WO2004010976A1

WO2004010976A1 - Solid dispersion comprising amlodipine, method thereof and pharmaceutical composition comprising the solid dispersion

Info

Publication number: WO2004010976A1
Application number: PCT/KR2003/001512
Authority: WO
Inventors: Kye Kwan Lee; Dong Soo Lee; Yun Seok Rhee; Sang Jin Kim
Original assignee: Whan In Pharm. Co., Ltd
Priority date: 2002-07-30
Filing date: 2003-07-29
Publication date: 2004-02-05
Also published as: AU2003251167A1; KR20040011248A

Abstract

The present invention relates to solid dispersion comprising amlodipine which enables formulations adequate for oral administration through raising the solubility and dissolution rate of amlodipine with low water solubility, one of the therapeutics for hypertension, and manufacturing method thereof and a pharmaceutical composition comprising the solid dispersion. The present invention can provide pharmaceutical composition comprising solid dispersion of amlodipine which, compared to the conventional amlodipine besylate, exhibits a unique combination of properties important for the preparation of pharmaceutical composition, i.e. superior stability, nonhygroscopicity and superior processibility, in particular, excellent sticking-preventing property.

Description

Solid dispersion comprising amlodipine, method thereof and pharmaceutical composition comprising the solid dispersion

Technical Field The present invention relates to a solid dispersion comprising amlodipine which enables formulations adequate for oral administration through increasing the solubility and dissolution rate of amlodipine with a low water solubility, one of the therapeutics for hypertension, and manufacturing method thereof and a pharmaceutical composition comprising the solid dispersion.

Background Art

Amlodipine whose chemical name is "3-ethyl-5-methyl-2-(2-aιninoethoxy methyl)-4-(2-chlorophenyl)-l,4-dihydro-6-methylpyridine-3,5-dicarboxylate" is a pote nt and long-acting calcium channel blocker, and useful as a remedy for ischemia and hypertension.

European Patent Laid-open No. 89167 discloses varied types of pharmaceutically acceptable salts of amlodipine. In particular, the pharmaceutically acceptable acid addition salt is formed from an acid forming nontoxic acid addition salt including pharmaceutically permeable anion, and hydrochloride, hydrobromide, sulfate, phosphate or acidic phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate can be enumerated. Among these salts, maleate is described to be particularly preferred.

Korean Patent Laid-open No. 1989-3375 describes that benzene sulfonate (hereinafter, "besylate") exhibits many advantages compared to known amlodipine salts. Amlodipine as free base is useful, yet, because of low water solubility, it has been administered in a form of salt with pharmaceutically permeable acid. Through such salt formation, improved solubility could be guaranteed, however, it was difficult to completely satisfy physico-chemical criteria such as stability, nonhygroscopicity and processibihty toward tablet formulation. That is, majority of the previous salts of amlodipine satisfied a part of said requirement, yet no previous amlodipine salt completely satisfied said three criteria, and even the besylate and maleate described above as preferred have high solubility and nonhygroscopicity, but exhibit sticking problem in the manufacture of tablets. Amlodipine free base exhibits superior stability, nonhygroscopicity and excellent processibility for tablet preparation, while defective for low solubility.

On the other hand, as a method for increasing dissolution rate of drug with low solubility, method based on solid dispersion was known, and this is advantageous for no need for solubilizer such as surfactant. Manufacturing method of solid dispersion is generally divided into fusion method and solvent method, and according to the fusion method, a drug and carrier are mixed to homogeneity, melted by heating, then cooled to form solid dispersion. According to the solvent method, a drug and carrier are dissolved in an organic solvent and the solvent is evaporized to form solid dispersion.

The inventors of the present invention have made efforts to solve the problems of conventional technology as described above, and as a result, discovered that in case amlodipine free base (hereinafter, amlodipine) which has superior stability, non hygroscopicity and processibility to tablet formulation is to be prepared into solid dispersion, the disadvantage of the amlodipine free base, low solubility can be remarkably improved, and based on this, completed the present invention. That is, object of the present invention is to provide a novel solid dispersion comprising amlodipine with improved dissolution rate compared to amlodipine, and method thereof and a pharmaceutical composition comprising the amlodipine solid dispersion.

