Patent Description:
Conventionally, polyalkylene oxide particles typified by polyethylene oxide are known to be used as binders for pharmaceutical preparations etc. For example, PTL <NUM> discloses polyalkylene oxide particles whose particle size distribution is controlled in a specific range, and which can be applied to a binder for pharmaceutical preparations.

In recent years, preparations are required to have low performance variation. For example, there is a demand for the development of preparations that have the function of suppressing the variation in the dissolution of drugs etc. From this point of view, it is also important to develop polyalkylene oxide particles that can reduce performance variation in preparations. In this respect, for example, the stability of various physical properties of polyalkylene oxide particles is maintained by controlling the aqueous solution viscosity as a representative physical property value. Such polyalkylene particles are applied to preparations to thereby stabilize the performance of the preparations.

However, as a result of examination, the present inventors found that the aqueous solution viscosity of polyalkylene oxide particles having a particle size distribution varies depending on each particle size, and that as the difference in aqueous solution viscosity between particle sizes is larger, the performance of preparations is more likely to vary, and the dissolution of preparations is particularly more likely to fluctuate. In particular, the inventors found the problem that if the uniformity of polyalkylene oxide particles is disturbed by segregation or breakdown of uniformity due to vibration or the like during transfer of the polyalkylene oxide particles, variation in the performance (particularly dissolution) of preparations using such particles is particularly increased.

The present invention was made in view of the above, and its object is to provide polyalkylene oxide particles that can reduce the variation in the degree of dissolution of preparations, and that can make variation less likely to occur in the degree of dissolution of preparations even if the uniformity of the polyalkylene oxide particles is disturbed by vibration or the like. Another object of the present invention is to provide a pharmaceutical composition comprising the polyalkylene oxide particles, and a preparation composition comprising the pharmaceutical composition.

The present inventors conducted extensive research to achieve the above object, and consequently found that the above object can be achieved by polyalkylene oxide particles having specific aqueous solution viscosity characteristics. Thus, the present invention has been completed.

Specifically, the present invention includes, for example, the main subjects described in the following items.

Polyalkylene oxide particles that satisfy a viscosity ratio A (%) of <NUM>% or more and <NUM>% or less, wherein the viscosity ratio A is represented by the following formula (<NUM>): <MAT> wherein A1 is the <NUM> mass% aqueous solution viscosity (mPa·s) of particles having a particle size of <NUM> or more, and A2 is the <NUM> mass% aqueous solution viscosity (mPa·s) of particles having a particle size of less than <NUM>, and wherein the viscosity and the particle size are measured as indicated in the description below.

The polyalkylene oxide particles according to Item <NUM>, wherein when X parts by mass of the polyalkylene oxide particles are sieved in sequence by a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, and a saucer, the mass ratios of polyalkylene oxide particles remaining on the sieves and the saucer are all <NUM> mass% or more based on X.

Use of the polyalkylene oxide particles according to Item <NUM> or <NUM> for a preparation.

A pharmaceutical composition comprising the polyalkylene oxide particles according to any one of Items <NUM> to <NUM>.

A preparation composition comprising the pharmaceutical composition according to Item <NUM>.

The preparation composition according to Item <NUM>, which comprises <NUM> mass% or more of the polyalkylene oxide particles.

A preparation comprising the preparation composition according to Item <NUM> or <NUM>.

The polyalkylene oxide particles of the present invention can reduce the variation in the degree of dissolution of preparations, and can make variation less likely to occur in the degree of dissolution of preparations even if the uniformity of the polyalkylene oxide particles is disturbed by vibration or the like.

Embodiments of the present invention are described in detail below. In the present specification, the terms "comprising" and "containing" include the concepts of "comprising," "containing," "consisting essentially of," and "consisting of.

In the numerical range described in stages in the present specification, the upper or lower limit of the numerical range at one stage can be optionally combined with the upper or lower limit of the numerical range at another stage. In the numerical range described in the present specification, the upper or lower limit of the numerical range may be replaced with a value shown in the Examples or a value that can be uniquely derived from the Examples. Further, in the present specification, the numerical values connected by "to" mean the numerical range including the numerical values before and after "to" as the lower limit and the upper limit.

The preparation polyalkylene oxide particles of the present invention (hereinafter simply referred to as "the polyalkylene oxide particles of the present invention" or "the polyalkylene oxide particles") satisfy a viscosity ratio A (%) of <NUM>% or more and <NUM>% or less, wherein the viscosity ratio A is represented by the following formula (<NUM>): <MAT> wherein A1 is the <NUM> mass% aqueous solution viscosity (mPa·s) of particles having a particle size of <NUM> or more, and A2 is the <NUM> mass% aqueous solution viscosity (mPa·s) of particles having a particle size of less than <NUM>.

