JP5705562B2 - Candesartan cilexetil-containing tablet and method for producing the same - Google Patents

Description

  The present invention relates to a candesartan cilexetil-containing tablet useful for the treatment of patients with hypertension, renal parenchymal hypertension, chronic heart failure and the like, and a method for producing the same.

  In general, when an active ingredient is excessively absorbed in pharmaceuticals, side effects such as nausea and vomiting may occur. Therefore, there is a demand for a preparation that suppresses excessive absorption of an active ingredient, thereby suppressing side effects and improving patient pain.

  It is known that candesartan cilexetil can suppress blood concentration by adjusting the crystal particle size (see Non-Patent Document 1). However, on the other hand, in candesartan cilexetil, crystal distortion occurs due to pressure, friction, heat, etc. in the formulation process, and the daily content may decrease (see Patent Document 1). It is difficult to adjust the particle size of the drug substance by the method.

  As described above, candesartan cilexetil causes distortion of crystals due to pressure and the like, so that crystals are deformed in the preparation process, causing a decrease in purity and degradation over time. Therefore, various methods for stabilizing candesartan cilexetil formulations have been proposed (see Patent Document 1 and Patent Document 2). For example, Patent Document 1 proposes to add a low melting point oily substance to suppress the decomposition of the active ingredient in order to stabilize the candesartan cilexetil preparation. For the same purpose, Patent Document 2 proposes that a hydrophilic substance having hydrocolloid properties is added to appropriately stabilize the active ingredient against deterioration during tableting. However, the patent literature on these candesartan cilexetil formulations has no description or suggestion about suppression of excessive absorption of candesartan cilexetil.

JP-A-5-194218 Special table 2008-528456 gazette

“Drug Bioavailability” P521-523 (The Biopharmaceutical Classification System), published by WILEY-VCH, 2003

  The purpose of the present invention is not only to suppress and stabilize the degradation of candesartan cilexetil in tablets containing candesartan cilexetil, but also to suppress excessive absorption of candesartan cilexetil, which leads to a rapid decrease in blood pressure. An object of the present invention is to provide a candesartan cilexetil-containing tablet in which the side effects involved are suppressed and the patient's pain is improved and a method for producing the same.

  As a result of diligent research to achieve the above object, the present inventor, as a substance that stabilizes candesartan cilexetil, particularly by selecting and using stearic acid, candesartan cilexetil in candesartan cilexetil-containing tablets It was found that the excessive absorption of candesartan cilexetil was suppressed while the decomposition of was suppressed and stabilized. The present inventor has made further studies based on such knowledge, and has completed the present invention.

  The present invention provides the following candesartan cilexetil-containing tablets and methods for producing the same.

  1. Candesartan cilexetil-containing tablet comprising candesartan cilexetil and stearic acid.

  2. The candesartan cilexetil-containing tablet according to item 1, wherein the stearic acid content is 0.5 to 40% by weight based on the total weight of the tablet.

  3. A method for producing a candesartan cilexetil-containing tablet, wherein stearic acid is added to candesartan cilexetil.

  According to the candesartan cilexetil-containing tablet of the present invention, the following remarkable effects can be obtained by mixing stearic acid with candesartan cilexetil.

  (1) A candesartan cilexetil-containing tablet in which decomposition of candesartan cilexetil in a candesartan cilexetil-containing tablet is suppressed and stabilized is provided.

  (2) In addition to suppressing the degradation of candesartan cilexetil in the candesartan cilexetil-containing preparation, excessive absorption of candesartan cilexetil is further suppressed, which leads to nausea and vomiting associated with rapid blood pressure reduction. The present invention provides candesartan cilexetil-containing tablets in which side effects such as dizziness and rash are suppressed and the patient's pain is improved.

