JP2012162467A - Method for producing candesartan cilexetil-containing granule and method for producing candesartan cilexetil-containing tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing candesartan cilexetil-containing granules wherein candesartan cilexetil is prevented from decomposing and stabilized, and a method for producing a candesartan cilexetil-containing tablet wherein candesartan cilexetil is prevented from decomposing and stabilized.SOLUTION: In the method for producing candesartan cilexetil-containing granules, a mixture containing candesartan cilexetil and D-mannitol is granulated in a fluidized bed. Granules obtained by this method, the method for producing a candesartan cilexetil-containing tablet by forming the granules into a tablet, and the candesartan cilexetil-containing tablet obtained by the method are also provided.

Description

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

  Since candesartan cilexetil is distorted by pressure, friction, heat, etc., the crystals are deformed in the preparation process, resulting in 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.

  Usually, lactose or D-mannitol is used as an excipient for the preparation. However, in the case of lactose intolerance, lactose causes symptoms such as indigestion and diarrhea. On the other hand, D-mannitol does not have such a problem, and since a refreshing feeling derived from a sugar alcohol is obtained, it is often used as an excipient for preparations. However, when D-mannitol is used as an excipient, the resulting granulated product may be heavy and hard.

  In the formulation process of candesartan cilexetil, if the granulated product becomes heavy and hard, even if the low melting point oily substance or hydrophilic substance is added for stabilization, the granulation process or In the subsequent tableting process, the crystal form is deformed, and the candesartan cilexetil preparation cannot be stabilized.

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

  An object of the present invention is to provide a method for producing a candesartan cilexetil-containing granulated product in which decomposition of candesartan cilexetil in the granulated product is suppressed and stabilized, and decomposition of candesartan cilexetil in a tablet is suppressed. It is providing the manufacturing method of the tablet containing the candesartan cilexetil containing stabilized.

  As a result of intensive studies to achieve the above object, the present inventor granulated a mixture containing candesartan cilexetil and D-mannitol by a fluidized bed granulation method, thereby producing a candesartan cilexetil-containing granulated product. It was found that the decomposition of candesartan cilexetil in the tablet obtained by compressing the inside thereof was suppressed and stabilized. The present inventor has made further studies based on such knowledge, and has completed the present invention.

  The present invention relates to the following method for producing candesartan cilexetil-containing granulated product, granulated product obtained by the method, and method for producing candesartan cilexetil-containing tablet and candesartan cilexetil-containing tablet obtained by the method Is to provide.

  1. A method for producing a candesartan cilexetil-containing granulated product, comprising subjecting a mixture containing candesartan cilexetil and D-mannitol to fluidized bed granulation.

  2. Item 2. The method for producing a candesartan cilexetil-containing granulated product according to Item 1, wherein the content of D-mannitol is 20 to 95% by weight.

  3. A candesartan cilexetil-containing granulated product obtained by the method according to item 1 or 2.

  4). A method for producing a candesartan cilexetil-containing tablet, wherein the candesartan cilexetil-containing granulated product according to item 3 is tableted.

  5). A candesartan cilexetil-containing tablet obtained by the production method according to Item 4.

  6). Item 6. The candesartan cilexetil-containing tablet according to item 5, which is an orally disintegrating tablet.

  According to the granulated product manufacturing method and tablet manufacturing method containing candesartan cilexetil of the present invention, the following remarkable effects can be obtained.

  (1) Decomposition of candesartan cilexetil in the resulting candesartan cilexetil-containing granulated product is suppressed and stabilized.

  (2) The decomposition | disassembly of the candesartan cilexetil in the candesartan cilexetil containing tablet obtained by tableting the said candesartan cilexetil containing granule is suppressed and stabilized. Therefore, a candesartan cilexetil-containing tablet having excellent stability over time can be obtained.

  (3) Moreover, according to the manufacturing method of the candesartan cilexetil containing tablet of this invention, since mouth solubility is improving with D-mannitol, a candesartan cilexetil containing tablet is manufactured as an orally disintegrating tablet. Can be easily done. Orally disintegrating tablets can be taken without water, and are easy to drink for elderly people, children, patients with difficulty swallowing, etc., and are desirable from the viewpoint of the arrival of an aging society and improved patient compliance It is a dosage form.

