WO2023042534A1 - Poly(alkylene oxide), composition for solid preparation, method for producing same, and composition for sustained release preparation - Google Patents

Abstract

The present invention provides: a poly(alkylene oxide) able to be advantageously used for easily adjusting the speed of elution of a drug; a composition for a solid preparation, which contains said poly(alkylene oxide); a method for producing same; and a composition for a sustained release preparation.　This poly(alkylene oxide) has a polydispersity of 7-9, a gel strength of 20,000 Pa or less, and an erosion of 48-55%. This composition for a solid preparation contains at least the poly(alkylene oxide), an active ingredient and an excipient.

Description

Polyalkylene oxide, composition for solid formulation, method for producing the same, and composition for sustained release formulation

The present invention relates to a polyalkylene oxide, a solid formulation composition containing the polyalkylene oxide, a method for producing the same, and a sustained-release formulation composition.

Solid formulations are widely used in pharmaceutical applications. Among them, sustained-release solid formulations control the elution rate of the active ingredient from the formulation to keep the concentration of the active ingredient in the blood within a certain range for a long period of time. Therefore, it is indispensable for medical applications.

Patent Document 1 and others disclose a technique for obtaining a solid preparation with controlled sustained release by using a specific processed starch and a dissolution controlling agent. As typified by such techniques, in recent years, efforts have been made to control the dissolution rate of solid preparations from various viewpoints.

JP-A-2014-9208

In general, when trying to control the dissolution rate of an active ingredient in a formulation, the type and content of the drug contained in the solid formulation are fixed, so the type and content of the drug should be changed. cannot control the elution rate.

It is conceivable to adjust the dissolution rate of the active ingredient by changing the shape and dimensions of the formulation, but in this case, it is necessary to change the design of the equipment used to formulate the formulation. from unrealistic. It is also possible to fine-tune the dissolution rate by changing the type and content of excipients contained in the drug product. Not only that, it is also necessary to conduct dissolution rate confirmation tests multiple times, and it takes an enormous amount of time and money to establish an optimal manufacturing process. From the above viewpoints, it has been desired to establish a technique that can easily control the dissolution rate of the active ingredient without significantly changing the formulation process.

The present invention has been made in view of the above, and a polyalkylene oxide that can be suitably used to easily adjust the dissolution rate of a drug, a composition for a solid formulation containing the polyalkylene oxide, and the same An object of the present invention is to provide a production method and a composition for sustained release formulations.

The inventors of the present invention have made intensive studies to achieve the above objects, and as a result, found that the above objects can be achieved by adjusting the polydispersity, gel strength and erosion of the polyalkylene oxide to predetermined ranges, and have completed the present invention. Completed.

That is, the present invention includes, for example, the subject matter described in the following sections.
Item 1
The polydispersity is 7 to 9,
The gel strength is 20000 Pa or less,
A polyalkylene oxide having an erosion of 48-55%.
Item 2
A composition for solid formulation, comprising at least the polyalkylene oxide according to Item 1, an active ingredient, and an excipient.
Item 3
A composition for a sustained release formulation, comprising at least the polyalkylene oxide according to Item 1, an active ingredient, and an excipient.
Item 4
A step of dry mixing the polyalkylene oxide according to item 1 and an active ingredient to obtain a mixture, and
A method for producing a composition for solid formulation, comprising a step of compressing the mixture to obtain a tablet.
Item 5
A step of obtaining a granule containing the polyalkylene oxide of item 1 and an active ingredient, and
A method for producing a composition for solid preparation, comprising a step of compressing the granule to obtain a tablet.
Item 6
Use of the polyalkylene oxide according to item 1 in a sustained release formulation.

The polyalkylene oxide according to the present invention can be suitably used as a pharmaceutical raw material for easily adjusting the drug dissolution rate.

Since the composition for solid preparations according to the present invention contains the polyalkylene oxide, it is possible to form a preparation in which the dissolution rate of the drug can be easily adjusted.

Hereinafter, embodiments of the present invention will be described in detail. In this specification, the expressions "contain" and "include" include the concepts of "contain", "include", "substantially consist of" and "consist only of".

In the numerical ranges described stepwise in this specification, the upper limit or lower limit of the numerical range at one stage can be arbitrarily combined with the upper limit or lower limit of the numerical range at another stage. In the numerical ranges described herein, the upper and lower limits of the numerical ranges may be replaced with values shown in Examples or values that can be uniquely derived from Examples. Further, in this specification, a numerical value connected with "-" means a numerical range including numerical values before and after "-" as lower and upper limits.

