KR20060036271A - Pharmaceutical composition of amlodipine maleate with improved stability - Google Patents

Abstract

The present invention relates to an amlodipine maleate pharmaceutical composition with improved stability, and more particularly, to a pharmaceutical composition comprising amlodipine maleate as an active ingredient, comprising 3 to 85% by weight of cyclodextrins as a stabilizer, such as tablets. It is manufactured as an oral dosage form to prevent rapid decomposition of amlodipine maleate as an active ingredient even when exposed to high temperature and high humidity conditions for a long time, and it is economically enhanced by eliminating the need for additional equipment and processes for preventing the hardness of the product. The present invention relates to amlodipine maleate pharmaceutical compositions having improved stability.

Amlodipine Maleate, Cyclodextrins, Stabilizers

Description

Pharmaceutical composition of amlodipine maleate with improved stability}             

1 is a graph showing the content of amlodipine maleate in a formulation prepared with a pharmaceutical composition and a conventional composition according to the present invention over time.

The present invention relates to an amlodipine maleate pharmaceutical composition with improved stability, and more particularly, to a pharmaceutical composition comprising amlodipine maleate as an active ingredient, comprising 3 to 85% by weight of cyclodextrins as a stabilizer, such as tablets. It is manufactured as an oral dosage form to prevent rapid decomposition of amlodipine maleate as an active ingredient even when exposed to high temperature and high humidity conditions for a long time, and it is economically enhanced by eliminating the need for additional equipment and processes for preventing the hardness of the product. The present invention relates to amlodipine maleate pharmaceutical compositions having improved stability.

Amlodipine has the generic name 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chloro phenyl) -1,4-dihydro-6-methylpyridine-3,5-dica It is a drug that is a carboxylate and is a long-acting calcium channel blocker (CCB) in the human body and is useful for the treatment of cardiovascular diseases such as angina, hypertension and congestive heart failure.

Amlodipine formulations are generally made by combining amlodipine, an active ingredient, with salts that aid in the activation and formulation of the drug. The salt is a part which helps stabilize the amlodipine, which is an active ingredient, and the amlodipine is useful in the free base form, but is preferably administered in the form of a salt with a pharmaceutically acceptable acid because of its low solubility in water.

U.S. Patent No. 4,572,909 discloses various forms of pharmaceutically acceptable salts of amlodipine. Pharmaceutically acceptable acid addition salts of amlodipine are formed from acids forming non-toxic acid addition salts containing anions, such as hydrochloride, hydrobromide, sulfate, phosphate or acid phosphate, acetate, maleate, fumarate , Lactate, tartrate, citrate and gluconate salts, of which maleate salts are described as particularly preferred.

Korean Patent Laid-Open Publication No. 2003-0070594 proposes a pharmaceutical composition comprising an amlodipine besylate (NOVASC) and a bioequivalent amlodipine maleate as the active ingredient. In this patent, by selecting excipients such as potassium phosphate and microcrystalline cellulose, the pH of the composition is adjusted to 5.5 to 7.0 to obtain a stabilized pharmaceutical composition. In the case of this technology, the tablet formulation of amlodipine maleate was possible, but when it was commercialized as a product, there was a problem in that it was costly and economical.

In addition, US Patent Publication 2004/0001886 A1 proposes a pharmaceutical formulation comprising amlodipine maleate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate and colloidal silica in certain proportions. This technique has the advantage of overcoming the shortcomings of amlodipine maleate, which has not been commercialized due to stability problems in the prior art, and makes the pharmaceutical composition easy to fall from the tableting punch, but the moisture stability and storage stability are poor, and the manufacturing cost is similar to the above technique. There is a high disadvantage that needs to be improved.

