KR101460783B1 - Pharmaceutical composition of candesartan cilexetil with improved stability and method for preparing thereof - Google Patents

Abstract

The present invention relates to a solid preparation for oral administration with improved stability comprising candesartan cilexetil and a method for producing the solid preparation.

Description

[0001] The present invention relates to a pharmaceutical composition containing candesartan cilexetil having improved stability and a method for preparing the same,

The present invention relates to a solid preparation for oral administration with improved stability comprising candesartan cilexetil and a method for producing the solid preparation.

Candesartan belongs to the Angiotensin II receptor blocker and is a therapeutic agent for circulatory diseases such as hypertension, heart disease, stroke, stroke and nephritis. Candesartan has excellent efficacy, but its absorption rate by oral administration is very low. Therefore, prodrug candesartan cilexetil has been developed, and candesartan cilexetil has been released from the candesartan cilexetil while being absorbed into the gastrointestinal tract. Lt; RTI ID = 0.0 > and / or < / RTI > The compound of the candesartan is 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-benzimidazole-7- , And the compound of the candesartan cilexetil is (±) -1 - [[(cyclohexyloxy) carbonyl] oxy] ethyl- Yl) [1,1'-biphenyl] -4-yl] methyl] -1H-benzimidazole-7-carboxylate.

Candesartan cilexetil is a white to off-white powder and is almost insoluble in water and methanol. In addition, it is known that the stability is drastically lowered by tablet pressures and heat generated in the process of forming tablets. Therefore, a technique for improving the stability of candesartan cilexetil and improving the bioavailability by physical changes during tablet molding A number of studies have been carried out.

Korean Patent Application No. 1992-0021902, for example, discloses a method for improving the stability of candesartan cilexetil using a hydrocarbon having a low melting point, higher fatty acids, higher alcohols, fatty acid esters of polyhydric alcohols, higher ethers of polyhydric alcohols, Oxides, or copolymers of ethylene oxide and propylene oxide. ≪ Desc / Clms Page number 2 > However, when such an ointment is prepared by mixing, the release characteristics of candesartan cilexetil, which is poorly soluble, are not constantly controlled by the influence of the remnant materials, which causes a disadvantage in that there is a large variation among individuals upon administration.

Also, U.S. Patent Publication No. 2008-01188564 describes a method for preventing the degradation of active ingredients during tableting by mixing carrageenan, a hydrophilic colloid-forming material, with a stabilizing agent in a process immediately before tableting. However, the use of carrageenan to form such a hydrophilic colloid gel has a disadvantage in that it is difficult to reproduce the release of a certain drug since the initial drug release is delayed from the tablet, and there is a disadvantage that the granules containing candesartan cilexetil and the carrageenan It is difficult to guarantee uniform mixing.

Candesartan cilexetil is not very compatible with each additive, and storage stability is also poor. The compatibility with the additives means the compatibility of the candesartan cilexetil with the respective additives, and it refers to the effect of additives such as candesartan cilexetil, as well as physical and chemical effects due to additives, as well as ease of taking. In order to stabilize the unstable candesartan cilexetil, crystallinity must be prevented from being broken by external factors. In addition, the stability of candesartan cilexetil pharmaceutical compositions is associated with desethylcandesatan or a variety of other degradation products, an increase in the level of desethylcandesate produces unstable or less stable formulations.

Accordingly, the inventors of the present invention conducted studies to overcome the above problems, and as a result, it was confirmed that the stability of candesartan cilexetil can be maintained by adjusting the range of Loss on Drying (LOD) The present invention has been completed.

It is an object of the present invention to provide a solid preparation for oral administration containing candesartan cilexetil having improved stability and a preparation method thereof.

More specifically, one object of the present invention is to provide a pharmaceutical composition comprising candesartan cilexetil or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the improvement in stability with an LOD of 3.5 to 4.5% And to provide a solid preparation for oral administration.

It is still another object of the present invention to provide a method for preparing the solid preparation for oral administration with improved stability.

The present invention relates to a solid preparation for oral administration containing candesartan cilexetil having improved stability and a method for producing the same.

The present invention has revealed that the stability of candesartan cilexetil in candesartan cilexetil-containing preparations depends on the water content in the preparation, and particularly when the LOD value is 3.5% or more, Is remarkably reduced and stability is improved. Accordingly, the present invention provides a solid preparation for oral administration comprising candesartan cilexetil having a LOD of not less than 3.5%, more preferably not less than 3.5% and not more than 4.5%, and a method for producing the same.