For example, when used as a binder (excipient) for forming preparations in a dosage form such as tablets, the polyalkylene oxide particles can reduce the variation in the degree of dissolution of the preparations. That is, when the polyalkylene oxide particles of the present invention are used to prepare multiple preparations, the variation in the degree of dissolution is low between the preparations. In addition, even if the uniformity of the polyalkylene oxide particles is disturbed by vibration or the like, the polyalkylene oxide particles of the present invention can make variation less likely to occur in the degree of dissolution of the preparations. Therefore, the polyalkylene oxide particles of the present invention can be preferably used to form preparations.

The polyalkylene oxide particles have a particle form, and the type thereof is not particularly limited as long as the viscosity ratio A (%) is <NUM>% or more and <NUM>% or less.

In the polyalkylene oxide particles, the type of polyalkylene oxide is not particularly limited, and examples include a wide range of known polyalkylene oxides.

In the polyalkylene oxide, the number of carbon atoms in the alkylene moiety is preferably <NUM> or more and <NUM> or less, for example. Because the effects of the present invention can be easily exhibited, it is particularly preferable that the alkylene moiety has <NUM> carbon atoms; that is, the polyalkylene oxide is preferably polyethylene oxide. Specific examples of polyalkylene oxides other than polyethylene oxide include polypropylene oxide, polybutylene oxide, ethylene oxide/propylene oxide copolymers, ethylene oxide/butylene oxide copolymers, and the like.

The polyalkylene oxide is generally a homopolymer, but is not limited thereto, and may be a copolymer. When the polyalkylene oxide is a copolymer, the polyalkylene oxide has, for example, two or more structural units with alkylene moieties having different number of carbon atoms.

The alkylene moiety of the polyalkylene oxide particles preferably contains at least an ethylene oxide unit, in terms of ease of production and ease of reduction of the variation in the degree of dissolution of preparations. That is, in the polyalkylene oxide particles, the polyalkylene oxide is preferably polyethylene oxide, or a copolymer of an ethylene oxide unit and other units (e.g., an ethylene oxide/propylene oxide copolymer or an ethylene oxide/butylene oxide copolymer, mentioned above).

The polyalkylene oxide particles may contain one type of polyalkylene oxide, or two or more types of polyalkylene oxides.

The polyalkylene oxide particles have a particle size distribution, and the particle size distribution is not particularly limited as long as the viscosity ratio A satisfies the above range.

For example, when X parts by mass of the polyalkylene oxide particles are sieved using a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, and a saucer in this order, the mass ratios P (%) of polyalkylene oxide particles remaining on the sieves and the saucer are all preferably <NUM> mass% or more based on X. In this case, when applied to preparations, the polyalkylene oxide particles are likely to reduce the variation in the degree of dissolution of the preparations.

In the above sieving, the mass ratio P of polyalkylene oxide particles remaining on the sieve with a mesh opening of <NUM> is preferably <NUM> to <NUM> mass%, and more preferably <NUM> to <NUM> mass%. In the sieving, the mass ratio P of polyalkylene oxide particles remaining on the sieve with a mesh opening of <NUM> is preferably <NUM> to <NUM> mass%, and more preferably <NUM> to <NUM> mass%. In the sieving, the mass ratio P of polyalkylene oxide particles remaining on the sieve with a mesh opening of <NUM> is preferably <NUM> to <NUM> mass%, and more preferably <NUM> to <NUM> mass%. In the sieving, the mass ratio P of polyalkylene oxide particles remaining on the sieve with a mesh opening of <NUM> is preferably <NUM> to <NUM> mass%, and more preferably <NUM> to <NUM> mass%. In the sieving, the mass ratio P of polyalkylene oxide particles remaining on the sieve with a mesh opening of <NUM> is preferably <NUM> to <NUM> mass%, and more preferably <NUM> to <NUM> mass%. In the sieving, the mass ratio P of polyalkylene oxide particles remaining on the sieve with a mesh opening of <NUM> is preferably <NUM> to <NUM> mass%, and more preferably <NUM> to <NUM> mass%. In the sieving, the mass ratio P of polyalkylene oxide particles remaining on the saucer is preferably <NUM> to <NUM> mass%, and more preferably <NUM> to <NUM> mass%.

The content ratio of particles having a particle size of <NUM> or more in the polyalkylene oxide particles of the present invention is preferably <NUM> to <NUM> mass%, and more preferably <NUM> to <NUM> mass%. Further, the content ratio of particles having a particle size of <NUM> or more in the polyalkylene oxide particles of the present invention is preferably less than <NUM> mass%.

