JP5809467B2 - Pitavastatin-containing composition and method for producing the same - Google Patents

Description

  The present invention relates to a pitavastatin-containing composition stabilized with pitavastatin, which is a therapeutic agent for hyperlipidemia, a therapeutic agent for high cholesterol, and a therapeutic agent for atherosclerosis, and a method for producing the same, and is an invention in the medical field.

  Pitavastatin is a kind of HMG-CoA reductase inhibitor that inhibits the activity of HMG-CoA reductase necessary for the synthesis of cholesterol. It is a useful therapeutic agent for circulatory diseases such as arteriosclerosis. In addition, statin compounds such as fluvastatin and pravastatin are known as compounds showing similar HMG-CoA reductase inhibitory activity.

Conventionally, statin compounds such as fluvastatin and pravastatin are known to be unstable at low pH, and special measures have to be taken when formulating these compounds.
For example, in the case of fluvastatin, a pharmaceutical composition is disclosed in which fluvastatin is stabilized by using in combination with an alkaline medium that imparts at least pH 8, such as calcium carbonate and sodium carbonate (see Patent Document 1).
In the case of pravastatin, a pharmaceutical composition in which pravastatin is stabilized by using a basifying agent that imparts pH 9 or higher, such as magnesium oxide or sodium hydroxide, is disclosed (see Patent Document 2).

  On the other hand, pitavastatin is a kind of statin compound, but unlike conventional statin compounds, it has been unexpectedly found to be unstable in a high pH range. Specifically, it has been shown that appearance changes are observed in a storage test at 60 ° C. for 3 days when the pH exceeds 8, and includes pitavastatin and a basic substance as a pharmaceutical composition containing pitavastatin having excellent temporal stability. A pharmaceutical composition having a pH of 7 to 8 is disclosed (see Patent Document 3).

  Therefore, there is a need for a stabilized pitavastatin-containing composition that reduces the change in appearance over time and has excellent temperature stability, and a method for producing the same, without being limited to a specific pH range. The current situation is that what is possible is not provided.

JP-A-5-246844 Japanese Patent Laid-Open No. 2-6406 Japanese National Patent Publication No. 11-503763

  An object of the present invention is to solve the conventional problems and achieve the following objects. That is, an object of the present invention is to provide a stabilized pitavastatin-containing composition having a reduced temperature change over time and excellent in temperature stability, and a method for producing the same, without being limited to a specific pH range.

Means for solving the problems are as follows. That is,
<1> A composition comprising pitavastatin or a salt thereof and a synthetic hydrotalcite.
<2> The composition according to <1>, wherein the pitavastatin or a salt thereof is pitavastatin calcium.
<3> The composition according to any one of <1> to <2>, wherein the content of the synthetic hydrotalcite is 0.05% by mass to 20% by mass.
<4> The composition according to <3>, wherein the content of the synthetic hydrotalcite is 0.5% by mass to 15% by mass.
<5> The composition according to <3>, wherein the content of the synthetic hydrotalcite is 0.5% by mass to 3% by mass.
<6> The composition according to any one of <1> to <5>, wherein the pH is 8.1 to 9.1.
<7> A method for producing a composition comprising a step of mixing pitavastatin or a salt thereof and a synthetic hydrotalcite.
<8> The method for producing a composition according to <7>, wherein the pitavastatin or a salt thereof is pitavastatin calcium.
<9> The method for producing a composition according to any one of <7> to <8>, wherein the content of the synthetic hydrotalcite is 0.05% by mass to 20% by mass.
<10> The method for producing a composition according to <9>, wherein the content of the synthetic hydrotalcite is 0.5% by mass to 15% by mass.
<11> The method for producing a composition according to <9>, wherein the content of the synthetic hydrotalcite is 0.5% by mass to 3% by mass.
<12> The method for producing a composition according to any one of <7> to <11>, wherein the pH is 8.1 to 9.1.

  According to the present invention, the conventional problems can be solved, the object can be achieved, and the change in appearance over time can be reduced without being limited to a specific pH range, and the temperature stability is excellent. A pitavastatin-containing composition and a method for producing the same can be provided.

1 is a graph showing the dissolution rate of the pitavastatin-containing composition (tablet) of Example 12. FIG.

