JP2017132724A - Orally disintegrating tablet formulation comprising amlodipine-containing coated granulated material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide technical means for producing orally disintegrating tablet formulations of irbesartan/amlodipine besylate in which the chemical stability of drug substances in the case of storage under severe conditions, such as high temperature high humidity environment, is highly improved.SOLUTION: The present invention provides an orally disintegrating tablet containing irbesartan and amlodipine besylate, wherein a granulated material comprising amlodipine besylate is coated with a coating agent and the coating agent is a pH independent water-insoluble polymer. Preferably, the pH independent water-insoluble polymer is selected from an ethylcellulose, ethylcellulose water dispersion, and the like.SELECTED DRAWING: None

Description

  The present invention relates to a combination tablet containing amlodipine or a salt thereof (especially amlodipine besylate) as an active ingredient (especially containing irbesartan as an active ingredient), and the stability of the active ingredient at the time of drug storage Detailed methods for improvement are presented.

  Amlodipine (generic name) has the chemical name 2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylate 3-ethyl 5- It is a long-lasting calcium antagonist, denoted as methyl, and generally a salt with benzenesulfonic acid, ie amlodipine besylate, is particularly preferably used for treatment. Irbesartan (generic name) has a chemical name of 2-butyl-3- {4- [2- (1H-tetrazol-5-yl) phenyl] benzyl} -1,3-diazaspiro [4.4] non- It is a long acting angiotensin II receptor antagonist labeled 1-en-4-one. Irbesartan / amlodipine besylate combination tablets are widely provided in the medical field as useful antihypertensive drugs (see Non-Patent Document 1, etc.).

About the combination tablet of irbesartan / amlodipine besilate, the following prescription patent documents 1-3 introduce the formulation and manufacturing method.
Patent Document 1 describes a granule containing irbesartan and a tablet containing amlodipine besylate physically separated and located outside the granule, and the tablet is a drug substance under long-term storage conditions. High chemical stability has been shown. Patent Document 2 describes a granulated product obtained by wet granulation containing irbesartan, an amlodipine besylate salt, and a polyvinyl alcohol-containing tablet, and shows that the tablet has a high dissolution rate for 30 minutes. Patent Document 3 describes a tablet containing a wet granulated product containing irbesartan and a binder selected from amlodipine besylic acid, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and the like. The chemical stability of the drug substance under high humidity storage conditions has been shown to be high.
As related patent documents, Patent Document 4 describes a combination tablet of olmesartan medoxomil / amlodipine besylate, and Patent Document 5 describes a tablet containing a coated granule containing amlodipine.

However, at present, irbesartan / amlodipine besylate combination tablets are not provided in the medical field in the form of orally disintegrating tablets.
An orally disintegrating tablet is a dosage form developed in recent years, and since it has a property of rapidly disintegrating with a small amount of water such as saliva, it is generally known that it is more convenient when taken than ordinary tablets. Therefore, the development of an orally disintegrating tablet is naturally desired to improve the patient's ingestion of a combination tablet of irbesartan / amlodipine besylate. However, in general, orally disintegrating tablets have more technical restrictions than ordinary tablets in order to achieve important purposes such as rapid disintegration in the oral cavity and suppression of the bitter taste of the drug substance. In many cases, it is difficult to guarantee a stable stability.
Based on the prior art, the present inventor aims to produce a higher-quality irbesartan / amlodipine besylate combination tablet orally disintegrating tablet (combination orally disintegrating tablet), and good disintegration rate in the oral cavity We aimed to develop a technical means to sufficiently improve the chemical stability of irbesartan under harsh storage conditions, while maintaining bitterness and maintaining bitterness.

Japanese Patent No. 5763063 Japanese Patent No. 5421945 JP 2013-75893 A Japanese Patent No. 5344620 Japanese Patent Laying-Open No. 2015-147812

"AIMIX (registered trademark) Combination Tablets LD IMIX (registered trademark) Combination Tablets HD" Pharmaceutical Interview Form Revised January 2016 (8th Edition)

  The present invention relates to the preparation of an orally disintegrating tablet containing irbesartan / amlodipine besylate which has an improved chemical stability of the drug substance when stored under severe conditions such as high temperature and high humidity. It provides technical means.

  As a result of diligent studies to solve the above problems, the present inventor used a specific coating agent when coating a granulated product containing amlodipine besylate with a coating agent for bitterness suppression, so that It was found that the chemical stability of amlodipine besylate contained in an internally disintegrating tablet can be improved under storage conditions in a high temperature and high humidity environment. The inventor has conducted further intensive studies based on the findings, and has completed the present invention described below.