1. Polyalkylene Oxide The polyalkylene oxide of the present invention has a polydispersity of 7-9, a gel strength of 20000 Pa or less, and an erosion of 48-55%. Such polyalkylene oxides can be suitably used as raw materials for pharmaceutical preparations (especially raw materials for sustained-release pharmaceutical preparations) for easily adjusting the dissolution rate of drugs. It becomes possible.

In the polyalkylene oxide, the number of carbon atoms in the alkylene moiety is not particularly limited. For example, it is preferably 2 or more and 4 or less. From the viewpoint that the effects of the present invention are likely to be exhibited, it is particularly preferable that the number of carbon atoms in the alkylene moiety is 2, that is, the polyalkylene oxide is polyethylene oxide.

The mass average molecular weight of the polyalkylene oxide is not particularly limited, and is, for example, 200,000 or more, preferably 500,000 or more, more preferably 1,000,000 or more, still more preferably 1,200,000 or more, and particularly preferably 1,500,000 or more. The weight-average molecular weight of the polyalkylene oxide as used herein means a value measured by gel permeation chromatography, and particularly means a value calculated from a calibration curve prepared using a known polyethylene oxide standard sample.

The polydispersity of the polyalkylene oxide, that is, the value of mass average molecular weight (Mw)/number average molecular weight (Mn) is 7 to 9 (7 or more, 9 or less) as described above. If the polydispersity is below 7 or above 9, the dissolution rate cannot be controlled within the desired range. That is, when the polydispersity of the polyalkylene oxide is 7 to 9, the erosion (elution rate) of the polyalkylene oxide can be easily adjusted within a desired range, and the elution rate can be increased. The polydispersity of the polyalkylene oxide is preferably 7.0 or more and preferably 8.5 or less.

The method for adjusting the weight average molecular weight and polydispersity of the polyalkylene oxide is not particularly limited, and widely known methods can be adopted. For example, in the production of polyalkylene oxide, it can be adjusted according to the conditions of the polymerization reaction. Specifically, the weight average molecular weight and polydispersity of the polyalkylene oxide can be adjusted by adjusting the type and amount of raw materials used in the polymerization reaction. can do. Also, the weight average molecular weight and polydispersity of the polyalkylene oxide can be adjusted by using the chain transfer agent described later during the polymerization reaction. A particularly preferred method is to adjust the weight average molecular weight and polydispersity of the polyalkylene oxide by irradiating the polyalkylene oxide, which has been previously adjusted to have a higher molecular weight than the target molecular weight, with an active energy ray such as gamma rays as described later. It is a way to

The gel strength of polyalkylene oxide is 20000 Pa or less, as described above. If the gel strength exceeds 20000 Pa, the gel strength increases and the dissolution rate becomes low, making it impossible to control the dissolution rate within the desired range. That is, when the gel strength of the polyalkylene oxide is 20000 Pa or less, the erosion (elution rate) of the polyalkylene oxide can be easily adjusted within a desired range, and the elution rate can be increased. The gel strength of the polyalkylene oxide is preferably 19000 Pa or less, more preferably 18800 Pa or less. Moreover, the lower limit of the gel strength of the polyalkylene oxide is not particularly limited, and is 16600 Pa, for example.

As used herein, the gel strength of polyalkylene oxide means a value measured by the following method. First, a cylindrical die with a diameter of 10 mm is filled with 200 mg of polyalkylene oxide and compressed with a compression force of 5 kN to obtain a tablet. Using this tablet, a dissolution test is carried out according to the Japanese Pharmacopoeia (paddle method). In this dissolution test, deionized water is used as the test liquid, the test temperature is 38° C., and the stirring speed is 200 rpm. A dissolution test is performed by stirring under these conditions for 2.5 hours to gel the tablet. Using the thus gelled tablet as a measurement sample, a compression test is performed using a compact compression/tensile tester ("EZ-Test" manufactured by Shimadzu Corporation). In this compression test, an indenter with a diameter of 10 mm is used, and the displacement speed is set at 5 mm/min. Based on the stress-strain curve obtained in the compression test, the slope S (Pa) when the gelled tablet is displaced from 5% to 10% is derived. The series of operations described above is performed three times on different tablets, the slope S (Pa) of each is derived, and the average value of these is taken as the gel strength of the polyalkylene oxide.