(Composition)
The composition of the present invention comprises at least pitavastatin or a salt thereof and a synthetic hydrotalcite, and further contains other components such as a saccharide and a binder as necessary.

<Pitavastatin or its salt>
Pitavastatin or a salt thereof is a kind of HMG-CoA reductase inhibitor that inhibits the activity of HMG-CoA reductase necessary for cholesterol synthesis.
The chemical name of pitavastatin is (E) -3,5-dihydroxy-7- [4'-4 "-fluorophenyl-2'-cyclopropyl-quinolin-3'-yl] -6-heptenoic acid, the molecular formula is , C ₂₅ H ₂₄ FNO ₄ , and the structural formula thereof is as shown in the following structural formula (1).
The pitavastatin may be produced by a conventionally known method, or a commercially available product may be used.

There is no restriction | limiting in particular as a salt of the said pitavastatin, According to the objective, the salt which can be used pharmacologically can be selected suitably, For example, pitavastatin calcium etc. are mentioned.
The chemical name of the pitavastatin calcium is (+)-monocalcium bis {(3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl] -3,5- Dihydroxy-6-heptenoic acid}, the molecular formula is C ₅₀ H ₄₆ CaF ₂ N ₂ O ₈ , and the structural formula is as shown in the following structural formula (2).
The salt of pitavastatin may be produced by a conventionally known method, or a commercially available product may be used. Examples of the commercially available product include pitavastatin calcium (manufactured by Estech Pharma Co., Ltd., manufactured by CU Chemie Uetikon GmbH, manufactured by Boryung Pharma Co., Ltd., manufactured by Daito Corporation), and the like.

  There is no restriction | limiting in particular as content in the said composition of the said pitavastatin or its salt, Although it can select suitably according to the objective, 0.5 mass%-3 mass% are preferable, 1 mass%-2 mass % Is more preferable.

<Synthetic hydrotalcite>
The synthetic hydrotalcite is a kind of clay mineral and is a double hydroxide represented by Mg ₆ Al ₂ (OH) ₁₆ CO ₂ .4H ₂ O.
There is no restriction | limiting in particular as said synthetic hydrotalcite, According to the objective, it can select suitably, A commercial item can be used. Examples of the commercially available products include Alkamak (manufactured by Kyowa Chemical Industry Co., Ltd.), synthetic hydrotalcite (manufactured by Tomita Pharmaceutical Co., Ltd.), and Apacit (manufactured by Fuji Chemical Industry Co., Ltd.).
There is no restriction | limiting in particular as content in the said composition of the said synthetic hydrotalcite, Although it can select suitably according to the objective, 0.05 mass%-20 mass% are preferable, 0.5 mass%- 15 mass% is more preferable, 0.5 mass%-8.25 mass% is still more preferable, 0.5 mass%-3 mass% is especially preferable. When the content is less than 0.05% by mass, stability may be worse than that of the prior art at 50 ° C. and 90% RH, and when the content exceeds 20% by mass, coloring may occur. On the other hand, when the content is in a particularly preferable range, there is no change in appearance, and it is advantageous in that stability is excellent under both conditions of 60 ° C., 50 ° C., and 90% RH.
The pH of the composition is not limited to the range of pH 7 to 8, but is within the range of pH adjustment due to pH increase due to addition of synthetic hydrotalcite or the like or a pH adjuster usually used in pharmaceutical compositions, Although it can be appropriately selected according to the purpose, 8.1 to 9.4 is preferable in that it is remarkably excellent in stability under both conditions of 60 ° C. and 50 ° C. and 90% RH, and 8.1 to 9 .1 is more preferable in that it has no change in appearance and remarkably excellent stability under both conditions of 60 ° C., 50 ° C. and 90% RH.

<Other ingredients>
There is no restriction | limiting in particular as said other component, Usually, the well-known component which can be used for a pharmaceutical composition can be suitably selected according to the objective, For example, saccharides, a binder, a lubricant, a disintegrating agent. , Flavoring agents, flavoring agents, coloring agents, fluidizing agents, coating agents and the like.

<< saccharides >>
There is no restriction | limiting in particular as said saccharides, According to the objective, it can select suitably, For example, lactose, a mannitol, a xylitol, sorbitol etc. are mentioned. Among these, lactose and mannitol are preferable.