That is, this invention relates to the combination tablet (preferably orally disintegrating tablet) containing the granule containing the amlodipine besylate salt coat | covered with the specific coating agent, A suitable form is the following (1)-(6) Is described.
(1) An orally disintegrating tablet comprising irbesartan and amlodipine besylate, wherein a granulated product containing amlodipine besylate is coated with a coating agent, and the coating agent is a pH-independent water-insoluble polymer.
(2) The orally disintegrating tablet according to (1), wherein the pH-independent water-insoluble polymer is ethyl cellulose or an aqueous dispersion of ethyl cellulose.
(3) In the coated granule containing amlodipine besylate coated with a coating agent, the coating agent is contained in the range of 5.0 to 40.0 parts by weight with respect to 100.0 parts by weight of amlodipine besylate. The orally disintegrating tablet according to (1) or (2).
(4) In the coated granule containing amlodipine besylate coated with a coating agent, the coating agent is contained in the range of 8.0 to 20.0 parts by weight with respect to 100.0 parts by weight of amlodipine besylate. The orally disintegrating tablet according to any one of (1) to (3).
(5) The pharmaceutical additive according to any one of (1) to (4), wherein a pharmaceutical additive not contained in the granulated product is contained in a range of 8.0 to 20.0% by weight relative to the total weight of the uncoated tablet. Orally disintegrating tablets.
(6) comprising the step of physically mixing an uncoated granule containing irbesartan that is not coated with a coating agent and a coated granule containing amlodipine besylate coated with a coating agent, (1) The method to manufacture the orally disintegrating tablet in any one of (5).

  The compound orally disintegrating tablet containing irbesartan / amlodipine besylate of the present invention is improved in chemical stability because the amount of related substances in the drug substance is suppressed when stored in a high temperature and high humidity environment. This makes it possible to provide high-quality tablets for the medical field.

  Hereinafter, the formulation and production method of the compound orally disintegrating tablet containing irbesartan / amlodipine besylate of the present invention will be described in detail. However, the following description is an example for explaining the present invention, and is not intended to specifically limit the present invention to this description range.

<Tablet form>
The tablet of the present invention is a combination tablet containing two or more drug substances, and is an uncoated tablet (refers to a tablet that is not covered with a film coating layer, a sugar-coating layer, etc., and is still formed by tableting, etc.). It is preferable that it is an orally disintegrating tablet which is an uncoated tablet. Orally disintegrating tablets have an oral disintegration time of less than 60 seconds, with those having a disintegration time of less than 40 seconds being particularly preferred.
The shape of the tablet according to the present invention is not particularly limited, and any of round tablets {circular flat tablets (including corner locks, etc.), round R tablets (including corner locks, 2-stage R locks, etc.)}, deformed tablets, etc. However, a round R tablet is preferable.

<Physical properties of API>
The median diameter (d ₅₀ ) of amlodipine besylate used for the production of the tablet of the present invention is preferably 0.1 to 100.0 μm, more preferably 1.0 to 50.0 μm. Amlodipine besylate can be adjusted to an arbitrary particle size by appropriately performing dry or wet grinding as required. Amlodipine besylate is contained only in the uncoated tablet part, preferably in the range of 2.0 to 10.0% by weight, more preferably 4.0 to 8.0% by weight based on the total weight of the uncoated tablet. Contained in a range.
The median diameter (d ₅₀ ) of irbesartan used for producing the tablet of the present invention is preferably 1.0 to 100.0 μm, more preferably 5.0 to 50.0 μm. Irbesartan can be adjusted to an arbitrary particle size by appropriately performing dry or wet pulverization as necessary. Irbesartan is contained only in the uncoated tablet part, preferably in the range of 25.0 to 65.0% by weight, more preferably in the range of 30.0 to 50.0% by weight based on the total weight of the uncoated tablet Is done.

<Pharmaceutical additives that can be used in the manufacture of uncoated tablets>
Examples of the pharmaceutically acceptable pharmaceutical additive used in the production of the uncoated tablet according to the present invention include commonly used excipients, disintegrants, binders, plasticizers, lubricants, and flavoring agents. , Surfactants, colorants and the like can be used.

<Excipient>
The excipient according to the present invention is selected from, for example, lactose hydrate, crystalline cellulose, anhydrous lactose, D-mannitol, corn starch and the like, preferably D-mannitol, corn starch. The excipient is preferably contained in the uncoated tablet in the range of 25.0 to 50.0% by weight based on the total weight of the uncoated tablet.