The content ratio of polyalkylene oxide particles having a particle size of <NUM> or more in the polyalkylene oxide particles can be calculated by classifying the polyalkylene oxide particles by a sieve with a mesh opening of <NUM> (JIS Z <NUM>-<NUM> standard sieve). Specifically, the polyalkylene oxide particles are classified by a sieve with a mesh opening of <NUM>, the mass of polyalkylene oxide particles remaining on the sieve is measured, and the ratio thereof based on the total mass of the polyalkylene oxide particles used in classification is calculated to thereby determine the content ratio of polyalkylene oxide particles having a particle size of <NUM> or more. As is clear from this explanation, the phrase "polyalkylene oxide particles having a particle size of <NUM> or more" refers to, after the polyalkylene oxide particles are classified by a sieve with a mesh opening of <NUM>, particles remaining on the sieve.

In the polyalkylene oxide particles, as described above, the viscosity ratio A (%) represented by the following formula (<NUM>): <MAT> is <NUM>% or more and <NUM>% or less. In the formula, A1 is the <NUM> mass% aqueous solution viscosity (mPa·s) of particles having a particle size of <NUM> or more, and A2 is the <NUM> mass% aqueous solution viscosity (mPa·s) of particles having a particle size of less than <NUM>.

In formula (<NUM>), the particles having a particle size of <NUM> or more can refer to, when the polyalkylene oxide particles are classified by a sieve with a mesh opening of <NUM>, polyalkylene oxide particles remaining on the sieve. Alternatively, in formula (<NUM>), the particles having a particle size of <NUM> or more can refer to, when a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, and a sieve with a mesh opening of <NUM> are stacked in sequence from above, and the polyalkylene oxide particles are put in the uppermost sieve with a mesh opening of <NUM> for classification, polyalkylene oxide particles remaining on each sieve. Further, the particles having a particle size of less than <NUM> refer to, when the polyalkylene oxide particles are classified by a sieve with a mesh opening of <NUM>, polyalkylene oxide particles passing through the sieve.

Because the viscosity ratio A falls within the above range, the polyalkylene oxide particles of the present invention can reduce the variation in the degree of dissolution of preparations; that is, when the polyalkylene oxide particles of the present invention are used to prepare multiple preparations, the variation in the degree of dissolution can be reduced between the preparations. In addition, even if the uniformity of the polyalkylene oxide particles is disturbed by vibration or the like, the variation in the degree of dissolution of the preparations can be suppressed.

The viscosity ratio A is preferably <NUM>% or more, more preferably <NUM>% or more, and even more preferably <NUM>% or more. Further, the viscosity ratio A is preferably <NUM>% or less, more preferably <NUM>% or less, and even more preferably <NUM>% or less.

The <NUM> mass% aqueous solution viscosity (A1 (mPa·s)) of polyalkylene oxide particles having a particle size of <NUM> or more is <NUM> to <NUM> mPa·s, or the <NUM> mass% aqueous solution viscosity is preferably <NUM> to <NUM> mPa·s. The <NUM> mass% aqueous solution viscosity is preferably <NUM> mPa·s or more, and more preferably <NUM> mPa·s or more, and is more preferably <NUM> mPa·s or less, and particularly preferably <NUM> mPa·s or less. The <NUM> mass% aqueous solution viscosity is preferably <NUM> to <NUM> mPa·s, more preferably <NUM> mPa·s or more, and even more preferably <NUM> mPa·s or more. The <NUM> mass% aqueous solution viscosity and <NUM> mass% aqueous solution viscosity, described later, of the polyalkylene oxide particles can be measured using a rotational viscometer (RV DVII+, produced by Brookfield).

The <NUM> mass% aqueous solution viscosity (A1 (mPa·s)) of polyalkylene oxide particles having a particle size of less than <NUM> is <NUM> to <NUM> mPa·s, or the <NUM> mass% aqueous solution viscosity is preferably <NUM> to <NUM> mPa·s. The <NUM> mass% aqueous solution viscosity is preferably <NUM> mPa·s or more, and more preferably <NUM> mPa·s or more, and is more preferably <NUM> mPa·s or less, and particularly preferably <NUM> mPa·s or less. The <NUM> mass% aqueous solution viscosity is preferably <NUM> to <NUM> mPa·s, more preferably <NUM> mPa·s or more, and even more preferably <NUM> mPa·s or more. The <NUM> mass% aqueous solution viscosity and <NUM> mass% aqueous solution viscosity, described later, of the polyalkylene oxide particles can be measured using a rotational viscometer (RV DVII+, produced by Brookfield).

The <NUM> mass% aqueous solution viscosity of the polyalkylene oxide particles of the present invention is <NUM> to <NUM> mPa·s, or the <NUM> mass% aqueous solution viscosity is preferably <NUM> to <NUM> mPa·s. The <NUM> mass% aqueous solution viscosity and <NUM> mass% aqueous solution viscosity as mentioned herein each refer to the aqueous solution viscosity of the entire polyalkylene oxide particles (total particle size). In this case, the variation in the degree of dissolution of preparations can be reduced, and even if the uniformity of the polyalkylene oxide particles is disturbed by vibration or the like, the variation in the degree of dissolution of preparations is more likely to be suppressed.

