KR100825039B1 - Amlodipine maleate salt tablet improved stability - Google Patents

Abstract

The present invention relates to amlodipine maleate salt tablets with improved stability.

The amlodipine maleate salt tablet according to the present invention has a high purity because less than 1% of a flexible substance is produced under severe conditions as a small amount of a pharmaceutically acceptable additive is used.

Description

Amlodipine maleate salt tablet improved stability

The present invention relates to amlodipine maleate salt tablets with improved stability.

Amlodipine {2-[(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine} Is a calcium channel blocker that is strongly active for a long time in the human body as a treatment for ischemia and hypertension.

Amlodipine is effective as a free base, but EP 089 167 and US Pat. No. 4,572,909 disclose various acid addition salts of amlodipine, for example hydrochloride, hydrobromide, sulfate, phosphate or acid phosphate, acetate, malate. , Fumarate, lactate, tartrate, citrate and gluconate salts are described, of which maleate salts have been found to be most preferred. The salts described above are pharmaceutically acceptable, but because many of the acid addition salts are in amorphous form, the salt compounds are less stable and difficult to prepare in pharmaceutically suitable formulations, and are not easy to prepare on a large scale.

Therefore, in order to meet the above objectives, pharmaceutically acceptable salts must meet physicochemical criteria such as good solubility, good stability, non-hygroscopicity. Accordingly, many studies have been conducted to improve the solubility and stability of amlodipine, and among these salts, the besylate salt of amlodipine is known to have superior solubility, stability, and non-hygroscopicity as compared to known salts.

However, amlodipine acid addition salts have a problem of lowering purity in combination with amines, and in the case of amlodipine maleate salt, which is being presented in the most preferred pharmaceutical form, when the tablet is prepared with pharmaceutical additives, there is always a problem of lowering purity. Has been.

As described above, despite the studies for improving the solubility, stability, and non-hygroscopicity of amlodipine, the problem of purity has not been solved yet, and studies to improve the purity of amlodipine are urgently needed.

Accordingly, the present inventors, while studying to improve the purity of the amlodipine maleate salt, confirmed that the production of a flexible material is significantly reduced by using a small amount of additives to increase the purity and completed the present invention.

The present invention is to provide amlodipine maleate salt tablets with improved stability.

The present invention provides amlodipine maleate salt tablets with improved stability.

Hereinafter, the present invention will be described in detail.

The amlodipine maleate salt tablet of the present invention is characterized in that it comprises one or more units consisting of 8.0 to 99.9% by weight of amlodipine maleate salt and 0.1 to 92.0% by weight of a pharmaceutically acceptable additive.

In addition, the amlodipine maleate salt tablet of the present invention is characterized in that it comprises one or more units consisting of only 100% by weight of amlodipine maleate salt.

The form of the amlodipine maleate salt used in the present invention is not particularly limited and may have anhydrides, solvates, hydrates, partial hydrates, crystalline forms and amorphous forms. The content of amlodipine maleate salt used in the present invention is 8.0 to 100.0% by weight, if less than 8.0% by weight, a lot of flexible materials are generated, which leads to a problem of significantly lowered purity.

Additives used in the present invention are pharmaceutically acceptable inert ingredients, including excipients, binders, disintegrants, glidants, colorants, flavoring agents, preservatives and the like. Additives are selected based on certain physical properties of the final form, such as obtaining a tablet with a predetermined hardness and friability, rapid dispersibility and easy to swallow.

Excipients used in the present invention include excipients such as starch, modified starch, cellulose, calcium hydrogen phosphate, hard silicic anhydride, lactose, mannitol and the like; Binders such as microcrystalline cellulose or modified cellulose, povidone and the like; Disintegrants such as sodium starch glycolate, crospovidone, croscarmellose sodium; Lubricants such as magnesium stearate, sodium stearyl fumarate, talc, polyethylene glycol, glyceryl bicarbonate, glyceryl palmitostearate, glyceryl monostearate, and the like; And the like. The additive used in the present invention may have some influence depending on the type of the additive, but it may be used by forming only an acceptable level of the flexible material, but affects the purity of the tablet depending on the content of the additive. The content of the additive used in the present invention is 0.1 to 92.0% by weight, and if it exceeds 92.0% by weight, a lot of flexible materials are generated, resulting in a drop in purity.

Amlodipine maleate salt tablets according to the present invention may be prepared by techniques generally known in the art. In general, amlodipine maleate salts are mixed with apples with one or more additives to form a blend. After any further process, the blend is compressed into tablets.

