JP2003095939A - Stable pravastatin sodium tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pravastatin sodium tablet stable around a neutral condition and preferable to living bodies without using a strongly basic compound which is not preferable to the formulation technique and handling of oral formulation or without using magnesium oxide which may cause discoloration by solving the conventional technique. SOLUTION: This stable pravastatin sodium tablet contains pravastatin sodium 2-8 wt.% magnesium stearate and a water-retaining excipient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a stable tablet containing pravastatin sodium which is a therapeutic agent for hyperlipidemia as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Pravastatin is an HMG-CoA reductase inhibitor disclosed in US Pat. No. 4,346,227 and has the formula

[Chemical 1] It is represented by.

Since pravastatin decomposes into a lactone or the like in a low pH region, the patent publication of JP 2935220 discloses that the aqueous dispersion of a pharmaceutical composition containing pravastatin contains 9 or more pravastatins. p
It has been proposed to add one or more basifying agents that impart H, especially magnesium oxide.

[0004]

However, a pH of 9 or more is required.
The use of a strongly basic compound that imparts a
Further, magnesium oxide has a drawback that it may cause coloration or lead to a decrease in content.

[0005]

The present invention has been made for the purpose of solving the above-mentioned drawbacks of the prior art and providing a stable pravastatin-containing preparation near neutral, which is preferable for living bodies.

The stable pravastatin sodium tablet adopted by the present invention to achieve the above object is characterized by containing pravastatin sodium, 2 to 8% by weight of magnesium stearate and a water-retaining excipient. To do.

That is, the inventors of the present invention diligently studied the development of a stable pravastatin sodium tablet near neutral, which is preferable for living bodies, without being trapped in a high pH, and as a result, it was widely used as a lubricant in tablet formulation. It was found that stabilization can be easily achieved by adjusting the amount of magnesium stearate added. Further, it was found that the stability is remarkably improved by controlling the water content in the preparation by a water-retaining excipient, and based on these findings, further studies were conducted to complete the present invention. .

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below.

The main drug in the stable pravastatin sodium tablet of the present invention is pravastatin sodium, which is a sodium salt of pravastatin known as an HMG-CoA reductase inhibitor as described above. The content of pravastatin sodium in the pravastatin sodium tablet of the present invention can be appropriately determined.
It is 7.5% by weight.

In the pravastatin sodium tablet of the present invention, magnesium stearate is used as another component, and the amount thereof is 2 to 8% by weight. If the amount of magnesium stearate is less than 2% by weight, the pH of pravastatin sodium tablets will be less than 7.5, and if it exceeds 8% by weight, the pH will be more than 9, which is not preferable. If it exceeds 8% by weight, the disintegration time is delayed.

In the pravastatin sodium tablet of the present invention, a water-retaining excipient is further used. Examples of the water-retaining excipient include lactose, lactose granules, crystalline cellulose and powder. 1 selected from reduced maltose syrup, sugar alcohol (D-mannitol, xylitol, erythritol, maltitol, etc.), calcium acetate
There may be mentioned one kind or two or more kinds.

The content of the water-retaining excipient in the pravastatin sodium tablet of the present invention can be appropriately determined and is, for example, 50 to 85% by weight.

That is, according to the present invention, the magnesium stearate added for the purpose of maintaining lubricity during tableting has a pH of 9
Since it is before and after, by adjusting the addition amount, it is preferable to adjust the pH without adding a particularly strong basic substance.
It becomes possible to adjust to any pH within the range of 7.5 to 9, and at the same time, by adding a water-retaining additive, water is adsorbed therein, and pravastatin sodium and magnesium stearate are adsorbed in the water. By melting,
It has been found to form and stabilize a "micro-pH" of at least pH 7.5-9.

The pravastatin sodium tablet of the present invention may further contain a binder, and the binder may be, for example, one selected from hydroxypropyl cellulose, partially pregelatinized starch, hydroxypropyl starch and crystalline cellulose, or Two or more types can be mentioned.

The pravastatin sodium tablet of the present invention may further contain a disintegrant, which is selected from, for example, sodium carboxymethyl starch, partially pregelatinized starch, hydroxypropyl starch and crystalline cellulose. There may be mentioned one kind or two or more kinds.

The content of the binder and the disintegrant in the pravastatin sodium tablet of the present invention can be appropriately determined. For example, 10 to 35% by weight and 2 to 9% by weight, respectively.
Is.

The pravastatin sodium tablet of the present invention is
It can be easily produced by a dry method or a wet method using the above-mentioned components, according to a conventional method, for example, a method described in the general rules for preparation of the Japanese Pharmacopoeia.

