JP2014037356A - Candesartan cilexetil oral formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a candesartan cilexetil oral formulation, specifically a tablet and a tablet disintegrating in an oral cavity, having improved stability, a good disintegrating property, and a good elution property of candesartan cilexetil.SOLUTION: The candesartan cilexetil oral formulation contains candesartan cilexetil as an active ingredient, and stearic acid as a stabilizer. Further, the candesartan cilexetil oral formulation may contain lactose and crystalline cellulose as excipients, and the oral formulation containing the lactose and the crystalline cellulose, especially a tablet containing a tablet disintegrating in an oral cavity, is one of the preferable embodiments.

Description

  The present invention relates to a stable oral preparation containing candesartan cilexetil or a physiologically acceptable salt thereof (hereinafter simply referred to as “candesartan cilexetil”).

  Candesartan is known as a potent long-acting selective AT1 subtype angiotensin II receptor antagonist, particularly cardiovascular diseases such as hypertensive diseases, heart diseases (eg cardiac hypertrophy, heart failure, myocardial infarction, etc.) ), A therapeutic drug useful for the treatment of seizures, strokes, nephritis and the like. However, since candesartan is difficult to be absorbed by oral administration, candesartan cilexetil, which is a prodrug (Patent Document 1), has been developed and marketed in order to enhance bioavailability.

Candesartan cilexetil is a drug that is often used in medicine due to its powerful pharmacological action. The chemical name of candesartan cilexetil is (±) -1-[[(cyclohexyloxy) carbonyl] oxy] ethyl-2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) [1,1-biphenyl] ] -4-yl] methyl] -1H-benzimidazole-7-carboxylate, a white to light gray powder, hardly soluble in water and methanol. Candesartan cilexetil has an asymmetric center in the ester portion of the molecule, but is sold as a racemic mixture.
However, although candesartan cilexetil alone is stable to temperature, humidity, and light in the solid state, it is known that degradation can be accelerated when it is made into a solid formulation together with other formulation components, which may be a problem in quality assurance. (Patent Document 2). Some preparations containing candesartan cilexetil have been known so far.

For example, by blending an angiotensin II receptor antagonist typified by candesartan cilexetil with a low-melting point oily substance, the oral pharmaceutical composition can be prevented from being decomposed by molding over time. As an intraoral quick disintegrating tablet containing candesartan cilexetil, it can be practically used even at a low dry compression pressure by containing, for example, sugar or sugar alcohol, a disintegrating agent and cellulose. It has a hardness that does not cause any problems, and has obtained a title preparation that rapidly disintegrates in the presence of a small amount of water in the presence of saliva in the oral cavity (Patent Document 4), containing sugar or sugar alcohol and cellulose A rapidly disintegrating solid preparation containing Group 1 and Group 2 containing sugar and / or sugar alcohol and cellulose and further containing a dissolution aid (Patent Document 5) ), A water-soluble sugar alcohol such as sorbitol and a solid preparation (Patent Document 6) containing a low-substituted hydroxypropyl cellulose having a hydroxypropoxyl group content of 7.0 to 9.9% by weight Are known.
Atacand (registered trademark) tablets marketed in the United States are active ingredient candesartan cilexetil, and additives such as excipients such as hydroxypropyl cellulose, polyethylene glycol, lactose, corn starch, carboxymethylcellulose calcium, and stearic acid Contains magnesium.

EP0459136A1 JP 2009-107944 A JP-A-5-194218 JP 2001-58944 A JP 2003-34655 A JP 2009-292843 A

  Conventional oral formulations of candesartan cilexetil are not sufficient for tablet stability and disintegration. Accordingly, an object of the present invention is to provide a candesartan cilexetil oral preparation, specifically a tablet and an intraorally rapidly disintegrating tablet, which have improved stability, good disintegration, and good dissolution of candesartan cilexetil.