Method for producing candesartan cilexetil-containing granulated product In the method for producing candesartan cilexetil-containing granulated product of the present invention, the mixture containing candesartan cilexetil and D-mannitol is fluidized-bed granulated to produce candesartan. A granule containing cilexetil is prepared.

  In the method for producing a candesartan cilexetil-containing granulated product of the present invention, a commercial product such as a multiplex can be used as the fluidized bed granulating apparatus.

  In the mixture containing candesartan cilexetil and D-mannitol, D-mannitol is used as an excipient, and the content thereof is usually 20 to 20 in the resulting granule containing candesartan cilexetil. The amount is preferably about 95% by weight.

  In the method for producing a candesartan cilexetil-containing granulated product of the present invention, a mixture containing candesartan cilexetil and D-mannitol is usually fluidized bed granulated to obtain a desired granulated product. Here, if necessary, a plurality of fluidized bed granulation steps can be performed. In addition, as preparation raw materials other than candesartan cilexetil and D-mannitol, stabilizers for candesartan cilexetil, excipients other than D-mannitol, disintegrants, binders, coloring agents, lubricants, fragrances, fluids Addition of agents, antistatic agents, surfactants, taste-masking agents (for example, sweeteners), wetting agents, fillers, extenders, adsorbents, preservatives (for example, preservatives), buffers, disintegration extenders, etc. An appropriate amount of the agent can be used as necessary.

Candesartan cilexetil candesartan cilexetil is a medicinal component of the granulated product and tablet obtained in the present invention, and its chemical name is (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 following can be mentioned as a specific example of the additive which is a pharmaceutical raw material other than the additive candesartan cilexetil and D-mannitol.

  Examples of stabilizers for candesartan cilexetil include low melting point oily substances such as stearic acid, sodium stearyl fumarate, polyethylene glycol 6000, stearyl alcohol, sucrose fatty acid ester, sorbitan fatty acid ester; citric acid, malic acid and the like Organic acids; hydrophilic substances having hydrocolloid properties such as carrageenan. These stabilizers can be used alone or in combination of two or more.

  Excipients other than mannitol include, for example, starches such as crystalline cellulose and corn starch; lactose, powdered sugar, granulated sugar, glucose, light anhydrous silicic acid, talc, magnesium oxide, magnesium carbonate, calcium carbonate, phosphoric anhydride Examples thereof include calcium hydrogen, 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.

  Examples of the binder include 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.

  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 sucrose, lactose, mannitol, xylitol, saccharin, saccharin sodium, aspartame, stevioside, sucralose, acesulfame potassium, thaumatin, and erythritol. Examples of the wetting agent include polyethylene glycol (macrogol), glycerin, propylene glycol and the like.

  The candesartan cilexetil-containing granulated product thus obtained is useful as a granule or a dry syrup itself, and can be suitably used for producing a candesartan cilexetil-containing tablet.

Method for producing candesartan cilexetil-containing tablet The method for producing a candesartan cilexetil-containing tablet according to the present invention is generally obtained by subjecting a granulated product obtained by fluid bed granulation to a mixture containing candesartan cilexetil and D-mannitol. This can be done by tableting according to the law. The obtained candesartan cilexetil-containing tablet may be any tablet such as a plain tablet, an orally disintegrating tablet, a coated tablet, a sustained release tablet, and a chewable tablet. Of these, orally disintegrating tablets can be taken without water, and are preferable from the viewpoint of the arrival of an aging society and the improvement of patient compliance.

  The water content of the candesartan cilexetil-containing granulated product is not particularly limited. This granulated product is subjected to a tableting step after drying and, if necessary, after granulation.

  The granulated product is preferably sized using a granulator after drying. There are no particular restrictions on the apparatus used for sizing, but for example, “Power Mill” (manufactured by Dalton Co., Ltd.), “Komil” (manufactured by Paulek), “Roll Granulator” (manufactured by Nippon Granulator Co., Ltd.) ) And the like. Moreover, you may size-size using a sieve etc.

  In tableting the candesartan cilexetil-containing granulated product, if necessary, a disintegrating agent, a lubricant and the like may be further mixed before tableting. Tableting can be performed using a commercially available tableting machine.

