JP2000264843A - Tablet containing enalapril maleate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a tablet which does not contain a cellulosic compound and magnesium stearate and can stably be preserved by compounding enalapril maleate, a polysaccharide and a hardened oil. SOLUTION: This tablet comprises (A) enalapril maleate preferably having an average-particle diameter of about 10-100 μm, (B) a polysaccharide for example, selected from lactose, sucrose, corn starch, and gelatinized starch, and (C) a hardened oil. The tablet preferably comprises 5 pts.wt. of the component A, 50-100 pts.wt. of the component B and 0.5-5 pts.wt. of the component C. The tablet especially preferably comprises 5 pts.wt. of the component A, 70-90 pts.wt. of lactose as the component B, 0-10 pts.wt. of gelatinized starch, 3-15 pts.wt. of partially gelatinized starch, and 0.5-3 pts.wt. of the hardened oil. The tablet may, if necessary, furthermore be compounded with preparation additives such as a coloring agent, a flavor and an antistatic agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a stable tablet of enalapril maleate useful as an antihypertensive.

[0002]

2. Description of the Related Art Enalapril [Chemical name: (S) -1-]
[N- [1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl] -L-proline maleate has a functional group such as an amino group, a carboxyl group, an amide residue and an ester residue. It is susceptible to oxidation and hydrolysis by oxygen and moisture in the air. Therefore, the formulation of enalapril maleate by conventional methods using conventional additives without special measures,
There is a problem that discoloration occurs in a short time and the drug content decreases. Therefore, the stable formulation has been studied, and some improvement measures have been proposed. For example, Japanese Patent No. 26199
No. 04 discloses a method of processing a composition containing an angiotensin converting enzyme inhibitor such as enalapril, an alkali metal or alkaline earth metal carbonate, and a saccharide such as lactose by a wet granulation method. . Also, Japanese Patent Application Laid-Open No. 10-511103 discloses that enalapril maleate, a sodium-containing alkaline compound, at least one excipient and an appropriate amount of water are mixed, a wet mass is formed and dried, and other additives are mixed. Compression molding has been proposed. However, these methods involve a neutralization reaction between an acid and an alkali in the process of mixing the composition,
It is difficult to maintain a certain quality in mass production,
It is hard to say that it is industrially suitable.

[0003]

An object of the present invention is to provide a tablet which can be produced industrially advantageously and which can stably maintain enalapril maleate.

[0004]

DISCLOSURE OF THE INVENTION The present inventors first searched for a composition obtained by variously combining enalapril maleate and a commonly used pharmaceutical additive in order to search for conditions that can be produced industrially advantageously. The tablets were tableted in a usual manner, and the storage stability of enalapril was examined. As a result, in a tablet composition containing enalapril maleate, when a conventional cellulose compound or magnesium stearate is included as a pharmaceutical additive, the storage stability of enalapril is poor, and instead of these additives, The use of lactose and hydrogenated oil has been found to significantly improve its stability. Based on this finding, the present inventors were able to complete the present invention by further study.

That is, according to the present invention, there are provided (1) tablets containing no cellulose compound and magnesium stearate and containing enalapril maleate, polysaccharide and hydrogenated oil, (2) lactose as polysaccharide, The tablet according to the above (1), which is one or a mixture of two or more kinds selected from the group consisting of sucrose, corn starch, pregelatinized starch and partially pregelatinized starch, and (3) 5 parts by weight of enalapril maleate. , 50-1 polysaccharides
The tablet according to the above (1), which contains 00 parts by weight and 0.5 to 5 parts by weight of a hardened oil, (4) enalapril maleate 5
70 to 90 parts by weight of lactose, 3 to 2 parts of pregelatinized starch and / or partially pregelatinized starch,
The tablet according to the above (2), which contains 5 parts by weight and 0.5 to 3 parts by weight of a hardened oil, can be provided.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Enalapril maleate, which is an active agent of the present invention, is a white crystal, and is preferably powdered to have an average particle diameter of about 10 to 100 μm when formulated. The polysaccharide used in the present invention is used as an excipient, binder or disintegrant. For example, examples of the excipient include lactose, sucrose, corn starch, and the like, and among them, lactose is preferable. Examples of the binder include pregelatinized starch, partially pregelatinized starch, and pullulan. Further, examples of the disintegrant include partially pregelatinized starch, corn starch, hydroxypropyl starch and the like, and partially pregelatinized starch which also has a function as a binder is particularly preferable.