The <NUM> mass% aqueous solution viscosity of the polyalkylene oxide particles in the total particle size range (total particle size) is preferably <NUM> mPa·s or more, and more preferably <NUM> mPa·s or more, and is more preferably <NUM> mPa·s or less, and even more preferably <NUM> mPa·s or less. Further, the <NUM> mass% aqueous solution viscosity of the polyalkylene oxide particles (total particle size) is preferably <NUM> to <NUM> mPa·s, more preferably <NUM> mPa·s or more, and even more preferably <NUM> mPa·s or more. When the <NUM> mass% aqueous solution viscosity of the polyalkylene oxide particles (total particle size) is <NUM> to <NUM> mPa·s, the <NUM> mass% aqueous solution viscosity is preferably less than <NUM> mPa·s.

The methods for adjusting the viscosity ratio A of polyalkylene oxide particles and the aqueous solution viscosity of the particle size of polyalkylene oxide particles are not particularly limited. For example, known methods can be widely used.

As the method for adjusting the viscosity ratio A of polyalkylene oxide particles, polyalkylene oxide particles that satisfy the above viscosity ratio A can be obtained, for example, by mixing polyalkylene oxide particles sieved by a sieve with a mesh opening of <NUM> and having a particle size of <NUM> or more and a specific <NUM> mass% aqueous solution viscosity, with polyalkylene oxide particles having a particle size of less than <NUM> and a specific <NUM> mass% aqueous solution viscosity. For example, the viscosity ratio A can be easily adjusted by mixing polyalkylene oxide particles having a particle size of <NUM> or more and a known <NUM> mass% aqueous solution viscosity, with polyalkylene oxide particles having a particle size of less than <NUM>.

In another method for adjusting the viscosity ratio A, two or more types of polyalkylene oxide particles having different particle size distributions are prepared, and these particles are mixed at a prescribed ratio. Furthermore, polyalkylene oxide particles that satisfy the viscosity ratio A can be obtained by sieving two or more types of polyalkylene oxide particles having different particle size distributions to produce various particle size groups, and mixing two or more of the particle groups at a prescribed ratio. In an embodiment thereof, for example, two types of polyalkylene oxide particles PA and PB having different particle size distributions are prepared. These particles are each sieved in such a manner that a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, and a saucer are stacked in sequence from above, and the polyalkylene oxide particles are put in the uppermost sieve with a mesh opening of <NUM> for sieving. As a result of the sieving operation, polyalkylene oxide particles having <NUM> particle sizes derived from polyalkylene oxide particles PA and PB, i.e., a total of <NUM> polyalkylene oxide particle groups, are obtained. The <NUM> mass% aqueous solution viscosity of each of the <NUM> polyalkylene oxide particle groups is measured in the manner described above, and with reference to the measurement results, any two or more of the groups are combined and mixed. Then, the viscosity ratio A of the resulting polyalkylene oxide particles is measured, and polyalkylene oxide particles having a viscosity ratio A of <NUM>% or more and <NUM>% or less can be obtained as the polyalkylene oxide particles of the present invention.

The method for adjusting the <NUM> mass% aqueous solution viscosity or <NUM> mass% aqueous solution viscosity of polyalkylene oxide particles is not particularly limited. Examples include methods of adjusting the type of raw material used in the production of polyalkylene oxide particles, the ratio of raw material used, polymerization temperature, polymerization time, the amounts of solvent and chain transfer agent, and other conditions.

The bulk specific gravity (loose) of the polyalkylene oxide particles is preferably <NUM> to <NUM>/mL. In this case, production efficiency and transport efficiency are excellent, and the formability of the preparation tends to be good. The bulk specific gravity (loose) of the polyalkylene oxide particles is more preferably <NUM> to <NUM>/mL. In the present invention, the loose bulk density of the polyalkylene oxide particles refers to a value measured according to JIS K6720 <NUM>.

The mass average molecular weight of the polyalkylene oxide particles is not particularly limited. In terms of easily imparting low friability to the preparation and reducing thermal expansion coefficient, the mass average molecular weight of the polyalkylene oxide particles is preferably <NUM>,<NUM> or more and <NUM> million or less. The mass average molecular weight of the polyalkylene oxide particles is more preferably <NUM>,<NUM> to <NUM> million, even more preferably <NUM> million to <NUM> million, and particularly preferably <NUM> million to <NUM> million. The mass average molecular weight of the polyalkylene oxide particles as mentioned herein refers to a value measured by gel permeation chromatography, and particularly refers to a value calculated from a calibration curve created using a known polyethylene oxide standard sample.