Disclosure of the Invention

The present invention relates to a solid dispersion of amlodipine comprising amlodipine and inert carrier for solid dispersion.

The inert carrier for solid dispersion used for the preparation of solid dispersion comprising amlodipine in the present invention is an ingredient used to increase the solubility of amlodipine to water, and the weight ratio of inert carrier to amlodipine is preferred to be 0.1-179 : 1, and 1-100 : 1 is particularly preferred. Weight ratio of inert carrier against amlodipine can be easily determined through simple experiment. Lower limit is detennined by substantial consideration. Actually, the lower ratio against the given therapeutically effective amount of amlodipine(approximately 5 mg to lOmg, preferably approximately 5 mg per a day)is determined based on the maximum amount of mixture that can be processed to a unit dosage form of substantial size. When relative amount of the inert carrier is too large, the absolute amount of mixture needed to reach therapeutic level becomes too huge, thus it cannot be processed to a single capsule or tablet. Tablets have maximum weight, e.g. about lg, and solid dispersion within tablet can reach about 90%(w/w) at most. Therefore, lower limit of inert carrier to amlodipine will be approximately 179:1 (amlodipine 5 mg + inert carrier 895mg).

As such inert carrier, one or a combination of two or more selected among water soluble polymers, water soluble sugars, organic acids and phosphoric acid which makes the formation of solid dispersion easy, can be used.

Representative example of such water soluble polymer can be selected from a group consisting of alkylcellulose such as methylcellulose; hydroxyalkylcellulose such as hydroxymetliylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkylalkylcellulose such as hydroxyethylmethylcellu lose and hydroxypropylmethylcellulose; carboxyalkylcellulose such as carboxymethyl cellulose; alkali metal salt of carboxyalkylcellulose such as sodium carboxymethyl cellulose; carboxyalkylalkylcellulose such as carboxymethyleth ylcellulose; carboxy alkylcellulose ester; starch; pectin such as sodium carboxy methylamylopectm; chitin derivatives such as chitosan; polysaccharides such as alginic acid, its alkali metal salts and ammonium salt, carrageenan, galactomannane, tragacanth, agar-agar, Arabia gum, gua gum and xanthan gum; polyacrylic acid and its salts; polymethacrylic acid and its salts, methacrylate copolymer, aminoalkyl methacrylate copolymer; polyvinylacetal diethylaminoacetate; sugar surfactant such as sucrose distearate, sucrose monodistearate and sucrose monopalmitate; polyvinylalcohol; polyvinylpyrrolidone, copolymer of polyvinylpyrrolidone and vinyl acetate; poly alkylene oxide such as polyethylene oxide and polypropylene oxide; and copolymer of ethylene oxide and propylene oxide.

Representative water soluble sugar can be selected among sucrose, mannitol, glucose, sorbitol, xylitol, inositol, lactose and fructose.

Representative organic acid can be selected among citric acid, tartaric acid, ascorbic acid, lactic acid, maleic acid, malic acid and succinic acid.

In addition, another object of the present invention relates to manufacturing method of said solid dispersion of amlodipine. The preparation of solid dispersion can be conducted by fusion method or solvent method.

In case of the preparation of solid dispersion of amlodipine of the present invention according to fusion method, amlodipine and inert carrier are homogeneously mixed, the mixture is heated to 160 to 240°C to homogeneous melting, solidified on ice water under cooling, pulverized to prepare solid dispersion.

In case of the preparation of solid dispersion of amlodipine of the present invention according to solvent method, amlodipine and inert carrier are dissolved in an organic solvent and the solvent is evaporized or if necessary, optionally incorporated with conventional diluents and solvent is evaporized to prepare solid dispersion. In the method according to the present invention, for easier dissolving of amlodipine and inert carrier in organic solvent, the mixture can be heated, and preferred range of heating is 40 to 80°C.

