HK1227745A1 - Solid pharmaceutical composition comprising amlodipine and losartan with improved stability - Google Patents

Description

Solid pharmaceutical composition comprising amlodipine and losartan with improved stability

The present application is a divisional application of chinese patent application 200980155069.9 entitled "solid pharmaceutical composition comprising amlodipine and losartan with improved stability" filed on 6/5/2009.

Technical Field

The present invention relates to a solid pharmaceutical composition for preventing or treating cardiovascular diseases comprising amlodipine and losartan, which has improved storage stability.

Background

In the treatment of hypertension, it is more important to keep blood pressure within a normal range continuously than to simply lower blood pressure itself in order to reduce the risk of complications such as coronary heart disease and cardiovascular diseases such as stroke, heart failure and myocardial infarction. Therefore, an antihypertensive agent is required to be effective for the long-term treatment of hypertension. In addition, advanced therapy using a combination of two or more drugs having different pharmacological effects makes it possible to improve the preventive or therapeutic efficacy while reducing the side effects caused by long-term administration of a single drug.

Important antihypertensive drugs include diuretics, sympatholytic agents, and vasodilators. Vasodilators are the most widely prescribed antihypertensive drugs, and can be classified into several groups according to their pharmacological effects, including ACE (angiotensin converting enzyme) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers.

Amlodipine is the common name for 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -6-methyl-1, 4-dihydro-3, 5-pyridinedicarboxylate. Amlodipine benzenesulphonic acid is currently marketed as Novasc (trade mark). Amlodipine is a long-acting calcium channel blocker which is useful in the treatment of cardiovascular diseases such as angina, hypertension and congestive heart failure.

Losartan is the common name for 2-butyl-4-chloro-1- [ [2'- (1H-tetrazol-5-yl) [1,1' -biphenyl ] -4-yl ] methyl ] -1H-imidazole-5-methanol and is disclosed in U.S. patents 5,608,075, 5,138,069, and 5,153,197. Losartan potassium is commercially available as Cozaar (trade mark). Losartan blocks the interaction of angiotensin II and its receptor, and is mainly used for the treatment of hypertension, heart failure, ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris), diabetic neuropathy, and glaucoma, and also for the prevention of the progression of heart failure after myocardial infarction.

The present inventors have found that a combined formulation comprising amlodipine and losartan having different pharmacological activities is useful for the prevention or treatment of cardiovascular diseases, and have conducted extensive studies on such combined formulation. However, mainly due to difficulties in handling of these two drugs, it is difficult to develop a stable amlodipine-losartan combined formulation which can be reproducibly and simply prepared.

Amlodipine is generally used in formulations in the form of an acid addition salt with a pharmaceutically acceptable acid, which is more stable and exhibits higher water solubility than amlodipine in the free base form.

It is reported that one of such amlodipine acid addition salts, amlodipine malate, is easily degraded with time after formulation into amlodipine aspartate of formula (I) or amo-pyridine of formula (II), thereby reducing the efficacy of the pharmaceutical composition comprising it (us patent 6,919,087). Amlodipine besylate, which is commercially available and disclosed in EP 244944 (corresponding to U.S. Pat. No. 4,879,303), has recently been widely used, but it also suffers from the above-mentioned problems such as degradation and poor storage stability.

The present inventors have developed a camphorsulfonic acid salt of amlodipine showing improved properties over amlodipine besylate in terms of solubility and stability, and the camphorsulfonic acid salt is currently sold as Amodipine (trademark). However, it was found that amlodipine camsylate exhibits very poor storage stability when formulated by simple mixing with losartan, possibly due to adverse chemical interactions between amlodipine, losartan and excipients.

It is well known that losartan potassium also degrades to form a product called degradant E or F when heated under acidic conditions (see [ z.zhao et al, j.pharm.biomed.anal,20:129-136,1999 ]). In addition, when losartan is prepared in the form of a combined preparation by simply mixing with an acid addition salt of amlodipine, the acid component of the amlodipine salt destabilizes losartan.

Disclosure of Invention

Accordingly, it is an object of the present invention to provide a solid pharmaceutical composition comprising amlodipine and losartan, which has improved storage stability due to minimized interaction between the two drugs amlodipine and losartan.

