HK1163539B - Solid pharmaceutical composition comprising amlodipine and losartan - Google Patents

Description

Solid pharmaceutical composition comprising amlodipine and losartan

Technical Field

The present invention relates to a solid pharmaceutical composition for preventing or treating cardiovascular diseases comprising amlodipine and losartan, which is capable of maintaining high and stable amlodipine and losartan dissolution rate levels even under low pH conditions.

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 can be used for treating hypertension, and have conducted extensive studies on such combined formulation.

However, when a combined formulation of amlodipine and losartan is prepared by simply mixing the two drugs, unfavorable gelation of losartan occurs: losartan is readily soluble in purified water and easily released at a relatively high pH (e.g., pH 6.8), but it is released very slowly at a low pH (e.g., pH2.0 or pH1.2) due to the gelation. In the case of using such a commercially available losartan formulation, Cozaar (trademark), the amount of losartan released in the first 30 minutes is less than 30% at a pH of 1.2-2.0. In such a combined formulation of amlodipine and losartan, amlodipine may also be blocked within the losartan gel.

Orally administered formulations usually disintegrate and dissolve in the stomach with a low pH, and therefore, the low dissolution rate of the active ingredient in the formulation at a low pH leads to a significant reduction in its bioavailability.

In addition, the pH of the stomach of healthy adults is largely varied in the range of 1.0 to 3.5 and C of losartan after ingestion of food_maxAbout 10% reduction, so there is a need to develop such amlodipine-losartan combined formulation capable of maintaining a relatively constant dissolution rate over a range of gastric pH variation.

Disclosure of Invention

Therefore, it is an object of the present invention to provide a solid pharmaceutical composition comprising amlodipine and losartan, which exhibits minimal fluctuation in the dissolution rate of an active ingredient with pH change, i.e., exhibits high and stable levels of amlodipine and losartan dissolution rates even under low pH conditions.

According to an aspect of the present invention, there is provided a solid pharmaceutical composition for preventing or treating cardiovascular diseases, comprising amlodipine and losartan as active ingredients and a disintegrant which is a mixture of at least two components selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone.

Brief Description of Drawings

The above and other objects and features of the present invention will become apparent from the following description of the invention when taken in conjunction with the accompanying drawings, in which:

FIGS. 1 and 2: the dissolution rates of losartan from artificial gastric juice (pH1.2) and 0.01N HCl (pH2.0) of the tablets prepared in examples 3 and 4 and comparative examples 1 and 5, respectively, and Cozaar tablet (trademark) were observed (test example 2).

Detailed Description

The solid pharmaceutical composition of the present invention comprising amlodipine and losartan active ingredients and at least two specific disintegrants selected from sodium starch glycolate, croscarmellose sodium and crospovidone exhibits high amlodipine and losartan dissolution rates in a wide pH range while exhibiting sufficient structural strength at the time of formulation.

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

In one embodiment, losartan potassium is conventionally used in an amount of about 10 to about 500mg, based on a unit formulation (solid administration form). In another embodiment, losartan potassium is conventionally used in an amount of about 25 to about 250 mg. In another embodiment, losartan potassium is conventionally used in an amount of about 50 to about 200 mg. In another embodiment, losartan potassium is conventionally used in an amount of about 50 to about 100 mg.

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. In one embodiment, the pharmaceutically acceptable salt of amlodipine is amlodipine besylate or amlodipine camsylate. Also, amlodipine used in the present invention may be racemic amlodipine or S-amlodipine.

In one embodiment, amlodipine is conventionally employed in amounts of about 1.25 to about 20mg, in unit formulations (solid dosage forms). In another embodiment, amlodipine is conventionally employed in amounts of about 1.875 to about 15 mg. In another embodiment, amlodipine is conventionally employed in amounts of about 2.5 to about 10 mg. In another embodiment, amlodipine is conventionally employed in amounts of about 5 to about 10 mg. The prescribed amount of amlodipine represents the amount of free amlodipine present in the corresponding solid administration form.

The composition of the present invention comprises pharmaceutically acceptable additives suitable for the desired amlodipine-losartan combined solid administration formulation, particularly, critically, specific disintegrants. In this regard, the present inventors have found that the dissolution rate of amlodipine and losartan depends significantly on the type and amount of disintegrant used, particularly at low pH. Accordingly, the present invention provides a solid pharmaceutical composition having a specific kind and amount of disintegrant, which is capable of exhibiting an optimized dissolution rate.

