JP3284353B2 - Solid formulation containing aluminum hydroxide and magnesium hydroxide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a solid preparation containing aluminum hydroxide and magnesium hydroxide containing low-substituted hydroxypropylcellulose (L-HPC) as a main component.

[0002]

BACKGROUND ART A preparation containing aluminum hydroxide and magnesium hydroxide has an antacid action and a gastric mucosa protective action,
It is used to improve symptoms caused by gastric and duodenal ulcers, gastritis and abnormalities of the upper gastrointestinal tract. Conventionally, the most frequently used solution is a solution in which aluminum hydroxide and magnesium hydroxide are suspended.
Inconvenience is associated with storage. On the other hand, solid preparations are improved in terms of transportation and storage, but aluminum hydroxide and magnesium hydroxide are insoluble in water, so they are not sufficiently dispersed in the stomach as they are, and the expected effects are obtained. Absent.

In order to improve these problems, a method using sodium carboxymethyl starch as a disintegrant (Japanese Patent Application Laid-Open No. 54-11902) and a tablet using crosslinked polyvinylpyrrolidone as a disintegrant (Japanese Unexamined Patent Application Publication No.
-18826) has been proposed. Also recently,
Granules for suspension are commercially available as solid preparations instead of suspensions.

[0004]

The tablet obtained by using sodium carboxymethyl starch as the above-mentioned disintegrant is convenient for transportation and storage.
The disintegration and dispersibility in the stomach have not been sufficiently satisfactory. Tablets using crosslinked polyvinylpyrrolidone (hereinafter referred to as crospopidone) as a disintegrant have excellent properties such that they are easy to swallow and do not remain in the mouth after being anchored or adhered. Due to the long time, disintegration and dispersibility inside the stomach are not satisfactory. In addition, recently commercially available granules for suspension, when added to water, disintegrate into fine particles, but have poor dispersibility and do not form a uniform suspension.

The present invention has been made in view of such circumstances, and it is an object of the present invention to provide a hydroxide having improved stability, which is excellent in disintegration and dispersibility, convenient to carry and store. An object of the present invention is to provide a fine granular or granular solid preparation containing aluminum and magnesium hydroxide.

[0006]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have solved the above-mentioned problems of the conventional solid preparations of aluminum hydroxide and magnesium hydroxide. The successful manufacture of a solid preparation led to the completion of the present invention. That is, the present invention provides a fine or granular suspension solid preparation containing aluminum hydroxide and magnesium hydroxide as main components, by adding a low-substituted hydroxypropylcellulose as a disintegrant, An object of the present invention is to provide a fine or granular solid preparation containing aluminum hydroxide and magnesium hydroxide as main components, which is excellent in disintegration and dispersibility and has improved stability.

[0007] Disintegrants conventionally used in solid preparations include starch disintegrants represented by sodium carboxymethyl starch, partially pregelatinized starch (PCS) and hydroxypropyl starch (HPS) and carmellose (CMC). , Carmellose Calcium (CM
C-Ca), croscarmellose sodium (Ac-D)
i-Sol), cellulose-based disintegrants represented by low-substituted hydroxypropylcellulose, and synthetic polymer-based disintegrants such as crospopidone.

[0008] Among these disintegrants, nonionic starch-based disintegrants such as PCS and HPS have weak disintegration power.
Since CMC-Na, Ac-Di-Sol and sodium carboxymethyl starch are ionic, they have a large pH dependency and have a disadvantage that they are hardly disintegrated under acidic conditions. In addition, synthetic polymer disintegrators such as crospovidone have a limitation in the amount used, and have a disadvantage that sufficient disintegration power cannot be obtained, and all of these disintegrants contain aluminum hydroxide and magnesium hydroxide. It is not suitable for use as a solid preparation.

The low-substituted hydroxypropylcellulose used in the solid preparation of the present invention is a cellulose obtained by etherifying a very small portion of the hydroxyl groups of cellulose with propylene oxide, and is insoluble in water and many organic solvents. It has the property of swelling, is excellent in stability, has no human toxicity, and is generally available.