The present inventors have studied an oral preparation of candesartan cilexetil, and surprisingly, it has been found that if stearic acid is used as a stabilizer, the stability of the active ingredient is significantly improved. If lactose and / or crystalline cellulose is used, disintegration and the like can be improved, and the above problems can be solved, that is, the release of active ingredients from the preparation is good, and the preparation is stable over time. The present invention has been completed by discovering that the preparation has good properties and does not cause decomposition products in the preparation and is excellent in change in formulation.
Specifically, it relates to an oral preparation of candesartan cilexetil which has increased stability. More specifically, the present invention relates to a candesartan cilexetil tablet or an orally rapidly disintegrating tablet using stearic acid as a stabilizer and further using crystalline cellulose and / or lactose as an excipient.
Furthermore, regarding an intraoral quick disintegrating tablet, it is related with the manufacturing method characterized by manufacturing a tablet.

That is, the present invention relates to the inventions described in 1 to 7 below.
1. A candesartan cilexetil oral preparation containing candesartan cilexetil as an active ingredient and stearic acid as a stabilizer.
2. The candesartan cilexetil oral preparation according to the above 1, which contains lactose as an excipient.
3. Furthermore, the candesartan cilexetil oral formulation of said 1 or 2 containing a crystalline cellulose as an excipient | filler.
4). The candesartan cilexetil oral formulation according to any one of 1 to 3 above, wherein the ratio of lactose to crystalline cellulose is 1: 1 to 6: 1.
5. The candesartan cilexetil oral preparation according to any one of 1 to 4 above, wherein the oral preparation is a tablet or a rapidly disintegrating tablet in the oral cavity.
6). 6. The oral preparation of candesartan cilexetil according to 5 above, which is an intraoral rapidly disintegrating tablet compressed at 2 to 20 kN.
7). In the first step, granules containing candesartan cilexetil, excipients and binders other than crystalline cellulose are produced, and then the obtained granules and crystalline cellulose, disintegrant and lubricant are mixed uniformly, A method for producing candesartan cilexetil tablets for molding.
The above-mentioned present invention can be similarly applied to angiotensin II receptor antagonists other than candesartan cilexetil.

The oral preparation of the present invention, especially the tablet, candesartan cilexetil tablets, which have good stability over time of the preparation, do not cause degradation products in the preparation, have excellent compounding changes, and have excellent moldability and disintegration (drug release properties). Can be obtained. Therefore, the candesartan cilexetil tablet of the present invention is extremely useful as a pharmaceutical product.
In particular, the tablet of the present invention can ensure a certain hardness by molding under reduced tableting pressure, and can be easily disintegrated by saliva in the oral cavity when taken (OD tablet). It can also be. In addition, there is no problem with texture and taste in the oral cavity. Therefore, it is easy for patients and elderly people who have difficulty in swallowing the drug, can be easily taken without water, and can be a preparation excellent for patients and QOL (Quality of Life). In addition, there is no problem such as easy formulation and lack of tablets during transportation.

The present invention relates to candesartan cilexetil oral preparations, and more specifically to tablets and intraoral quick disintegrating tablets. Hereinafter, the present invention will be described in detail.
Examples of the oral preparation of the present invention include tablets, capsules, powders, fine granules, granules, troches and the like. The oral preparation of the present invention has no problem as long as it is an oral preparation containing candesartan cilexetil and stearic acid.
The candesartan cilexetil oral preparation of the present invention is usually preferably a tablet.
Of the tablets, ordinary oral tablets or intraoral quick disintegrating tablets are preferred.
The present invention relates to an oral preparation of candesartan cilexetil containing candesartan cilexetil as an active ingredient and stearic acid as a stabilizer, particularly a tablet.
The content of candesartan cilexetil in the preparation of the present invention may be contained in the range of 0.5 to 20% by mass, preferably 1 to 10% by mass with respect to the total amount of the formulation.