Organic solvent that can be used for the present invention should be able to dissolve amlodipine and inert carrier, and methanol, ethanol, isopropanol, acetone, methylene chloride or a mixture thereof is preferred, and the amount (weight) of solvent to total weight of amlodipine and inert carrier is preferred to be 1-50 : 1, and 4-20 : 1 is particularly preferred.

Of the solvent method in the present invention, in case of preparing amlodipine solid dispersion via incorporating with diluents, amlodipine and inert carrier are dissolved in organic solvent, incorporated homogeneously with diluents and solvent is removed, thereby effectively resolving the problems of conventional solvent method such as residual organic solvent, difficulty in stirring due to high viscosity in the later part of drying and content inequality. Additionally, the present invention relates to preparation of pharmaceutical composition comprising said solid dispersion of amlodipine. Pharmaceutical comp osition comprising the solid dispersion of amlodipine of the present invention can further contain diluents, disintegrants and lubricants, if necessary.

The composition of the present invention can be prepared into formulation such as tablets, capsules, granules and fine granules, and in particular, tablet is preferred. For example, granules can be directly filled into gelatin capsule or with addition of lubricant and other pharmaceutical excipients, powder or granule can be filled into gelatin capsule or can be compressed into tablets with addition of necessary pharmaceutical excipients for tableting.

In the below, the present invention is described in further detail through Examples. These Examples are for more specific explanation of the present invention, and the scope of the present invention is not limited by them.

Brief Explanation of Drawings

Fig. 1 shows the result of the dissolution test of Experimental example 1 (V: Comparative Example 1, O: Example 12, ■: Example 13, D: Example 14, A: Example 15, Δ: Example 18, T: Example 20, 9: commercial preparation (manufacturer: Pfizer, product name: Norvask tablets)).

Fig. 2 shows the result of the dissolution test of Experimental example 2 (Δ: Comparative Example 1, O: Example 16, ■: Example 17, D: Example 19, A: Example 21, •: commercial preparation (manufacturer: Pfizer, product name: Norvask tablets)). Best mode for carrying out the invention

The present invention is described in more detail with the following Examples, yet they do not limit the scope of the present invention.

Example 1

First, amlodipine 5 g and hydroxypropylmethylcellulose 5 g were homo geneously mixed and the mixture was melted by heating at 200 to 240°C under stirring to form homogeneous melted mixture and quickly cooled on ice water. After sufficient cooling, it was pulverized and screened with 60 mesh sieve to finally obtain amlodipine-hydroxypropyl methylcellulose solid dispersion.

Example 2

First, amlodipine 0.5 g and hydroxypropylmethylcellulose 50 g were homo geneously mixed and the mixture was melted by heating at 200 to 240°C under stirring to form homogeneous melted mixture and quickly cooled on ice water. After sufficient cooling, it was pulverized and screened with 60 mesh sieve to finally obtain amlodipine-hydroxypropylmethylcellulose solid dispersion.

Example 3

First, amlodipine 5 g and polyvinylpyrrolidone K30 5 g were homogeneously mixed and the mixture was melted by heating at 160 to 180°C under stirring to form homogeneous melted mixture and quickly cooled on ice water. After sufficient cooling, it was pulverized and screened with 60 mesh sieve to finally obtain amlodipine-polyvinylpyrrolidone solid dispersion.

Example 4

First, amlodipine 0.5 g and polyvinylpyrrolidone K30 50 g were homogen eously mixed and the mixture was melted by heating at 160 to 180°C under stirring to form homogeneous melted mixture and quickly cooled on ice water. After sufficient cooling, it was pulverized and screened with 60 mesh sieve to finally obtain amlodipine-polyvinylpyrrolidone solid dispersion.