The method for adjusting the gel strength of polyalkylene oxide is not particularly limited, and a wide range of known methods can be adopted. For example, the desired gel strength can be adjusted by adjusting the weight average molecular weight and polydispersity of the polyalkylene oxide.

The erosion (elution rate) of polyalkylene oxide is 48 to 55% (48% or more and 55% or less) as described above. By setting the erosion of the polyalkylene oxide to 48 to 55%, it becomes possible to control the elution rate of the polyalkylene oxide at a high level. If the polyalkylene oxide erosion is less than 48%, it is not suitable for formulations that require a high dissolution rate. Moreover, when the erosion of the polyalkylene oxide exceeds 55%, the dissolution rate is too high, making it difficult to apply to formulations. Erosion of the polyalkylene oxide is preferably 52% or less.

As used herein, the erosion (elution rate) of polyalkylene oxide means a value measured by the following method. First, a cylindrical die with a diameter of 10 mm is filled with 200 mg of polyalkylene oxide and compressed with a compression force of 5 kN to obtain a tablet. Using this tablet, a dissolution test is carried out according to the Japanese Pharmacopoeia (paddle method). In this elution test, deionized water is used as the test liquid, the test temperature is 37° C., and the stirring speed is 200 rpm. A dissolution test is performed by stirring under these conditions for 4.5 hours to gel the tablet. The gelled tablet is taken out, dried at 80° C. for 5 hours, and the erosion (dissolution rate) is calculated from the following formula (1).
Erosion (%) = {1-(A/B)} x 100 (1)
In formula (1), A means the weight of the tablet after drying after the dissolution test, and B means the weight of the tablet before the dissolution test.

The erosion of the polyalkylene oxide can be adjusted within a desired range, for example, by adjusting the weight average molecular weight and polydispersity of the polyalkylene oxide.

The viscosity of polyethylene oxide (2% aqueous solution viscosity) is not particularly limited. Also, the upper limit is 6000 mPa/s or less, preferably 5000 mPa/s or less, more preferably 4500 mPa/s or less, and particularly preferably 4000 mPa/s or less. The 2% aqueous solution viscosity can be measured using a rotational viscometer ("RV DVII+" manufactured by BROOK FIELD).

A polyalkylene oxide is usually a homopolymer, but is not limited to this, and may be a copolymer. When the polyalkylene oxide is a copolymer, the polyalkylene oxide has, for example, two or more structural units with different carbon numbers in the alkylene moieties.

The polyalkylene oxide of the present invention may be a single polyalkylene oxide or a mixture of two or more polyalkylene oxides, for example a mixture of polyalkylene oxides produced by different production methods. may be

The method for producing the polyalkylene oxide is not particularly limited, and for example, a wide range of known polyalkylene oxide production methods can be adopted. Specifically, a polyalkylene oxide can be produced by a polymerization reaction of an alkylene oxide in the presence of a catalyst.

Alkylene oxides used in the production of polyalkylene oxides include, for example, aliphatic alkylene oxides, specifically ethylene oxide, propylene oxide and butylene oxide, with ethylene oxide or propylene oxide being preferred, and ethylene oxide being particularly preferred. .

The type of catalyst used in the production of polyalkylene oxide is also not particularly limited, and for example, a wide range of catalysts used in known methods for producing polyalkylene oxide can be used. Specifically, metal catalysts such as zinc can be used. The amount of the catalyst to be used is also not particularly limited, and can be, for example, within the same range as in known methods for producing polyalkylene oxide.

A chain transfer agent can also be used in carrying out the polymerization reaction of the alkylene oxide. This facilitates adjustment of the molecular weight of the polyalkylene oxide. The type of chain transfer agent is not particularly limited, and a wide range of known chain transfer agents that can be used in alkylene oxide polymerization reactions can be used. Examples of chain transfer agents include alcohol compounds having 1 to 5 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol.

When using a chain transfer agent, the amount used is not particularly limited, and can be, for example, 0.002 to 0.3 mol% relative to the alkylene oxide.

A solvent can be used as necessary in carrying out the polymerization reaction of the alkylene oxide. For example, a wide range of solvents used in known methods for producing polyalkylene oxide can be used.

The conditions such as the temperature for the polymerization reaction of alkylene oxide are not particularly limited, either, and can be the same as known conditions.