Tablets according to the invention can be prepared in the form of double- or multi-dose drug layers, cores, granules or pellets by adding pharmaceutically acceptable additives to the unit and may be coated with a suitable coating. The coating may be a moisture barrier or sustained release or delayed release coating composition that has storage stability as is well known in the art.

When prepared in double or multiple tablets, one or more pharmaceutical additive layers separate from the drug layer as the unit may be compressed into tablets of suitable size. When prepared as a unit in the form of a core, it can be prepared by placing it in the core of other pharmaceutical additives and compressing it. When prepared as a granule or pellet form unit, other pharmaceutical additives may be added to the unit, mixed and compressed to produce tablets of suitable size. It can also be prepared by the manufacturing process of wet granules, dry granules, direct tableting or general tablets using amlodipine maleate salts and additives according to the above ratio.

The amlodipine maleate salt tablet according to the present invention has a very high purity because less than 1% of the total analog is produced under severe conditions (after 16 hours at 80 ° C.) as a small amount of the pharmaceutically acceptable additive is used. In addition, when the content of the amlodipine maleate salt is 10% by weight or more, less than 1% of the total flexible material is produced, and less than 5% by weight of the total flexible material is produced by 1% or more.

Thus, tablets according to the invention are of purity and stability when the unit consists of 8.0 to 99.9% by weight of amlodipine maleate salt and 0.1 to 92.0% by weight of pharmaceutically acceptable additives or when it comprises only 100.0% by weight of amlodipine maleate salt. This is the best.

The dose of amlodipine malate salt tablet of the present invention can be adjusted according to the weight, age, sex, health condition, diet, time of administration, administration method, excretion rate and severity of disease of the patient, so that the single dose of amlodipine malate salt Or the daily dose is not particularly limited and may include any amount orally providing a pharmaceutical therapeutic effect. Generally the amount of amlodipine maleate salt in the unit dosage form is usually 2.5-10 mg, preferably 4.5-5.5 mg, as the amlodipine free base.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

Examples 1-5  : Tablet comprising unit consisting of amlodipine maleate salt and pharmaceutically acceptable additive

Example 1  : Preparation of stabilized amlodipine maleate salt tablets (1000 pcs.)

6.4 g of amlodipine malate salt, 70 g of microcrystalline cellulose, 0.8 g of hard silicic anhydride, 1.6 g of sodium starch glycolate, and 1.2 g of glyceryl bivinate were mixed with apples using No. 30 sieve. This was compressed to a final weight of 80 mg.

Example 2  : Preparation of stabilized amlodipine maleate salt tablets (1000 pcs.)

6.4 g of amlodipine maleate salt, 70 g of microcrystalline cellulose, 0.8 g of hard silicic anhydride, 1.6 g of sodium starch glycolate, and 1.2 g of glyceryl bicarbonate were mixed with apples using No. 30 sieve. The core was made to have a final weight of 80 mg.

114.6 g of microcrystalline cellulose, 1.2 g of hard silicic anhydride, 2.4 g of sodium starch glycolate, and 1.8 g of glyceryl bicarbonate were mixed with apples using No. 30 sieve. It was tableted with a final weight of 200 mg with the core.

Example 3  : Preparation of stabilized amlodipine maleate salt tablets (1000 pcs.)

6.4 g of amlodipine malate salt, 70 g of microcrystalline cellulose, 0.8 g of hard silicic anhydride, 1.6 g of sodium starch glycolate, and 1.2 g of glyceryl bicarbonate were mixed with apples using No. 30 sieve (granule 1).

114.6 g of microcrystalline cellulose, 1.2 g of hard silicic anhydride, 2.4 g of sodium starch glycolate, and 1.8 g of glyceryl bicarbonate were mixed with apples using a No. 30 sieve (granule 2).

The prepared granule 1 was 80 mg and granule 2 was 120 mg.

Example 4  : Preparation of stabilized amlodipine maleate salt tablets (1000 pcs.)

6.4 g of amlodipine maleate salt, 31.8 g of microcrystalline cellulose, 0.4 g of hard silicic anhydride, 0.8 g of sodium starch glycolate, and 0.6 g of glyceryl bicarbonate were mixed with apples using a No. 30 sieve (granule 1).

152.8 g of microcrystalline cellulose, 1.6 g of hard silicic anhydride, 3.2 g of sodium starch glycolate, and 2.4 g of glyceryl bicarbonate were mixed with apples using a No. 30 sieve (granule 2).

40 mg of the prepared granule 1 and 160 mg of the granule 2 were compressed into double tablets.

Example 5  : Preparation of stabilized amlodipine maleate salt tablets (1000 pcs.)

