gel permeation chromatography (hereinafter abbreviated as GPC) under the following conditions, and from the obtained molecular weight distribution curve, standard polyethylene glycol or the like can be used. It can be obtained by calculation using the calibration curve prepared as the reference substance of.

<Example of measurement conditions with GPC>
-Device: "HLC-8320GPC" [manufactured by Tosoh Corporation]
-Column: "TSK gel Super AW" [manufactured by Tosoh Corporation]
-Sample solution: 0.25 wt% N, N-dimethylformamide (DMF) solution-Solution injection volume: 10 μL
・ Flow rate: 0.6 mL / min ・ Measurement temperature: 40 ° C
-Mobile phase: DMF
・ Detection device: Refractive index detector

The weight ratio of the polyether (A) in the pre-sterilized polyether composition in the present invention is preferably 50 to 99.999% by weight based on the weight of the polyether composition.
Further, in (A) in the present invention, one type may be used alone, or two or more types may be used in combination.

The method for producing the polyether (A) represented by the general formula (1) of the present invention is not particularly limited, and examples thereof include the following methods.
^{For example, when producing a polyether in which X 1 to} X ⁴ in the general formula (1) is a substituent represented by the general formula (3), the following method or the like can be used.
In the presence of an alkaline catalyst such as potassium hydroxide, alkylene oxides such as ethylene oxide are added dropwise to the starting material (pentaerythritol, etc.) simultaneously or sequentially under the conditions of 100 to 200 ° C. under reduced pressure, and further at 100 to 200 ° C. After reacting for 0.5 to 10 hours and, if necessary, removing unreacted ethylene oxide under reduced pressure, the catalyst was adsorbed or neutralized with phosphoric acid, and the solid matter was filtered off to obtain the formula (1). X ^{1 to} X ⁴ give a hydrogen atom polyether.

Then, the solution X ¹ to X ⁴ in the general formula (1) was dissolved polyether is a hydrogen atom in an organic solvent (tetrahydrofuran, toluene, etc.), catalyst (t-butoxy potassium and t-butoxy sodium and the like) present below (through ^{R 5,} compound a halogen atom and a carboxy group is bonded: chloroacetic acid, etc.) halide was added dropwise at 25 to 40 ° C., allowed to 1-24 hours at further 25 to 40 ° C., min the by-product is removed by liquid, and recrystallized in an organic solvent such as isopropanol, X ¹ to X ⁴ in the general formula (1) to obtain the polyether is a carboxyalkyl group.

Then, the X ¹ to X ⁴ in the general formula (1) was dissolved polyether is a carboxyalkyl group in an organic solvent (N, N-dimethylformamide) solution, condensing agent [dicyclohexylcarbodiimide and 1-ethyl - 3- (3-Dimethylaminopropyl) carbodiimide hydrochloride, etc.] and N-hydroxysuccinimide are added, followed by reaction at 25-40 ° C. for 1 to 24 hours, filtration to remove by-products, and organics such as isopropanol. ^{By recrystallizing with a solvent, a polyether in which X 1 to} X ⁴ in the general formula (1) is a substituent represented by the general formula (3) can be obtained.

^{The polyether in which X 1 to} X ⁴ in the general formula (1) is a substituent represented by the general formula (2) can be obtained from the market as 4ARM-SG-20K [manufactured by Jenkem Technology] or the like. can.

In the method for producing a polyether composition of the present invention, the radical trapping agent (RS) is α-tocopherol, δ-tocopherol, trolox, a compound represented by the chemical formula (4), or a compound represented by the chemical formula (5). And at least one selected from the group consisting of the compounds represented by the chemical formula (6).

From the viewpoint of solubility, the weight ratio of the radical scavenger (RS) in the pre-sterilized polyether composition in the present invention is preferably 50% by weight or less based on the weight of the pre-sterilized polyether composition, and further. It is preferably 30% by weight or less.