In a specific embodiment, the present invention relates to a composition comprising a candesartan cilexetil or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the stability-improved oral dosage form has an LOD of 3.5 to 4.5% To a solid preparation for administration.

As used herein, the term "candesartan cilexetil" refers to a prodrug form of candesartan, a hypertension treating agent belonging to angiotensin II-receptor antagonist, and the compound name of candesartan cilexetil is (±) -1 - [[(2'- (1H-tetrazol-5-yl) [1,1'-biphenyl] -4- Yl] methyl] -1H-benzimidazole-7-carboxylate. Methods for producing candesartan cilexetil can be found in European Patent Publication Nos. 459,136, 5,578,733 and US 2005/0250827.

Candesartan cilexetil is administered intravenously and is absorbed through the gastrointestinal tract, while cilexetil is liberated and transformed into the active candesartan. In the present invention, candesartan cilexetil can be used to have a therapeutically effective amount per unit dosage form and is preferably prepared to contain from about 2 mg to about 40 mg, and preferably from about 4 mg to about 32 mg, per unit dosage form, For example, 2, 4, 8, 16, 32 mg.

Candesartan cilexetil raw materials are stable under ordinary storage conditions, but candesartan cilexetil is very unstable due to various factors (temperature, pressure, suitability with additives, etc.) in the process of formulation into tablets. The present inventors have conducted various studies to stabilize unstable candesartan cilexetil by preventing crystallization from being broken due to external factors. As a result, the stability of candesartan cilexetil in candesartan cilexetil- It was confirmed that it depends on the water content in the preparation.

In the present invention, Loss on Drying (LOD) means the total amount of water, crystal water and other volatile substances in a specimen which is lost when dried. For example, the LOD value in the present invention is a value obtained by measuring the reduced water content, the number of crystals, and the weight ratio of other volatile substances when the candesartan cilexetil formulation is dried at 105 ° C for 10 minutes. However, the LOD value is not necessarily measured only under the same conditions as described above, and the LOD value can be measured by different conditions depending on the physical properties and conditions of the sample. LOD can be measured using an infrared moisture analyzer and can be calculated according to the following equation. In the present invention, "%" used in connection with LOD means "% (w / w) ".

LOD (%) = (weight before drying - weight after drying) / weight before drying x100 (%)

The stabilizing agent of the present invention is characterized by having a loss on drying of 3.5% or more, more preferably 3.5 to 4.5%. For example, in the present invention, when the drying weight loss is 3.5% to 4.5%, it means that when the candesartan cilexetil is completely dried, the weight loss of the preparation is not less than 3.5% (w / w) and not more than 4.5% (w / w) do. As described above, in the specific embodiment of the present invention The drying weight loss was measured by drying at 105 ° C for 10 minutes, but the specific measuring conditions may vary depending on the physical properties and the state of the sample.

If the drying loss is less than 3.5%, the content of the softening material is high and the preparation is unstable. If the drying loss exceeds 4.5%, the content of the softening material decreases but it is not preferable. In the case of the commercially available candesartan cilexetil tablet (BLOPRESS®), the loss on drying is 2.0 ± 0.6%. In comparison, the present invention is characterized in that it provides a more stable candesartan cilexetil formulation by up-regulating the loss of dry weight .

In addition, the stabilizing agent of the present invention preferably has a hardness of less than 9.0 Kp, preferably 3.0 to 8.0 Kp, and more preferably 5.0 to 7.8 Kp.

The pharmaceutically acceptable additives included in the formulation of the present invention may include at least one selected from the group consisting of a plasticizer, an excipient, a binder, a disintegrant, a lubricant, and a colorant.

As the plasticizer, a polyvinyl alcohol-polyethylene glycol graft copolymer is preferable. Since the polyvinyl alcohol-polyethylene glycol graft copolymer is a water-soluble polymer having excellent flexibility and adhesion, and is a copolymer of polyethylene glycol and polyvinyl alcohol having a linear molecular structure and being flexible, it is stable between candesartan cilexetil raw materials The topic can be played efficiently. In particular, it can be placed evenly between the candesartan cilexetil raw materials to reduce the problem of compatibility with the additive, and serves as a buffering agent and lubricant for tabletting, thereby reducing the generation of the flexible substance.