6.4 g of amlodipine malate salt, 12.4 g of microcrystalline cellulose, 0.2 g of hard silicic anhydride, 0.4 g of sodium starch glycolate, and 0.6 g of glyceryl bicarbonate were mixed with apples using a No. 30 sieve (granule 1).

152.8 g of microcrystalline cellulose, 1.8 g of hard silicic anhydride, 3.6 g of sodium starch glycolate, and 2.7 g of glyceryl bicarbonate were mixed with apples using a No. 30 sieve (granule 2).

20 mg of the prepared granule 1 and 180 mg of the granule 2 were compressed into double tablets.

Example 6 : Preparation of stabilized amlodipine maleate salt tablet containing unit consisting of 100% of amlodipine maleate salt (1000)

6.4 g of amlodipine maleate salt was formed using a roller compactor, and then pulverized to pass through No. 18 to form 100% granules of amlodipine maleate salt having a size of 0.8-1.2 mm.

The granules and 188.2 g of microcrystalline cellulose, 1.2 g of hard silicic anhydride, 2.4 g of sodium starch glycolate, and 1.8 g of glyceryl bicarbonate were mixed with apples using No. 18 sieve. It was compressed to a final weight of 200 mg.

Comparative Example 1  :

6.4 g of amlodipine maleate salt, 184.6 g of microcrystalline cellulose, 2.0 g of hard silicic anhydride, 4.0 g of sodium starch glycolate, and 3.0 g of glyceryl bicarbonate were mixed with apples using No. 30 sieve. It was compressed to a final weight of 200 mg.

Comparative Example 2  :

6.4 g of amlodipine maleate salt, 124.6 g of microcrystalline cellulose, 60 g of hydrous calcium phosphate, 2.0 g of light anhydrous silicic acid, 4.0 g of sodium starch glycolate, and 3.0 g of magnesium stearate were mixed with apples using No. 30 sieve. It was compressed to a final weight of 200 mg.

Comparative Example 3  :

Anidipine tablets (amlodipine maleate salt) sold by Chong Kun Dang.

Comparative Example 4  :

Scard tablet (amlodipine maleate salt) sold by SK Pharmaceuticals.

Experimental Example 1  Purity Experiment

In order to determine the purity of the amlodipine maleate salt tablet according to the present invention under severe conditions, the following experiment was performed.

The amlodipine maleate salt tablets prepared in Examples 1 to 6 and Comparative Examples 1 to 4 were shielded and sealed for 16 hours at a temperature of 80 ° C., and then formation of a flexible material was observed.

The results are shown in Table 1.

Initial total lead (%) Total Lead (%) after 16 hours at 80 ℃ Example One 0.11% 0.55% 2 0.11% 0.71% 3 0.11% 0.84% 4 0.11% 0.58% 5 0.11% 0.37% 6 0.11% 0.86% Comparative example One 0.11% 1.32% 2 0.11% 17.00% 3 0.13% 1.61% 4 1.05% 5.53%

※ Total Lead (%) = {other peak area except amlodipine peak (excluding maleic acid peak) / amlodipine peak area} × 100

As shown in Table 1, the total flexible material of the amlodipine maleate salt tablets (Examples 1 to 6) according to the present invention was produced in less than 1% under severe conditions (after 16 hours at 80 ° C), which is very excellent in purity. It can be seen.

Experimental Example 2  Purity Experiment

In order to determine the purity according to the content of amlodipine maleate salt under severe conditions, the following experiment was performed.

100%, 20%, 10%, 7.5%, 5%, 2.5% of the amlodipine maleate salts were stored in a light-shielded seal at a temperature of 80 ° C. for 16 hours, and then formation of a flexible substance was observed.

The results are shown in Table 2.

Amlodipine Maleate (wt%) Microcrystalline Cellulose (wt%) Initial Lead Material (%) Total Lead (%) after 16 hours at 80 ℃ One 100 - 0.11% 0.12% 2 20 80 0.11% 0.32% 3 10 90 0.11% 0.74% 4 7.5 92.5 0.11% 1.02% 5 5 95 0.11% 1.26% 6 2.5 97.5 0.11% 2.13%

※ Total Lead (%) = {other peak area except amlodipine peak (excluding maleic acid peak) / amlodipine peak area} × 100

As shown in Table 2, when the content of amlodipine maleate salt was more than 10% by weight, the total soft substance was less than 1% under severe conditions (after 16 hours at 80 ° C), and the purity was very good, and 5% by weight. Below it produced more than 1% of total lead.

Thus, tablets according to the invention are of purity and stability when the unit consists of 8.0 to 99.9% by weight of amlodipine maleate salt and 0.1 to 92.0% by weight of pharmaceutically acceptable additives or when it comprises only 100.0% by weight of amlodipine maleate salt. It can be seen that this is the best.