Substances that can accelerate the disintegration of a solid composition in digestive fluids, thereby increasing the dissolution rate of the active ingredient contained therein, are referred to as "disintegrants". Meanwhile, the excessive use of the disintegrant causes the solid preparation not to have high strength to maintain its shape during its production, packaging, transportation or storage. In other words, it is very important to use the appropriate kind of disintegrant in an appropriate amount to enhance the solubility of solid formulations, in particular tablets, without causing adverse structural deformation.

In one embodiment, the disintegrant used in the present invention is a mixture of at least two components selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone. In another embodiment, the disintegrant is a mixture of sodium starch glycolate and crospovidone. In another embodiment, the disintegrant is a mixture of sodium starch glycolate and croscarmellose sodium. In one embodiment, the disintegrant may be used in an amount of about 2.5 to about 30 weight percent, based on the total weight of the composition. In another embodiment, the disintegrant may be used in an amount of about 5 to about 15 weight percent, based on the total weight of the composition.

The present inventors have found that the combination of two or more of the aforementioned three components results in the desired structural strength and dissolution aspects of the amlodipine-losartan combined formulation. In addition, by the above-mentioned technique, the present invention achieves a reduction in the total amount of the disintegrant used, which leads to an improvement in tabletability. When sodium starch glycolate, croscarmellose sodium or crospovidone is used alone, the dissolution delay due to gelation of losartan cannot be effectively suppressed despite its excessive amount, and it is often difficult to make an oral administration form due to unsatisfactory pressure and high abrasion.

The pharmaceutically acceptable additives may include diluents such as microcrystalline cellulose, lactose, mannitol, sodium citrate, calcium phosphate, glycerol, starch, and mixtures thereof. In one embodiment, the diluent may be used in an amount of about 15 to about 90 weight percent, based on the total weight of the composition. In another embodiment, the diluent may be used in an amount of about 30 to about 70 weight percent, based on the total weight of the composition.

The pharmaceutically acceptable additives may include a stabilizer, a binder and a lubricant, in addition to the diluent.

In one embodiment, the stabilizer used in the present invention may be an antioxidant. The use of the antioxidant enhances the stability of the active ingredient, prevents adverse reactions with other pharmaceutically acceptable additives during mixing, and prevents deformation (deformation) caused by heat or moisture with the passage of time, so that the stability of the amlodipine-losartan combined formulation is significantly increased.

Representative examples of antioxidants for use in the present invention include Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitate (ascorbyl palmitatic acid), ethylenediaminetetraacetic acid (EDTA), sodium metabisulfite, and mixtures thereof. In one embodiment, the antioxidant is butylated hydroxytoluene.

Representative examples of binders useful in the present invention include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone, polyethylene glycol, silicate derivatives such as hard silica (hard silica), synthetic aluminum silicate, calcium silicate, and magnesium aluminum silicate (magnesium metasilicate), phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, and mixtures thereof.

Representative examples of lubricants for use in the present invention include stearic acid, metal stearates such as calcium stearate and magnesium stearate, talc, colloidal silicon dioxide, sucrose fatty acid esters, hydrogenated vegetable oil, waxes having a high melting point, fatty acid glycerides, behenic acid glyceride, and mixtures thereof.

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.

The compositions of the present invention may be administered in the form of tablets, capsules or multiparticulates by various oral routes of administration including buccal, oral and sublingual. In one embodiment, the compositions of the present invention may be formulated in tablet form and administered orally. The composition of the present invention can be easily prepared in the form of the tablet by mixing the components and compressing them together.

In one embodiment, such tablets obtained from the composition of the invention may have an outer coating layer. The tablets should have a suitable hardness, i.e. an average hardness of 5-30 kp, measured before the formation of the optional outer coating layer.

The coating layer may be composed of any one of conventional high molecular 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 about 10% by weight based on the total weight of the formulation. In another embodiment, it may be about 3 to about 5 weight percent based on the total weight of the formulation.