[0007] The mixing ratio of the active agent and the pharmaceutical additive in the present invention is not particularly limited, but is usually within the range of (3), preferably (4) for each component. It is as follows. Enalapril maleate 5 parts by weight Lactose 70-90 parts by weight Alpha starch 0-10 parts by weight Partially pregelatinized starch 3-15 parts by weight Hardened oil 0.5-3 parts by weight The tablet of the present invention comprises In addition, if necessary, the composition may be produced using formulation additives such as coloring agents, flavoring agents, and antistatic agents.

[0008] The tablet of the present invention can be easily produced by a usual method, for example, a method described in General Rules for Preparations of the 13th Revised Japanese Pharmacopoeia.

[0009]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Example 1 150 g of enalapril maleate, 2520 g of lactose, 150 g of pregelatinized starch, 0.36 g of iron sesquioxide and 1.14 g of yellow iron sesquioxide were put into a high-speed stirring granulator (manufactured by Powrex Co., Ltd.) and stirred. Thereafter, 420 ml of water was added and granulated. The granulated product was dried with a fluidized granulating dryer (manufactured by Powrex Corporation) and sieved with a 25-mesh JIS standard sieve. The obtained granules were transferred to a tumbler mixer (manufactured by Showa Giken Co., Ltd.) and partially pregelatinized starch 1 was added.
After 50 g and 30 g of hardened oil were added and stirred, the mixture was compression-molded with a rotary tableting machine (manufactured by Kikusui Seisakusho) to obtain tablets (6.5 mm in diameter) having the following composition. [Ingredients] [Weight per tablet (mg)] Enalapril maleate 5 Lactose 84 Alpha starch 5 Partially pregelatinized starch 5 Hardened oil 1 Iron sesquioxide and yellow iron sesquioxide Trace total 100

Example 2 150 g of enalapril maleate, 300 g of lactose, 1.14 g of iron sesquioxide and yellow iron sesquioxide of 50 mesh JI
The mixture was sieved with an S standard sieve and mixed. To this mixture, 2430 g of lactose granulated powder, 90 g of partially pregelatinized starch and 30 g of hardened oil were added and mixed using a tumbler mixer.
Tablets having the following composition (diameter 6.
5 mm). [Ingredients] [Weight per tablet (mg)] Enalapril maleate 5 Lactose 91 Partially pregelatinized starch 3 Hardened oil 1 Trace amount of iron sesquioxide and yellow iron sesquioxide 100

Comparative Example 1 According to the procedure described in Example 1, tablets (diameter 6.5 mm) having the following composition were obtained. [Ingredients] [Weight per tablet (mg)] Enalapril maleate 5 Microcrystalline cellulose 84 Alpha starch 5 Partially pregelatinized starch 5 Hardened oil 1 Iron sesquioxide and yellow iron sesquioxide Trace total 100

Comparative Example 2 According to the procedure described in Example 2, a tablet (6.5 mm in diameter) having the following composition was obtained. [Ingredients] [Weight per tablet (mg)] Enalapril maleate 5 Lactose 91 Partially pregelatinized starch 3 Magnesium stearate 1 Trace amount of iron sesquioxide and yellow iron sesquioxide 100

Test Example (Comparative Storage Stability Test of Preparations) Each tablet obtained in the Examples and Comparative Examples was subjected to a temperature of 50 ° C.
After 10 days and 20 days, the residual amount of enalapril was measured by high performance liquid chromatography,
The remaining percentage (%) was calculated. The results are as follows. Example 1 Example 2 Comparative Example 1 Comparative Example 2 10 days 99.7 99.7 96.4 96.1 20 days 99.6 99.5 95.2 95.0

[0015]

According to the present invention, it is possible to provide a tablet which can stably maintain enalapril maleate which is easily deteriorated by oxidation or hydrolysis for a long period of time. Further, since the tablet of the present invention comprises enalapril maleate and a conventional pharmaceutical additive, it can be produced industrially advantageously without any difficulty in the production process.

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Claims (4)

[Claims] 1. A tablet containing no cellulose compound and magnesium stearate, wherein the tablet contains enalapril maleate, a polysaccharide and a hydrogenated oil. 2. The tablet according to claim 1, wherein the polysaccharide is one or a mixture of two or more kinds selected from the group consisting of lactose, sucrose, corn starch, pregelatinized starch and partially pregelatinized starch. (3) To 5 parts by weight of enalapril maleate,
The tablet according to claim 1, comprising 50 to 100 parts by weight of a polysaccharide and 0.5 to 5 parts by weight of a hardened oil. 4. An enalapril maleate (5 parts by weight)
70 to 90 parts by weight of lactose, pregelatinized starch and / or
3. The tablet according to claim 2, comprising 3 to 25 parts by weight of partially pregelatinized starch and 0.5 to 3 parts by weight of hydrogenated oil.