According to an aspect of the present invention, there is provided a solid pharmaceutical composition for preventing or treating cardiovascular diseases, comprising granular forms of amlodipine and losartan, which are separated from each other, and a stabilizer.

Preferably, the stabilizer is an antioxidant.

Detailed Description

The solid pharmaceutical composition of the present invention comprising amlodipine and losartan in the form of separate granules and a stabilizer has a feature that the interaction between the two drugs is minimized, which results in significantly improved storage stability.

Amlodipine for use in the present invention can be one of various forms of pharmaceutically acceptable salts. The pharmaceutically acceptable salts of amlodipine include, but are not limited to, hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzenesulfonate and camphorsulfonate. Among these salts, amlodipine besylate and camphorsulfonate are preferable, and amlodipine camphorsulfonate is more preferable. Also, amlodipine used in the present invention may be racemic amlodipine and S-amlodipine.

Losartan used in the present invention may be one of various forms of pharmaceutically acceptable salts. A preferred pharmaceutically acceptable salt of losartan is losartan potassium.

In the composition of the present invention, amlodipine and losartan may be used in an amount corresponding to a weight ratio of 1:1 to 1:40, preferably 1:2 to 1: 20.

When a combined formulation of amlodipine and losartan is prepared by simply mixing the two drugs, unfavorable gelation of losartan occurs, and amlodipine may be encapsulated in the gel, making it difficult to release amlodipine.

In order to overcome such losartan gelation problem, korean patent application publication No. 2008 0052852 discloses a method of applying a separation layer between amlodipine and losartan. However, the separation layer formed by this method cannot significantly improve the storage stability because: the relatively fast decomposition of amlodipine occurs due to the inability to completely prevent the chemical interaction between amlodipine or its acid addition salt and losartan. In fact, the combined formulations of comparative examples 3 and 4, which were prepared by physically separating amlodipine and losartan and granulating them separately, yielded impurities associated with decomposition of amlodipine in an amount as much as 10 times higher than that observed in the single amlodipine formulations of comparative examples 1 and 2.

In order to enhance the stability of the amlodipine-losartan combined preparation, a method of optimizing the pH of the composition using an acidifying agent or an alkalifying agent has been proposed. However, this method is also problematic in that high pH causes hydrolysis of amlodipine ester group and low pH causes rapid decomposition of losartan. For example, us patent 6,919,087 discloses the following facts: the amlodipine-losartan combined formulation of which pH is adjusted to 5.5 to 7.0 does not show sufficient stability.

One of the methods for enhancing the stability of the amlodipine-losartan combined preparation is to coat the active ingredient with a coating material, but this method requires an additional coating process and uses a fluid bed granulator (fluid layer granulation machine). In addition, according to this method, it is difficult to reproducibly produce a uniform combined preparation.

According to a preferred embodiment, the stabilizing agent of the composition of the present invention is confined within said amlodipine granules. The stabilizer used in the present invention functions to enhance the stability of amlodipine, prevent adverse reactions with losartan or other pharmaceutically acceptable excipients during mixing, and prevent deformation (deformation) of amlodipine with the passage of time due to light or moisture. The use of the stabilizer is also expected to result in enhanced stability of losartan.

Preferably, the stabilizer used in the present invention may be an antioxidant. Substances capable of inhibiting the autoxidation chain reaction, decomposing peroxides or inhibiting the oxidation acceleration of metals are called "antioxidants". It has been surprisingly verified that the use of an antioxidant causes a significant increase in the storage stability of the amlodipine-losartan combination formulation (see table 2), because the antioxidant unexpectedly inhibits the accelerating effect of losartan on the decomposition of amlodipine and reduces the production of unknown impurities associated with amlodipine.

Representative examples of antioxidants for use in the present invention include Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), tocopherol, ascorbic acid, erythorbic acid, citric acid, ascorbyl palmitate (ascorbyl palmitatic acid), ethylenediaminetetraacetic acid (EDTA), sodium metabisulfite, and mixtures thereof. Of the above antioxidants, the most preferred are neutral antioxidants of the present invention, such as butylated hydroxytoluene, butylated hydroxyanisole and tocopherol. Acidic and basic antioxidants more or less destabilize losartan and amlodipine, respectively.