In the method for producing a polyether composition of the present invention, the water content in the pre-sterilized polyether composition is 0 to 30% by weight based on the weight of the pre-sterilized polyether composition, and the stability of the polyether is obtained. From the viewpoint of, it is preferably 0 to 15% by weight.
In the method for producing a polyether composition of the present invention, the pre-sterilization polyether composition may be dried before the sterilization step.
Examples of the method for drying the pre-sterilization polyether composition include heat drying and the like.

In the method for producing a polyether composition of the present invention, the weight ratio of the radical trapping agent (RS) in the pre-sterilized polyether composition to the polyether (A) [radical trapping agent (RS) / polyether (A)). ] Is 0.00001 to 1.0, preferably 0.0001 to 0.9, and more preferably 0.001 to 0.8, from the viewpoint of mechanical properties after radiation sterilization.

In the method for producing a polyether composition of the present invention, the pre-sterilization polyether composition may contain any additive other than the polyether (A) and the radical scavenger (RS).
Optional additives include antioxidants, preservatives, stabilizers, solubilizers, buffer components and the like.

The method for producing a polyether composition of the present invention includes a sterilization step of sterilizing a pre-sterilization polyether composition by radiation.
Further, in the method for producing a polyether composition of the present invention, even if a step such as a pre-sterilization polyether composition preparation step for preparing a pre-sterilization polyether composition is carried out before the sterilization step as follows. good.

Examples of the method for producing the pre-sterilization polyether composition include a production method including a step of mixing the radical trapping agent (RS) and the polyether (A). Among them, the radical trapping agent (RS) and the polyether ( A) and a solvent (acetone, methanol, ethanol, N, N-dimethylformamide, tetrahydrofuran, etc.) are mixed at room temperature to dissolve them, and then the solvent and the like are removed under a reduced pressure environment.
In a reduced pressure environment, the temperature is preferably 5 to 60 ° C. (more preferably 20 to 40 ° C., particularly preferably 25 to 35 ° C.), and the degree of vacuum is preferably 0.1 to 5 kPa (further). It is preferably 0.2 to 3 kPa), and the depressurization time is preferably 30 minutes to 10 hours (more preferably 1 hour to 5 hours).
Further, as another preferable method for producing a pre-sterilization polyether composition, for example, a radical trapping agent (RS) and a polyether (A) are used in a good solvent (methanol, ethanol, N, N-dimethylformamide, toluene, etc.). Dissolve in methylene chloride, acetone, dimethylsulfoxide, tetrahydrofuran, 4-methyltetrahydropyran, etc. at room temperature, and then add a poor solvent (pentane, hexane, heptane, t-butylmethyl ether, diethyl ether, etc.) to precipitate. , A method of collecting by filtration can also be mentioned.

Examples of the sterilization step of sterilizing the pre-sterilization-polyether composition by radiation include a method of irradiating the pre-sterilization-polyether composition with radiation (γ-rays, electron beams, etc.).
As the conditions for irradiating an electron beam as radiation, it is preferable that the integrated irradiation amount is 1 to 50 kGy, and specific examples thereof include the following conditions.
<Irradiation conditions>
Irradiation equipment: Electronic accelerator Roadtron TT200 (manufactured by IBA)
Type of radiation: 10MeV electron beam irradiation method: Irradiation at 10 kGy was performed 3 times.

The irradiation may be carried out by filling the vial with the pre-sterilization polyether composition and irradiating the filled vial with radiation.
Further, the radiation-sterilized polyether composition may be provided in a form in which a vial containing the radiation-sterilized polyether composition obtained in the above step is packed in a cosmetic box.

The polyether composition produced by the method for producing a polyether composition of the present invention is also the polyether composition of the present invention.
That is, the polyether composition of the present invention is a polyether composition containing the above-mentioned polyether (A), and the above-mentioned polyether composition further contains the above-mentioned radical scavenger (RS).
The weight ratio of the radical scavenger (RS) to the polyether (A) in the polyether composition [radical scavenger (RS) / polyether (A)] is 0.00001 to 1.0. Is.
Moreover, the above-mentioned polyether composition is radiation sterilized.
As the polyether (A) and the radical scavenger (RS) in the polyether composition of the present invention, the polyether (A) and the radical scavenger (RS) described in the method for producing the polyether composition of the present invention shall be used. And the same is true for preferred ones.