Preferably, the polyvinyl alcohol-polyethylene glycol graft copolymer is dissolved in a solvent of 20 to 50% and used alone or in combination with other binders, specifically polyvinylpyrrolidone having various K values, hydroxypropylcellulose, Hydroxypropylmethylcellulose, and vinylpyrrolidonevinyl acetate copolymer, to bind the active ingredient together with a pharmaceutically acceptable excipient in the form of a binding liquid at the time of granulation, And it is possible to provide the flexibility to cope with the change of the crystal form of the active ingredient due to the pressure applied at the time of tableting. Examples of commercially available polyvinyl alcohol-polyethylene glycol graft copolymers include KollicoatIR (R), BASF, Kollicoat Protect (R), BASF, and the like.

Preferably, the formulation of the present invention comprises candesartan cilexetil or a pharmaceutically acceptable salt thereof and a polyvinyl alcohol-polyethylene glycol graft copolymer in a weight ratio of 5: 1 to 1: 5, more preferably 4: 1 to 1: 4, more preferably in a weight ratio of 3: 1 to 1: 3. If the weight ratio is less than the above range, there is a problem that the stability of the candesartan cilexetil is remarkably reduced due to insufficient binding force due to insufficient binding force and lack of the role of the plasticizer. If the weight ratio is exceeded, And the disintegration of the preparation is delayed, which may cause problems such as lowered dissolution rate.

The excipient is an additive which is used for the purpose of diluting or increasing the amount, and is preferably at least one selected from the group consisting of saccharides, lactose, cellulose and pre-classified. Lactose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose salts (e.g., carboxycellulose calcium, carboxycellulose Sodium starch glycolate, other substituted and unsubstituted cellulose, corn starch, starch, lactose, anhydrous lactose, sugar alcohols such as mannitol, sorbitol, sucrose, xylitol, acrylate polymers and copolymers, dextrates, dextrin, dextrose, But are not limited to, dextrin, pectin, gelatin, inorganic diluents (such as calcium carbonate dibasic calcium phosphate dihydrate, calcium dihydrogen phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium chloride) It is not.

The binder is an additive capable of maintaining the form of the formulation. Examples of the binder include polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinylpyrrolidone vinyl acetate, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, But is not limited to, any one or more selected from the group consisting of methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid, gelatin, propylene glycol, sodium alginate, and mixtures thereof.

The disintegrating agent is an additive for accelerating the disintegration of the preparation. Examples of the additive include croscarmellose sodium, crospovidone, carboxymethylcellulose salts (e.g., carboxycellulose calcium, carboxycellulose sodium), hydroxypropylcellulose, microcrystalline cellulose, Starch, glycolate, and sodium starch glycolate, but is not limited thereto.

The lubricant may be any one or more selected from the group consisting of magnesium stearate, sodium stearyl fumarate and glyceryl behenate as additives for smoothly compressing granules, but is not limited thereto.

In addition, other additives that may be incorporated into the formulation may include lubricants, preservatives, surfactants, antioxidants, colorants (e.g., red iron oxide), flavoring agents, flavor enhancers, or any other additives commonly used in the art have.

In one embodiment, the composition of the present invention comprises from 0.5 to 30% by weight of candesartan cilexetil or a pharmaceutically acceptable salt thereof, from 0.5 to 30% by weight of polyvinyl alcohol-polyethylene glycol graft copolymer % Of lactose, 20 to 70 wt% of lactose, 5 to 30 wt% of corn starch, 0.5 to 20 wt% of carboxymethylcellulose calcium, and 0.01 to 3 wt% of magnesium stearate. However, this is only a representative example, and the scope of the present invention is not limited thereto.

In order to more effectively treat hypertension or related cardiovascular diseases, the preparation of the present invention may also contain a therapeutically effective amount of a diuretic, a beta receptor, an alpha blocker, an alpha-beta blocker, a sympathomimetic inhibitor, an angiotensin converting enzyme inhibitor, , An angiotensin receptor blocker, an inorganic corticosteroid receptor antagonist, and the like in the same formulation

Preferably, the stabilizing agent of the present invention is a solid preparation, and may take any form. And suitable solid formulations may be in the form of tablets (e. G., Immediate release tablets, sustained release tablets, coated tablets, gel coated tablets, enteric coated tablets), capsules (e. G., Soft gelatine capsules, Capsules), granules, pellets, powders and the like.

When the preparation of the present invention is a tablet, it may be prepared by wet or dry granulation, or by direct compression, preferably in the form of tablets prepared by wet or dry granulation, more preferably by wet granulation.