The polyalkylene oxide obtained by the above polymerization reaction can be irradiated with an active energy ray, if necessary. As a result, the polyalkylene oxide is decomposed and the molecular weight can be adjusted to the desired range. Active energy rays include, for example, radiation such as gamma rays, ultraviolet rays, X-rays, ion beams, and the like, and gamma rays are preferred because the molecular weight can be easily adjusted.

The conditions for irradiating the active energy ray are also not particularly limited, and can be appropriately set, for example, so as to achieve the desired molecular weight and polydispersity. For example, depending on the type of polyalkylene oxide, gamma ray irradiation can be performed in the range of 0.1 to 20 kGy. By irradiating a polyalkylene oxide with 3 kGy of gamma rays, a polyalkylene oxide having a desired molecular weight can be easily obtained.

The polyalkylene oxide of the present invention may be a mixture of two or more polyalkylene oxides, for example, a mixture of polyalkylene oxides obtained by irradiation with gamma rays of different doses. That is, it can be obtained by mixing a polyalkylene oxide obtained by irradiating a gamma ray with a radiation dose X1 and a polyalkylene oxide obtained by irradiating a gamma ray with a radiation dose X2 different from the radiation dose X1. For physical properties such as polydispersity, gel strength and erosion of the polyalkylene oxide mixture, the values obtained by measuring the mixture are used.

2. Composition for Solid Preparation The composition for solid preparation of the present invention contains at least the polyalkylene oxide, an active ingredient, and an excipient. The composition for solid formulations of the present invention is suitable as a raw material for obtaining solid formulations. In particular, since the composition for solid preparations of the present invention contains the polyalkylene oxide, it is possible to prepare a preparation in which the dissolution rate of the active ingredient is controlled. Are suitable.

In the composition for solid preparations, the type of active ingredient is not particularly limited, and a wide range of known active ingredients can be applied.

In the composition for solid formulations, excipients that are pharmaceutically acceptable can be widely applied, for example, known excipients can be widely applied.

In the composition for solid preparations, the content of the active ingredient is not particularly limited, and can be set within an appropriate range according to the dosage and usage of the preparation.

In the composition for solid preparations, the content of the excipient is not particularly limited, and can be set within an appropriate range according to the dosage and usage of the preparation.

In the solid formulation composition, the content ratio of the polyalkylene oxide, the active ingredient and the excipient is not particularly limited, and can be, for example, the same as in known solid formulation compositions.

The composition for solid formulations may consist only of the polyalkylene oxide, the active ingredient and the excipients, or the composition for solid formulations may contain various ingredients in addition to the polyalkylene oxide, the active ingredient and the excipients. Ingredients can be included, for example, various additives used in formulations. Examples of such additives include disintegrants, fluidizers, lubricants, fragrances, colorants and the like.

The composition for solid formulations can be widely used as a raw material for producing various solid formulations, and is suitable, for example, as a raw material for producing the sustained-release formulations described below. Therefore, in the solid formulation composition of the present invention, it is a preferred embodiment that the solid formulation is a sustained-release formulation.

The method of preparing a formulation from the solid formulation composition is not particularly limited, and for example, the same method as known formulation preparation methods can be adopted.

The dosage form of the formulation is not particularly limited, and a wide range of known dosage forms such as capsules, tablets, and granules can be applied.

(Method for producing composition for solid formulation)
The method for producing the composition for solid formulation is not particularly limited, and for example, a wide range of known methods for preparing a composition for solid formulation can be employed. For example, when the composition for solid formulation is a tablet, the composition for solid formulation can be produced by production method A or production method B described below.

The manufacturing method A includes the following steps A1 and A2.
Step A1: A step of dry mixing said polyalkylene oxide and an active ingredient to obtain a mixture.
Step A2: Compressing the mixture to obtain tablets.

In step A1, a polyalkylene oxide and an active ingredient are dry mixed. The polyalkylene oxide used in step A1 is the polyalkylene oxide of the invention described above. In this dry blending, together with the polyalkylene oxide and the active ingredient, excipients and optional additives can be added and mixed.

In step A1, the dry mixing method is not particularly limited, and for example, known dry mixing means can be applied. The mixing conditions are also not particularly limited, and can be appropriately set according to the types and amounts of raw materials used.

In step A2, tablets are obtained by compressing the mixture obtained in step A1. The tableting method is not particularly limited, and for example, a known tableting method can be applied.