Candesartan cilexetil-containing preparation The candesartan cilexetil-containing preparation , which is the candesartan cilexetil-containing granule and tablet of the present invention, may be further coated as necessary. 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 preparation 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 candesartan cilexetil-containing preparation of the present invention may be PTP packaging, bottle packaging (eg, plastic bottle, glass bottle, aluminum can), stick packaging, sachet packaging, and the like. Moreover, those packaged preparations 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.), candesartan cilexetil 20.0 g, D-mannitol 512 g, stearic acid 20.0 g, low-substituted hydroxypropylcellulose 70.0 g, powdered reduced maltose water candy 2 0.000 g was mixed, fluidized bed granulated while sprayed with an aqueous solution of hydroxypropylcellulose, and dried. The dried granulated product was sized using a No. 22 sieve. The obtained sized product, 6.50 g of light anhydrous silicic acid, and 13.0 g of sodium stearyl fumarate were mixed with a V-type mixer (manufactured by Fuji Powder Co., Ltd.), and the resulting mixed powder was rotary-type. Tableting was performed with a tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 650 kg so that the weight per tablet was 130.0 mg and the thickness was 3.3 mm to obtain an uncoated tablet. The content of candesartan cilexetil as a medicinal ingredient per tablet is 4 mg.

Comparative Example 1
In a high-speed agitation granulator (Fukae Pautech Co., Ltd.), candesartan cilexetil 10.0 g, D-mannitol 259.3 g, stearic acid 10.0 g, low-substituted hydroxypropylcellulose 35.0 g, powdered reduced maltose 1.00 g of water candy was mixed and kneaded and granulated with purified water. This was sized with a No. 16 sieve. The obtained sized product was dried and sized using a No. 22 sieve. The obtained sized product, 3.25 g of light anhydrous silicic acid, and 6.50 g of sodium stearyl fumarate were mixed using a V-type mixer (manufactured by Fuji Powder Co., Ltd.), and the resulting mixed powder was rotary-type. Using a tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.), tableting was performed at a tableting pressure of 650 kg so that the weight per tablet was 130.0 mg and the thickness was 3.3 mm, to obtain a plain tablet. The content of candesartan cilexetil as a medicinal ingredient per tablet is 4 mg.

  Next, with respect to the candesartan cilexetil-containing preparations obtained in Example 1 and Comparative Example 1, the peak area of candesartan cilexetil was examined using HPLC, and the purity of the candesartan cilexetil drug substance was reduced with respect to the peak area. The rate was examined. The sample solution is obtained by pulverizing the test granulated product or test tablet, adding a mixed solution of water / methanol (1/9 volume ratio), extracting with ultrasonic waves for 10 minutes, and filtering the filtrate. 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 1 shows the purity of drug substance used (%), the purity (%) of the active ingredient (candesartan cilexetil) contained in candesartan cilexetil-containing granule obtained in Example 1 and Comparative Example 1, and tablets The total related substances (%) of impurities were shown.

  From Table 1, although the granule of Example 1 which granulated the mixture containing candesartan cilexetil and D-mannitol by the fluidized-bed granulation method, the purity reduction of candesartan cilexetil was not seen, but this mixture In the granulated product of Comparative Example 1 that was granulated by the stirring granulation method, a decrease in purity was observed. Therefore, it is clear that if the method of the present invention is used, the decomposition of candesartan cilexetil in the granulated product is sufficiently suppressed and stabilized. In addition, the tablet obtained in Example 1 is significantly less in the purity of candesartan cilexetil than the tablet obtained in Comparative Example 1, and the degradation of candesartan cilexetil in the tablet is sufficiently suppressed. It is clear that it is stabilized.

The candesartan cilexetil-containing granulated product and tablet of the present invention are 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 (6)

  A method for producing a candesartan cilexetil-containing granulated product, comprising subjecting a mixture containing candesartan cilexetil and D-mannitol to fluidized bed granulation.   The method for producing a candesartan cilexetil-containing granulated product according to claim 1, wherein the content of D-mannitol is 20 to 95% by weight.   A candesartan cilexetil-containing granulated product obtained by the method according to claim 1 or 2.   A method for producing a candesartan cilexetil-containing tablet, wherein the granulated product containing candesartan cilexetil according to claim 3 is compressed.   A tablet containing candesartan cilexetil obtained by the production method according to claim 4. The tablet containing candesartan cilexetil according to claim 5, which is an orally disintegrating tablet.