<< Binder >>
The binder is not particularly limited and may be appropriately selected depending on the intended purpose. For example, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl alcohol-polyethylene glycol-graft copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer Examples include coalescence, hydroxypropylcellulose, hypromellose, sodium hydroxypropylmethylcellulose, sodium starch glycolate, hydroxyethylcellulose, pregelatinized starch, partially pregelatinized starch, corn starch, and ethylcellulose.
The binder may not necessarily be included in the composition, but when it is included, the content of the binder in the composition is 0.01% by mass to 5% by mass. Preferably, 0.05 mass%-3 mass% are more preferable. When the content is within a more preferable range, it is advantageous in that sufficient tablet strength can be maintained and suitable tablet physical properties can be obtained.

Examples of the lubricant include magnesium stearate, polyethylene glycol, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, stearic acid, talc, light anhydrous silicic acid, hydrous silicon dioxide and the like.
Examples of the disintegrant include starch (such as corn starch), crystalline cellulose, carmellose calcium, sodium starch glycolate, crospovidone, croscarmellose sodium, croscarmellose calcium, and low-substituted hydroxypropylcellulose.
Examples of the flavoring agent include sucralose, aspartame, acesulfame potassium, thaumatin and the like.
Examples of the fragrances include l-menthol, vanillin, orange oil, peppermint and the like.

(Method for producing composition)
The method for producing the composition of the present invention includes at least a mixing step, and further includes other steps such as a granulation step, a tableting step, and a coating step, which are appropriately selected as necessary.

<Mixing process>
The mixing step is a step of mixing at least the pitavastatin or a salt thereof and the synthetic hydrotalcite.
The mixing method is not particularly limited as long as the pitavastatin or a salt thereof and the synthetic hydrotalcite are mixed, and a known method can be appropriately selected according to the purpose. For example, kneading, Examples include kneading, sieving, stirring, and spraying.
Examples of the apparatus used for the mixing include an agitation granulator, a high speed agitation granulator, and a fluidized bed granulator.

<Other processes>
<< Granulation process >>
The granulation step is a step of granulating at least the pitavastatin or a salt thereof, the synthetic hydrotalcite, and other components.
The granulation method is not particularly limited, and a known granulation method can be appropriately selected according to the purpose. For example, an extrusion granulation method using a cylindrical granulator, a pelleter, a speed mill, a power mill. Crushing granulation method that crushes wet kneaded material using, etc., minimizer, power kneader, speed mill, melmerizer etc., rolling granulation method that mainly granulates for rolling operation, spray drying, etc. Examples thereof include a fluidized bed granulation method according to the above method, a stirring granulation method using a stirring granulation device, a high speed stirring granulation device and the like.

<< Tablet molding process >>
The tableting molding step is a step of tableting the mixture obtained in the mixing step.
The pressure of the filling pressurization in the tableting molding step is not particularly limited and may be appropriately selected depending on the intended ^purpose, preferably ^{7.8kg / cm 2 ~39kg / cm 2} , 19.5kg / More preferred is cm ^{2 to} 26 kg / cm ² . Said pressure is less than 7.8 kg / cm ^2, may not be molded with suitable hardness, exceeds 39 kg / cm ^2, it may take a burden on punch. On the other hand, when the pressure is in a more preferable range, it is advantageous in that molding can be performed with suitable hardness.
As an apparatus used for the tableting molding, for example, Autograph (manufactured by Shimadzu Corporation), single shot tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., Hata Iron Works Co., Ltd.), rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) , Manufactured by Hata Iron Works Co., Ltd.).

  EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example, this invention is not restrict | limited to a following example.

(Example 1)
-Mixing process-
As shown in Table 1 below, 120 mg of 1 tablet (25 times the amount used per batch) 2 mg of pitavastatin calcium, 104.2 mg of lactose granule, 12 mg of low-substituted hydroxypropylcellulose, and 0.6 mg of synthetic hydrotalcite Were mixed in a mortar. To the obtained mixture, 1.2 mg of magnesium stearate was added and mixed for 1 minute to obtain a tableting mixture.
-Tableting molding process-
120 mg of the obtained tableting mixture was punched one tablet at a time with a tableting pressure of 19.9 kg / cm ² (7,500 N) using Autograph (AGS-1000D TYPE III, Shimadzu Corporation) and a 7 mm flat punch. A pitavastatin-containing composition (tablet) of Example 1 was prepared by tableting.