In the polyether composition of the present invention, the weight ratio [radical scavenger (RS) / polyether (A)] of the radical scavenger (RS) and the polyether (A) in the polyether composition is 0.00001. It is ~ 1.0, preferably 0.0001 to 0.9, and even more preferably 0.001 to 0.8.
As described above, the polyether composition of the present invention is produced by being sterilized by radiation. When the weight ratio [radical trapping agent (RS) / polyether (A)] of the radical trapping agent (RS) and the polyether (A) in the polyether composition is 0.00001 to 1.0, it depends on radiation. By sterilization, deterioration of the polyether (A) is less likely to occur, and it becomes easier to maintain the mechanical properties of the polyether (A).

The polyether composition of the present invention is radiation sterilized.
Therefore, when the polyether composition of the present invention is used for medical use or biochemical use, it can be used in an aseptic state.
Further, the polyether composition of the present invention is preferably radiation sterilized at 1 to 50 kGy.

In the polyether composition of the present invention, the water content in the polyether composition is preferably 0 to 30% by weight, preferably 0 to 15% by weight, based on the weight of the polyether composition. More preferred.
When the water content in the polyether composition is 0 to 30% by weight based on the weight of the polyether composition, the stability of the polyether (A) contained in the polyether composition is improved.

Since the polyether composition obtained by the production method of the present invention contains the polyether (A) having a branched structure as represented by the general formula (1), a gelled product can be obtained by cross-linking.
As a method for producing a gelled product, a compound having two or more functional groups [functional groups having active hydrogen (hydroxyl group, amino group, thiol group, etc.)] that react with ^{X 1 to} X ^{4 and the above-mentioned polyether composition are used.} Examples include a method of reacting an object.
In the above reaction, the reaction temperature is preferably 0 to 50 ° C.
Further, the above reaction may be carried out in a solvent (physiological saline, phosphate buffer, etc.) or may be carried out without a solvent.
Further, as a method for producing a gelled product, X ^{1 to} X ⁴ in the above-mentioned polyether (A) are modified with a compound having a reactive group (acrylic group, epoxy group, etc.), and the modified functional group is reacted. It is also possible to use a method or the like in which the gelation reaction is allowed to proceed.

The polyether composition obtained by the production method of the present invention can be used to produce a gelled product containing a medicinal ingredient. Method as a method of the gelled containing the medicinal ingredient is via the X ¹ to X ⁴ in the polyether (A), to bind the medicinal ingredient is allowed to proceed the gelling reaction and, Examples thereof include a method of advancing the gelation reaction described above in the presence of a medicinal ingredient.
Although the gelled product containing the above-mentioned medicinal ingredient is a gelled product using a radiation-sterilized material, it suppresses the release of the medicinal ingredient at once due to the disintegration of the gel in a short period of time. It is useful because it can be done.

In addition, the polyether composition obtained by the production method of the present invention can also be used as a sealant. Specific examples of the method of use include a method of sticking the gelled product obtained by the above gelation reaction to a place where the sealant treatment is desired.

The polyether composition obtained by the production method of the present invention is a radiation-sterilized polyether, but has excellent mechanical properties, and is therefore useful as a polyether for medical and biochemical applications.

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to these Examples.
In the following, the part represents the weight part.