Accordingly, the present inventors have conducted research and efforts to solve such a conventional problem, and as a result, when a certain amount of cyclodextrins are included as a stabilizer in a pharmaceutical composition containing amlodipine maleate as an active ingredient, even if left in the air or in a high temperature and high humidity environment for a long time, The present invention was completed by knowing that rapid decomposition of amlodipine maleate as an active ingredient does not occur and stability to temperature and moisture is improved.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for treating cardiovascular diseases, wherein the pharmaceutical composition comprising amlodipine maleate as an active ingredient contains 3 to 85% by weight of cyclodextrins as a stabilizer.

The present invention is a pharmaceutical composition comprising amlodipine maleate as an active ingredient, characterized in that the pharmaceutical composition contains 3 to 85% by weight of cyclodextrins as a stabilizer.

The present invention will be described in more detail as follows.

The present invention relates to an amlodipine maleate pharmaceutical composition with improved stability, and more particularly, to a pharmaceutical composition comprising amlodipine maleate as an active ingredient, comprising 3 to 85% by weight of cyclodextrins as a stabilizer, such as tablets. It is manufactured as an oral dosage form to prevent rapid decomposition of amlodipine maleate as an active ingredient even when exposed to high temperature and high humidity conditions for a long time, and it is economically enhanced by eliminating the need for additional equipment and processes for preventing the hardness of the product. The present invention relates to amlodipine maleate pharmaceutical compositions having improved stability.

The pharmaceutical composition of the present invention may contain amlodipine maleate as an active ingredient and cyclodextrins as a stabilizer, and may further include pharmaceutically acceptable excipients, binders, disintegrants and glidants.

Amlodipine maleate, which is an active ingredient of the pharmaceutical composition of the present invention, is contained in 1 to 60% by weight of the total pharmaceutical composition.

In the present invention, it is an important feature to use cyclodextrins as stabilizers. The cyclodextrins are compounds that have been used in pharmaceutical compositions, as seen in US Pat. No. 4,727,064, WO 85/002767, WO 94/011031, etc., and conventionally form clathrate compounds. It has been used to propose a method of encapsulating under water-soluble or poorly soluble drug-soluble medium using the properties of improving or encapsulating bioavailability or dissolution rate in a specific part of the body. However, in the present invention, it is used as a stabilizer of amlodipine maleate and is designed to prevent the active ingredient from being degraded or the formulation broken in an environment of high temperature and high humidity. That is, the cyclodextrins are used to encapsulate amlodipine maleate, thereby contributing to stabilization by inhibiting reactions generated or decomposed by by-products such as amlodipine aspartate and amlopyridine in a high temperature and high humidity environment.

The cyclodextrins of the present invention are not limited in form, such as being dissolved in a wettable solvent (a mixture of water and / or an organic solvent) or mixed in powder form. In particular, when used in powder form, there is no need for a wet solvent, heat, additional equipment, etc., and can effectively stabilize the amlodipine maleate, which is an active ingredient, and thus, there is an advantage of reducing manufacturing costs.

The cyclodextrins include pharmaceutically acceptable water-soluble substituted or unsubstituted cyclodextrins and derivatives thereof. For example, α-cyclodextrins and derivatives thereof, β-cyclodextrins and derivatives thereof, and γ-cyclodextrins and derivatives thereof and the like. In particular, among derivatives of cyclodextrins, at least one hydroxy group is alkyl, hydroxyalkyl, carboxyalkyl, alkylcarbonyl, carboxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl or hydroxy- (mono or polyalkoxy) Derivatives substituted with an alkyl group and having 1 to 6 carbon atoms in the alkyl or alkylene moiety can be preferably used. For example, β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin , (2-carboxymethoxy) propyl-β-cyclodextrin and the like.

The stabilizer comprises 3 to 85% by weight, preferably 5 to 70% by weight, more preferably 10 to 55% by weight in the total pharmaceutical composition, if the content is less than 3% by weight sufficiently stabilizes amlodipine maleate Failure to do so results in degradation of amlodipine maleate at temperatures and humidity conditions similar to those of the atmosphere, and above 85% by weight can cause problems in formulation.