Manufacturing method B includes the following steps B1 and B2.
Step B1: A step of obtaining granules containing the polyalkylene oxide and an active ingredient.
Step B2: A step of compressing the granules to obtain tablets.

In step B1, granules containing a polyalkylene oxide and an active ingredient are obtained. The polyalkylene oxides used in step B1 are the polyalkylene oxides of the invention described above. In the process of obtaining the granules, excipients and optional additives can be used along with the polyalkylene oxide and the active ingredient.

In the step B1, the method for obtaining the granules is not particularly limited, and for example, widely known granulation methods can be applied.

In step B2, tablets are obtained by compressing the granulated material obtained in step B1. The tableting method is not particularly limited, and for example, a known tableting method can be applied.

3. Composition for Sustained-Release Preparation The composition for sustained-release preparation of the present invention includes the composition for solid preparation. That is, the composition for sustained release formulation of the present invention contains at least the polyalkylene oxide, the active ingredient, and the excipient. The composition for sustained-release formulations of the present invention is suitable as a raw material for obtaining sustained-release formulations, and particularly contains the above-mentioned polyalkylene oxide. It can be prepared and is suitable for obtaining a sustained release formulation with a high dissolution rate.

The composition for sustained-release formulations may consist only of the composition for solid formulations, or may contain other additives in addition to the compositions for solid formulations, if necessary. good.

The method for preparing a sustained-release formulation from the composition for sustained-release formulation is not particularly limited, and, for example, the same method as a known formulation preparation method can be adopted.

The dosage form of the sustained-release preparation is not particularly limited, and known dosage forms such as capsules, tablets, and granules can be widely applied.

Since the above-described compositions for solid formulations and compositions for sustained-release formulations contain the polyalkylene oxide, formulations prepared from these compositions can easily control the dissolution rate of the active ingredient. highly controllable. Therefore, formulations obtained using the composition for solid formulations and the composition for sustained-release formulations are excellent in fast-acting properties and the like.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the embodiments of these examples.

(Production Example 1; Production of zinc catalyst)
The inside of a 500 mL round-bottomed flask with an inner diameter of 80 mm and equipped with a cooling device, a dropping funnel, a nitrogen gas inlet tube, and a stirring blade having four paddle blades (45 degrees inclined) with a blade diameter of 53 mm as a stirrer was replaced with nitrogen. After that, 87.1 g of n-hexane and 9.90 g of diethylzinc (Et2Zn) were added into this flask. While maintaining the inner temperature of the flask at 20 ° C., while stirring the inside of the flask at a tip peripheral speed of 0.97 m / sec (stirring rotation speed of 350 rpm), ethyl alcohol (EtOH) 11.03 g (0.240) mol) was added dropwise at a rate of 0.2 g/min, and the reaction was carried out to obtain a reaction solution. Next, in the second step, 6.49 g (0.072 mol) of 1,4-butanediol (1,4-BDO) and 13.27 g (0.288 mol) of ethyl alcohol were added to the reaction solution cooled to 10°C. ) was added dropwise at 0.2 g/min. After the completion of dropping, the temperature inside the flask was raised to 30° C. and the mixture was further reacted for 1 hour, and then heated to 50° C. and reacted for 1 hour. Unreacted components were then removed by distillation with the flask heated to 80°C. After the distillation, the inside of the flask was allowed to cool to room temperature, 52.4 g of n-hexane was added, and the mixture was heated to 80° C. for the second distillation. This operation was performed one more time for a total of three distillations. Then, it was cooled and diluted with 264 g of n-hexane to obtain 297 g of zinc catalyst containing 1.8% by mass of zinc.

(Production Example 2-1: Production of high molecular weight polyalkylene oxide)
After sufficiently replacing the inside of a pressure-resistant reaction vessel with an inner diameter of 94 mm and a volume of 1 L equipped with a dropping funnel, a nitrogen gas introduction tube, and a stirring blade having anchor-type paddle blades with a blade diameter of 47 mm as a stirrer, the inside of this pressure-resistant reaction vessel is 340 g of n-hexane was added to the flask, and 0.975 g of the zinc catalyst obtained in Production Example 1 (0.0004 mol as zinc) was uniformly dispersed in this n-hexane to obtain a dispersion liquid. After adding 0.088 g (0.0012 mol) of t-butanol and 81 g (1.84 mol) of ethylene oxide to this dispersion, the vessel was sealed and the polymerization reaction was carried out while maintaining the temperature at 40° C. and stirring. rice field. A white product obtained by the polymerization reaction was separated by filtration and dried under reduced pressure at 40° C. to obtain 81.0 g of high molecular weight polyethylene oxide.