Stearic acid used as a stabilizer in the present invention is a saturated fatty acid (higher fatty acid) that is most abundant in animal and vegetable fats. The IUPAC organization name is octadecanoic acid and has the molecular formula C17H35COOH. The free acid is a white solid at room temperature. As stearic acid, various salts such as sodium salt and potassium salt are known. For pharmaceutical use, magnesium stearate is often used as a lubricant in pharmaceutical preparations, particularly tablets. When used as a stabilizer which is the object of the present invention, stearic acid which is a free acid is used. Although various grades of stearic acid are known, any grade can be used in the present invention as long as it is a grade used for pharmaceutical use. The amount of stearic acid used in the present invention can be 10 to 900% by mass, preferably 20 to 300% by mass, and more preferably 30 to 250% by mass with respect to candesartan cilexetil.
The content ratio with respect to 100 parts by mass of the total amount of the preparation is usually about 1 to 10 parts by mass, preferably 2 to 7 parts by mass, more preferably 2 to 6 parts by mass, and most preferably 2 to 4 parts by mass. .

  The oral preparation of the present invention can contain a pharmaceutical preparation additive in addition to the active ingredient and the stabilizer. The pharmaceutical preparation additive may be any pharmaceutically acceptable additive. If necessary, for example, an excipient, a binder, a disintegrant, a disintegration aid, a lubricant, a fluidizing agent, a glossy agent. Agent, foaming agent, moisture-proofing agent, surfactant, stabilizer, emulsifier, antioxidant, filler, preservative, preservative, sweetener, flavoring agent, cooling agent, flavoring agent / fragrance, fragrance Any additive selected from colorants and the like can be contained. In particular, when the oral preparation is a tablet, those conventionally used for tablet production can be used.

The oral preparation of the present invention contains excipients used for normal oral preparations.
Examples of the excipient include corn starch, potato starch, rice starch, powdered sugar, lactose, D-mannitol, trehalose, crystalline cellulose, crystalline cellulose / carmellose sodium, magnesium aluminate metasilicate, calcium hydrogen phosphate, hydro Examples include talcite and silicic anhydride.
Any of these grades can be used as long as they are used in pharmaceuticals. In the present invention, a preparation containing lactose as an excipient is preferred. Lactose is preferred because it adversely affects the stability of candesartan cilexetil but has relatively few adverse effects. In particular, the formation of related substances is remarkably suppressed by the combined use with stearic acid used as a stabilizer in the present invention. For example, the generation of related substances under warming and humidification is significantly suppressed as compared with polyethylene glycol used in Examples in Patent Document 3.
As the lactose, those usually used for pharmaceuticals can be used, and those of any particle size can be used. The content of lactose is preferably about 10 to 90% by weight, more preferably about 20 to 80% by weight, still more preferably about 30 to 80% by weight, based on the total amount of the oral preparation of the present invention, preferably tablets. Especially preferably, it is about 40-80 mass%. Most preferably, it is about 45-75 mass%.
Moreover, when a tablet is an intraoral quick disintegrating tablet, content of lactose may be the same as the above, However, Preferably, it is about 40 to 70 weight%, and about 50 to 60 weight% is still more preferable depending on the case.

The oral preparation of the present invention is also preferred when it contains crystalline cellulose as an excipient. When crystalline cellulose is included, moderate hardness and disintegration can be imparted to the tablet.
As the crystalline cellulose, those usually used for pharmaceuticals can be used. Crystalline cellulose may be microcrystalline. Specific examples of crystalline cellulose include Theola PH101, Theola PH102, Theola PH301, Theola PH302, Theola PH-F20, Theola KG801, Theola KG802, Theola KG1000 (above, manufactured by Asahi Kasei), VIVAPUR (Grades 101, 301, 102, 12) ), ARBOCEL (grades M80, F120, A300), Prosolv SMCC50, Prosolv SMCC90 (manufactured by JRS PHARMA) and the like, and crystalline cellulose can be used singly or in combination of two or more.
The content of crystalline cellulose is preferably about 5 to 60% by weight, more preferably about 10 to 50% by weight, and still more preferably about 15 to 40% by weight, based on the total amount of the tablet. If it is the range of content of said crystalline cellulose, practically sufficient hardness will be obtained.