Example 5

First, amlodipine 5 g and sucrose monopalmitate 5 g were homogeneously mixed and the mixture was melted by heating at 190 to 220°C under stirring to form homogeneous melted mixture and quickly cooled on ice water. After sufficient cooling, it was pulverized and screened with 60 mesh sieve to finally obtain amlodipine-sucrose monopalmitate solid dispersion.

Example 6

First, amlodipine 0.5 g and sucrose monopalmitate 50 g were homogeneously mixed and the mixture was melted by heating at 190 to 220°C under stirring to form homogeneous melted mixture and quickly cooled on ice water. After sufficient cooling, it was pulverized and screened with 60 mesh sieve to finally obtain amlodipine-sucrose monopalmitate solid dispersion. Example 7

First, amlodipine 5 g and sucrose 5 g were homogeneously mixed and the mixture was melted by heating at 160 to 180°C under stirring to form homogeneous melted mixture and quickly cooled on ice water. After sufficient cooling, it was pulverized and screened with 60 mesh sieve to finally obtain amlodipine-sucrose solid dispersion.

Example 8 First, amlodipine 0.5 g and sucrose 50 g were homogeneously mixed and the mixture was melted by heating at 160 to 180°C under stirring to form homogeneous melted mixture and quickly cooled on ice water. After sufficient cooling, it was pulverized and screened with 60 mesh sieve to finally obtain amlodipine-sucrose solid dispersion.

Example 9

First, amlodipine 5 g and citric acid 5 g were homogeneously mixed and the mixture was melted by heating at 160 to 180°C under stirring to form homogeneous melted mixture and quickly cooled on ice water. After sufficient cooling, it was pulverized and screened with 60 mesh sieve to finally obtain amlodipine-citric acid solid dispersion. Example 10

First, amlodipine 0.5 g and citric acid 50 g were homogeneously mixed and the mixture was melted by heating at 160 to 180°C under stirring to form homogeneous melted mixture and quickly cooled on ice water. After sufficient cooling, it was pulverized and screened with 60 mesh sieve to finally obtain amlodipine-citric acid solid dispersion.

Example 11

First, amlodipine 5 g, sucrose monopalmitate 5g and citric acid 5 g were homogeneously mixed and the mixture was melted by heating at 180 to 200°C under stirring to form homogeneous melted mixture and quickly cooled on ice water. After sufficient cooling, it was pulverized and screened with 60 mesh sieve to finally obtain amlodipine-sucrose monopalmitate-citric acid solid dispersion.

Example 12

The amlodipine-hydroxypropylmethylcellulose solid dispersion (10 g) which was prepared in Example 1, lactose (100 g) as diluents, and calcium carboxymethyl cellulose (88 g) as disintegrant were mixed to homogeneity, granules were formed by using roller compactor according to dry granulation, and the granules were mixed with magnesium stearate (2 g) as lubricant to compressed into tablets.

Example 13

The amlodipine-hydroxypropylmethylcellulose solid dispersion (50.5 g) which was prepared in Example 2, lactose (10 g) as diluents, and calcium carboxymethyl cellulose (20 g) as disintegrant were mixed to homogeneity, granules were formed by using roller compactor according to dry granulation, and the granules were mixed with magnesium stearate (1.5 g) as lubricant to compressed into tablets.

Example 14

The amlodipine-sucrose solid dispersion (10 g) which was prepared in Example

7, lactose (50 g) as diluents, and calcium carboxymethylcellulose(100 g) as disintegrant were mixed to homogeneity, granules were formed by using roller compactor according to dry granulation, and said granules were mixed with magnesium stearate (2 g) as lubricant and filled into gelatin capsule to prepare capsules.

Example 15

The amlodipine-sucrose solid dispersion (50.5 g) which was prepared in

Example 8, lactose (20 g) as diluents, and calcium carboxymefhylcellulose(20 g) as disintegrant were mixed to homogeneity, granules were formed by using roller compactor according to dry granulation, and said granules were mixed with magnesium stearate (1.5 g) as lubricant to compressed into tablets.