The form of the polyalkylene oxide particles is not particularly limited, and may be, for example, spherical, ellipsoidal, or amorphous.

The viscosity ratio A of the polyalkylene oxide particles satisfies the specific range, and when used as a binder (excipient) for forming preparations in a dosage form such as tablets, the polyalkylene oxide particles can reduce the variation in the degree of dissolution of the preparations. In addition, even if the uniformity of the polyalkylene oxide particles is disturbed by vibration or the like, the polyalkylene oxide particles of the present invention can make variation less likely to occur in the degree of dissolution of preparations.

When used as an excipient for preparations, the polyalkylene oxide particles of the present invention can suppress the variation in the performance of the preparations without changing the composition of the preparations. Therefore, the polyalkylene oxide particles of the present invention are preferable for pharmaceuticals and preparations, and particularly preferable as an excipient for tablets.

As the method for producing the polyalkylene oxide particles of the present invention, for example, methods for producing known polyalkylene oxide particles can be widely used.

For example, the polyalkylene oxide particles can be obtained by polymerization reaction of an alkylene oxide in the presence of an alkali or a metal catalyst. Examples of the alkylene oxide used herein include aliphatic alkylene oxides. Specific examples include ethylene oxide, propylene oxide, and butylene oxide; preferably ethylene oxide or propylene oxide; and particularly preferably ethylene oxide. Alkylene oxides can be used singly or in combination of two or more.

The catalyst can be, for example, an alkali catalyst or a metal catalyst. As the metal catalyst, for example, metal catalysts conventionally used in the production of polyalkylene oxide can be widely used. Of these, an organic zinc catalyst is preferred. Organic zinc catalysts can be obtained by known production methods, preferably by reacting organic zinc compounds with aliphatic polyhydric alcohols and monohydric alcohols to form particulate reaction products.

The amount of catalyst used can be the same as in methods for producing known polyalkylene oxide particles. For example, the catalyst can be used in a catalytic amount.

The polymerization reaction of the alkylene oxide can be performed in a solvent. As such solvents, those used in methods for producing known polyalkylene oxides can be widely used. Examples include at least one hydrocarbon solvent selected from the group consisting of <NUM>-methylpentane, n-pentane, n-hexane, n-heptane, isopentane, and cyclohexane; aromatic hydrocarbons, such as benzene, toluene, and xylene; and the like. N-hexane or n-pentane is preferably used because they are easily available industrially, and because they have a boiling point lower than the melting point of the resulting polyalkylene oxide and are easy to remove after the polymerization reaction. The amount of polymerization solvent used is preferably <NUM> to <NUM> parts by mass, more preferably <NUM> to <NUM> parts by mass, and even more preferably <NUM> to <NUM> parts by mass, based on <NUM> parts by mass of alkylene oxide, in terms of removing the heat of polymerization and easily controlling the polymerization reaction.

A C<NUM>-<NUM> alcohol compound can be used in the polymerization reaction of the alkylene oxide. Examples include C<NUM>-<NUM> alcohol compounds, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol.

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

The pharmaceutical composition of the present invention comprises the preparation polyalkylene oxide particles of the present invention described above. Therefore, when used as an excipient for forming preparations in a dosage form such as tablets, the pharmaceutical composition of the present invention can reduce the variation in the degree of dissolution of the preparations. In addition, even if the uniformity of the polyalkylene oxide particles is disturbed by vibration or the like, the pharmaceutical composition of the present invention can make variation less likely to occur in the degree of dissolution of preparations. Therefore, the pharmaceutical composition of the present invention is suitable as a raw material for preparing preparation compositions.

The pharmaceutical composition of the present invention may consist of the polyalkylene oxide particles, or may contain components other than the polyalkylene oxide particles.

The preparation composition of the present invention comprises the pharmaceutical composition of the present invention described above. Specifically, the pharmaceutical composition of the present invention may contain the polyalkylene oxide particles and components other than the polyalkylene oxide particles.

As components other than the polyalkylene oxide particles (hereinafter referred to as other components), for example, various components contained in known preparation compositions can be widely applied. Specific examples of other components include active components, fillers, excipients other than polyalkylene oxide particles, diluents, lubricants, dyes, pigments, osmotic agents, and the like.

The preparation composition of the present invention may contain the polyalkylene oxide particles and silica as a filler. When the preparation composition of the present invention contains the polyalkylene oxide particles and silica, the preparation composition of the present invention preferably contains silica in an amount of <NUM> parts by mass or less based on <NUM> parts by mass of the polyalkylene oxide particles. This tends to enhance the fluidity etc. of the polyalkylene oxide particles. The content of silica based on <NUM> parts by mass of the polyalkylene oxide particles is, for example, more preferably <NUM> parts by mass or less, and even more preferably <NUM> parts by mass or less. In terms of easily enhancing the fluidity etc., the content of silica based on <NUM> parts by mass of the polyalkylene oxide particles is, for example, more preferably <NUM> parts by mass or more.