In the present invention, the preparation containing both lactose and crystalline cellulose has a certain hardness even at a low tableting pressure and is excellent in disintegration, particularly a tablet, more preferably an intraoral quick disintegrating tablet. Can be obtained.
When both lactose and crystalline cellulose are included, the total content of both is preferably about 40 to 90% by weight, more preferably about 50 to 85% by weight, and still more preferably 60 to 80% by weight, based on the total amount of the preparation. .
When both lactose and crystalline cellulose are included, the mass ratio of crystalline cellulose to lactose (crystalline cellulose: lactose) is about 1: 0.5-10. Among these, about 1: 1 to 8 is preferable, about 1: 1 to 6 is more preferable, and about 1: 1 to 4 is more preferable. The most preferable ratio is a ratio of 1: 1.5 to 4 parts by mass. Lactose improves tablet hardness, and crystalline cellulose improves fast disintegration. When the content of crystalline cellulose relative to lactose is in the above range, a practically stable product is obtained, and a tablet having good dissolution and good hardness and rapid disintegration is obtained.

The oral preparation of the present invention, preferably a tablet, may further contain an excipient other than the aforementioned lactose and crystalline cellulose. One preferred excipient that may be included is starch. Any starch can be used, but corn starch is a preferred one.
The above-mentioned excipients other than lactose and crystalline cellulose may be optionally added as necessary, and the content thereof is usually in the range of 0 to 40% by mass with respect to the total amount of the preparation. Preferably it is the range of 10-30 mass%.

The oral preparation of the present invention can optionally contain the above-mentioned pharmaceutical preparation additives other than the above active ingredients, stabilizers and excipients. In particular, when the oral preparation of the present invention is a tablet (including an intraoral quick disintegrating tablet), it is preferable to include a disintegrant, a binder, and a lubricant. Moreover, what is necessary is just to add a coloring agent, a sweetener, etc. as needed.
These will be described in more detail below.
Disintegrants include crospovidone, carboxymethylcellulose calcium (carmellose calcium), croscarmellose sodium, sodium carboxystarch, low-substituted hydroxypropylcellulose, starch, partially pregelatinized starch, alginic acid, calcium alginate, tragacanth powder, agar powder Etc.
Any of the above can be used in the oral preparation of the present invention, particularly tablets (including intraorally rapidly disintegrating tablets). Preferred disintegrants include crospovidone, carboxymethylcellulose calcium (carmellose calcium), croscarmellose sodium, and the like.
The content of the disintegrant is usually 0 to 10% by mass, preferably 1 to 10% by mass, more preferably about 2 to 8% by mass, and further preferably about 2 to 6% by mass with respect to the total amount of the preparation. is there.

A binder is used at the time of granulation, and any binder used for granulation of a normal pharmaceutical preparation can be used. Examples of the binder include carmellose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, alginic acid, gelatin, partially pregelatinized starch, popidone, gum arabic, pullulan, and dextrin. Cellulosic binders such as hydroxypropylcellulose are preferred.
The content of the binder is usually 0.01 to 5% by mass, preferably 0.05 to 2% by mass, more preferably about 0.1 to 2% by mass, and still more preferably 0% with respect to the total amount of the preparation. .About 1-1 mass%.
As the lubricant in the oral preparation of the present invention, particularly tablets (including intraorally rapidly disintegrating tablets), it can be appropriately selected from those usually used such as magnesium stearate or calcium stearate. In the present invention, magnesium stearate is preferred. When using a lubricant, the content of the lubricant with respect to the total amount of the preparation of the present invention is usually about 0.01 to 5% by mass, preferably about 0.05 to 3% by mass, more preferably 0.1. About 2% by mass, more preferably about 0.1-1% by mass.