The water content of the pravastatin sodium tablet of the present invention thus obtained is preferably 5.5% or more, and excessive drying adversely affects the stability.

The present invention will be further described below with reference to examples. The examples are, of course, illustrative and not limiting.

Example 1 (per tablet) pravastatin sodium 5 mg, lactose 61 mg,
Crystalline cellulose 20 mg, calcium acetate 2 mg, magnesium stearate 2 mg (about 2.2% by weight),
90 mg in total

[0021] Of the above ingredients, other ingredients except magnesium stearate are mixed, wet granulated, dried and sized, and magnesium stearate is added to the mixture to form tablets, each containing 5 mg of pravastatin sodium. It was

Example 2 (per tablet) Pravastatin sodium 5 mg, D-mannitol
61 mg, crystalline cellulose 20 mg, calcium acetate 2 mg, magnesium stearate 2 mg (about 2.2
% By weight, total 90 mg

A tablet containing 5 mg of pravastatin sodium per tablet was prepared in the same manner as in Example 1.

Example 3 (per tablet) Pravastatin sodium 5 mg, lactose granulated product 61 m
g, crystalline cellulose 20 mg, sodium carboxymethyl starch 2 mg, magnesium stearate 2
mg (about 2.2% by weight), total 90 mg

The above ingredients are mixed and compressed into tablets by a dry method.
Tablets containing 5 mg pravastatin sodium per tablet were obtained.

Example 4 (per tablet) pravastatin sodium 5 mg, erythritol 7
3 mg, partially pregelatinized starch 10 mg, magnesium stearate 2 mg (about 2.2% by weight), total 9
0 mg

Of the above ingredients, erythritol and partially pregelatinized starch were wet-granulated, dried and sized, and the other ingredients were added to the resulting mixture to form tablets, each containing 5 mg of pravastatin sodium.

Example 5 (per tablet) Pravastatin sodium 5 mg, erythritol 6
3 mg, partially pregelatinized starch 10 mg, hydroxypropyl starch 10 mg, magnesium stearate 2 mg (about 2.2% by weight), total 90 mg

Of the above ingredients, erythritol, partially pregelatinized starch and hydroxypropyl starch are wet granulated, dried and sized, and the other ingredients are added to the resulting mixture to form tablets, each containing 5 mg of pravastatin sodium. Got

Example 6 (per tablet) Pravastatin sodium 5 mg, powdered reduced maltose starch syrup 73 mg, hydroxypropyl starch 10 mg,
Magnesium stearate 2 mg (about 2.2% by weight), total 90 mg

Of the above ingredients, powdered reduced maltose starch syrup and hydroxypropyl starch were wet granulated, dried and sized, and the other ingredients were added to the resulting mixture to form tablets, each containing 5 mg of pravastatin sodium. It was

Example 7 (per tablet) Pravastatin sodium 5 mg, maltitol 61
mg, crystalline cellulose 22 mg, magnesium stearate 2 mg (about 2.2% by weight), total 90 mg

The above ingredients were mixed and compressed into tablets by a dry method.
Tablets containing 5 mg pravastatin sodium per tablet were obtained.

Example 8 (per tablet) pravastatin sodium 5 mg, erythritol 6
0 mg, crystalline cellulose 21 mg, calcium acetate
2 mg, magnesium stearate 2 mg (about 2.2
% By weight, total 90 mg

The above ingredients are mixed and compressed into tablets by a dry method.
Tablets containing 5 mg pravastatin sodium per tablet were obtained.

Example 9 (per tablet) Pravastatin sodium 5 mg, lactose granules 58.
5 mg, crystalline cellulose 20 mg, sodium carboxymethyl starch 2 mg, magnesium stearate 4.5 mg (5% by weight), total 90 mg

The above ingredients are mixed and compressed into tablets by a dry method.
Tablets containing 5 mg pravastatin sodium per tablet were obtained.

Example 10 (per tablet) Pravastatin sodium 5 mg, lactose granulated product 55.
8 mg, crystalline cellulose 20 mg, sodium carboxymethyl starch 2 mg, magnesium stearate 7.2 mg (8% by weight), total 90 mg

The above ingredients are mixed and compressed into tablets by a dry method.
Tablets containing 5 mg pravastatin sodium per tablet were obtained.

Comparative Example 1 (per tablet) Pravastatin sodium 5 mg, lactose granulated product 61.
4 mg, crystalline cellulose 20 mg, sodium carboxymethyl starch 2 mg, magnesium stearate 1.6 mg (about 1.8% by weight), total 90 mg

A tablet containing 5 mg of pravastatin sodium per tablet was prepared in the same manner as in Example 3.