The stabilizer may be used in an amount of preferably 0.005 to 5% by weight, more preferably 0.01 to 1% by weight, most preferably 0.02 to 0.5% by weight, based on the total weight of the composition.

The composition of the present invention may comprise a pharmaceutically acceptable carrier or excipient in the respective amlodipine and losartan granules. The pharmaceutically acceptable carriers or excipients may include microcrystalline cellulose, lactose, mannitol, sodium citrate, calcium phosphate, glycerol, starch, disintegrants (e.g., sodium starch glycolate, croscarmellose sodium, complex silicates, and crospovidone), and granulation binders (e.g., polyvinylpyrrolidone, Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), sucrose, gelatin, and acacia). Furthermore, the composition of the present invention may further comprise a lubricant such as magnesium stearate, stearic acid, glyceryl behenate and talc.

The composition of the present invention comprising said amlodipine and losartan can provide improved preventive or therapeutic efficacy against cardiovascular diseases such as angina pectoris, hypertension, arterial vasospasm, deep vein, cardiac hypertrophy, cerebral infarction, congestive heart failure and myocardial infarction.

According to a preferred embodiment, in order to confine the stabilizer within the amlodipine granule, when the amlodipine granule is prepared by granulating and drying a mixture of amlodipine and pharmaceutically acceptable excipients, the stabilizer may be added to the mixture in the form of powder or a solution dissolved in a solvent. Alternatively, a mixed powder of amlodipine and the stabilizer may be prepared by dissolving them together in a solvent and then spray-drying the resulting solution before the granulation process.

In the respective granulation processes of the amlodipine and the losartan granules, conventional extrusion granulation, crushing granulation, dry granulation, fluidized bed granulation, electric fluidized bed granulation (fluidized layer-granulation), electric fluidized bed granulation, or high-speed stirring granulation techniques may be used. Among them, dry granulation, fluidized bed granulation and high-speed stirring granulation techniques are preferable.

The compositions of the present invention may be administered by various oral routes of administration (including buccal, oral and sublingual) in the form of tablets, capsules or multiparticulates. It will be understood, however, that the route of administration of the compositions of the present invention will be determined by the attending physician, according to the symptoms and requirements of the patient.

The composition of the present invention may preferably be formulated in the form of tablets. Preferably, such tablets obtained from the composition of the present invention may have an outer coating layer, and the coating layer may consist of any one of conventional polymeric compounds capable of forming a film coating. The amount of the coating should be minimized to facilitate administration and improve production efficiency, and it may be about 1 to 10% by weight, preferably about 3 to 5% by weight, based on the total weight of the formulation. The coating may be carried out according to any of the conventional tablet coating methods. The tablets having the above composition prepared by the above method are very stable under ordinary storage conditions and can protect from light and moisture.

The following examples are intended to further illustrate the invention without limiting its scope.

Example 1: preparation of Combined tablet- (I)

-amlodipine granules-

Losartan granules

Losartan potassium 100.0mg

Microcrystalline cellulose 150.0mg

Crospovidone 12.0mg

Lubricants-

Magnesium stearate 4.0mg

Amlodipine camsylate, microcrystalline cellulose, mannitol, and sodium starch glycolate were separately sieved through a #16 sieve and mixed in a high speed mixer for 3min, to which a solution of butylated hydroxytoluene and polyvinylpyrrolidone contained in a mixture of purified water and ethanol was added and stirred for 5 min. The material deposited on the inner wall of the high-speed mixer was discarded and the resultant mixture was further stirred for 2min, dried at 60 c, and granulated to prepare amlodipine granules having the designated amounts of ingredients.

On the other hand, losartan potassium, microcrystalline cellulose and crospovidone were mixed and dry granulated with a roll press (rolecrompactor) to prepare losartan granules having the specified amounts of ingredients.

Amlodipine granules and losartan granules were mixed for 30 minutes with a mixer. An appropriate amount of magnesium stearate (lubricant) was then added thereto, mixed for 5min, and the resulting mixture was prepared in the form of a combination tablet.

Example 2: preparation of Combined tablet- (II)

A combination tablet was prepared by repeating the procedure of example 1 except that butylated hydroxytoluene was used in an amount of 1.0 mg.

Example 3: preparation of Combined tablet- (III)

A combination tablet was prepared by repeating the procedure of example 1 except that 6.94mg of amlodipine besylate (amlodipine 5mg) was used instead of 7.84mg of amlodipine camsylate.