(Production Example 2-2: Production of high-molecular-weight polyalkylene oxide)
After sufficiently replacing the inside of a pressure-resistant reaction vessel with an inner diameter of 94 mm and a volume of 1 L equipped with a dropping funnel, a nitrogen gas introduction tube, and a stirring blade having anchor-type paddle blades with a blade diameter of 47 mm as a stirrer, the inside of this pressure-resistant reaction vessel is 340 g of n-hexane was added to the flask, and 0.975 g of the zinc catalyst obtained in Production Example 1 (0.0004 mol as zinc) was uniformly dispersed in this n-hexane to obtain a dispersion liquid. After 81 g (1.84 mol) of ethylene oxide was added to this dispersion, the vessel was sealed, and the polymerization reaction was carried out while maintaining the temperature at 40° C. and stirring. A white product obtained by the polymerization reaction was separated by filtration and dried under reduced pressure at 40° C. to obtain 81.0 g of high molecular weight polyethylene oxide.

(Example 1-1)
By irradiating 40.0 g of the high-molecular-weight polyethylene oxide obtained in Production Example 2-1 with 0.3 kGy of gamma rays, 40.0 g of the intended polyethylene oxide was obtained.

(Example 1-2)
40.0 g of the intended polyethylene oxide was obtained in the same manner as in Example 1-1.

(Example 2-1)
40.0 g of the desired polyethylene oxide was obtained in the same manner as in Example 1-1, except that the irradiation was changed to 0.2 kGy of gamma rays.

(Example 2-2)
40.0 g of the intended polyethylene oxide was obtained in the same manner as in Example 2-1.

(Comparative Example 1-1)
By irradiating 40.0 g of the high molecular weight polyethylene oxide obtained in Production Example 2-2 with 0.8 kGy of gamma rays, 40.0 g of the desired polyethylene oxide was obtained.

(Comparative Example 1-2)
20.0 g of polyethylene oxide obtained by irradiating 20.0 g of high molecular weight polyethylene oxide obtained in Production Example 2-2 with a gamma ray of 0.6 kGy, and 0.8 kGy to 20.0 g of high molecular weight polyethylene oxide obtained in Production Example 2-2. 40.0 g of the desired polyethylene oxide was obtained by mixing 20.0 g of polyethylene oxide irradiated with gamma rays.

(Comparative Example 1-3)
By irradiating 40.0 g of the high molecular weight polyethylene oxide obtained in Production Example 2-2 with 0.6 kGy of gamma rays, 40.0 g of the desired polyethylene oxide was obtained.

(Comparative Example 2-1)
40.0 g of the desired polyethylene oxide was obtained in the same manner as in Comparative Example 1-1, except that the irradiation was changed to 0.6 kGy of gamma rays.

(Comparative Example 2-2)
20.0 g of the high-molecular-weight polyethylene oxide obtained in Production Example 2-2 was irradiated with 0.75 kGy gamma rays, and 20.0 g of the high-molecular-weight polyethylene oxide obtained in Production Example 2-2 was irradiated with 0.8 kGy. By mixing 20.0 g of polyethylene oxide irradiated with gamma rays, 40.0 g of the desired polyethylene oxide was obtained.

(Comparative Example 2-3)
40.0 g of the desired polyethylene oxide was obtained in the same manner as in Comparative Example 1-1, except that the irradiation was changed to 0.5 kGy of gamma rays.

(Comparative Example 2-4)
40.0 g of the desired polyethylene oxide was obtained in the same manner as in Comparative Example 2-3.

Table 1 shows the weight average molecular weight (Mw), number average molecular weight (Mn), polydispersity, 2% aqueous solution viscosity, gel strength, and erosion (elution rate) of the polyethylene oxide obtained in each example and comparative example. showing.

From the results in Table 1, a polyalkylene oxide having a polydispersity of 7 to 9 and a gel strength of 20000 Pa or less was obtained, and the erosion was 48 to 55%. Therefore, it was found that the polyalkylene oxides obtained in the examples can highly control the dissolution rate of drugs (active ingredients) when used for pharmaceutical applications.