Excipients that can be used in the present invention include lactose, white sugar, glucose, fructose, mannitol, corn starch, potato starch, wheat starch, pregelatinized starch, microcrystalline cellulose or cellulose derivatives, dextrin, calcium dihydrogen phosphate, phosphate Calcium hydrogen, calcium carbonate, potassium chlorinate, glyceryl behenate, acetic acid, ammonium carbonate, ammonium phosphate, boric acid, lactic acid, citric acid, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate, sodium lactate, ascorbic acid, ascorbic acid One or two selected from the group consisting of bilparmitate, butylhydroxyanisole, butylhydroxytoluene, hypophosphite, monothioglycerol, potassium metabisulfite, molsulfatepropyl, sodium metabisulfite, sodium sulfite, sulfur dioxide, tocopherol There are more than one kind, and the excipient is preferably contained in 2 to 90% by weight in the total pharmaceutical composition.

Binders that can be used in the present invention include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxy cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, gelatin, dextrin, microcrystalline There is one or two or more selected from the group consisting of cellulose, and the binder is preferably included in the total pharmaceutical composition 2 to 40% by weight.

Disintegrants that can be used in the present invention include one or two selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, crospovidone There are more than one species, and the disintegrant is preferably contained in 0.1 to 30% by weight in the total pharmaceutical composition.

The glidants which may be used in the present invention include one or two or more selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, talc, silicon dioxide, and colloidal silicon dioxide, and the glidants may be used in the entire pharmaceutical industry. It is preferable that 0.1-20 weight% is contained in a composition.

The pharmaceutical composition according to the present invention may be formulated into solid preparations for oral administration such as tablets, capsules, granules, powders, pills, dry syrups, and more preferably in the form of tablets or capsules.

When preparing the pharmaceutical compositions according to the invention in individual unit dosage forms, 1 to 100 mg, more typically 1 to 25 mg of amlodipine maleate are included. Tablets or capsule formulations for oral administration in amlodipine 1.25 mg, 2.5 mg, 5 mg or 10 mg equivalents are preferred for achieving the effect according to the invention. The pharmaceutical composition is administered 1-3 times a day, preferably once a day.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to Examples.

Examples and Comparative Examples

In the case of Example 1, amlodipine maleate and β-cyclodextrin were sieved through a No. 35 sieve and mixed, followed by mixing the components of Table 1 except magnesium stearate. Magnesium stearate was added thereto, mixed well, and then compressed.

For Example 2, tableting was carried out in the same manner using 2-hydroxypropyl-β-cyclodextrin instead of the β-cyclodextrin of Example 1 as a stabilizer.

In the case of Example 3, tableting was carried out in the same manner using dimethyl-β-cyclodextrin instead of β-cyclodextrin of Example 1 as a stabilizer.

In Example 4, tableting was carried out in the same manner as in Example 1, but the content of the excipient was increased, and 10 mg of hydroxypropyl cellulose was added as a binder instead of polyvinylpyrrolidone.

In Comparative Example 1, amlodipine maleate and potassium polyacrylic acid were sieved through a No. 35 sieve, and the components of Table 1 were mixed except for magnesium stearate. Magnesium stearate was added thereto, mixed and tableted.

In Comparative Example 2, magnesium silicate aluminate was put in place of potassium chlorinate and tableted in the same manner as in Comparative Example 1.

In the case of Comparative Example 3, glyceryl behenate (compritol 888) was added instead of potassium chlorinate and tableted in the same manner as in Comparative Example 1.

In Comparative Example 4, amlodipine maleate and Celactose 80 were mixed, in the case of Comparative Example 5, amlodipine maleate and pregelatinized starch were mixed, and in Comparative Example 6, amlodipine maleate and lactose were first mixed after sieving. After mixing in the same manner as in the tableting.