Example 4: preparation of Combined tablet- (IV)

A combination tablet was prepared by repeating the procedure of example 3 except that butylated hydroxytoluene was used in an amount of 1.0 mg.

Example 5: preparation of Combined tablet- (V)

A combination tablet was prepared by repeating the procedure of example 1 except that 0.5mg of butylated hydroxyanisole was used instead of 0.2mg of butylated hydroxytoluene.

Example 6: preparation of Combined tablet- (VI)

A combination tablet was prepared by repeating the procedure of example 1 except that 2.0mg of tocopherol was used instead of 0.2mg of butylated hydroxytoluene.

Example 7: preparation of Combined tablet- (VII)

A combination tablet was prepared by repeating the procedure of example 1 except that 2.0mg of erythorbic acid was used instead of 0.2mg of butylated hydroxytoluene.

Example 8: preparation of Combined tablet- (VIII)

A coated combination tablet was prepared by coating the combination tablet obtained in example 1 with an aqueous Opadry Y-1-7000 (trade Mark) solution.

Comparative example 1: preparation of amlodipine single tablet- (I)

-amlodipine granules-

Lubricants-

Magnesium stearate 3.0mg

Amlodipine camsylate, microcrystalline cellulose, mannitol, and sodium starch glycolate were separately sieved through a #16 sieve and mixed in a high speed mixer for 3min, to which a solution of polyvinylpyrrolidone contained in a mixture of purified water and ethanol was added and stirred for 5 min. The material deposited on the inner wall of the high-speed mixer was discarded and the resultant mixture was further stirred for 2min, dried at 60 c, and granulated to prepare amlodipine granules having the designated amounts of ingredients. Then, an appropriate amount of magnesium stearate (lubricant) was mixed with the amlodipine granules for 5min, and the resulting mixture was prepared in the form of tablets.

Comparative example 2: preparation of amlodipine single tablet- (II)

Tablets were prepared by repeating the procedure of comparative example 1 except that 6.94mg of amlodipine besylate (amlodipine 5mg) was used instead of 7.84mg of amlodipine camsylate.

Comparative example 3: preparation of Combined tablet- (IX)

-amlodipine granules-

Losartan granules

Losartan potassium 100.0mg

Microcrystalline cellulose 150.0mg

Crospovidone 12.0mg

Lubricants-

Magnesium stearate 4.0mg

A combination tablet was prepared by repeating the procedure of example 1 except that butylated hydroxytoluene was not used.

Comparative example 4: preparation of Combined tablet- (X)

A combination tablet was prepared by repeating the procedure of comparative example 3, except that 6.94mg of amlodipine besylate (amlodipine 5mg) was used instead of 7.84mg of amlodipine camsylate.

Comparative example 5: preparation of Combined tablet- (XI)

Particles-

Lubricants-

Magnesium stearate 4.0mg

Amlodipine camsylate, losartan potassium, butylated hydroxytoluene, microcrystalline cellulose, mannitol, and sodium starch glycolate were respectively passed through a #16 sieve and mixed in a high speed mixer for 3min, a solution of polyvinylpyrrolidone contained in a mixture of purified water and ethanol was added thereto, and stirred for 5 min. The material deposited on the inner wall of the high-speed stirrer was discarded and the resulting mixture was stirred for another 2min, dried at 60 c, and granulated to prepare granules having the specified amounts of ingredients. An appropriate amount of magnesium stearate (lubricant) was then mixed with the granules for 5min, and the resulting mixture was made into the form of a combination tablet.

Hereinafter, the compositions of the formulations obtained in examples 1 to 8 and comparative examples 1 to 5 are shown in Table 1.