The following methods were adopted as various evaluation methods.
(Weight average molecular weight and polydispersity)
The weight average molecular weight and polydispersity of polyethylene oxide were determined by gel permeation chromatography. Specifically, 0.02 g of polyethylene oxide was added to 40 mL of 0.19 M sodium nitrate aqueous solution and dissolved over 3 hours. The solution was filtered using a 0.8 μm membrane filter, and the obtained filtrate was subjected to gel permeation chromatography It was measured by lithography (“HLC-8220GPC” manufactured by Tosoh Corporation, guard column: TSKgel guardcolumn PWXL). In this measurement, TSKgel G6000PWXL, TSKgel GMPWXL and TSKgel G3000PWXL were used as size exclusion columns, the mobile phase was 0.20 M sodium nitrate aqueous solution, the flow rate was 0.5 mL/min, the column temperature was 40°C, and the differential refractometer temperature was 40°C. , the injection amount was 500 μL, and the measurement time was 90 minutes. Separately, the weight average molecular weight, number average molecular weight, and polydispersity were similarly measured using a polyethylene oxide standard sample with known polydispersity to prepare a calibration curve. The weight average molecular weight, number average molecular weight and polydispersity of polyethylene oxide in the range of 7.2 were calculated.

(2% aqueous solution viscosity)
12 g of polyethylene oxide and 125 mL of isopropanol were added to a 1 L beaker, and while stirring at 300 to 400 rpm using a stirring blade, 588 g of ion-exchanged water was added and stirred for 1 minute. After that, the stirring rotation speed was changed to 60 rpm, and stirring was continued for 3 hours to obtain a 2% aqueous solution of polyethylene oxide. This aqueous solution was kept at 25° C., and the viscosity was measured using a rotational viscometer (“RV DVII+” manufactured by BROOK FIELD), and this value was taken as the viscosity of the 2% aqueous solution.

(gel strength)
A tablet was obtained by filling a cylindrical die with a diameter of 10 mm with 200 mg of polyethylene oxide and compressing with a compression force of 5 kN. Using this tablet, a dissolution test was carried out according to the Japanese Pharmacopoeia (paddle method). In this dissolution test, deionized water was used as the test liquid, the test temperature was 37° C., and the stirring speed was 200 rpm. A dissolution test was performed by stirring for 2.5 hours under these conditions, and the tablets were gelled. Using the thus gelled tablet as a measurement sample, a compression test was performed using a compact compression/tensile tester ("EZ-Test" manufactured by Shimadzu Corporation). In this compression test, an indenter with a diameter of 10 mm was used, and the displacement speed was set at 5 mm/min. Based on the stress-strain curve obtained in the compression test, the slope S (Pa) when the gelled tablet is displaced from 5% to 10% is derived, and the above series of operations are performed a total of three times with different tablets. was derived, and the average value of these was taken as the gel strength of the polyalkylene oxide.

(Erosion; elution rate)
A cylindrical die with a diameter of 10 mm was filled with 200 mg of polyalkylene oxide and compressed with a compression force of 5 kN to obtain tablets. Using this tablet, a dissolution test was carried out according to the Japanese Pharmacopoeia (paddle method). In this dissolution test, deionized water was used as the test liquid, the test temperature was 37° C., and the stirring speed was 200 rpm. A dissolution test was performed by stirring for 4.5 hours under these conditions, and the tablets were gelled. The gelled tablet was taken out, dried at 80° C. for 5 hours, and the erosion (dissolution rate) was calculated from the following formula (1).
Erosion (%) = {1-(A/B)} x 100 (1)
(In formula (1), A means the weight of the tablet after drying after the dissolution test, and B means the weight of the tablet before the dissolution test.)

Claims (5)

The polydispersity is 7 to 9,
The gel strength is 20000 Pa or less,
A polyalkylene oxide having an erosion of 48-55%. A composition for solid formulation, comprising at least the polyalkylene oxide according to claim 1, an active ingredient, and an excipient. A composition for sustained release formulation, comprising at least the polyalkylene oxide according to claim 1, an active ingredient, and an excipient. dry mixing the polyalkylene oxide of claim 1 with an active ingredient to obtain a mixture; and
A method for producing a composition for solid formulation, comprising a step of tableting the mixture to obtain a tablet. A method for producing a composition for solid preparation, comprising the steps of obtaining a granule containing the polyalkylene oxide according to claim 1 and an active ingredient, and compressing the granule to obtain a tablet.