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

Example 1: preparation of Combined tablet- (I)

Mixing section-

Lubricants-

Magnesium stearate 4.0mg

Losartan potassium, amlodipine camsylate, microcrystalline cellulose, mannitol, sodium starch glycolate, crospovidone, and polyvinylpyrrolidone were separately sieved through #20 mesh and mixed with a V-type mixer for 30 min. Then, an appropriate amount of magnesium stearate (lubricant) was added thereto, mixed for 5min, and the resulting mixture was compressed using a rotary tablet press (Sejong Pharmatek, MRC-45) at a pressure of about 20kN to prepare losartan 100 mg-amlodipine 5mg combination tablet.

The average hardness and abrasion degree of the thus-obtained tablet when measured using Erweka hardness and abrasion measuring instrument (25rpm, 100 times free fall) were 19.7kp and 0.1%, respectively, indicating that the strength of the tablet was good.

Example 2: preparation of Combined tablet- (II)

A combination tablet was prepared by repeating the procedure of example 1 except that 15mg of croscarmellose sodium was used instead of 15mg of crospovidone. The average hardness and the abrasion degree of the thus-obtained tablet were 18.5kp and 0.0%, respectively, which indicates that the strength of the tablet was good.

Example 3: preparation of Combined tablet- (III)

A combination tablet was prepared by repeating the procedure of example 1 except that 25mg each of sodium starch glycolate and crospovidone was used. The average hardness and the abrasion degree of the thus-obtained tablet were 15.3kp and 0.2%, respectively, which indicates that the strength of the tablet was good.

Example 4: preparation of Combined tablet- (IV)

A combination tablet was prepared by repeating the procedure of example 1 except that 25mg of sodium starch glycolate was used and 25mg of croscarmellose sodium was used simultaneously instead of 15mg of crospovidone. The average hardness and the abrasion degree of the thus-obtained tablet were 14.5kp and 0.1%, respectively, which indicates that the strength of the tablet was good.

Example 5: preparation of Combined tablet- (V)

A combination tablet was prepared by repeating the procedure of example 1 except that crospovidone was used in an amount of 25mg and at the same time 25mg of croscarmellose sodium was used instead of 15mg of sodium starch glycolate. The average hardness and the abrasion degree of the thus-obtained tablet were 17.1kp and 0.1%, respectively, which indicates that the strength of the tablet was good.

Example 6: preparation of Combined tablet- (VI)

A combination tablet was prepared by repeating the procedure of example 1 except that 25mg amounts of each of sodium starch glycolate and crospovidone were used and at the same time 25mg amounts of croscarmellose sodium were also used. The average hardness and the abrasion degree of the thus-obtained tablet were 11.7kp and 0.3%, respectively, which indicates that the strength of the tablet was good.

Example 7: preparation of Combined tablet- (VII)

A combination tablet was prepared by repeating the procedure of example 1 except that each of the 40mg amounts of sodium starch glycolate and crospovidone was used. The average hardness and the abrasion degree of the thus-obtained tablets were 11.2kp and 0.2%, respectively, which indicates that the strength of the tablets was good.

Example 8: preparation of Combined tablet- (VIII)

A losartan 50 mg-amlodipine 5mg combination tablet is prepared by repeating the procedure of example 1 except that losartan potassium is used in an amount of 50 mg. The average hardness and the abrasion degree of the thus-obtained tablet were 16.9kp and 0.3%, respectively, which indicates that the strength of the tablet was good.

Comparative example 1: preparation of Combined tablet- (IX)

Mixing section-

Lubricants-

Magnesium stearate 4.0mg

A losartan 100 mg-amlodipine 5mg combination tablet is prepared by repeating the procedure of example 1 using the specific components shown above. The average hardness and the abrasion degree of the thus-obtained tablet were 14.3kp and 0.3%, respectively, which indicates that the strength of the tablet was good.

Comparative example 2: preparation of Combined tablet- (X)

A combination tablet was prepared by repeating the procedure of comparative example 1 except that sodium starch glycolate was used in an amount of 80 mg. The average hardness and the abrasion of the thus obtained tablets were 4.7kp and 1.2%, respectively, indicating that the strength of the tablets was insufficient and poor.

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

A combination tablet was prepared by repeating the procedure of comparative example 1 except that 40mg of croscarmellose sodium was used instead of 40mg of sodium starch glycolate. The average hardness and the abrasion degree of the thus-obtained tablet were 12.5kp and 0.2%, respectively, which indicates that the strength of the tablet was good.