Accordingly, in another aspect, the present invention relates to a method for preparing a solid preparation for oral administration comprising candesartan cilexetil having improved stability.

Preferably, the method comprises

(a) associating a mixture comprising candesartan cilexetil or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive with a binding liquid comprising a polyvinyl alcohol-polyethylene glycol graft copolymer,

(b) drying the association of step (a) to a LOD of from 3.5 to 4.5%

(c) drying the dried material of step (b)

(d) mixing the sizing agent of step (c) with a lubricant and a disintegrant; And

(e) titrating the mixture of step (d).

In particular, in the preparation process of the present invention, the stability of candesartan cilexetil can be more efficiently maintained by adjusting the temperature, humidity, and tableting pressure to appropriate levels.

Specifically, in step (a), candesartan cilexetil or a pharmaceutically acceptable salt thereof and a polyvinyl alcohol-polyethylene glycol graft copolymer are mixed in a weight ratio of 5: 1 to 1: 5, more preferably 4 : 1 to 1: 4, more preferably in a weight ratio of 3: 1 to 1: 3.

The drying process of step (b) may be carried out at a temperature of 30 to 80 ° C, particularly preferably 30 to 35 ° C at the end of drying.

The tableting process of step (e) may be performed at a tableting pressure of 390 Kg or less, preferably 260 to 380 Kg, and the hardness of the preparation is preferably 9.0 Kp or less, preferably 3.0 to 8.0 Kp.

The preparation of the present invention may further include a step of coating after compression to improve the taste of the tablet component or for the purpose of soft and easy swallowing of the tablet or for increasing the shelf life by increasing the resistance to the environment . The tablets can be coated with various coating agents known in the art, for example, tablets can be coated with sugar, gelatin or enteric coating, and two-layer tablets and multi-layer tablets are also possible.

The preparation of the present invention can be used for the pharmaceutical use for treating circulatory diseases such as hypertension, heart disease, seizure, stroke and nephritis, and the administration method is not particularly limited and may be appropriately administered according to the age, sex, And oral administration is preferred. The amount of candesartan cilexetil contained in the formulation according to the present invention is not particularly limited, but may be included in a dosage sufficient to treat, alleviate or alleviate the symptoms associated with the circulatory system disease, and will depend upon the method of use, age, But preferably it can contain from about 4 mg to about 32 mg of candesartan cilexetil in the dosage unit and the total weight of the formulation can be from 10 to 400 mg.

According to the present invention, the stability of candesartan cilexetil can be excellently maintained by adjusting the range of Loss on Drying.

Fig. 1 shows the content (%) of the flexible substance according to the LOD value.
FIG. 2 shows the tabletable range according to the LOD value.
FIG. 3 shows the content (%) of the substance according to the LOD value in terms of time (days).
FIG. 4 shows the content (%) of the flexible material according to the static pressure in terms of time (days).

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Manufacturing example  One. Candesartan  Manufacture of tablets

Composition content( mg ) chief ingredient Candesartan cilexetil 8 Excipient Lactose baggage 63.63 Excipient Corn starch 20 Disintegration Carboxymethylcellulose calcium 11 Binder Colicorteir 7 Lubricant Magnesium stearate 0.33 coloring agent Red iron oxide 0.04 gun 110

Corn starch cilexetil, lactose hydrate, corn starch, carboxymethyl cellulose calcium, colicort eye and red iron oxide were mixed, and the resulting mixture was mixed with a binding liquid containing colicot eye and purified water, followed by drying in a fluidized bed dryer The mixture was dried for 60 minutes so that the temperature of the granules at the time point became 32 DEG C, and after sizing, the mixture was mixed with carboxymethylcellulose calcium and magnesium stearate and tableted to prepare tablets.

Example  1. Dry weight loss ( LOD )In accordance Flexible material ( impurity ) Content change

The tablets were prepared by varying the LOD value in the drying process during the preparation of tablets. The LOD was measured by using an infrared moisture analyzer (Japan A & D, MX-50, Hana Machine) at 105 ° C / 10 min (weight loss after 10 minutes of drying at 105 ° C) of the dried product.

The suppositories were measured by the liquid chromatography method in the General Test Methods for the Korean Pharmacopoeia.