  (3) Moreover, according to the manufacturing method of the candesartan cilexetil-containing tablet of the present invention, candesartan cilexetil in the candesartan cilexetil-containing tablet can be obtained by a simple method in which stearic acid is added to candesartan cilexetil. Contains candesartan cilexetil, which not only suppresses and stabilizes but also prevents excessive absorption of candesartan cilexetil, which in turn suppresses side effects associated with rapid blood pressure reduction and improves patient pain Tablets can be easily prepared.

FIG. 1 is a graph showing the results of measuring the plasma concentration of candesartan over time when the candesartan cilexetil-containing tablets obtained in Example 1 and Comparative Example 1 were taken. FIG. 2 is a graph showing the results of a dissolution test of candesartan cilexetil-containing tablets obtained in Example 1 and Comparative Example 1.

Candesartan cilexetil-containing tablet The candesartan cilexetil-containing tablet of the present invention comprises candesartan cilexetil and stearic acid as a substance that stabilizes candesartan cilexetil. Not only is decomposition and stabilization of cetyl suppressed, but excessive absorption of candesartan cilexetil is suppressed.

  The candesartan cilexetil-containing tablet of the present invention contains candesartan cilexetil and stearic acid, and candesartan cilexetil, stearic acid, and a pharmacologically acceptable drug usually used in the pharmaceutical field. Various additives such as excipients, disintegrants, binders and the like mixed and contained.

  Candesartan cilexetil-containing tablets include plain tablets, coated tablets, sustained release tablets, orally disintegrating tablets, chewable tablets and the like.

Candesartan cilexetil candesartan cilexetil is a medicinal component of the tablet of the present invention and has a chemical name of (RS) -1-[(cyclohexyloxy) carbonyloxy] ethyl 2-ethoxy-1-{[2 ′-(1H -Tetrazol-5-yl) -biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylate. Candesartan cilexetil has a persistent angiotensin II receptor antagonistic action and is useful as a therapeutic agent for hypertension, renal parenchymal hypertension and the like.

The additives candesartan cilexetil and stearic acid are usually used in combination with at least one pharmacologically acceptable additive of excipients, disintegrants and binders.

  Examples of excipients include starches such as crystalline cellulose and corn starch; lactose, powdered sugar, granulated sugar, glucose, mannitol, light anhydrous silicic acid, talc, magnesium oxide, magnesium carbonate, calcium carbonate, anhydrous hydrogen phosphate Examples include calcium, tricalcium phosphate, xylitol, sorbitol and the like. These excipients can be used alone or in combination of two or more.

  Examples of the disintegrant include crystalline cellulose, sodium carboxymethyl starch, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, cross-linked polyvinyl pyrrolidone, low-substituted hydroxypropyl cellulose, starches and the like. These disintegrants can be used alone or in combination of two or more.

  As binders, conventional binders such as sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose (carmellose), crystalline cellulose / sodium carboxymethylcellulose, polyvinylpyrrolidone, pullulan, dextrin Tragacanth, sodium alginate, pregelatinized starch, polyvinyl alcohol and the like. These binders can be used alone or in combination of two or more.

  The ratio of the additive which is at least one of these excipients, disintegrants and binders can be selected from a range of about 500 to 10,000 parts by weight with respect to 100 parts by weight of candesartan cilexetil, and usually 700 to The amount is preferably about 8000 parts by weight, and more preferably about 900 to 7000 parts by weight.

  In addition to pharmacologically acceptable additives such as excipients, disintegrants and binders, candesartan cilexetil includes other conventional pharmaceutically acceptable additives such as lubricants. Reagents, fluidizers, antistatic agents, surfactants, corrigents, wetting agents, fillers, extenders, adsorbents, preservatives (eg preservatives), buffers, disintegration extenders, colorants, etc. May be added.

  Examples of the lubricant include magnesium stearate, light anhydrous silicic acid, talc, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, L-leucine and the like. Examples of the antistatic agent include light anhydrous silicic acid. Examples of surfactants include anionic surfactants such as sodium alkyl sulfate; nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, and polyoxyethylene castor oil derivatives. Can do. Examples of the corrigent include sweeteners such as sucrose, lactose, mannitol, xylitol, saccharin, sodium saccharin, aspartame, stevioside, sucralose, acesulfame potassium, thaumatin, and erythritol; and flavoring agents. Examples of the wetting agent include polyethylene glycol (macrogol), glycerin, propylene glycol and the like.