[0010] Low-substituted hydroxypropylcellulose is already widely used as a tablet disintegrant or binder for medical use. However, there are no practical examples of fine or granular solid preparations of aluminum hydroxide and magnesium hydroxide. Compared with conventionally known disintegrants, the results are far beyond expectations in terms of dispersibility when using low-substituted hydroxypropylcellulose in finely divided or granular solid formulations of aluminum hydroxide and magnesium hydroxide. It became. That is, as compared with finely divided or granular solid and commercially available suspension granules of aluminum hydroxide and magnesium hydroxide to which a conventionally known starch disintegrant and ionic cellulose disintegrant are added, the disintegration is extremely high. A preparation having good dispersibility and good dispersibility was obtained. In addition, a suspension of this formulation in water becomes a uniform suspension, and has an antacid equivalent to that of a commercially available antacid, and has an extremely high dispersion in an antacid test by the modified Fuchs method. Thus, a solid preparation maintaining the properties was obtained. This solid preparation can be taken as it is or by suspending it in water at the time of use.

Low-substituted hydroxypropylcellulose is classified into several types according to its average particle size (hereinafter simply referred to as particle size) and the degree of substitution of hydroxylpropyl groups. Generally, those having a substitution degree of 7 to 16% are commercially available, and among them, those having a substitution degree of 10 to 13% are known to have the best disintegration and binding properties. Further, the particle diameter is known to be 1 μm to 18 μm. In general, as the particle size of the low-substituted hydroxypropylcellulose is larger, the disintegration is higher, but the dispersibility after the disintegration tends to be better when the particle size is somewhat small. As the low-substituted hydroxypropylcellulose used in the preparation of the present invention, almost satisfactory results can be obtained using any particle size, preferably, the particle size of the low-substituted hydroxypropylcellulose is 1 μm to 1
The best results were obtained with 4 μm. The blending ratio of the low-substituted hydroxypropylcellulose is 2% or more, preferably 3% to 50%, more preferably 3 to 1%.
By manufacturing at a blending ratio of 5%, it is possible to obtain a desired preparation having good dispersibility.

[0012] In addition to the low-substituted hydroxypropylcellulose, various additives commonly used in solid preparations can be used in the fine or granular solid preparation containing aluminum hydroxide and magnesium hydroxide as main components according to the present invention. Can be added. For example, hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), tragacanth powder, binders such as gum arabic, corn starch or gelatin, excipients such as crystalline cellulose, mannitol, etc., corn starch, pregelatinized starch, Disintegrants such as alginic acid, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, flavoring agents such as peppermint, peppermint oil or cherry, preservatives and the like.

In producing the preparation of the present invention, a conventionally known granulation method can be used as the granulation method. That is, either a wet granulation method or a dry granulation method may be used, but preferably, a wet granulation method is suitable for management. As the wet granulation method, it can be produced by any of granulation methods such as stirring granulation, tumbling granulation, and extrusion granulation.

When the preparation of the present invention is to be taken as a medicine, it is usually 1.56 g to 4.8 g per day for an adult.
(0.717 to 2.150 g as aluminum hydroxide,
It is preferable that 0.640 to 1.920 g of magnesium hydroxide be divided into several portions, suspended in water at the time of use, and taken orally. In addition, it is increased or decreased as appropriate according to age, symptoms and the like.

[0015]

The solid preparation of the present invention can be produced by a commonly used production method using low-substituted hydroxypropylcellulose, and the resulting preparation is excellent as shown in the experimental examples described later. It is a fine granular or granular solid preparation having excellent dispersibility and antacidity. Therefore, according to the present invention, compared to the conventional formulation, disintegration, excellent dispersibility,
A fine or granular solid preparation containing aluminum hydroxide and magnesium hydroxide as a main component, which is convenient to carry and store, is provided.

[0016]

【Example】

Example 1 Dry aluminum hydroxide gel, magnesium hydroxide and low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.)
(Trade name: L-HPC-LH-31), and the mixture was charged into a stirring granulator and mixed at a rotation speed of 1500 to 2000 rpm for 30 seconds, and then hydroxypropyl cellulose (Nippon Soda)
(Trade name: HPC-L), an ethanol solution of
Granulation was performed by mixing for about 2 minutes. Then, it was dried at 60 ° C. for 6 hours and passed through a 30-mesh sieve to obtain a fine-grained preparation. The mixing ratio of each component is as follows. Dry aluminum hydroxide gel 448 g Magnesium hydroxide 400 g Low substituted hydroxypropylcellulose 122 g Hydroxypropylcellulose 30 g