<Production Example 1> [Production of polyether (PPA) in which ^{X 1 to} X ^{4 of the general formula (1) are hydrogen atoms]}
As a starting material polyol, 2.9 parts of pentaerythritol [manufactured by Perstop], 1.2 parts of pentaerythritol ethylene oxide 4 mol adduct ["PNT-40" manufactured by Nippon Emulsifier Industry Co., Ltd.] and 0 sodium hydroxide .027 parts were charged in an autoclave, replaced with argon gas, reduced in pressure, and heated to 95 ° C.
After dehydration at 0.001 to 0.003 MPa for 1 hour at 95 ° C., the temperature was lowered to 130 ° C., and 1210 parts of ethylene oxide was used as an alkylene oxide so that the internal pressure of the autoclave did not exceed 0.2 MPa. The mixture was gradually added dropwise over 18 hours in the range of ~ 135 ° C. After completion of the dropping, the autoclave is aged at 145 to 155 ° C. for 2 hours until the internal pressure of the autoclave shows the same pressure as at the start of dropping, and treated at 0.001 to 0.003 MPa for 1 hour at 95 ° C. to remove unreacted alkylene oxide. After that, a polyether (PPA-1) [a compound represented by the following general formula (13) (e to h in the general formula (13) represents an integer of 0 or more)] was obtained.
No unreacted ethylene oxide was detected in the obtained (PPA-1), and the Mn of (PPA-1) was 4,000,000 [the average value of each value of e to h in the general formula (13) was 227. ], Mw / Mn = 1.06.

<Evaluation conditions in GPC>
-Device: "HLC-8320GPC" [manufactured by Tosoh Corporation]
-Column: "TSK gel Super AW" [manufactured by Tosoh Corporation]
-Sample solution: 0.25 wt% N, N-dimethylformamide (DMF) solution-Solution injection volume: 10 μL
・ Flow rate: 0.6 mL / min ・ Measurement temperature: 40 ° C
-Mobile phase: DMF
・ Detection device: Refractive index detector ・ Reference material: Standard polyethylene glycol

<Production Examples 2 to 5 and Comparative Production Examples 1 to 2> [Production of polyether (PPA) in which ^{X 1 to} X ^{4 of the general formula (1) are hydrogen atoms]}
Polyether (PPA-2) is the same as in Example 1 except that the polyols and alkylene oxides as starting materials are changed to the raw materials shown in Table 1 and the amount charged is changed to the number of copies as shown in Table 1. )-(PPA-5) and comparative polyethers (PPA'-1)-(PPA'-2) were obtained.
No unreacted alkylene oxide was detected in the obtained (PPA-2) to (PPA-5) and (PPA'-1) to (PPA'-2).
Table 1 shows the average values of Mn, Mw / Mn of (PPA-2) to (PPA-5) and (PPA'-1) to (PPA'-2), and e to h in the general formula (13). Shown in.

<Production Examples 6 to 10 and Comparative Production Examples 3 to 4> [Production of (PA) in which ^{X 1 to} X ^{4 of the general formula (1) are carboxymethyl groups]}
The polyether compositions of the polyethers (PPA-1) to (PPA-5) and (PPA'-1) to (PPA'-2) obtained in Production Examples 1 to 5 and Comparative Production Examples 1 to 2 are respectively. After dissolving 5 parts of the product and 1 part of t-butoxy sodium in 100 parts of toluene, 1 part of sodium chloroacetate was added dropwise at 25 ° C. over 10 hours, and then the mixture was stirred at 40 ° C. for 10 hours. Then, a 1 M aqueous solution of hydrochloric acid is added, the organic phase is recovered by separation, the organic phase is washed three times with a saturated aqueous solution of sodium chloride, toluene is distilled off under reduced pressure, and then recrystallized with isopropanol to carry out a polyether (PA). -1) to (PA-5) and 5.1 parts each of comparative polyethers (PA'-1) to (PA'-2) were obtained.