In Comparative Example 7, amlodipine maleate and lactose were sieved through a No. 35 sieve and mixed well. Microcrystalline cellulose and polyvinylpyrrolidone were added thereto, mixed thoroughly, granulated with an aqueous buffer solution (aqueous solution of citric acid and sodium monohydrogen phosphate), and dried in an oven maintained at a temperature of 40 ° C. The dried product was sized using a No. 20 sieve, mixed with crospovidone, sodium pyrosulfite and magnesium stearate, and then compressed.

The contents of Examples 1 to 4 and Comparative Examples 1 to 7 are summarized in Table 1 below.

Ingredient (mg) Example Comparative example One 2 3 4 One 2 3 4 5 6 7 Active ingredient Amlodipine Maleate 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 6.4 Stabilizer β-cyclodextrin 80 - - 80 - - - - - - - 2-hydroxypropyl-β-cyclodextrin - 80 - - - - - - - - - Dimethyl-β-cyclodextrin - - 80 - - - - - - - - Potassium chlorine - - - - 80 - - - - - - Magnesium Aluminate - - - - - 80 - - - - - Glyceryl Behenate - - - - - - 80 - - - - Excipient Cellactoose 80 96.6 - - 106.6 96.6 96.6 96.6 96.6 - - - Lactose - 66.6 - - - - - - - 126.6 86.4 Corn starch - 30 - - - - - - - 60 - Pregelatinized starch - - 71.6 - - - - - 116.6 - - Citric acid - - - - - - - - - - 4.8 Sodium hydrogen phosphate - - - - - - - - - - 30.4 Sodium pyrosulfite - - - - - - - - - - 5 Binder Polyvinylpyrrolidone 20 20 45 - 20 20 20 20 - - 20 Hydroxypropyl cellulose - - - 10 - - - - - 10 - Microcrystalline cellulose - - - - - - - - 80 - 50 Disintegrant Crospovidone 35 35 35 35 35 35 35 35 - 35 35 Low Substituted Hydroxypropyl Cellulose - - - - - - - - 35 - - Lubricant Magnesium stearate 2 2 2 2 2 2 2 2 2 2 2

Experimental Example 1: Comparison of the stability of amlodipine maleate itself and its preparation

In order to compare the stability of the amlodipine maleate raw material itself and the stability according to the formulation, the content change and degradation products were measured under accelerated conditions (40 ° C., 75% RH) by liquid chromatography. The results are shown in Table 2 below.

division(%) Amount of amlodipine maleate ¹⁾ Amount of decomposition products ²⁾ Start of test Day 7 Day 15 Elapsed 33 days Start of test Day 7 Day 15 Elapsed 33 days Raw material 100 99.8 99.2 99.0 0.02 0.16 0.78 0.97 Comparative Example 1 100 95.2 91.9 88.6 0.02 4.83 8.15 11.39  1) Amount of amlodipine maleate remaining undecomposed (%) 2) Amount of degradation products resulting from degradation of amlodipine maleate (%)

As can be seen from Table 2, it was found that the amlodipine maleate raw material itself is excellent in stability, but when formulated as in the prior art, amlodipine maleate was better decomposed and the stability was lowered.

Experimental Example 2: Comparison of the stability with or without the stabilizer according to the present invention

For final formulations made with the pharmaceutical compositions of the present invention, the content change and degradation products were measured by liquid chromatography at accelerated conditions (40 ° C., 75% RH). The results are shown in Table 3 and FIG. 1.

division(%) Amount of amlodipine maleate ¹⁾ Amount of decomposition products ²⁾ Start of test Day 7 Day 15 Elapsed 33 days Start of test Day 7 Day 15 Elapsed 33 days Example One 100 99.8 99.6 99.2 0.02 0.16 0.35 0.76 2 100 99.8 99.7 99.3 0.02 0.17 0.34 0.73 3 100 99.8 99.7 99.2 0.02 0.25 0.34 0.78 4 100 99.8 99.6 99.2 0.02 0.16 0.35 0.80 Comparative example One 100 95.8 91.9 88.6 0.02 4.22 8.13 11.39 2 100 99.2 98.5 92.3 0.02 0.81 1.46 7.71 3 100 95.8 91.3 87.1 0.02 4.23 8.66 12.88 4 100 97.4 94.2 92.7 0.02 2.60 5.81 7.34 5 100 96.1 92.2 88.3 0.02 3.89 7.79 11.72 6 100 96.9 92.7 87.9 0.02 3.07 7.26 12.08 7 100 96.1 92.3 85.4 0.02 3.92 7.67 14.56  1) Amount of amlodipine maleate remaining undecomposed (%) 2) Amount of degradation products resulting from degradation of amlodipine maleate (%)