<Evaluation>
The produced pitavastatin-containing composition was evaluated as follows.
<< Measurement of related substances of pitavastatin >>
With respect to the prepared pitavastatin-containing composition, the amount of pitavastatin-related substance, that is, the degradation substance of pitavastatin was measured under the following UPLC conditions. The amount of related substance of pitavastatin was expressed as% of the peak area of the related substance in the total peak area derived from UPLC pitavastatin drug substance.
-UPLC conditions-
Equipment: Nihon Waters ACQUITY
Column: ACQUITY UPLC BEH C18
2.1mm x 100mm, 1.7μm
Injection volume: 1.7 μL
Detection: UV 250nm
Flow rate: 0.6mL / min
Mobile phase A: Solution of buffer: acetonitrile = 90: 10 (volume ratio) Mobile phase B: Solution of acetonitrile: water = 95: 10 (volume ratio)

Gradient schedule:
A B
0min ~ 4.32min 68% 32%
4.32 min to 7.96 min 68%-> 10% 32%-> 90%
7.96 min to 9.78 min 10% 90%
9.78 min to 9.79 min 10%-> 68% 90%-> 32%
Collection time: 12 min
As the “buffer”, 0.82 mg of sodium acetate dissolved in 1,000 mL of water and adjusted to pH 3.8 with acetic acid was used.

<< Stability evaluation test >>
The obtained pitavastatin-containing composition was placed in a brown glass bottle and capped with Kimwipe (manufactured by Nippon Paper Crecia Co., Ltd.), as shown in Table 2 below, under the conditions of 60 ° C., 50 ° C., and 90% RH. After storage for one week or one month, pitavastatin-related substances were measured using the above measurement method. The results are shown in Table 2.
In Table 2, “initial value” refers to a value measured after 2 weeks of storage in an aluminum bag at room temperature after tableting.

<< Appearance change >>
In Japanese Laid-Open Patent Publication No. 11-503763, which is a prior art document, as a conventional problem, the stability over time is low in a high pH region of pH 8 or higher, and there is a change in appearance (denaturation, yellowing) particularly over time. It is described. Therefore, as described above, the appearance change (yellowing) after storage for 1 month under the conditions of 60 ° C., 50 ° C. and 90% RH was examined, and the results are shown in Table 2.

<< pH measurement >>
As the pH of the obtained pitavastatin-containing composition, the pH of a 5% by mass suspension prepared by suspending the tableting mixture in water was measured.

(Examples 2 to 6)
In Example 1, as shown in Table 1 below, the pitavastatin-containing composition of Examples 2 to 6 was used in the same manner as in Example 1 except that the addition amount of the synthetic hydrotalcite and the addition amount of the lactose granule were changed. A product (tablet) was prepared and evaluated in the same manner as in Example 1. The results are shown in Table 2.

(Comparative Example 1)
In Example 1, as shown in Table 1 below, the pitavastatin-containing composition of Comparative Example 1 was used in the same manner as in Example 1 except that the synthetic hydrotalcite was not added and the addition amount of the lactose granulated product was changed. Tablet) and the above evaluation was performed in the same manner as in Example 1. The results are shown in Table 2.

(Comparative Example 2)
As a pitavastatin-containing composition of Comparative Example 2, “LIVALO TABLET 2 mg” (manufactured by Kowa Co., Ltd.), which is a starting preparation mainly composed of pitavastatin calcium, was used. The above evaluation was performed in the same manner as in Example 1. The results are shown in Table 2. “Rivalo Tablets 2 mg” corresponds to the invention described in JP-A-11-503763, which is a prior art.
“Rivalo tablet 2 mg” was different from Examples 1 to 6 and Comparative Example 1 in that it was a film coating agent in addition to the composition, but the stability evaluation test was conducted in the same manner as in Example 1. The appearance change was not observed because it was a film coating agent and could not be compared. Moreover, about pH measurement, 5 mass% aqueous solution was prepared similarly to Example 1 using the tablet of "Rivalo tablet 2 mg", and measured pH was made into pH of the pitavastatin containing composition of the comparative example 2. The results are shown in Table 2.