Example 16 The amlodipine-citric acid solid dispersion (10 g) which was prepared in

Example 9, lactose (50 g) as diluents, and calcium carboxymethylcellulose (100 g) as disintegrant were mixed to homogeneity, granules were formed by using roller compactor according to dry granulation, and said granules were mixed with magnesium stearate (1 g) as lubricant and filled into gelatin capsule to prepare capsules. Example 17

The amlodipine-sucroester-citric acid solid dispersion (15 g) which was prepared in Example 11, lactose (100 g) as diluents, and calcium carboxymethyl cellulose (100 g) as disintegrant were mixed to homogeneity, granules were formed by using roller compactor according to dry granulation, and said granules were mixed with magnesium stearate (2 g) as lubricant to compressed into tablets.

Example 18

Amlodipine 5 g and sucrose monopalmitate 5 g were added to approximately 40 ml of ethanol and heated to about 60°C under stirring to prepare transparent mixture. Said mixture was added to and incorporated with a homogeneous mixture of lactose 125 g and microcrystalline cellulose 40 g as diluents, and granulated and dried. This was screened, and calcium carboxymethylcellulose 22 g as disintegrant and magnesium stearate 3 g as lubricant were added and mixed, and compressed to prepare tablets containing 5 mg of amlodipine per tablet.

Example 19

Amlodipine 5 g and polyvinylpyrrolidone K30 5 g were added to approximately 40 ml of ethanol and heated to about 60°C under stirring to prepare transparent mixture. Said mixture was added to and incorporated with a homogeneous mixture of lactose 100 g and microcrystalline cellulose 50 g as diluents, and granulated and dried. This was screened, and calcium carboxymethylcellulose 20 g, low degree- substituted hydroxy pro pylcellulose 17 g as disintegrant and magnesium stearate 3 g as lubricant were added and mixed, and compressed to prepare tablets containing 5 mg of amlodipine per tablet.

Example 20

Amlodipine 5 g and citric acid 5 g were added to approximately 40 ml of ethanol and heated to about 60°C under stirring to prepare transparent mixture. Said mixture was added to and incorporated with a homogeneous mixture of lactose 120 g and microcrystalline cellulose 50 g as lubricant, and granulated and dried. This was screened, and calcium carboxymethylcellulose 18 g as disintegrant and magnesium stearate 2 g as lubricant were added and mixed, and compressed to prepare tablets containing 5 mg of amlodipine per tablet.

Example 21

Amlodipine 5 g, sucrose monopalmitate 5 g and citric acid 4 g were added to approximately 40 ml of ethanol and heated to about 60°C under stirring to prepare transparent mixture. Said mixture was added to and incorporated with a homogeneous mixture of lactose 140 g and microcrystalline cellulose 30 g as lubricant, and granulated and dried. This was screened, and calcium carboxymethylcellulose 10 g, low degree- substituted hydroxypropylcellulose 4 g as disintegrant and magnesium stearate 2 g as lubricant were added and mixed, and compressed to prepare tablets containing 5 mg of amlodipine per tablet.

Comparative Example 1. Tablets based on amlodipine

Amlodipine 5 g, lactose 100 g, diluents, and calcium carboxymethylcellulose 93 g as disintegrant were mixed to homogeneity and granules were prepared by using roller compactor according to dry granulation, and said granules were mixed with magnesium stearate 2 g as lubricant and compressed to prepare tablets.

Experimental Example 1. Dissolution test The tablets and capsules prepared in Comparative Example 1 and Examples 12,

13, 14, 15, 18 and 20 and commercial preparation containing amlodipine besylate as major ingredient (manufacturer: Pfizer, product name; Norvask tablets) which were adjusted to be 5 mg as amlodipine, were subjected to dissolution test. As dissolution solution, 0.01M hydrochloric acid was used, and the content of amlodipine was determined by high performance liquid chromatography (HPLC).

