JP2000229855A - Pravastatin sodium tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prevent a change of properties due to change of pravastatin sodium which is a main medicine in tablet into a lactone substance. SOLUTION: Pravastatin sodium tablet is produced according to ordinary method by using a substance which is neutral of pH <9 as a vehicle component of tablet. A substance having buffer action or antiacid action is preferably used as a part of vehicle component. A tablet obtained by direct tableting of a substance comprising a mixture of pravastatin sodium with mannitol as a base does not only prevent change into lactone substance, but does not delay also decay time and elution time.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to a tablet containing pravastatin sodium as a therapeutic agent for hyperlipidemia as an active ingredient.

[0002] Pravastatin sodium is known to change to a lactone form in a low pH range and substantially lose its pharmacological effect. For this reason, Japanese Patent Application Laid-Open No. 2-6406 discloses that in a pharmaceutical composition containing pravastatin sodium, particularly a tablet, it is necessary to add a basic compound, particularly magnesium oxide, which raises the aqueous dispersion of the whole composition to a pH of 9 or more. is suggesting.

[0003] However, the use of such a strongly basic compound is not preferred in terms of formulation technology and handling. Accordingly, the present invention provides pravastatin sodium tablets having excellent stability without using a strong basic compound.

[0004]

DISCLOSURE OF THE INVENTION According to the present invention, there is provided a pravastatin sodium tablet characterized by containing an excipient having a neutral to pH of less than 9.

[0005] The excipient as referred to herein means all substances contained in tablets except pravastatin sodium. Examples of such substances are lactose, excipients in a narrow sense such as starch, microcrystalline cellulose, disintegrants such as calcium carboxymethylcellulose, hydroxypropylcellulose,
Includes binders such as sodium carboxymethylcellulose and sodium carboxymethyl starch, and lubricants such as magnesium stearate and talc. These components are conventional components used in the manufacture of tablets, and specific examples thereof are well known to those skilled in the art.

In a preferred embodiment of the present invention, in addition to the above-mentioned conventional excipient, a substance having a neutral or less than pH 9 as a part of the excipient but having a buffering action or an antacid action is added. . Examples of such substances are aluminum silicate, calcium hydrogen phosphate, calcium lactate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, magnesium aluminate metasilicate. Calcium hydrogenphosphate and magnesium aluminate metasilicate are particularly preferred.

[0007] Tablets can be compressed by a conventional method, that is, a dry method or a wet method, but a dry method is preferred.
The tablets thus produced are substantially prevented from being converted into the lactone form of pravastatin sodium as the main drug during storage, and can be stored for a long time.

[0008] The most commonly used substance as an excipient for tablets is lactose. However, it was found that pravastatin sodium tablets manufactured by direct compression method based on lactose have a delayed disintegration time and dissolution time in water even if a disintegrant such as microcrystalline cellulose is added. This shortcoming is overcome by tableting by a direct method based on mannitol instead of lactose.

Thus, in another embodiment of the present invention, a mixture comprising pravastatin sodium, mannitol, and a lubricant such as magnesium stearate is tableted by a direct tableting method. The mixture may include a disintegrant such as microcrystalline cellulose. This satisfies all of the stability of the base drug and the disintegration time and dissolution time of the tablet. Even if granules are once made by wet granulation based on the same mannitol as a base and then compressed, the stability of the base drug is not satisfied.

Hereinafter, the present invention will be further described with reference to examples.

Example 1 Formulation Example 1 (per tablet) Pravastatin sodium 5 mg Lactose 64 mg Calcium hydrogen phosphate 15 mg Carboxymethyl cellulose calcium 5 mg Hydroxypropyl cellulose 2 mg Magnesium stearate 1 mg ────────────── 92mg in total

Formulation Example 2 (per tablet) Pravastine sodium 5 mg Lactose 64 mg Magnesium aluminate metasilicate 15 mg Carboxymethyl cellulose calcium 5 mg Hydroxypropyl cellulose 2 mg Magnesium stearate 1 mg ──────────── 92mg in total

The above components were mixed and tableted by a dry method to obtain tablets containing 5 mg of pravastatin per tablet.