The test solution was prepared by dissolving 20 mg of the purified tablets prepared in Preparation Example 1 in 60% acetonitrile aqueous solution to the amount of 80 mg of candesartan cilexetil to make 200 mL, and then adding 20 mL of a 60% acetonitrile aqueous solution To make 50 mL, which was then filtered through a 0.45 μm membrane filter. The standard solution was prepared by dissolving about 16 mg of candesartan cilexetil standard in 60% acetonitrile aqueous solution to make 100 mL, and then adding 10 mL of this solution to 60 mL of acetonitrile aqueous solution to make 100 mL, which was then filtered through a 0.45 μm membrane filter Compared to 8.0%). The relative retention time (RRT) of the suppositories was measured under the following liquid chromatography conditions.

≪ Liquid chromatography conditions >

- mobile phase A: acetonitrile: water: acetic acid = 57: 43: 1

- mobile phase B: acetonitrile: water: acetic acid = 90: 10: 1

Time (minutes) Mobile phase A Mobile phase B 0 100 0 30 0 100 40 100 0

- Column: Stainless steel column packed with 5 탆 octadecylsilylated silica gel having an inside diameter of 3.0 mm and a length of 150 mm

- Column temperature: 40 ° C

- Flow rate: 0.8 mL / min

- Detection wavelength: 254 nm

- Injection amount: 20 μl

- Concentration of the Candesartan cilexetil standard solution (mg / ml) / concentration of the test solution (mg / ml) X 100 (%) =

≪ Relative Holding Time of Flexible Substance >

Flexible material Chemical name Relative Holding Time (RRT) Tolerance (%) Flexible Substance I Candesartan ethylester 0.37 0.5% or less Flexible Substance II Candesartan desethyl 0.51 2.0% or less Flexible Substance V 1N-ethyl candesartan 1.56 0.5% or less Flexible Substance VI 2N-ethyl candesartan 2.07 Not more than 1.0% chief ingredient Candesartan Cilexetil 1.0 (standard)

The results are shown in Table 4 and Fig. In the case of commercially available candesartan cilexetil tablets (BLOPRESS®), the loss on drying is known to be 2.0 ± 0.6%. According to this experiment, when the loss on drying is 3.5% or more, Can be maintained.

Conduct No. One 2 3 4 5 6 7 8 9 10 11 LOD  (%) 2.5 3.0 3.3 3.5 3.8 4.0 4.3 4.5 4.8 5.0 5.5 Total Impurity (%) 2.57 1.48 1.26 0.98 0.95 0.92 0.91 0.87 0.86 0.87 0.84 Impurity
(%) RRT 0.4 0.03 0.03 0.03 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 RRT 0.5 0.99 0.35 0.39 0.28 0.27 0.25 0.26 0.24 0.24 0.24 0.23 RRT 0.8 0.21 0.12 0.05 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.04 RRT 1.1 0.44 0.18 0.15 0.08 0.07 0.08 0.08 0.07 0.07 0.08 0.08 RRT 1.5 0.28 0.26 0.16 0.13 0.12 0.13 0.12 0.12 0.12 0.12 0.12 RRT 2.0 0.61 0.52 0.46 0.41 0.42 0.38 0.37 0.36 0.35 0.35 0.34 Unknown 0.01 0.02 0.02 0.02 0.01 0.02 0.02 0.02 0.01 0.02 0.01

* RRT: Relative Retention Time

Example  2. Depending on drying loss Feasible range

As shown in Table 5 and FIG. 2, when the loss on drying was more than 4.5%, the hardness of the tablets was measured to be less than 3 Kp, indicating that tableting was impossible.

Conduct No. One 2 3 4 5 6 7 8 9 10 11 LOD  (%) 2.5 3.0 3.3 3.5 3.8 4.0 4.3 4.5 4.8 5.0 5.5 Hardness (Kp) 8.6 8.3 6.9 6.7 6.1 6.2 5.3 4.1 2.1 1.3 -

Example  3. Hourly by weight loss Flexible material  Content change

For the commercially available candesartan cilexetil tablet (BLOPRESS®), the loss on drying is 2.0 ± 0.6%. When tablets were prepared by the method of Preparation Example 1, the tablets were prepared by varying the drying weight loss values of 3.7% and 4.2%, respectively, in the drying step, and then the commercial tablets and the content of the suppositories were compared and analyzed. The contents of the substances were measured at 3 days, 5 days, 7 days and 14 days after the preparation of the tablets, respectively. The method of measuring the flexible substance is the same as that described in Example 1. As a result, as shown in FIG. 3, the tablets having a weight loss of 3.7% and 4.2% showed a decrease in the amount of the suppositories rather than those of the commercial tablets. Especially, on the 14th day, 3.7% and 4.2%, respectively, were found to be stable.