Analysis result was represented in Fig.l, and it could be confirmed that

Examples 12, 13, 14, 15, 18 and 20 all showed remarkably increased dissolution rate compared to the Comparative Example 1 using amlodipine free base, and exhibited dissolution profiles similar to that of tablets containing amlodipine besylate(Norvask tablets).

Experimental Example 2. Dissolution test

The tablets and capsules prepared in Comparative Example 1 and Examples 16, 17, 19 and 21 and commercial preparations containing amlodipine besylate as major ingredient (manufacturer: Pfizer, product name; Norvask tablets) which were adjusted to be 5mg as amlodipine, were subjected to dissolution test. As dissolution solution, water was used, and the content of amlodipine was determined by HPLC. Analysis result was represented in Fig.2, and it could be confirmed that Examples 16, 17, 19 and 21 all showed remarkably increased dissolution rate compared to the Comparative Example 1 using amlodipine, and exhibited dissolution profiles similar or superior to that of tablets containing amlodipine besylate(Norvask tablets).

Experimental Example 3. Stability test

To determine chemical stability, solid dispersion of amlodipine from Examples 1, 3 and 5 according to the present invention and conventional besylate, maleate and hydrochloride of amlodipine were respectively mixed with powder vehicle to form tablets. The vehicle consists of mixture (50:50) of microcrystalline cellulose and anhydrous dibasic calcium phosphate. The tablets were stored within sealed vial at 50 to 75°C for three weeks. Pharmaceuticals and possible degradation products were extracted with methanol : chloroform mixture (50:50), and separated by using various solvent system on silica thin layer chromatography (TLC). The results were compared, and the salts were classified according to the number and amount of the formed degradation products.

Comparing the results, it could be seen that the solid dispersion of amlodipine of Examples 1, 3 and 5 all showed higher stability relative to the conventional amlodipine salts. Table 1

Experimental Example 4. Hygroscopicity test

To determine hygroscopicity of amlodipine solid dispersion of the present invention and conventional amlodipine salts, amlodipine solid dispersion of Examples 1, 3 and 5 and conventional maleate and besylate were exposed to 75% relative humidity, 37°C for 24 hours, and as result, none of them absorbed moisture. In addition, even in case of exposure to 95% relative humidity, 30°C for 3 days, the solid dispersion and besylate and maleate all remained as being anhydrous. Based on this, it could be confirmed that solid dispersion is also regarded as nonhygroscopic, and can provide stable formulation while reducing the risk of unique chemical degradation.

Experimental Example 5. Test on stickiness to punch

To compare stickiness between amlodipine solid dispersion of the present invention and conventional amlodipine besylate, the following procedure was conducted using conventional tablet processes.

First, to test stickiness of amlodipine besyltae, 50 tablets containing calcium sulfate dihydrate, microcrystalline cellulose and amlodipine besylate (ratio of each ingredient 47.5 : 47.5 : 5) were prepared, and substance stuck to punch was extracted with methanol, and the amount was determined with spectrometer. Said procedure was repeated with 100, 150, 220, 250 and 300 tablets, respectively. After conducting respective procedure, substance stuck to punch was extracted with methanol and the amount was determined. The values were plotted and based on the slope of the line, average value was calculated.

Same procedure as described above was repeated for amlodipine solid dispersion of Examples 1, 3 and 5. Amount of amlodipine determined to be sticking to punch was represented in Table 2 as relative ratio against besylate.

Table 2

As can be seen from the result of said Table 2, amlodipine solid dispersion of the present invention showed relative stickiness of 10% or less compared to conventional amlodipine besylate, confirming excellent sticking-preventing property.

Industrial applicability

Solid dispersion according to the present invention can effectively increase the solubility of amlodipine and the manufacturing method for solid dispersion of the present invention enables effective formulation of amlodipine. Based on this, the present invention can provide pharmaceutical composition comprising amlodipine solid dispersion which, compared to conventional amlodipine besylate, exhibits a unique combination of properties very important for the preparation of pharmaceutical formulation, superior stability, nonhygroscopicity and superior processibility, especially, excellent sticking-preventing property.