Comparative Example 2 (per tablet) Pravastatin sodium 5 mg, lactose granules 54.
9 mg, crystalline cellulose 20 mg, sodium carboxymethyl starch 2 mg, magnesium stearate 8.1 mg (9% by weight), total 90 mg

Tablets containing 5 mg of pravastatin sodium per tablet were prepared in the same manner as in Example 3.

Comparative Example 3 (per tablet) Pravastatin sodium 5 mg, lactose granulated product 61 m
g, crystalline cellulose 20 mg, sodium carboxymethyl starch 2 mg, magnesium stearate 2
mg (about 2.2% by weight), total 90 mg

[0045] Of the above ingredients, other ingredients except magnesium stearate were mixed and thoroughly dried, and then magnesium stearate was added to the mixture to form tablets, and tablets each containing 5 mg of pravastatin sodium were obtained. The water content was 5.10%.

Comparative Example 4 (per tablet) Pravastatin sodium 5 mg, lactose granulated product 61.
4 mg, crystalline cellulose 20 mg, sodium carboxymethyl starch 2 mg, magnesium stearate 1.6 mg (about 1.8% by weight), total 90 mg

Of the above ingredients, other ingredients except magnesium stearate were mixed, dried sufficiently, magnesium stearate was added thereto, and the mixture was tableted to give tablets each containing 5 mg of pravastatin sodium. The water content was 5.05%.

Comparative Example 5 (per tablet) Pravastatin sodium 5 mg, lactose granule 59 m
g, crystalline cellulose 20 mg, sodium carboxymethyl starch 2 mg, magnesium oxide 2 mg, magnesium stearate 2 mg (about 2.2% by weight),
90 mg in total

Preparation was carried out in the same manner as in Example 3, the pH was adjusted with magnesium oxide, and tablets each containing 5 mg of pravastatin sodium were obtained.

The tablets obtained in the examples and comparative examples were treated at 40 ° C. for 75 minutes.
It was left at% HR for 2 months. Changes in appearance and content of these tablets were observed. The results are shown in Tables 1 and 2.

[0051]

[Table 1]

[0052]

[Table 2]

The pH of pravastatin sodium tablets shown in Tables 1 and 2 was measured by suspending 10 tablets of each tablet obtained in Examples and Comparative Examples in 100 mL of purified water.

The water content of pravastatin sodium tablets was measured by the Karl Fischer method, and 0.2 g of powder obtained by crushing each tablet obtained in Examples and Comparative Examples was collected,
The direct titration method was used. Regarding the storage state, Comparative Example 3,
Only 4 was a glass bottle (closed stopper), and the others were aerated glass bottles.

[0055]

INDUSTRIAL APPLICABILITY According to the present invention, unstable pravastatin sodium can be stabilized for a long period of time, and a tablet without discoloration or lactonization can be provided. The pravastatin sodium tablet of the present invention comprises pravastatin sodium and a conventional pharmaceutical additive,
Stabilization is achieved by adjusting the amount of magnesium stearate, which is an essential component of tablets, so special equipment is not required for manufacturing, and there are no difficulties in the process, making it extremely useful in industry. It is expensive.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/38 A61K 47/38 A61P 3/06 A61P 3/06 43/00 111 43/00 111 (72) Inventor Hirotaka Yamaguchi F-Term (reference) 4C076 AA36 BB01 CC21 DD37A DD41A EE30A EE31A FF04 4C206 AA01 AA02 DB03 DB56 MA02 MA05 MA55 NA14 ZC33, Kobayashi Kako Co., Ltd.

Claims (6)

[Claims] 1. A stable pravastatin sodium tablet comprising pravastatin sodium, 2 to 8% by weight of magnesium stearate and a water-retaining excipient. 2. The water-retaining excipient is one or more selected from lactose, lactose granules, crystalline cellulose, powdered reduced maltose starch syrup, sugar alcohol, and calcium acetate. The stable pravastatin sodium tablet described. 3. The stable pravastatin according to claim 1, which comprises a binder, and the binder is one or more selected from hydroxypropyl cellulose, partially pregelatinized starch, hydroxypropyl starch and crystalline cellulose. Sodium tablets. 4. The stable dispersant according to claim 1, wherein the disintegrant is one or more selected from sodium carboxymethyl starch, partially pregelatinized starch, hydroxypropyl starch and crystalline cellulose. Pravastatin sodium tablets. 5. The stable pravastatin sodium tablet according to claim 1, which has a water content of 5.5% or more. 6. The tablet having a pH of 7.5 to 9.
The stable pravastatin sodium tablet according to.