Example 2 Tablets containing 5 mg of pravastane Na per tablet were produced by the direct compression method according to the formulation shown in Table 1 based on mannitol, and the hardness, disintegration time and dissolution rate were measured.

Table 1 Formulation Example {1 2 3} ───────────── Pravastatin Na 5 mg 5 mg 5 mg Mannitol 85 mg 80 mg 75 mg crystalline cellulose ── 5 mg 10 mg Mg stearate 1 mg 1 mg 1 mg ────────────────合計 Total 91mg 91mg 91mg ─────────────────────────────硬度 Hardness (kg) 62 60 61 Disintegration time (min) 3.5 4.0 4.2 Dissolution rate after 10 minutes (%) 88.6 90.5 94.5 Dissolution rate after 15 minutes ( %) 97.7 99.4 106.6 Elution rate after 30 minutes (%) 98.5 99.8 106.7 ───────────────────────────────

Next, in order to evaluate the stability of the active ingredient in the tablet, the lactone form of the tablet of Formulation Example 1 immediately after production and after storage at 60 ° C. for 7 days and 14 days was quantified, and the change of the active ingredient into the lactone form was made. The ratio was calculated, and the lactone body change rate in a mannitol-based comparative tablet prepared by wet granulation was compared. As shown in Table 2, the tablets made by the direct compression method had better storage stability even when they were based on the same mannitol than the tablets made by the wet granulation method.

[0017]

Table 2 Rate of change of lactone (%) ───────────────────── Tablet of the present invention Comparative tablet ─────────── ─────────────────── Initial 0.0 1.7 60 ° C, 7 days later 0.5 10.2 60 ° C, 14 days 0.7 25.5． ────────────────────────────

Comparative Example Tablets containing 5 mg of plus vasvastatin Na in one tablet were manufactured by the direct compression method according to the formulation shown in Table 3 based on lactose, and the same measurement as in Example 2 was carried out.

Table 3 Formulation Example {1 2 3} ───────────── Pravastatin Na 5 mg 5 mg 5 mg Lactose 85 mg 80 mg 75 mg Microcrystalline cellulose ５ 5 mg 10 mg Mg stearate 1 mg 1 mg 1 mg ───────────────合計 Total 91mg 91mg 91mg ──────────────────────────── ───── Hardness (kg) 5.9 6.0 63 Disintegration time (min) 7.5 8.5 9.0 Elution rate after 10 minutes (%) 54.5 53.5 49.5 15 minutes Dissolution rate (%) after 70.4 70.6 66.4 Dissolution rate after 30 minutes (%) 90.2 91.6 91.2 ────────────────────────────

As can be seen from Tables 1 and 3, mannitol based is superior in disintegration time and dissolution rate to lactose based.

Test Method 1. Dissolution test method: JP13 second method Test solution: 900 mL of water at 37 ° C. Rotation number: 50 rpm Measurement number: N = 3 Collapse test method: JP13 Number of measurements: N = 6

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 47/26 A61K 47/26

Claims (5)

[Claims] 1. A pravastatin sodium tablet comprising a neutral or excipient having a pH of less than 9. 2. The pravastatin sodium tablet according to claim 1, wherein the excipient having a neutral or pH less than 9 is calcium hydrogen phosphate or magnesium aluminate metasilicate. 3. A tablet prepared by direct compression of a mixture consisting of pravastatin sodium, lactose, calcium hydrogen phosphate or magnesium aluminate metasilicate, a disintegrant and a lubricant. 4. A tablet produced by direct compression of a mixture consisting of pravastatin sodium, mannitol and a lubricant. 5. Pravastatin sodium, mannitol,
Tablets made by direct compression of a mixture of a disintegrant and a lubricant.