Claims

1. A solid dispersion of amlodipine comprising amlodipine and inert carrier for solid dispersion.

2. The solid dispersion of amlodipine in Claim 1, which comprises as the inert carrier for solid dispersion, at least one selected among water soluble polymers, water soluble sugars, organic acids and phosphoric acid.

3. The solid dispersion of amlodipine in Claim 1 , characterized in that the weight ratio of inert carrier for solid dispersion to amlodipine is 0.1-179 : 1

4. The solid dispersion of amlodipine according to Claim 2 wherein the water soluble polymer is at least one selected from the group consisting of alkylcellulose, hydroxyalkylcellulose, hydroxyalkylalkylcellulose, carboxyalkylcellulose, alkali metal salt of carboxyalkylcellulose, carboxyalkylalkylcellulose, carboxyalkylcellulose ester, starch, pectin, chitin derivatives, polysaccharides, polyacrylic acid and its salts, polymethacrylic acid and its salts, methacrylate copolymer, aminoalkyl methacrylate copolymer; polyvinylacetal diethylaminoacetate, sugar surfactant, polyvinylalcohol, polyvinylpyrrolidone, copolymer of polyvinyl pyrrolidone and vinyl acetate, polyalkylene oxide, and copolymer of ethylene oxide and propylene oxide.

5. The solid dispersion of amlodipine according to Claim 4 wherein the alkylcellulose is methylcellulose; the hydroxyalkylcellulose is at least one selected from the group consisting of hydroxymetliylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and hydroxybutylcellulose; the hydroxyalkylalkylcellulose is at least one selected from the group consisting of hydroxyethylmethylcellulose and hydroxypropyl methylcellulose; the carboxyalkylcellulose is carboxy methylcellulose; the alkali metal salt of carboxyalkylcellulose is sodium carboxy methylcellulose; the carboxyalkylalkylcellulose is carboxymethylethylcellulose; the pectin is sodium carboxymethylamylo pectin; the chitin derivatives is chitosan; the polysaccharides is at least one selected from the group consisting of alginic acid, its alkali metal salts and ammonium salt, carrageenan, galactomannane, tragacanth, agar-agar, Arabia gum, gua gum and xanthan gum; the sugar surfactant is at least one selected from the group consisting of sucrose distearate, sucrose monodistearate and sucrose monopalmitate; and the polyalkylene oxide is at least one selected from the group consisting of polyethylene oxide and polypropylene oxide;

6. The solid dispersion of amlodipine according to Claim 2 wherein the water soluble sugar is at least one selected from the group consisting of sucrose, mannitol, glucose, sorbitol, xylitol, inositol, lactose and fructose.

7. The solid dispersion of amlodipine according to Claim 2 wherein the organic acid is at least one selected from the group consisting of citric acid, tartaric acid, ascorbic acid, lactic acid, maleic acid, malic acid or succinic acid.

8. A method for preparing the solid dispersion of amlodipine of Claim 1 characterized in that amlodipine and inert carrier is mixed to homogeneity, melted by heating to 160 to 240°C, and this melting mixture is solidified on ice water under cooling, and pulverized.

9. A method for preparing the solid dispersion of amlodipine of Claim 1 characterized in that amlodipine and inert carrier is dissolved in an organic acid and the solvent is evaporized, or incorporated with diluents and solvent is evaporized.

10. The method in Claim 9, characterized in that weight content of said organic solvent to total weight of amlodipine and inert carrier is 1-50 : 1.

11. The method in Claim 9, characterized in that said organic solvent is one or a mixture of at least two selected from a group consisting of methanol, ethanol, isopropanol, acetone and methylene chloride.

12. Pharmaceutical composition of amlodipine comprising the solid dispersion of amlodipine in any one of Claims 1 to 7.

13. The pharmaceutical composition in Claim 12, characterized by having formulation selected among tablets, capsules, granules and fine granules.