  These other conventional additives can be used alone or in combination of two or more. These components are not particularly limited in content in the final tablet.

  The method for producing a candesartan cilexetil-containing tablet of the present invention is characterized in that stearic acid is added to candesartan cilexetil. Tablets containing candesartan cilexetil and stearic acid can be produced according to methods known in the pharmaceutical art. For example, candesartan cilexetil, stearic acid, and additives such as excipients, disintegrants, binders, etc. are mixed, granulated, dried, granulated, tableted, etc. using commonly used solvents A tablet can be manufactured by performing each operation of according to a method well known in the art. You may mix a disintegrating agent, a lubricant, etc. after sizing and before tableting. Among these operations, the granulation operation may be performed using an apparatus such as a stirring granulator, a fluidized bed granulator, a Brabender, or a twin screw granulator. Tableting can be performed using a commercially available tableting machine.

  In the candesartan cilexetil-containing tablet of the present invention, the content of stearic acid is usually preferably about 0.5 to 40% by weight, and about 1 to 20% by weight with respect to the total weight of the tablet. Is more preferable.

  In the production of the candesartan cilexetil-containing tablet of the present invention, the uncoated tablet or granulated elementary granule may be coated. When coating, it is preferable to carry out by means of a film coating machine, a fluidized bed granulator or the like. Coatings include, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, hydroxypropylmethylcellulose acetate succinate, hypromellose phthalate, cellulose acetate phthalate, aminoalkyl methacrylate copolymer E, Use coating agents well known in the art such as aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, dry methacrylic acid copolymer LD, ethyl acrylate / methyl methacrylate copolymer dispersion, sucrose, etc. be able to.

  When the candesartan cilexetil-containing tablet of the present invention is used, an effective amount of treatment for patients with hypertension, renal parenchymal hypertension, chronic heart failure and the like may be administered to humans. The dose may vary depending on the patient's age, weight, symptoms, sex, etc., but is usually 1 to 50 mg in terms of candesartan cilexetil, once a day or divided into several as needed. The degree can be administered orally.

  The tablet of the present invention has, for example, a reduction in purity of candesartan cilexetil, which is the main drug after storage for 2 weeks under the condition of 50 ° C. tight plug, less than 0.4%, and has sufficient stability over time, In addition, by suppressing the plasma concentration of candesartan cilexetil, an effect of reducing side effects associated with a rapid decrease in blood pressure can be obtained.

  The tablet of the present invention may be packaged in PTP or bottle (eg, plastic bottle, glass bottle, aluminum can). Moreover, those packaged tablets may be further subjected to secondary packaging such as pillow packaging. A deodorant, a desiccant, an oxygen scavenger and the like may be enclosed during packaging.

  EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated further more concretely, this invention is not restrict | limited at all by these Examples.

Example 1
In a fluidized bed granulator (manufactured by Paulec Co., Ltd.), 24.0 g of candesartan cilexetil, 552 g of lactose hydrate, 120 g of corn starch, and 24.0 g of stearic acid were mixed, and an aqueous solution of hydroxypropylcellulose was sprayed. Granulated and dried. This was sized with a No. 22 sieve. The obtained sized product, 33.6 g of carmellose calcium and 2.40 g of magnesium stearate were mixed with a V-type mixer (manufactured by Fuji Powder Co., Ltd.), and the resulting mixed powder was rotary-type tableted. Tablets were obtained using a machine (manufactured by Kikusui Seisakusho Co., Ltd.) so that the weight per tablet was 130.0 mg and the thickness was 2.7 mm.