As silica, for example, known silica can be widely used. Specifically, Aerosil and the like can be used.

The content ratio of the polyalkylene oxide particles in the preparation composition is not particularly limited as long as the effects of the present invention are not impaired. In terms of easily imparting particularly low friability to the preparation, the preparation composition preferably contains the polyalkylene oxide particles in an amount of <NUM> mass% or more, preferably <NUM> mass% or more, more preferably <NUM> mass% or more, and even more preferably <NUM> mass% or more, based on the total mass of the polyalkylene oxide particles and the other components (or the total mass of the preparation composition). Further, the polyalkylene oxide particles are preferably contained in an amount of <NUM> mass% or less based on the total mass of the polyalkylene oxide particles and the other components (or the total mass of the preparation composition).

In particular, the preparation composition of the present invention contains the polyalkylene oxide particles, and thus has excellent compression molding properties, and a compression molded article can be easily obtained. The method for obtaining the compression molded article is not particularly limited. For example, known compression molding methods can be widely used.

The method for preparing the preparation composition of the present invention is not particularly limited, and can be the same as, for example, methods for preparing known preparation compositions. For example, the preparation composition can be prepared by mixing polyalkylene oxide particles and a filler (e.g., silica) to obtain, for example, filler-coated polyalkylene oxide particles, and then mixing the polyalkylene oxide particles with various other components at a specific ratio.

The preparation composition of the present invention can be used to prepare various preparations. Since such preparations contain the preparation composition of the present invention, i.e., the polyalkylene oxide particles, the variation in the degree of dissolution of the preparations can be easily reduced.

The preparation of the present invention may contain a compression molded article of the preparation composition. In this case, the preparation can be formed into various dosage forms, including compression molded articles. Examples include tablets.

The present invention is described in more detail below with reference to Examples; however, the present invention is not limited to these Examples.

Diethyl zinc was diluted with n-hexane to a concentration of <NUM> mol/L in terms of zinc in a vessel purged with nitrogen. The vessel was then cooled to <NUM>, and <NUM>,<NUM>-butanediol was added to the vessel under stirring until the concentrations of <NUM>,<NUM>-butanediol and ethanol reached <NUM> mol/L and <NUM> mol/L, respectively, with respect to n-hexane. After the completion of the addition, the temperature in the vessel was raised to <NUM>, and diethyl zinc was reacted with <NUM>,<NUM>-butanediol and ethanol for <NUM> hour. Next, the temperature was raised to <NUM>, and the reaction was performed for <NUM> hour. The temperature in the vessel was then raised to <NUM>, and distillation was performed. After cooling, the reaction liquid in the vessel was diluted with n-hexane so that the concentration of the organic zinc catalyst was <NUM> mass%, thereby obtaining a dispersion containing the organic zinc catalyst.

Subsequently, in a pressure-resistant vessel purged with nitrogen, an organic zinc catalyst, a C<NUM>-<NUM> alcohol compound, and n-hexane were added so that the concentration of the organic zinc catalyst in terms of zinc was <NUM> mol/L with respect to n-hexane and the concentration of t-butanol was <NUM> mol/L with respect to n-hexane, and they were uniformed dispersed. Then, ethylene oxide was added to a concentration of <NUM> mol/L with respect to hexane, the vessel was sealed, and the mixture was polymerized with stirring in a thermostatic bath at <NUM>. After the completion of the polymerization, the produced white product was filtered out and dried at <NUM>. The resulting dried particles were mixed with <NUM> mass% of amorphous silica (Aerosil, produced by Nippon Aerosil Co. ), and the mixture was transferred to a JIS Z <NUM>-<NUM> standard sieve (<NUM>), thereby obtaining polyethylene oxide particles PA passing through the sieve.

Polyethylene oxide particles PB were obtained in the same manner as in Production Example <NUM>, except that the concentration of t-butanol with respect to n-hexane was changed to <NUM> mol/L.

For polyethylene oxide particles PA obtained in Production Example <NUM>, as JIS Z <NUM>-<NUM> standard sieves, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, a sieve with a mesh opening of <NUM>, and a sieve with a mesh opening of <NUM> were stacked in this order on a saucer. The polyethylene oxide particles were placed in the uppermost sieve with a mesh opening of <NUM>. The sieves were shaken using a rotating-tapping shaker for <NUM> minutes to classify the polyethylene oxide particles. After classification, the mass of polyethylene oxide particles remaining on each sieve was measured, and the percentage of each mass relative to the total mass (particle size distribution) was calculated.