Example 2 By the same operation as in Example 1, a granular preparation containing fine granules was obtained according to the following formulation. Dry aluminum hydroxide gel 448 g Magnesium hydroxide 400 g Low-substituted hydroxypropylcellulose 122 g (Shin-Etsu Chemical Co., Ltd., trade name: L-HPC-LH-21) Polyvinylpyrrolidone 30 g

Example 3 By the same operation as in Example 1, a granular preparation containing fine granules was obtained according to the following formulation. Dry aluminum hydroxide gel 448 g Magnesium hydroxide 400 g Low substituted hydroxypropylcellulose 100 g (Shin-Etsu Chemical Co., Ltd., trade name: L-HPC-LH-31) Hydroxypropylcellulose 30 g

Example 4 By the same operation as in Example 1, a granular preparation containing fine granules was obtained according to the following formulation. Dry aluminum hydroxide gel 448 g Magnesium hydroxide 400 g Low-substituted hydroxypropylcellulose 60 g (L-HPC-LH-41, manufactured by Shin-Etsu Chemical Co., Ltd.) Mannitol 61 g Hydroxypropylcellulose 30 g Saccharin sodium 1 g Mentha oil 0.5 g

Example 5 By the same operation as in Example 1, a granular preparation containing fine granules was obtained according to the following formulation. Dry aluminum hydroxide gel 448 g Magnesium hydroxide 400 g Low-substituted hydroxypropylcellulose 61 g (Shin-Etsu Chemical Co., Ltd., trade name: L-HPC-LH-31) Sucrose 60 g Hydroxypropylcellulose 30 g

[0021]

[Comparative example]

Comparative Example 1 By the same operation as in Example 1, a granular preparation containing fine granules was obtained with the following formulation. Dry aluminum hydroxide gel 448 g Magnesium hydroxide 400 g Hydroxypropyl cellulose 30 g

Comparative Example 2 By the same operation as in Example 1, a granular preparation containing fine granules was obtained according to the following formulation. Dry aluminum hydroxide gel 448 g Magnesium hydroxide 400 g Ac-Di-Sol (manufactured by Asahi Kasei Corporation) 100 g Hydroxypropyl cellulose 30 g

Comparative Example 3 By the same operation as in Example 1, a granular preparation containing fine granules was obtained according to the following formulation. Dry aluminum hydroxide gel 448 g Magnesium hydroxide 400 g CMC 100 g Hydroxypropyl cellulose 30 g

Comparative Example 4 By the same operation as in Example 1, a granular preparation containing fine granules was obtained according to the following formulation. Dry aluminum hydroxide gel 448 g Magnesium hydroxide 400 g CMC-Ca 100 g Hydroxypropyl cellulose 30 g

Comparative Example 5 By the same operation as in Example 1, a granular preparation containing fine granules was obtained according to the following formulation. Dry aluminum hydroxide gel 448 g Magnesium hydroxide 400 g Sodium carboxymethyl starch 100 g Hydroxypropyl cellulose 30 g

Comparative Example 6 By the same operation as in Example 1, a granular preparation containing fine granules was obtained according to the following formulation. Dry aluminum hydroxide gel 448 g Magnesium hydroxide 400 g Partially pregelatinized starch 100 g Hydroxypropyl cellulose 30 g

Comparative Example 7 By the same operation as in Example 1, a granular preparation containing fine granules was obtained according to the following formulation. Dry aluminum hydroxide gel 448 g Magnesium hydroxide 400 g Hydroxypropyl starch 100 g Hydroxypropyl cellulose 30 g

[0028]

[Experimental example]

Experimental Example 1 (Dispersibility test in water) Dispersibility in water was compared by the following method. That is, 0.5 g of each of the preparations of Example 3 and Comparative Examples 1 to 7 was added to 5 ml of water.
Test tube made of plastic (with lid, SPR-C-10A,
In addition to Iwaki glass, outer diameter 16.2mm, height 106mm), seal it tightly, and shaker (Iwaki glass KM SHAKER VS type, about 300SP)
M) for 1 minute to disperse, and then allowed to stand. After 5 minutes, the height of the cloudy portion was measured. Then, invert the test tube,
The height of the precipitate remaining at the bottom was measured. Evaluation of dispersibility is
The determination was performed based on the ratio of the suspension calculated by the following equation. Table 1 shows the results.

[0029]

(Equation 1)

[0030]

[Table 1] The formulation of the present invention showed very good dispersibility with almost no precipitation. In Comparative Example, Comparative Example 5 showed relatively good dispersibility probably because of viscosity.