TABLE 1

(a) Amlodipine camsylate (b) amlodipine besylate

(c) Microcrystalline cellulose (d) butylated hydroxytoluene

(e) Butylated hydroxyanisole (f) tocopherol

(g) Isoascorbic acid (h) mannitol

(i) Sodium starch glycolate (j) polyvinylpyrrolidone

(k) Losartan potassium (l) microcrystalline cellulose

(m) crospovidone (n) magnesium stearate

(o)Opadry Y-1-7000

Test example 1: light stability test

The tablets obtained in examples 1 to 8 and comparative examples 1 to 5 were subjected to a photostability test by measuring the amount of impurities generated under the following conditions. The results are shown in Table 2

Test chamber conditions-

The instrument comprises the following steps: Xe-3-HC from Q-Lab Company

Temperature and humidity: 25 ℃ plus or minus 2 ℃/60% + orminus 5% RH

Illumination: 0.80W/m²/nm (1,200,000lux-ICH guide), 18.44hr

And (3) sample preservation: culture dish

Test points-

Before testing and after 1,200,000lux light exposure

Analysis conditions (impurities related to amlodipine) -

Column: stainless Steel column filled with octadecylsilylated silica gel for 5 μm liquid chromatography (inner diameter: 4.6mm, length: 15cm)

Mobile phase: phosphate buffer acetonitrile (58:42, v/v)

A detector: ultraviolet spectrophotometer (237nm)

Flow rate: 1.2ml/min

Temperature: 40 deg.C

Sample introduction volume: 10 μ l

Extracting liquid: mobile phase

Analytical conditions (impurities associated with losartan) -

Column: stainless Steel column filled with octadecylsilylated silica gel for 5 μm liquid chromatography (inner diameter: 4.6mm, length: 15cm)

Mobile phase A: phosphate buffer acetonitrile (850:150, v/v)

Mobile phase B: acetonitrile

Concentration gradient system

Time (min)	Flow ofPhase A%	Mobile phase B%
			0	80	20
10	40	60
			11	80	20
15	80	20

A detector: ultraviolet spectrophotometer (250nm)

Flow rate: 1.5ml/min

Sample introduction volume: 10 μ l

Extracting liquid: mobile phase

Test example 2: accelerated stability test

The tablets obtained in examples 1 to 8 and comparative examples 1 to 5 were subjected to accelerated stability tests by measuring the amounts of impurities generated under the following conditions. The results are shown in Table 2.

Test chamber conditions-

Temperature: 50 ℃ plus or minus 2 DEG C

And (3) sample preservation: HDPE bottle

Test points-

Before testing and after 28 days of storage

Analytical conditions-

Same as in test example 1

TABLE 2

(a) Amlo-pyridine

(b) Impurities related to amlodipine

(c) Impurities related to losartan

As can be seen from table 2, the combination tablets prepared according to examples 1 to 8 by using the stabilizer and the separate granules of amlodipine and losartan produced smaller amounts of amolo-pyridine and impurities related to amlodipine and losartan under light exposure or severe storage conditions, as compared to the combination tablets obtained in comparative examples 3 to 5, and thus exhibited higher storage stability. In addition, some of the combination tablets prepared in examples produced less amount of impurities even compared to the single amlodipine formulations obtained in comparative examples 1 and 2, thereby exhibiting higher storage stability.

In particular, it was confirmed that the tablets prepared in comparative examples 3 to 5 did not satisfy the stability criteria required in the ICH guidelines, i.e., produced 0.5 wt% or less of impurities related to amlodipine under storage conditions even though the structures of the impurities are well known.

Although the present invention has been described with reference to the above specific embodiments, it is to be understood that various modifications and changes may be made to the present invention by those skilled in the art, which also fall within the scope of the present invention defined by the appended claims.

Claims (5)

1. A solid pharmaceutical composition for preventing or treating cardiovascular diseases, comprising amlodipine and losartan in the form of granules separated from each other, and a stabilizer, wherein the amount of the stabilizer is 0.005 to 5% by weight based on the total weight of the composition, wherein the stabilizer is a neutral antioxidant selected from the group consisting of butylated hydroxytoluene, butylated hydroxyanisole and tocopherol.

2. The composition of claim 1, wherein the stabilizer is used in an amount of 0.01 to 1% by weight, based on the total weight of the composition.

3. The composition of claim 1, wherein the stabilizer is used in an amount of 0.02 to 0.5 wt.%, based on the total weight of the composition.

4. The composition of claim 1, wherein the cardiovascular disease is selected from the group consisting of angina, hypertension, arterial vasospasm, deep vein, cardiac hypertrophy, cerebral infarction, congestive heart failure, and myocardial infarction.

5. The composition of claim 1, wherein amlodipine and losartan are used in a weight ratio of 1:1 to 1: 40.