Comparative Example 1
In a fluidized bed granulator (manufactured by Paulec Co., Ltd.), 24.0 g of candesartan cilexetil, 576 g of lactose hydrate, and 120 g of corn starch were mixed, granulated and dried by spraying an aqueous solution of hydroxypropylcellulose. . This was sized with a No. 22 sieve. The obtained sized product, 33.6 g of carmellose calcium and 2.40 g of magnesium stearate were mixed with a V-type mixer (manufactured by Fuji Powder Co., Ltd.), and the resulting mixed powder was rotary-type tableted. Tablets were obtained using a machine (manufactured by Kikusui Seisakusho Co., Ltd.) so that the weight per tablet was 130.0 mg and the thickness was 2.7 mm.

Example 2
In a fluidized bed granulator (manufactured by Paulec Co., Ltd.), 48.0 g of candesartan cilexetil, 537.6 g of lactose hydrate, 120 g of corn starch and 24.0 g of stearic acid were mixed, and an aqueous solution of hydroxypropylcellulose was mixed. Sprayed granulated and dried. This was sized with a No. 22 sieve. The obtained sized product, 24.0 g of carmellose calcium and 2.40 g of magnesium stearate were mixed with a V-type mixer (manufactured by Fuji Powder Co., Ltd.), and the resulting mixed powder was rotary-type tableted. Tablets were obtained using a machine (manufactured by Kikusui Seisakusho Co., Ltd.) so that the weight per tablet was 130.0 mg and the thickness was 2.7 mm.

Example 3
In a fluidized bed granulator (manufactured by Paulec Co., Ltd.), 48.0 g of candesartan cilexetil, 513.6 g of lactose hydrate, 120 g of corn starch and 48.0 g of stearic acid were mixed, and an aqueous solution of hydroxypropyl cellulose was mixed. Sprayed granulated and dried. This was sized with a No. 22 sieve. The obtained sized product, 24.0 g of carmellose calcium and 2.40 g of magnesium stearate were mixed with a V-type mixer (manufactured by Fuji Powder Co., Ltd.), and the resulting mixed powder was rotary-type tableted. Tablets were obtained using a machine (manufactured by Kikusui Seisakusho Co., Ltd.) so that the weight per tablet was 130.0 mg and the thickness was 2.7 mm.

  Table 1 shows the ingredient formulation per tablet (130.0 mg).

  Next, the stability test of the candesartan cilexetil-containing tablet obtained in Examples 1 to 3 and Comparative Example 1 was performed. The stability test was performed by storing for 2 weeks under the storage condition of a 50 ° C. sealed stopper.

  About the tablet after a start and a stability test, the peak area of candesartan cilexetil was investigated using HPLC, and the ratio (purity) with respect to the peak area of a candesartan cilexetil pure product was computed. For the sample solution, take one test tablet, pulverize it, add a mixture of water / methanol (1/9 volume ratio), extract with ultrasonic waves for 10 minutes, and filter the filtrate obtained as a sample solution. The purity was examined by the following HPLC measurement method.

HPLC measurement method Detector: UV absorption photometer (measurement wavelength: 254 nm)
Column: Octadecylsilylated silica gel Column temperature: constant temperature around 35 ° C. Mobile phase: pH 3.0 phosphate buffer and methanol mixture Flow rate: 0.05 mL / min

  Table 2 shows the candesartan cilexetil-containing tablets obtained in Example 1, Comparative Example 1 and Examples 2 to 3, at the start of the stability test and after the completion of the test in which the stability test was conducted for 2 weeks. The purity (%) of lexetyl was indicated.

  From Table 2, it is clear that the tablet of Example 1 blended with stearic acid is significantly superior in the stability of candesartan cilexetil compared to the tablet of Comparative Example 1 blended without stearic acid. is there.

  Next, for each candesartan cilexetil-containing tablet obtained in Example 1 and Comparative Example 1, the plasma concentration of candesartan when it was administered to humans was measured. The administration method and plasma concentration measurement method are as follows.