Experimental Example 2 (Dispersibility test in acidic solution) As an index of dispersibility in gastric juice, dispersibility in 0.1 N hydrochloric acid was compared. That is, a plastic test tube containing 0.5 g of each of the preparations of Example 3 and Comparative Examples 1 to 7 and 5 ml of 0.1N hydrochloric acid (with a lid, SPR-C-10A, Iwaki Glass, outer diameter 1)
(6.2 mm, height 106 mm), sealed, shaken with a shaker (Iwaki Glass KM SHAKER VS type, about 300 SPM) for 1 minute, dispersed, and allowed to stand still. Was measured. Thereafter, the test tube was inverted, and the height of the precipitate remaining at the bottom was measured. Evaluation of dispersibility was performed in the same manner as in Experimental Example 1. Table 2 shows the results.

[0032]

[Table 2]

The preparation of the present invention showed very little dispersibility even with 0.1N hydrochloric acid and showed very good dispersibility.
In Comparative Examples, none had good dispersibility. From the results of Experimental Examples 1 and 2, it was confirmed that the solid preparation according to the present invention exhibited extremely good dispersibility in water and an acidic aqueous solution.

Experimental Example 3 (Dispersibility test of L-HPC blend ratio) In the formulation of the preparation of Example 4, the blend ratio of L-HPC was changed to 0, 2, 4, 6, 8, 10, and 12%. The prepared preparations were suspended in water in the same manner as in Experimental Example 1. The height of the cloudy portion after one minute was measured, and the ratio to the total liquid height was calculated in%. Table 3 shows the results.

[0035]

[Table 3] Relatively good dispersibility was obtained even with a formulation containing 2% L-HPC, and very good dispersibility was obtained with a formulation containing 4% or more.

Experimental Example 4 (Antiacidity Test) The antacidity of the preparation of Example 4 was measured by the antacidity test method specified in the Japanese Pharmacopoeia. As a control, the antacid power of a commercially available suspension and granules for suspension was measured, and the antacid strength was measured at 0.
The comparison was made as the consumption of 1N hydrochloric acid. Table 4 shows the results.

[0037]

[Table 4] The formulation of the present invention exhibited antacidity equivalent to that of a commercially available suspension. Therefore, it was confirmed that the preparation of the present invention exhibited antacidity equivalent to that of a commercially available suspension, despite being a solid preparation.

EXPERIMENTAL EXAMPLE 5 (Fuchs Modified Test) The Fuchs modified test was conducted using 50 ml of 0.1N hydrochloric acid (37 ° C.,
The sample was introduced at 300 rpm), the pH was measured after 10 minutes, and 0.1 N hydrochloric acid was added dropwise at a rate of 2 ml / minute from 10 minutes later, and the change in pH was observed, and the pH was maintained at 3.0 or more. It measures time. The formulation of Example 4, commercial suspensions and granules for suspension were tested and compared. Table 5 shows the results.

[0039]

[Table 5]

The preparation of the present invention showed a duration of pH 3.0 or more equivalent to that of a commercially available suspension in a modified Fuchs test. On the other hand, the commercially available granules for suspension had a duration of about 80% of the commercially available suspension. Therefore, it was confirmed that the preparation of the present invention is equivalent to a commercially available suspension and has excellent antacidity as compared with commercially available granules for suspension.

[0041]

EFFECTS OF THE INVENTION The fine or granular solid preparation containing low-substituted hydroxypropylcellulose of the present invention and containing aluminum hydroxide and magnesium hydroxide as main components is an advantage of the conventional suspension. While maintaining the dispersibility, it has improved the transportability and storage properties, which are the drawbacks of suspensions. Compared with commercially available granules for suspension, they are significantly superior in terms of dispersibility and antacidity. Therefore, they are extremely useful as pharmaceuticals.

────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ identification code FI A61P 1/04 A61P 1/04 (58) Investigated field (Int.Cl. ⁷ , DB name) A61K 33/08 A61K 9/14 A61K 9/16 A61K 47/36 A61P 1/00 A61P 1/04

Claims (2)

(57) [Claims] 1. A fine or granular solid preparation containing aluminum hydroxide and magnesium hydroxide as main components, characterized by containing low-substituted hydroxypropylcellulose. 2. The fine or granular solid preparation according to claim 1, wherein the low-substituted hydroxypropylcellulose is contained at a blending ratio of 3% to 15%.