Example  4. At a constant pressure  Following Flexible material  Content change

In order to set an appropriate pressure range for tablets having a dry weight loss of 3.5 to 4.5%, the present inventors conducted comparative analysis of commercial tablets and suppositories with a tablet pressurization of 260 Kg and 370 Kg, respectively. A tablet having a dry weight loss of 3.7% was prepared according to the method of Preparation Example 1, and the method for measuring the flexible material was measured according to the method of Example 1. As a result, as shown in FIG. 4, the formulation of the present invention, which had a loss on drying of 3.7%, showed improved stability over the commercially available candesartan cilexetil tablet (BLOPRESS®) at 260 kG and 370 kG pressure.

Claims (16)

 Which comprises a candesartan cilexetil or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive and has a loss on drying of 3.5 to 4.5% (w / w) Solid formulation. The solid preparation for oral administration according to claim 1, wherein the solid preparation is a tablet. The solid preparation for oral administration according to claim 1, which is a tablet having a hardness of 3.0 to 8.0 Kp. The solid preparation for oral administration according to claim 1, wherein the pharmaceutically acceptable additive comprises at least one selected from the group consisting of a plasticizer, an excipient, a binder, a disintegrant, a lubricant, and a colorant. The solid preparation for oral administration according to claim 4, wherein the plasticizer is a polyvinyl alcohol-polyethylene glycol graft copolymer. 6. The preparation according to claim 5, which comprises candesartan cilexetil or a pharmaceutically acceptable salt thereof and a polyvinyl alcohol-polyethylene glycol graft copolymer in a weight ratio of 3: 1 to 1: 3. 5. The composition of claim 4 wherein said excipient is selected from the group consisting of lactose hydrate, microcrystalline cellulose, microcrystalline cellulose-lactose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose salt, Selected from the group consisting of non-cellulosic cellulose, corn starch, starch, lactose, anhydrous lactose, sugar alcohols, sucrose, xylitol, acrylate polymers and copolymers, dextrates, dextrins, dextrose, maltodextrins, pectins, gelatins and inorganic diluents Or a pharmaceutically acceptable salt thereof. 5. The composition of claim 4, wherein the binder is selected from the group consisting of polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinylpyrrolidone vinyl acetate, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methylcellulose, poly Polyvinylpyrrolidone, polyacrylic acid, gelatin, propylene glycol, sodium alginate, and mixtures thereof. The solid preparation for oral administration according to claim 1, 5. The composition of claim 4 wherein said disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, carboxymethylcellulose salt, hydroxypropylcellulose, microcrystalline cellulose, starch, sodium starch glycolate and starch glycolate sodium Or a pharmaceutically acceptable salt thereof. The solid preparation for oral administration according to claim 4, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, and glyceryl behenate. The pharmaceutical composition according to claim 4, which comprises 0.5 to 30% by weight of candesartan cilexetil or a pharmaceutically acceptable salt thereof, 0.5 to 30% by weight of a polyvinyl alcohol-polyethylene glycol graft copolymer, 20 to 70% by weight of corn starch, 5 to 30% by weight of corn starch, 0.5 to 20% by weight of carboxymethylcellulose calcium and 0.01 to 3% by weight of magnesium stearate. (a) associating a mixture comprising candesartan cilexetil or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive with a binding liquid comprising a polyvinyl alcohol-polyethylene glycol graft copolymer,
(b) drying the coalesced product of step (a) to a Loss on Drying of 3.5 to 4.5% (w / w)
(c) drying the dried material of step (b)
(d) mixing the sizing agent of step (c) with a lubricant and a disintegrant; And
(e) titrating the mixture of step (d).
A method for preparing a solid preparation for oral administration according to any one of claims 1 to 6, The method according to claim 12, wherein the step (a) comprises combining candesartan cilexetil or a pharmaceutically acceptable salt thereof and a polyvinyl alcohol-polyethylene glycol graft copolymer in a weight ratio of 3: 1 to 1: 3 / RTI > 13. The method of claim 12, wherein the pharmaceutically acceptable excipient in step (a) is at least one selected from the group consisting of excipients, binders, disintegrants, and colorants. The method according to claim 12, wherein the temperature at the end of drying in step (b) is 30 to 35 占 폚. 13. The method of claim 12, wherein in step (e), the tableting pressure is 390 Kg or less and the hardness is 3.0 to 8.0 Kp.

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