As a result, the pH of the trial preparation was 6.7 when no synthetic hydrotalcite was added. When 0.6 mg (0.5% by mass) of synthetic hydrotalcite was added, the pH was higher than 7 to 8, which is the pH range of the invention of JP-T-11-503763. It was found that Examples 1 to 6 to which the synthetic hydrotalcite was added under the severe condition of 60 ° C. and the severe condition of 50 ° C. and 90% RH were more stable than Comparative Example 2 which was the original preparation. . When the addition amount of the synthetic hydrotalcite was 9.9 mg (8.25% by mass) and 18 mg (15% by mass), the tablet slightly turned yellow after storage at 60 ° C. for 1 month. When 1.2 mg (1% by mass) to 3.6 mg (3% by mass) of synthetic hydrotalcite is added, there is no change in appearance, and it is more stable than the original preparation at both 60 ° C., 50 ° C. and 90% RH. Met.
Therefore, in Examples 1 to 6 in which synthetic hydrotalcite was added, the stability was high even in a high pH region of pH 8 or higher, where pitavastatin had a low stability over time, and the appearance changed with time. It was found that there was no problem in use.

Subsequently, the following Reference Examples 7 to 11 were tested in order to examine whether or not the pitavastatin stabilization effect due to the addition of synthetic hydrotalcite was pH-dependent.

( Reference Example 7)
In Example 1, as shown in Table 3 below, the same procedure as in Example 1 was carried out except that the amount of synthetic hydrotalcite added was changed to 0.1 mg and the amount of lactose granule added was changed to 104.7 mg. A pitavastatin-containing composition (tablet) of Reference Example 7 was prepared, and a stability evaluation test and pH measurement were performed in the same manner as in Example 1. The results are shown in Table 4.

( Reference Examples 8 to 11)
In Examples 1, 3, and 5-6, as shown in Table 3 below, an appropriate amount of disodium hydrogen citrate 1.5H ₂ O was added so as to be in the range of pH 7-8, and disodium hydrogen citrate 1 The pitavastatin-containing compositions (tablets) of Reference Examples 8 to 11 were obtained in the same manner as in Examples 1, 3 and 5 to 6 except that the addition amount of the lactose granule was changed according to the addition amount of 5H ₂ O. Then, the stability evaluation test and the pH measurement were performed in the same manner as in Example 1. The results are shown in Table 4.

As a result, in Reference Example 7, even when the pH was less than 7, good temperature stability and high temperature and high humidity stability were observed due to the addition of synthetic hydrotalcite. Moreover, in Reference Examples 8-11, even if it adjusts to pH 7-8, the increase in a related substance is reduced rather than the comparative example 2 (equivalent to invention described in Japanese translations of PCT publication No. 11-503763) which is a starting formulation. I found out. Therefore, this invention showed the pitavastatin stabilization effect superior to the invention described in the Japanese translations of PCT publication No. 11-503763, and it turned out that the effect is not restricted to pH 7-8.
Further, in Examples 1 and 4 to 6 in which the pH was not adjusted and the pH was 8.1 or more, compared with Reference Examples 8 to 11 in which the pH was adjusted to 7 to 8, 50 ° C. and 90% RH. Since the amount of the related substance was reduced in each case, it was found that a superior pitavastatin stabilizing effect was obtained when the synthetic hydrotalcite was contained and the pH was 8.1 or higher. Above all, it was revealed that pH 8.1 to 9.1 is more preferable in that it has no change in appearance and is excellent in stability under both conditions of 60 ° C., 50 ° C. and 90% RH.

  Next, in Comparative Example 2 which is a starting preparation, since film coating is performed, in order to compare the invention described in JP-T-11-503763 and the pitavastatin-containing composition of the present invention, the following comparison was made. Examples 3-11 were tested.