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

A combination tablet was prepared by repeating the procedure of comparative example 1 except that 40mg of carboxymethylcellulose calcium was used instead of 40mg of sodium starch glycolate. The average hardness and the abrasion degree of the thus-obtained tablet were 14.9kp and 0.2%, respectively, which indicates that the strength of the tablet was good.

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

A combination tablet was prepared by repeating the procedure of comparative example 1 except that a mixture of 25mg of calcium carboxymethylcellulose and 25mg of corn starch was used instead of 40mg of sodium starch glycolate. The average hardness and the abrasion degree of the thus-obtained tablet were 15.3kp and 0.1%, respectively, which indicates that the strength of the tablet was good.

Hereinafter, Table 1 shows the compositions and properties (hardness and abrasion) of the formulations obtained in examples 1 to 8 and comparative examples 1 to 5.

TABLE 1

(a) Losartan potassium

(b) Amlodipine camsylate

(c) Sodium starch glycolate

(d) Crospovidone

(e) Croscarmellose sodium

(f) Calcium carboxymethylcellulose

(g) Corn starch

(h) Microcrystalline cellulose

(i) Mannitol

(j) Polyvinylpyrrolidone

(k) Magnesium stearate

Test example 1: dissolution test of amlodipine

The losartan-amlodipine combination tablets obtained in examples 1 to 8 and comparative examples 1 to 5 were subjected to a drug dissolution test under the following conditions. The results are shown in Table 2.

Test conditions-

And (3) effluent: 900ml artificial gastric juice (pH1.2)

Dissolution test system: USP Paddle method, 50rpm

Temperature: 37 deg.C

Analytical conditions-

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

Mobile phase: mixture of methanol and 0.03M Potassium dihydrogen phosphate (600: 400, v/v)

A detector: ultraviolet spectrophotometer (350nm)

Flow rate: 1.5ml/min

Sample introduction volume: 20 μ l

TABLE 2

(ii) dissolution rate of amlodipine at 30min (%)

(ii) dissolution rate of amlodipine at 60min (%)

As shown in table 2, the combined tablets obtained in examples 1 to 8 exhibited amlodipine dissolution rates of 75% or more and 90% or more at 30 and 60 minutes, respectively, while the tablets obtained in comparative examples 1 to 5 exhibited lower amlodipine dissolution rates. In particular, although the tablet obtained in comparative example 2 had a low hardness of 4.7kp, the dissolution rate of amlodipine at 30 minutes thereof did not exceed 60%.

Test example 2: losartan dissolution rate measurement

The combination tablets obtained in examples 3 and 4, comparative examples 1 and 5, and 100mg of Cozaar tablets (trademark) were subjected to drug dissolution test under the following conditions, respectively. The results are shown in FIGS. 1 and 2.

Test conditions-

And (3) effluent: 900ml artificial gastric juice (pH1.2) or 0.01N HCl (pH2.0)

Dissolution test system: USP Paddle method, 50rpm

Temperature: 37 deg.C

Analytical conditions-

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

Mobile phase:

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

Mobile phase B-acetonitrile

Concentration gradient system

Time (min)	Mobile phase 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

Results-

The dissolution test system described above (USP paddle method, 50rpm) is most commonly used to evaluate the drug dissolution rate of oral formulations, and the effluent used (artificial gastric juice (pH1.2) or 0.01N HCl (pH2.0)) has a pH similar to that of the gastrointestinal tract.

As shown in fig. 1 and 2, the combined tablets obtained in examples 3 and 4 exhibited a higher dissolution rate of losartan than the tablets obtained in comparative examples 1 and 5 and Cozaar tablet (trademark) which is a single losartan formulation.

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 as active ingredients and a disintegrant which is a mixture of at least two components selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone, wherein the disintegrant is used in an amount of 2.5 to 30 wt% based on the total weight of the composition.

2. The composition of claim 1, wherein the disintegrant is a mixture of sodium starch glycolate and crospovidone.

3. The composition of claim 1, wherein the disintegrant is a mixture of sodium starch glycolate and croscarmellose sodium.

4. The composition of claim 1, wherein the disintegrant is used in an amount of 5 to 15 weight percent, based on the total weight of the composition.

5. 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.