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Solid pharmaceutical formulations of ramipril and amlodipine besylate, and their preparation

A kind of technology of amlodipine besylate and amlodipine besylate, applied in the directions of drug combination, drug delivery, medical preparations containing active ingredients, etc., can solve problems such as low content of amlodipine

Inactive Publication Date: 2012-11-14
SANOFI AVENTIS DEUT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] Another challenge is the homogeneity of amlodipine in the lubricated blend, as the amount of amlodipine in the total tablet weight should be very low compared to the high amount of ramipril

Method used

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  • Solid pharmaceutical formulations of ramipril and amlodipine besylate, and their preparation
  • Solid pharmaceutical formulations of ramipril and amlodipine besylate, and their preparation
  • Solid pharmaceutical formulations of ramipril and amlodipine besylate, and their preparation

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0059] The preparation of stable pharmaceutical formulations of ramipril is complicated because of its susceptibility to certain types of pH-dependent degradation.

[0060] The formation of ramipril DKP is mainly dependent on the pH of the formulation, especially at very low pH values. It is reported in the literature that increasing the pH of the microenvironment of ramipril minimizes the formation of DKP impurities.

[0061] However, regarding amlodipine, the photodegradation product impurity-D of amlodipine was more formed in alkaline environment and less in weak acid environment. Istin tablets have a pH of 7.2 and Cardace has a pH of ~4.2-4.3. (In contrast, pH 4.7-5.0 in ramipril + amlodipine tablets).

[0062] Extragranular amlodipine besylate (special dry blended), which is naturally alkaline, was included in the FDC product to impart a pH of 4.7-5.0 to the FDC tablet. Therefore, the stability of ramipril in the combination formulation is improved.

[0063] Likewise,...

Embodiment 1

[0126] Example 1. Composition using a placebo with a pH of 6.2

[0127]

[0128] *Amount of material taken and dispersed in 50ml of purified water

[0129] step:

[0130] 1. Ramipril added as hydroxypropyl methylcellulose granules

[0131] 2. Geometrically mix ramipril granules with pregelatinized starch.

[0132] 3. Mix amlodipine besylate and microcrystalline cellulose geometrically and mix them with the material from step 2 and mix in a mixer for 20 minutes to achieve homogeneity.

[0133] 4. Lubricate the mixture with sodium stearyl fumarate.

[0134] 5. Compress the mixture into tablets using suitable punches on the tablet press.

[0135] 6. Tablets were packaged in opaque white double-layer packaging and subjected to a 6-month accelerated stability study, analyzing the percentage of potential degradants at the initial and 6-month intervals

[0136] Table 1

[0137]

[0138] Formulations In a further trial, placebo pH studies of the stability of the two active...

Embodiment 2

[0139] Example 2: Composition using placebo at pH 6.40

[0140]

[0141] *Amount of material taken and dispersed in 50ml of purified water

[0142] step:

[0143] 1. Ramipril added as hydroxypropyl methylcellulose granules

[0144] 2. Geometrically mix ramipril granules and microcrystalline cellulose

[0145] 3. Mix amlodipine besylate and pregelatinized starch geometrically and mix them with the material from step 2 and mix in a mixer for 25 minutes to achieve homogeneity.

[0146] 4. Lubricate the mixture with sodium stearyl fumarate.

[0147] 5. Compress the mixture into tablets using suitable punches on the tablet press.

[0148] 6. Tablets were packaged in opaque white double-layer packaging and subjected to a 6-month accelerated stability study, analyzing the percentage of potential degradants at the initial and 6-month intervals

[0149] Table 2

[0150]

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Abstract

The present invention is directed to solid stable pharmaceutical fixed dose compositions comprising ramipril, amlodipine besilate and pharmaceutically acceptable excipients, and to their preparation.

Description

technical field [0001] The present invention relates to a solid stable pharmaceutical composition comprising ramipril, amlodipine besylate and pharmaceutically acceptable excipients, its preparation and its therapeutic use. This means that in the composition the two active ingredients are together in a single dosage form. Background technique [0002] Amlodipine is a calcium channel blocker developed for the treatment of hypertension and other medical indications, as disclosed in USP4,572,909 and USP4,879,303. Its chemical name is 3-ethyl-5-methyl-(+-)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro -6-Methylpyridine-3,5-dicarboxylate. [0003] Amlodipine is commercially available as monobesylate-amlodipine besylate, and its trade name is or It is available in oral tablets in strengths of 2.5 mg, 5 mg and 10 mg. Inactive ingredients in the tablet include microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/20A61K45/06A61P9/12A61K31/403
CPCA61K9/2081A61K9/2077A61J3/10B65D11/20A61K31/403A61K31/4422A61K45/06B65B3/04A61P13/00A61P13/12A61P9/00A61P9/10A61P9/12A61K2300/00A61K9/0053A61K9/167
Inventor N.杰斯瓦尔P.库拉A.库尔卡尼D.普拉杰帕蒂
Owner SANOFI AVENTIS DEUT GMBH
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