Examples of the colorant include edible pigments such as yellow ferric oxide, red ferric oxide, edible yellow No. 5 and edible blue No. 2, and edible lake pigments. In the present invention, the colorant is used as necessary, and the content relative to the total amount of the preparation is in the range of 0 to 1% by mass.
Examples of the sweetener (or flavoring agent) include aspartame, sodium saccharin, stevia, glycyrrhizin dipotassium and the like. In the present invention, the sweetener is used as necessary, and the content of the preparation with respect to the total amount of the preparation is in the range of 0 to 1% by mass.
Other additives other than those that may be included in the oral preparation of the present invention include fluidizing agents, antioxidants, solubilizers, and fragrances.
Examples of the fluidizing agent include light anhydrous silicic acid, calcium silicate, and synthetic aluminum silicate. Examples of the antioxidant include ascorbic acid and tocopherol.
The solubilizing agent typically includes a surfactant, and more specifically, for example, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid ester, polysorbate, fatty acid glycerin ester, lauryl. Examples thereof include sodium sulfate. Each of these additive components can be used alone or in combination of two or more.
Examples of the flavor include L-menthol, lemon, orange, strawberry, mint and the like.
In the oral preparation of the present invention, there is no problem even if these are not usually contained.

An example of the composition of a preferred oral preparation of the present invention, for example, a tablet (including a rapidly disintegrating tablet in the oral cavity), shows that (a) 1-10 parts by mass of candesartan cilexetil, (b) with respect to 100 parts by mass of the total preparation. 1-6 parts by mass of stearic acid (preferably 2-4 parts by mass), (c)
Examples of pharmaceutical preparation additives other than those described above in the balance include excipients, disintegration aids, binders, lubricants, and the like, including at least one selected from the group consisting of them, and a total amount of 84. It is -98 mass parts.
When the oral preparation of the present invention is an intraoral rapidly disintegrating tablet, there is no problem in the above range, but preferably (a) 2-7 parts by mass of candesartan cilexetil with respect to 100 parts by mass of the intraoral rapidly disintegrating tablet. (B) 3-4 parts by mass of stearic acid, and (c) the balance is a pharmaceutical preparation additive other than the above.

  In the oral preparation of the present invention, the above active ingredient, the stabilizer stearic acid and the necessary pharmaceutical preparation additives may be appropriately mixed, granulated as necessary, and used as a granule preparation as it is. In the present invention, since a tablet is preferable, it is preferable to add a lubricant or the like to the granulated product (granules) obtained by the above granulation by a conventional method, and to form a tablet by tableting. The tablet can be produced using a tablet production method found in ordinary pharmaceutical products. Specifically, by a known method such as fluidized bed granulation method, spray drying method, kneading method, rolling granulation method, etc., for example, first of all, a mixture of active ingredient, stabilizer stearic acid and excipient Granulate. In the present invention, a kneading method is preferably employed. It is desirable that the granulated product is appropriately dried and used in the next step.

The composition (granulated product) obtained above is mixed with a lubricant and, if necessary, further necessary pharmaceutical preparation additives, and then compression-molded (tablet) (internal lubrication method). Alternatively, the composition before granulation is mixed with the composition (granulated product) before tableting obtained above, if necessary, without further mixing with a lubricant, and if necessary, further necessary pharmaceutical preparation additives are mixed. The tablet of the present invention can be obtained by molding the product by a method such as tableting (external lubrication method) while spraying the lubricant on the punch and die.
Further, in the present invention, a part of the excipient is granulated and then mixed with a lubricant and the like to obtain a tableting mixture, and the tableting mixture is tableted to obtain the tablet of the present invention. The method is also preferable. In particular, in the present invention, when at least lactose and crystalline cellulose are used in combination as excipients, excipients such as lactose, excluding the above active ingredients, stearic acid, and crystalline cellulose, can be obtained using a binder. To obtain a granulated product (granule), and together with a lubricant, crystal cellulose is blended and tableted to obtain a tablet of the present invention. The tablet produced by this method can suppress the increase in production of the related substance of candesartan cilexetil, which is an active ingredient, during storage, and can achieve a more favorable effect.