Classification was performed in the same manner as in Production Example <NUM>, except that polyethylene oxide particles PB obtained in Production Example <NUM> were used in place of polyethylene oxide particles PA. Then, the mass of polyethylene oxide particles remaining on each sieve was measured, and the percentage of each mass relative to the total mass (particle size distribution) was calculated.

Table <NUM> shows the classification results (classification results of polyethylene oxide particles PA and PB) in Production Examples <NUM> and <NUM>.

In the classification of polyethylene oxide particles PA, <NUM> of particles remaining on each sieve and the saucer were each collected (<NUM> types in total). In the classification of polyethylene oxide particles PB, <NUM> of particles remaining on each sieve and the saucer were each collected (<NUM> types in total). These <NUM> types of particles were uniformly mixed to obtain preparation polyethylene oxide particles. The preparation polyethylene oxide particles were classified by a <NUM>-µm sieve (JIS Z <NUM>-<NUM> standard sieve), and particles on the <NUM>-µm sieve and particles passing through the sieve were collected. The <NUM>% aqueous solution viscosities A1 (mPa·s) and A2 (mPa·s) of each type of particles were measured, and the viscosity ratio A (%) was calculated by the following formula (<NUM>): <MAT>.

The viscosity ratio A (%) was calculated in the same manner as in Example <NUM>, except that in the classification of polyethylene oxide particles PA, particles on the <NUM>-µm sieve, particles on the <NUM>-µm sieve, particles on the <NUM>-µm sieve, particles on the <NUM>-µm sieve, and particles remaining on the saucer were collected (<NUM> each) (<NUM> types in total), in the classification of polyethylene oxide particles PB, particles on the <NUM>-µm sieve and particles on the <NUM>-µm sieve were collected (<NUM> each) (<NUM> types in total), and these <NUM> types of particles were uniformly mixed to obtain preparation polyethylene oxide particles.

The viscosity ratio A (%) was calculated in the same manner as in Example <NUM>, except that in the classification of polyethylene oxide particles PA, particles on the <NUM>-µm sieve, particles on the <NUM>-µm sieve, particles on the <NUM>-µm sieve, and particles remaining on the saucer were collected (<NUM> each) (<NUM> types in total), in the classification of polyethylene oxide particles PB, particles on the <NUM>-µm sieve, particles on the <NUM>-µm sieve, and particles on the <NUM>-µm sieve were collected (<NUM> each) (<NUM> types in total), and these <NUM> types of particles were uniformly mixed to obtain preparation polyethylene oxide particles.

The viscosity ratio A (%) was calculated in the same manner as in Example <NUM>, except that in the classification of polyethylene oxide particles PA, particles on the <NUM>-µm sieve, particles on the <NUM>-µm sieve, and particles remaining on the saucer were collected (<NUM> each) (<NUM> types in total), in the classification of polyethylene oxide particles PB, particles on the <NUM>-µm sieve, particles on the <NUM>-µm sieve, particles on the <NUM>-µm sieve, and particles on the <NUM>-µm sieve were collected (<NUM> each) (<NUM> types in total), and these <NUM> types of particles were uniformly mixed to obtain preparation polyethylene oxide particles.

The viscosity ratio A (%) was calculated in the same manner as in Example <NUM>, except that in the classification of polyethylene oxide particles PA, particles on the <NUM>-µm sieve, particles on the <NUM>-µm sieve, particles on the <NUM>-µm sieve, and particles on the <NUM>-µm sieve were collected (<NUM> each) (<NUM> types), in the classification of polyethylene oxide particles PB, particles on the <NUM>-µm sieve, particles on the <NUM>-µm sieve, and particles remaining on the saucer were collected (<NUM> each) (<NUM> types), and these <NUM> types of particles were uniformly mixed to obtain preparation polyethylene oxide particles.

Table <NUM> shows the mixing conditions of the preparation polyethylene oxide particles obtained in the Examples and Comparative Examples, and the calculation results of the viscosity ratio A. Further, Table <NUM> shows the <NUM> mass% aqueous solution viscosity A1 (mPa·s) of particles having a particle size of <NUM> or more, and the <NUM> mass% aqueous solution viscosity A2 (mPa·s) of particles having a particle size of less than <NUM>, and also shows the <NUM> mass% aqueous solution viscosity of the entire particles (mixture of particles having a particle size of <NUM> or more and particles having a particle size of less than <NUM>).

From the results of Table <NUM>, all of the preparation polyethylene oxide particles obtained in Examples <NUM> to <NUM> had a viscosity ratio A (%) of <NUM>% or more and <NUM>% or less.

The <NUM> mass% aqueous solution viscosity was measured in the following manner.