As can be seen from Table 3, it was found that the pharmaceutical composition containing cyclodextrins as a stabilizer is more stable to temperature and humidity than the composition that is not.

In addition, the pharmaceutical composition comprising the stabilizer of the present invention was confirmed that the stability is much superior to Comparative Example 7 including a buffer and an antioxidant as a stabilizer.

As described above, the amlodipine maleate pharmaceutical composition having improved stability of the present invention is a pharmaceutical composition comprising amlodipine maleate as an active ingredient, and includes 3 to 85 wt% of cyclodextrins as a stabilizer for oral administration of tablets and the like. It is manufactured as a formulation and prevents rapid decomposition of amlodipine maleate as an active ingredient even when exposed to high temperature and high humidity conditions for a long time. It is advantageous for industrialization.

Claims (7)

In the pharmaceutical composition comprising amlodipine maleate as an active ingredient, Pharmaceutical composition, characterized in that 3 to 85% by weight of cyclodextrins are contained as a stabilizer. The method of claim 1, wherein the cyclodextrins are any one of α-cyclodextrins and derivatives thereof, β-cyclodextrins and derivatives thereof, and γ-cyclodextrins and derivatives thereof, and the derivatives are at least one of cyclodextrins. The hydroxy group is substituted with an alkyl, hydroxyalkyl, carboxyalkyl, alkylcarbonyl, carboxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl or hydroxy- (mono or polyalkoxy) alkyl group and the above alkyl or alkylene Silver C1-C6 pharmaceutical composition characterized by the above-mentioned. The pharmaceutical composition according to claim 1, wherein the amlodipine maleate is included in an amount of 1 to 60 wt%. The method of claim 1, wherein the excipients include lactose, white sugar, glucose, fructose, mannitol, corn starch, potato starch, wheat starch, pregelatinized starch, microcrystalline cellulose or cellulose derivatives, dextrin, calcium dihydrogen phosphate, dihydrogen phosphate. Calcium, Calcium Carbonate, Potassium Plaqueline, Glyceryl Behenate, Acetic Acid, Ammonium Carbonate, Ammonium Phosphate, Boric Acid, Lactic Acid, Citric Acid, Potassium Phosphate, Sodium Phosphate, Sodium Acetate, Sodium Citrate, Sodium Lactate, Ascorbic Acid, Ascorbyl One or two selected from the group consisting of parmitate, butylhydroxyanisole, butylhydroxytoluene, hypophosphite, monothioglycerol, potassium metabisulfite, molsulfatepropyl, sodium metabisulfite, sodium sulfite, sulfur dioxide and tocopherol A pharmaceutical composition comprising 2 to 90% by weight of the above. The hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxy cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, gelatin, dextrin and microcrystalline cellulose as binders. Pharmaceutical composition, characterized in that it comprises 2 to 40% by weight of one or two or more selected from the group consisting of. The method according to claim 1, wherein one or two selected from the group consisting of low-substituted hydroxypropyl cellulose, sodium croscarmellose, sodium starch glycolate, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose and crospovidone as a disintegrant A pharmaceutical composition comprising 0.1 to 30% by weight of the above. The method of claim 1, wherein the lubricant comprises 0.1 to 20% by weight of one or more selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, talc, silicon dioxide and colloidal silicon dioxide. Pharmaceutical composition.

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