JP3687025B2 - Stable enalapril maleate tablets - Google Patents

Description

【００１６】
例３（実施例）
１錠中、
マレイン酸エナラプリル ５．０ｍｇ
乳糖 適量
ＨＰＣ １．０ｍｇ
ＣＭＣカルシウム ３．０ｍｇ
タルク ５．０ｍｇ
──────────────────────────────
合計 １００．０ｍｇ
【００１７】
例１と同様に、主薬、乳糖およびＨＰＣの混合物から顆粒を製造し、ＣＭＣカルシウムおよびタルクを混合して打錠する。
【００１８】
例４（実施例）
例３においてタルク５．０ｍｇをタルク２．５ｍｇおよび硬化油２．５ｍｇに変更したことを除き例３に同じ。
【００１９】
例３および例４で製造した錠剤も上に述べた安定性試験において例１の錠剤に匹敵する安定性を示した。[0001]
Background of the invention Enalapril maleate is an antihypertensive agent having an angiotensin converting enzyme (ACE) inhibitory action. In general, tablets for oral administration are prepared by granulating the active ingredient and auxiliary ingredients such as excipients, disintegrants, lubricants, pigments, etc. into granules using a binder and compressing them, or combining the active ingredient and auxiliary ingredients. Manufactured by direct tableting without granulation.
However, enalapril maleate itself is stable, but when it is formulated into a tablet, the stability is significantly reduced by the combination with auxiliary components. For example, US Pat. 5,562,921 states that enalapril maleate is unstable in the presence of magnesium stearate, which is most commonly used as a lubricant.
[0002]
Japanese Patent No. 2619904 describes that the stability of an ACE inhibitor in a solid preparation for oral administration is improved by adding an alkali metal or an alkali metal carbonate as a stabilizer to the formulation. In addition to this stabilizer, a tablet using magnesium stearate as a lubricant is described in the Examples. In this case, the main agent ACE inhibitor is quinapril dihydrochloride, which is effective for enalapril maleate. Is not actually confirmed.
[0003]
DISCLOSURE OF THE INVENTION According to our studies, it has been found that the stability of enalapril maleate in tablets is greatly influenced by the lubricant used. For example, when magnesium stearate or calcium blended with 5% enalapril maleate is stored at 60 ° C., the residual rate decreases to 30% or less of the initial value after 20 days.
[0004]
Therefore, the present inventors have selected sucrose fatty acid ester, hydrogenated oil, talc or a mixture thereof as a lubricant, and enalapril maleate tablets tableted by a conventional method show unexpectedly excellent stability. discovered.
[0005]
As is well known, there are various grades of sucrose fatty acid esters depending on the type of fatty acid and the degree of substitution. Of these, those having a high degree of substitution, that is, those containing as many tri-substituted products as possible are preferable as the lubricant. The fatty acid generally has 12 or more carbon atoms, such as lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, behenic acid, erucic acid, mixed fatty acid such as beef tallow fatty acid. HLB is 7 or less, and 3 or less is particularly preferable. The lubricant is generally added in an amount of 0.5 to 10% by weight, preferably 2 to 7% by weight.
[0006]
The tablet of the present invention may contain conventional additive components such as excipients, binders and disintegrants in addition to the lubricants described above. Examples of preferred excipients include lactose (monohydrate and anhydride), mannitol, starch, microcrystalline cellulose. The binder is used to granulate the active ingredient and excipients into granules. Examples of preferred binders are hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone. Preferred examples of disintegrants are carboxymethylcellulose calcium (CMC calcium) and partially pregelatinized starch.
[0007]
One of the important benefits of the present invention is that maleic acid is stable by directly compressing a mixture containing the excipients and lubricants described above, the active ingredient, and optionally a disintegrant, without granulating into granules. The ability to produce enalapril tablets. Needless to say, the direct tableting method is advantageous because the granulation step can be omitted.
[0008]
Examples The effects of the present invention are illustrated by the following formulation examples and stability test results.
[0009]
Example 1 (Example)
1 tablet,
Enalapril maleate 5.0mg
Lactose appropriate amount HPC 1.0mg
CMC calcium 3.0mg
Sucrose fatty acid ester 2.5mg
Hardened oil 2.5mg
──────────────────────────────
Total 100.0mg
[0010]
After uniformly mixing the main ingredient, lactose and HPC, add about 10% purified water to the amount charged, knead, granulate with an extrusion granulator, and dry with hot air at 65 ° C using a flow coater. Sizing using a roll granulator. Sucrose fatty acid ester, hydrogenated oil and CMC calcium are added to the obtained granules and compressed into tablets of 100.0 mg.
[0011]
Example 2 (Example)
1 tablet,
Enalapril maleate 5.0mg
Lactose appropriate amount sucrose fatty acid ester 5.0mg
──────────────────────────────
Total 100.0mg
[0012]
The above three-component homogeneous mixture is directly compressed.
[0013]
Example 3 (comparative example)
Same as Example 1, except that 2.5 mg of sucrose fatty acid ester is changed to 2.5 mg of magnesium stearate in Example 1.
[0014]
Stability test The tablets of Examples 1 to 3 were stored at 60C for 5 days and 10 days, and the residual ratio of enalapril maleate to the initial value was determined. The results are shown in Table 1.
[0015]
[Table 1]

[0016]
Example 3 (Example)
1 tablet,
Enalapril maleate 5.0mg
Lactose appropriate amount HPC 1.0mg
CMC calcium 3.0mg
Talc 5.0mg
──────────────────────────────
Total 100.0mg
[0017]
As in Example 1, granules are produced from a mixture of the active ingredient, lactose and HPC, mixed with CMC calcium and talc and compressed into tablets.
[0018]
Example 4 (Example)
Same as Example 3 except that 5.0 mg talc was changed to 2.5 mg talc and 2.5 mg hardened oil in Example 3.
[0019]
The tablets produced in Examples 3 and 4 also showed stability comparable to the tablet of Example 1 in the stability test described above.

Claims (4)

  Mix sucrose fatty acid ester, talc, hydrogenated oil or a mixture thereof as a lubricant in granules containing enalapril maleate, excipients, and binder, and not containing alkali or alkaline earth metal carbonate, Stable enalapril maleate tablets formed by tableting.   The tablet of claim 1, wherein the binder is hydroxypropylcellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone.   Mix sucrose fatty acid ester, talc, hydrogenated oil or a mixture thereof as a lubricant in a mixture containing enalapril maleate and excipients and no alkali or alkaline earth metal carbonate, and compress directly. A stable enalapril maleate tablet.   The tablet according to any one of claims 1 to 3, wherein a disintegrant selected from carboxymethylcellulose calcium and partially pregelatinized starch is mixed with the lubricant and compressed.