<NUM> of the polyethylene oxide particles and <NUM> of isopropanol were added to a <NUM>-L beaker, and while stirring at <NUM> rpm using an impeller, <NUM> of ion-exchange water was added, and the mixture was stirred for <NUM> minute. Then, the stirring speed was changed to <NUM> rpm, and stirring was further continued for <NUM> hours, thereby obtaining a <NUM> mass% aqueous solution of polyethylene oxide. The aqueous solution was maintained at <NUM>, the viscosity was measured using a rotational viscometer (RV DVII+, produced by Brookfield; spindle: RV-<NUM>, rotation speed: <NUM> rpm), and this value was taken as the <NUM> mass% aqueous solution viscosity.

<NUM> of the polyethylene oxide particles and <NUM> of isopropanol were added to a <NUM>-L beaker, and while stirring at <NUM> rpm using an impeller, <NUM> of ion-exchange water was added, and the mixture was stirred for <NUM> minute. Then, the stirring speed was changed to <NUM> rpm, and stirring was further continued for <NUM> hours, thereby obtaining a <NUM> mass% aqueous solution of polyethylene oxide. The aqueous solution was maintained at <NUM>, the viscosity was measured using a rotational viscometer (RV DVII+, produced by Brookfield), and this value was taken as the <NUM> mass% aqueous solution viscosity.

Assuming the vibration applied during transportation of the preparation polyethylene oxide particles, shaking treatment was performed by the following procedure. <NUM> of the preparation polyethylene oxide particles were put into a <NUM>-mL poly beaker and shaken uniformly. The poly beaker was fixed vertically on a shaker (AS-1N, produced by AS ONE Corporation) and shaken at a frequency of <NUM> rpm for <NUM> minutes. Approximately <NUM> of particles were collected from each of the upper and lower parts of the shaken poly beaker (upper and lower samples, respectively).

<NUM> of sample collected by shaking treatment was put into a general-purpose autograph mortar (produced by Ichihashi Seiki Co. , Φ10, R10), and compression-molded using Autograph (AGS-T, produced by Shimadzu Corporation) with a test force of <NUM> kN at a compression speed of <NUM>/min to obtain a tablet of polyethylene oxide particles alone. The same operation was repeated to produce a total of <NUM> tablets for the particles collected from the upper part, and to also produce a total of <NUM> tablets for the particles collected from the lower part. Thus, a total of <NUM> tablets (i.e., n=<NUM> in total, n=<NUM> for the upper samples, and n=<NUM> for the lower samples) were obtained.

Using the tablets of polyethylene oxide particle alone obtained as described above, a dissolution test was performed according to the Japanese Pharmacopoeia (paddle method) (test liquid: ion-exchange water, test temperature: <NUM>, stirring speed: <NUM> rpm). In the dissolution test, the tablets taken after stirring for <NUM> hours were dried at <NUM> for <NUM> hours, and then the dissolution rate of the polyethylene oxide tablets (upper sample: n=<NUM>, lower sample: n=<NUM>) was calculated based on the following formula: <MAT>.

Further, from the obtained dissolution rates (%), the average dissolution rate of the total of <NUM> tablets was calculated.

From the dissolution test results of the tablets (total n=<NUM>, breakdown: upper sample: n=<NUM>, lower sample: n=<NUM>), the average dissolution rate (n=<NUM>) of the total of <NUM> tablets and the standard deviation (n=<NUM>) were calculated, and the coefficient of variation was calculated according to the following formula: Coefficient of variation = (standard deviation (n=<NUM>)/average dissolution rate (n=<NUM>))×<NUM>.

Table <NUM> shows the dissolution rates of the tablets obtained using the preparation polyethylene oxide particles produced in the Examples and Comparative Examples (total n=<NUM>, upper sample: n=<NUM>, lower sample: n=<NUM>), average dissolution rate, standard deviation, and coefficient of variation. In Table <NUM>, the terms "Upper" and "Lower" refer to the upper and lower samples, respectively.

The results shown in Table <NUM> reveal that tablets (preparations) obtained using polyethylene oxide particles that satisfy a viscosity ratio A (%) of <NUM>% or more and <NUM>% or less have a low coefficient of variation. That is, it was revealed that polyethylene oxide particles having a viscosity ratio A in the above range can reduce the variation in the degree of dissolution of preparations. In particular, it was revealed that even if the uniformity of polyethylene oxide particles is disturbed by vibration or the like, the above particles can make variation less likely to occur in the degree of dissolution of preparations.

Claim 1:
Polyalkylene oxide particles that satisfy a viscosity ratio A (%) of <NUM>% or more and <NUM>% or less, wherein the viscosity ratio A is represented by the following formula (<NUM>): <MAT>
wherein A1 is the <NUM> mass% aqueous solution viscosity (mPa·s) of particles having a particle size of <NUM> or more, and A2 is the <NUM> mass% aqueous solution viscosity (mPa·s) of particles having a particle size of less than <NUM>, and
wherein the viscosity and the particle size are measured as indicated in the description.