Administration method A crossover test was conducted with 9 healthy adult males 20 to 35 years old as one group and a total of 18 people from 2 groups as subjects. That is, after administering the tablets of Example 1 or Comparative Example 1 to each group and measuring the plasma concentration, a 7-day drug holiday was provided, and then the tablets to be administered were crossed and administered. The plasma concentration was measured. As for the dosage and administration method, one test tablet was orally administered with water under fasting.

Method for measuring plasma concentration Methanol is added to 0.1 mL of plasma to make a total volume of 1 mL, and after stirring, centrifuged. Take 0.1 mL of the supernatant, mix with 0.4 mL of a water / methanol (1/1 volume ratio) mixture, and use 5 μL of this solution with the following LC / MS / MS (manufactured by Shimadzu Corporation) to produce candesartan. The plasma concentration of is measured.

Column: Octadecylsilylated silica gel Mobile phase: Mixture of 0.1% formic acid aqueous solution and acetonitrile Determination range: 1 to 200 ng / mL

  Table 3 shows the results of measuring the concentration of candesartan in plasma (average of 18 cases and SD) when administered to humans for the candesartan cilexetil-containing tablets obtained in Example 1 and Comparative Example 1. In addition, the candesartan concentration before administration is zero.

  Moreover, the graph about the result (mean value +/- SD) which measured the plasma concentration when the candesartan cilexetil containing tablet of Example 1 and Comparative Example 1 which were shown in FIG. Indicated.

  From Table 3 and FIG. 1, the candesartan cilexetil-containing tablet of Example 1 blended with stearic acid in the plasma of candesartan compared to the candesartan cilexetil-containing tablet of Comparative Example 1 not blended with stearic acid. It is clear that the concentration is suppressed.

  Next, the dissolution test was performed on the candesartan cilexetil-containing tablets obtained in Example 1 and Comparative Example 1. The dissolution test method is as follows.

Dissolution test The test was conducted according to the second dissolution test method (paddle method) of 14 Japanese Pharmacopoeia, 5 minutes later, 10 minutes later, 15 minutes later, 30 minutes later, 45 minutes later, 60 minutes later The elution rate (%) of candesartan cilexetil after 90 minutes and 120 minutes was examined by the following HPLC measurement method.

HPLC measurement method Detector: UV absorption photometer (measurement wavelength: 254 nm)
Column: Octadecylsilylated silica gel Column temperature: Constant temperature around 35 ° C. Mobile phase: Mixed liquid of acetonitrile and dilute acetic acid Flow rate: 0.5 mL / min

The test conditions for the dissolution test are as follows.
Sample amount: 1 tablet Test solution: 0.01% (W / V) polysorbate 80 added pH 6.8 test solution Paddle rotation speed: 50 rpm

  Table 4 shows the results of the dissolution test. Each elution rate (%) is shown as a result of measuring an average value and SD of three cases. The dissolution rate before the test is 0%.

  In FIG. 2, the graph which showed the result (average value) of the dissolution test of the candesartan cilexetil containing tablet obtained in Example 1 and Comparative Example 1 was shown.

  From Table 4 and FIG. 2, it is clear that there is no substantial difference in dissolution rate regardless of the presence or absence of stearic acid in the candesartan cilexetil-containing tablets. Also, from the dissolution rate test results and the blood concentration test results of candesartan shown in Table 3 and FIG. 1, in the candesartan cilexetil-containing tablets, there is a difference in dissolution rate. Despite the absence, it is clear that blood levels can be suppressed.

The candesartan cilexetil-containing tablet of the present invention is useful for the treatment of patients with hypertension, renal parenchymal hypertension, chronic heart failure and the like, and the present invention is effectively used in the pharmaceutical field.

Claims (2)

A candesartan cilexetil-containing tablet comprising candesartan cilexetil and 1 to 20% by weight of stearic acid based on the total weight of the tablet. A method for producing a candesartan cilexetil-containing tablet, wherein 1 to 20% by weight of stearic acid is blended with candesartan cilexetil relative to the total weight of the tablet .

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