In tableting, it is effective to obtain a good disintegration by performing tableting by a method in which a small amount of lubricant is adhered to the tablet surface by an external lubrication method.
As described above, the blending amount of the lubricant in the tablet of the present invention is in the range of 0.05 to 5% by mass with respect to the total amount of the preparation. In the external lubrication method, the lubrication effect is shown in a smaller amount, so that it is usually 0.05 to 1 mass%. Tableting can be performed using an appropriate tableting machine such as a rotary tableting machine, a single-shot tableting machine, or a hydraulic press machine.
The tableting pressure of the candesartan cilexetil orally disintegrating tablet of the present invention is preferably 2 to 20 kN, more preferably 5 to 12 kN when the tablet diameter is 5 to 10 mm. Can do.
In the present invention, desirable stability can be obtained by carrying out at the above tableting pressure.
The oral disintegrating tablet of candesartan cilexetil of the present invention has a disintegration time of 60 seconds, preferably 50 seconds, and more preferably 40 seconds or less.
The shape of the tablet in the present invention is not particularly limited, and may be any of a round tablet, an oval tablet, various deformed tablets, and the like. Moreover, it is good also as a split tablet with a score line.

Example 1
Candesartan cilexetil 8.00 g, lactose hydrate 260.52 g, corn starch 68.00 g and stearic acid 70.40 g were charged into a high-speed agitation granulator (manufactured by Paulek: FM-VG-01 type), and hydroxypropylcellulose A solution obtained by dissolving 1.32 g in 25.34 g of purified water was added and granulated. The resulting granulated product is dried in a shelf dryer set at 80 ° C. and then sized, mixed with crystalline cellulose, croscarmellose sodium and magnesium stearate, and compression molded at a pressure of 4 to 6 kN. A tablet having a diameter of 7.0 mm and a mass of 130 mg and having the composition shown in Table 1 below was obtained.

Example 2
Candesartan cilexetil 12.00 g, lactose hydrate 295.62 g, corn starch 66.72 g, yellow iron sesquioxide 0.063 g and stearic acid 15.72 g were mixed with a high-speed agitation granulator (manufactured by Paulec: FM-VG-01 type) ), And a solution obtained by dissolving 1.26 g of hydroxypropylcellulose in 31.31 g of purified water was added and granulated. The resulting granulated product is dried in a shelf dryer set at 80 ° C. and then sized, and mixed with crystalline cellulose, aspartame, fragrance, yellow ferric oxide, croscarmellose sodium and magnesium stearate. Then, compression molding was performed at a pressure of 6 to 8 kN to obtain an orally rapidly disintegrating tablet having a composition shown in Table 2 below having a diameter of 6.0 mm and a mass of 85 mg.

Comparative Example 1
Candesartan cilexetil, lactose hydrate and corn starch were added to the mortar in the proportions shown in Table 3 below and mixed uniformly, and then a solution in which hydroxypropylcellulose was dissolved in purified water was added to granulate the mortar. The resulting granulated product is dried in a shelf dryer set at 60 ° C. and then sized, mixed with carboxymethyl cellulose calcium and magnesium stearate, compression molded, diameter 7 mm, mass 130 mg, hardness 5 kgf. Tablets having the compositions shown in Table 3 below were obtained.

Test example 1
Purity test after storage (warming condition) (measurement of content of related substances)
The candesartan cilexetil tablets obtained in Examples 1 and 2 and Comparative Example 1 were stored at 60 ° C. for 2 weeks, and the content of related substances before storage and the content of related substances after storage were measured by the following methods. . The results are shown in Table 4.

Method for measuring related substances Prepare this product as powder, take an amount corresponding to 25 mg of candesartan cilexetil according to the indicated amount, add acetonitrile / sodium dihydrogen phosphate buffer solution (3: 5) to make 25 mL, and shake. This solution is centrifuged, and the supernatant is used as a sample solution. Pipet 1 mL of this solution and add the mobile phase to make exactly 100 mL. Pipet 1 mL of this solution, add the mobile phase to make exactly 10 mL, and use this solution as the standard solution. Liquid chromatography was performed on 20 μL of the sample solution and standard solution under the following conditions.
Each peak area of each solution was measured by an automatic integration method.
When the retention time of candesartan cilexetil is 11.0 minutes, the related substances have peaks at retention times of 5.3 minutes, 8.5 minutes, 12.5 minutes, 16.9 minutes, 22.2 minutes. From the peak area, the content of related substances was determined.
As related substances, compounds represented by the following structural formula were measured.