(Comparative Examples 3 to 11)
In Example 1, instead of synthetic hydrotalcite, the addition amount of magnesium aluminate metasilicate shown in the following Tables 5 to 7 was added, and the addition amount of the lactose granule according to the addition amount of magnesium aluminate metasilicate Except having changed, the pitavastatin containing composition (tablet) of Comparative Examples 3-11 was produced like Example 1, and the stability evaluation test and pH measurement were performed similarly to Example 1. FIG. The results are shown in Table 4. These Comparative Examples 3 to 11 correspond to the invention (pH 7 to 8) described in JP-T-11-503763.
Since there are a plurality of grades of magnesium aluminate metasilicate, Neusilin (registered trademark) neutral grade (UFL2), neutral grade (US2), and alkaline grade (FL2) are available as three grades. ) (All manufactured by Fuji Chemical Industry Co., Ltd.) were used to prepare Comparative Examples 3-6, 7-10, and 11, respectively.

As a result, Examples 1, 3 and 5-6 were significantly superior in pitavastatin stability in that the amount of related substances at 60 ° C. was reduced as compared with Comparative Examples 3-6, 7-10 and 11. It was found to show the effect of conversion.
Further, in Comparative Examples 5 and 9 to which 9.9 mg of magnesium aluminate metasilicate was added, and Comparative Examples 6 and 10 to which 18 mg was added, yellowing occurred at 60 ° C., and 9.9 mg or 18 mg of synthetic hydrotalcite was added. The degree of yellowing was more pronounced than in Examples 5 and 6 (slightly yellowing).
From the above, it was found that the present invention can provide a stabilized pitavastatin that is not limited to a specific pH range, reduces the change in appearance over time, and has excellent temperature stability.

Furthermore, the dissolution property of the pitavastatin-containing composition of the present invention was examined by the following procedure.
(Example 12)
-Mixing process-
Per 120 mg of tablet (1,000 times the amount used per batch) 2.33 mg of pitavastatin calcium, 102.31 mg of lactose granule, 12 mg of low-substituted hydroxypropylcellulose, 0.36 mg of iron sesquioxide, and synthetic hydrotal 2.4 mg of the site was mixed with Mechanomyl (Okada Seiko Co., Ltd.). 0.6 mg of magnesium stearate was added to the obtained mixture and mixed for 30 seconds to obtain a tableting mixture.
-Tableting molding process-
120 mg of the obtained mixture for tableting was tableted one tablet at a time with a tableting pressure of 26 kg / cm ² (9,800 N) using a rotary tableting machine (VIRG, manufactured by Kikusui Seisakusho) and a 7 mm 9.1R punch. Thus, a pitavastatin-containing composition (tablet) of Example 12 was produced.

<Dissolution test>
The dissolution test was conducted according to the 16th revised Japanese Pharmacopoeia under the condition that the test solution was water and the paddle rotation speed was 50 rpm. As a control, the original preparation “Rivalo Tablets 2 mg” (Comparative Example 2) was used. The results are shown in FIG.

  As a result, it was found that an elution rate of 85% could be achieved in an elution time of 15 minutes, and the elution efficiency was equivalent to that of Comparative Example 2.

The specific content of each component used in Examples 1-6, Reference Examples 7-12 and Comparative Examples 1 to 11 are as shown in Table 8 below.

  The stabilized pitavastatin-containing composition of the present invention and the method for producing the same are not limited to a specific pH range, and the stabilized pitavastatin-containing composition and the method for producing the same are reduced in appearance change over time and excellent in temperature stability. Since it can provide, it can utilize suitably as a manufacturing method of a pharmaceutical composition.

Claims (6)

A composition comprising pitavastatin or a salt thereof and synthetic hydrotalcite , wherein a 5% by mass suspension prepared by suspending the composition in water has a pH of 8.1 or higher. Composition.   The composition according to claim 1, wherein the pitavastatin or a salt thereof is pitavastatin calcium.   The composition according to claim 1, wherein the content of the synthetic hydrotalcite is 0.05% by mass to 20% by mass.   The composition according to claim 3, wherein the content of the synthetic hydrotalcite is 0.5 mass% to 3 mass%. The composition according to any one of claims 1 to 4, wherein the pH of a 5 mass% suspension prepared by suspending the composition in water is 8.1 to 9.1. A method for producing a composition comprising a step of mixing pitavastatin or a salt thereof and synthetic hydrotalcite ,
A method for producing a composition, wherein the pH of a 5 mass% suspension prepared by suspending the composition in water is 8.1 or more .