<Production Examples 11 to 15 and Comparative Production Examples 5 to 6> [Production of (A) in which X ^{1 to} X ⁴ of the general formula (1) are substituents represented by the general formula (3)]
Each of the polyethers (PA-1) to (PA-5) and (PA'-1) to (PA'-2) obtained in Production Examples 6 to 10 and Comparative Production Examples 3 to 4 has a polyether composition. After dissolving 5 parts of the product, 1 part of dicyclohexylcarbodiimide and 1 part of N-hydroxysuccinimide in 100 parts of N, N-dimethylformamide, the mixture was stirred at 40 ° C. for 10 hours. Then, the insoluble matter was removed by filtration, 100 parts of isopropanol was added, the mixture was cooled to 5 ° C., and the precipitate was collected by filtration. Add 100 parts of isopropanol again, cool to 5 ° C., filter out the precipitates, and collect the polyethers (A-1) to (A-5) and the comparative polyethers (A'-1) to (A'-). 2) 4 copies each were obtained.
Table 2 shows the average values of Mn, Mw / Mn of (A-1) to (A-5) and (A'-1) to (A'-2) and each value of a to d in the general formula (1). Shown in.

<Examples 1 to 12 and Comparative Examples 1 to 4: Sterilization step (Radiation-sterilized polyether composition and method for producing a comparative polyether composition)>
The type and number of parts of the polyether (A) shown in Tables 2 and 3, the type and number of parts of the radical scavenger (RS) shown in Tables 2 and 3 and 920 parts of acetone are mixed and dissolved at 25 ° C. After that, acetone was removed under a reduced pressure environment under the following conditions to obtain a pre-sterilized polyether composition.
<Decompression environmental conditions>
Temperature: 25 ° C
Vacuum degree: 1 kPa
Decompression time: 3 hours

Each 30 mL vial was filled with 0.6 g of the above-mentioned pre-sterilized polyether composition.
The vial is irradiated with radiation (electron beam) under the following conditions, and the polyether compositions (B-1) to (B-12) after the radiation sterilization step and the comparative polyether composition (B'-). 1) to (B'-4) were obtained.
<Irradiation conditions>
Irradiation equipment: Electronic accelerator Roadtron TT200 (manufactured by IBA)
Type of radiation: 10MeV electron beam irradiation method: Irradiation at 10 kGy was performed 3 times.

Decomposition behavior and safety of the polyether compositions (B-1) to (B-12) and (B'-1) to (B'-4) produced in Examples 1 to 12 and Comparative Examples 1 to 4. , Evaluated by the following method. The results are shown in Tables 4-5.

<Evaluation of decomposition behavior>
For the decomposition behavior, the molecular weight distribution (Mw / Mn) of the polyether composition before and after the radiation sterilization operation was measured by the following method, and the ratio [(molecular weight distribution after radiation sterilization) / (molecular weight distribution before radiation sterilization)]. Was evaluated by calculating.
The smaller the above ratio, the more the decomposition of the polyether composition due to radiation sterilization is suppressed, and the mechanical properties of the polyether composition after radiation sterilization tend to be superior.
<Molecular weight distribution>
The molecular weight distribution of the polyether composition was measured using GPC (gel permeation chromatography) under the following conditions.
[GPC measurement conditions]
-Device: "HLC-8320GPC" [manufactured by Tosoh Corporation]
-Column: "TSK gel Super AW" [manufactured by Tosoh Corporation]
-Sample solution: 0.25 wt% N, N-dimethylformamide (DMF) solution-Solution injection volume: 10 μL
・ Flow rate: 0.6 mL / min ・ Measurement temperature: 40 ° C
-Mobile phase: DMF
・ Detection device: Refractive index detector ・ Reference material: Standard polyethylene glycol

<Safety judgment>
The safety of the polyether composition was evaluated according to the following criteria.
〇: As a component other than the polyether contained in the polyether composition, a component that may have carcinogenicity is not contained.
X: As a component other than the polyether contained in the polyether composition, a component that may have carcinogenicity is contained.