The amlodipine maleate salt tablet according to the present invention has a very good purity because less than 1% of a flexible substance is produced under severe conditions as the pharmaceutically acceptable additive is used.

Claims (9)

Made with amlodipine maleate salt and pharmaceutically acceptable additive glyceryl bicarbonate, starch, modified starch, cellulose, hard silicic anhydride, lactose, mannitol, microcrystalline cellulose, modified cellulose, povidone, sodium starch glycolate, It consists of one or more additives selected from the group consisting of crospovidone, croscarmellose sodium, sodium stearyl fumarate, talc, polyethylene glycol, glyceryl palmitostearate and glyceryl monostearate, said amlodipine maleate Salt is 8.0 to 99.9 wt% Amlodipine maleate salt tablet comprising one or more units of the total content of the at least one additive selected from the group of the glyceryl bihine hit and the additive is 0.1 to 92.0 wt%. delete The formulation of claim 1, wherein the unit is added with pharmaceutically acceptable additives such as microcrystalline cellulose, hard silicic anhydride, sodium starch glycolate and glyceryl bicarbonate to form a tablet double or multi-dose drug layer, core, granule or pellet. Amlodipine maleate salt formulation, characterized in that to be prepared as. 2. The stability of claim 1 comprising 8.0% by weight of amlodipine maleate salt, 87.5% by weight of microcrystalline cellulose, 1% by weight of hard silicic anhydride, 2% by weight of starch glycolate and 1.5% by weight of glyceryl bivinate. This improved amlodipine malate salt formulation. 4. The granules (granule 1) according to claim 3, comprising 8.0% by weight of amlodipine maleate salt, 87.5% by weight of microcrystalline cellulose, 1% by weight of hard silicic anhydride, 2% by weight of starch glycolate and 1.5% by weight of glyceryl bivinate; A granule (granule 2) consisting of 95.5% by weight of microcrystalline cellulose, 1% by weight of hard silicic anhydride, 2% by weight of sodium starch glycolate, and 1.5% by weight of glyceryl bicarbonate, has a weight ratio of granule 1: granule 2 to 1: 1.5, Amlodipine maleate salt formulation with improved stability in which granule 1 is compressed into a core form. 4. The granules (granule 1) according to claim 3, comprising 8.0% by weight of amlodipine maleate salt, 87.5% by weight of microcrystalline cellulose, 1% by weight of hard silicic anhydride, 2% by weight of starch glycolate and 1.5% by weight of glyceryl bivinate; Granules (granules 2) consisting of 95.5% by weight of microcrystalline cellulose, 1% by weight of hard silicic anhydride, 2% by weight of sodium starch glycolate and 1.5% by weight of glyceryl bicarbonate are doubled so that the weight ratio of Granule 1: Granule 2 is 1: 1.5. Amlodipine maleate salt formulation with improved stability. The granules (granule 1) according to claim 3, comprising 16% by weight of amlodipine maleate salt, 79.5% by weight of microcrystalline cellulose, 1% by weight of hard silicic anhydride, 2% by weight of starch glycolate, and 1.5% by weight of glyceryl bicarbonate; Granules (granule 2) consisting of 95.5% by weight of microcrystalline cellulose, 1% by weight of hard silicic anhydride, 2% by weight of sodium starch glycolate, and 1.5% by weight of glyceryl bicarbonate, are doubled so that the weight ratio of granule 1: granule 2 is 1: 4. Amlodipine maleate salt formulation with improved stability. The granules (granule 1) according to claim 3, comprising 32% by weight of amlodipine maleate salt, 62% by weight of microcrystalline cellulose, 1% by weight of hard silicic anhydride, 2% by weight of starch glycolate, and 3% by weight of glyceryl bicarbonate. A granule (granule 2) consisting of 95% by weight of microcrystalline cellulose, 1.1% by weight of hard silicic anhydride, 2.2% by weight of sodium starch glycolate, and 1.7% by weight of glyceryl bicarbonate was used so that the weight ratio of granule 1: granule 2 was 1: 9. Amlodipine maleate salt formulation with improved stability. Granules consisting of 100% by weight of amlodipine maleate salt (granule 1) and 97.3% by weight of microcrystalline cellulose, 0.6% by weight of light silicic anhydride, 1.2% by weight of sodium starch glycolate, and 0.9% by weight of glyceryl bivinate (granule 2) Amlodipine maleate salt formulation having improved tableting stability in a weight ratio of Granule 1 to Granule 2 at 1:30.