Measurement condition detector: UV absorption photometer (measurement wavelength: 220 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm is packed with 5 μm of phenylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 26 ° C. Mobile phase: 300 mL of acetonitrile and 3 mL of triethylamine are added to 500 mL of sodium dihydrogen phosphate buffer.
Flow rate: Adjust the flow rate so that the retention time of candesartan cilexetil is about 9 minutes.
Area measurement range: The sample solution is approximately 6 times the retention time of candesartan cilexetil, and the standard solution is approximately 2 times the retention time of candesartan cilexetil.

Example 3
Candesartan cilexetil, lactose hydrate, corn starch, and stearic acid were added to the mortar in the proportions shown in Table 5 below and mixed uniformly, and then a solution in which hydroxypropylcellulose was dissolved in purified water was added. did. The resulting granulated product is dried in a shelf dryer set at 60 ° C. and then sized, mixed with carboxymethyl cellulose calcium and magnesium stearate, compression molded, diameter 7 mm, mass 130 mg, hardness 5 kgf. Tablets having the compositions shown in Table 5 below were obtained.

Comparative Example 2
Candesartan cilexetil, lactose hydrate, polyethylene glycol 6000, and corn starch were added to the mortar in the proportions shown in Table 6 below, and a solution obtained by dissolving hydroxypropylcellulose in purified water was added to granulate the mortar. The obtained granulated product was dried in a shelf dryer set at 60 ° C. and then sized, mixed with carboxymethylcellulose calcium and magnesium stearate, tableted in the same manner as in Example 3, 7 mm in diameter, A tablet having the composition shown in Table 6 below and having a mass of 130 mg and a hardness of 5 kgf was obtained.

Test example 2
Purity test after storage (warm and humidified) (measurement of related substances)
The candesartan cilexetil tablets obtained in Example 3 and Comparative Example 2 were stored for 2 weeks under conditions of a temperature of 60 ° C. and a humidity of 75%, and the content of related substances before storage and the content of related substances after storage were determined. Measurement was performed in the same manner as in Test Example 1. The results are shown in Table 7.

Test example 3
Disintegration test A disintegration test was conducted using Example 2 and Comparative Example 1.
Test method:
Use a tester adjusted to perform 29-32 reciprocating vertical movements per minute. Place one sample per glass tube of the tester, and then operate the tester at 37.0 ± 2 ° C using water as the test solution. At this time, when the tester is at the highest position, the mesh surface of the tester should be at least 15 mm away from the liquid level. When the tester is at the lowest position, the mesh surface is at least 25 mm from the bottom of the beaker. It should not be allowed to sink completely. The test results are shown in Table 8 below.

The candesartan cilexetil oral preparation of the present invention, particularly tablets, has good stability over time, and even after storage, the increase in the related substances of candesartan cilexetil is extremely small, and the moldability and disintegration (drug release) are excellent. Excellent.
Therefore, the candesartan cilexetil tablet of the present invention is extremely useful as a pharmaceutical product.

Claims (7)

  A candesartan cilexetil oral preparation containing candesartan cilexetil as an active ingredient and stearic acid as a stabilizer.   The oral preparation of candesartan cilexetil according to claim 1, which contains lactose as an excipient.   Furthermore, the candesartan cilexetil oral formulation of Claim 1 or 2 containing a crystalline cellulose as an excipient | filler.   The ratio of lactose to crystalline cellulose is 1: 1 to 6: 1. The candesartan cilexetil oral preparation according to any one of claims 1 to 3.   The oral preparation of candesartan cilexetil according to any one of claims 1 to 4, wherein the oral preparation is a tablet or a rapidly disintegrating tablet in the oral cavity.   The oral preparation of candesartan cilexetil according to claim 5, which is an intraoral quick disintegrating tablet compressed at 2 to 20 kN.   In the first step, granules containing candesartan cilexetil, excipients and binders other than crystalline cellulose are produced, and then the obtained granules and crystalline cellulose, disintegrant and lubricant are mixed uniformly, A method for producing candesartan cilexetil tablets for molding.