The evaluation of carcinogenicity and / or mutagenicity of each component is as follows.
Edaravone: No mutagenicity was observed from the interview form of Radicut Intravenous Infusion Bag 30 mg. Therefore, in the present application, the safety was evaluated as a component having no risk of carcinogenicity.
Irganox 1010: No mutagenicity is observed from BASF's SDS. Therefore, in the present application, the safety was evaluated as a component having no risk of carcinogenicity.
α-tocopherol: EFSA Journal 2015, 13 (9), 4247 shows no mutagenicity. Therefore, in the present application, the safety was evaluated as a component having no risk of carcinogenicity.
δ-tocopherol: EFSA Journal 2015, 13 (9), 4247 shows no mutagenicity. Therefore, in the present application, the safety was evaluated as a component having no risk of carcinogenicity.
Trolox: No mutagenicity from SDS from Selleck Chemicals. Therefore, in the present application, the safety was evaluated as a component having no risk of carcinogenicity.
BHA: According to the classification by IARC (International Agency for Research on Cancer), it is treated as Group 2B (substance that may be carcinogenic to humans). Therefore, in the present application, safety was evaluated as a component that may have carcinogenicity.

The polyether composition obtained by the production method of the present invention is a radiation-sterilized polyether, but has excellent mechanical properties, and is therefore useful as a polyether for medical and biochemical applications.

Claims (2)

A method for producing a polyether composition containing a polyether (A) represented by the general formula (1) and a radical scavenger (RS).
The method for producing a polyether composition comprises a sterilization step of sterilizing the pre-sterilization polyether composition by radiation.
The pre-sterilized polyether composition contains the polyether (A) and the radical scavenger (RS).
The water content in the pre-sterilized polyether composition is 0 to 30% by weight based on the weight of the pre-sterilized polyether composition.
The radical scavenger (RS) is derived from α-tocopherol, δ-tocopherol, trolox, a compound represented by the chemical formula (4), a compound represented by the chemical formula (5), and a compound represented by the chemical formula (6). At least one selected from the group
The weight ratio of the radical scavenger (RS) to the polyether (A) in the pre-sterilized polyether composition [radical scavenger (RS) / polyether (A)] is 0.00001 to 1.0. A method for producing a certain polyether composition.

[In the formula (1), OR ¹ , R ² O, R ³ O and R ⁴ O are independently oxyalkylene groups having 2 to 8 carbon atoms, and OR ¹ , R ² O and R ^{3 when there are a plurality of them.} O and R ⁴ O may be the same or different, respectively, a, b, c and d are independently integers of 50 to 1200, and X ^{1 to} X ⁴ are independently represented by the general formula (2). It is a substituent or a substituent represented by the general formula (3), and m is an integer of 1 to 10. ]

[In the formulas (2) and (3), R ⁵ represents an alkylene group having 1 to 10 carbon atoms; when there are a plurality of substituents represented by the formula (2) or (3) in the formula (1), R ⁵ may be the same or different in their substituents. ]

A polyether composition containing a polyether (A) represented by the general formula (7) and a radical scavenger (RS).
The radical scavenger (RS) is derived from α-tocopherol, δ-tocopherol, trolox, a compound represented by the chemical formula (10), a compound represented by the chemical formula (11), and a compound represented by the chemical formula (12). At least one selected from the group
The weight ratio [radical scavenger (RS) / polyether (A)] of the radical scavenger (RS) to the polyether (A) in the polyether composition is 0.00001 to 1.0.
A radio-sterilized polyether composition.

[In the formula (7), OR ¹ , R ² O, R ³ O and R ⁴ O are independently oxyalkylene groups having 2 to 8 carbon atoms, and OR ¹ , R ² O and R ^{3 when there are a plurality of them.} O and R ⁴ O may be the same or different, respectively, a, b, c and d are independently integers of 50 to 1200, and X ^{1 to} X ⁴ are independently represented by the general formula (8). It is a substituent or a substituent represented by the general formula (9), and m is an integer of 1 to 10. ]

[In the formulas (8) and (9), R ⁵ represents an alkylene group having 1 to 10 carbon atoms; when there are a plurality of substituents represented by the formula (8) or (9) in the formula (7), R ⁵ may be the same or different in their substituents. ]