<Disintegrant>
The disintegrant according to the present invention is selected from, for example, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, and preferably crospovidone. . The disintegrant is preferably contained in the uncoated tablet in the range of 2.0 to 15.0% by weight, more preferably in the range of 5.0 to 10.0% by weight based on the total weight of the uncoated tablet. Contained in

<Binder>
The binder according to the present invention is selected from, for example, hypromellose, hydroxypropyl cellulose, povidone, gelatinized starch, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and preferably polyvinyl alcohol / acrylic acid / It is a methyl methacrylate copolymer. The binder is preferably contained in the uncoated tablet in the range of 0.1 to 5.0% by weight with respect to the total weight of the uncoated tablet.

<Plasticizer>
The plasticizer according to the present invention is selected from, for example, triethyl citrate, glycerin, glycerin fatty acid ester, polyethylene glycol, polysorbate and the like, and preferably triethyl citrate. The plasticizer is preferably contained in the uncoated tablet in a range of 0.05 to 2.0% by weight based on the total weight of the uncoated tablet.

<Lubricant>
The lubricant according to the present invention is selected from, for example, magnesium stearate, calcium stearate, sodium stearyl fumarate, etc., preferably magnesium stearate. The lubricant is preferably contained in the uncoated tablet in the range of 0.5 to 3.0% by weight based on the total weight of the uncoated tablet.

<Flavoring agent>
The taste-masking agent according to the present invention is selected from, for example, sucralose, sorbitol, trehalose, fumaric acid, monosodium fumarate, etc., preferably sucralose. The corrigent is preferably contained in the uncoated tablet in the range of 1.0 to 10.0% by weight based on the total weight of the uncoated tablet.

<Coating agent>
The coating agent according to the present invention is preferably a pH-independent water-insoluble polymer, and is selected from, for example, ethyl cellulose, ethyl cellulose dispersion, ethyl acrylate / methyl methacrylate copolymer dispersion, dimethylamino methacrylate / methyl methacrylate copolymer, and the like. Particularly preferred is ethyl cellulose or an aqueous dispersion of ethyl cellulose. The coating agent is preferably contained in the uncoated tablet in a range of 0.05 to 10.0% by weight based on the total weight of the uncoated tablet.

<Coated / uncoated granules>
The tablet of the present invention includes a coated granulated product obtained by coating a granulated product containing amlodipine besylate with a specific coating agent. In the coated granulated product, 100.0 parts by weight of amlodipine besylate is used. The coating agent is contained in the range of 5.0 to 80.0 parts by weight, preferably in the range of 5.0 to 40.0 parts by weight, more preferably in the range of 8.0 to 20.0 parts by weight. Amlodipine besylate is in the range of 10.0 to 90.0 parts by weight, preferably in the range of 25.0 to 90.0 parts by weight, more preferably 100.0 parts by weight of the coated granule. It is contained in the coated granulated product in the range of 60.0 to 80.0 parts by weight.
The granulated product according to the tablet of the present invention can be produced by a method such as stirring granulation, fluidized bed granulation, spray drying granulation or the like using a solution containing a binder. Specific examples of the method for producing the coated granulated product according to the tablet of the present invention include a fluidized bed coating method (including a Wurster method).
In the tablet of the present invention, the granulated product containing irbesartan can contain an uncoated granulated product that is not coated with a coating agent. In addition, after physically mixing the coated granulated product containing amlodipine besylate and the uncoated granulated product containing irbesartan, tableting (including the case of performing other steps such as drying and granulation after mixing and before tableting) This is a particularly desirable step in the tablet production method of the present invention.
In the tablet of the present invention, the pharmaceutical additive not contained in the granulated product is preferably contained in the uncoated tablet in a range of 5.0 to 30.0% by weight based on the total weight of the uncoated tablet, more preferably Is contained in the uncoated tablet in the range of 8.0 to 20.0% by weight. In the pharmaceutical additive not contained in the granulated product, the disintegrant is preferably contained in the range of 5.0 to 10.0 parts by weight with respect to 100.0 parts by weight of the uncoated tablet.

<Manufacturing method of uncoated tablet>
The uncoated tablet according to the tablet of the present invention can be prepared by a general manufacturing method, for example, by the following manufacturing method.
First, a binder dissolved in water is added to a powder in which irbesartan, an excipient, a disintegrant, and a corrigent are mixed, and wet high speed agitation granulation is performed to produce an uncoated granulated product. The high-speed agitation granulator used in the present invention is, for example, a vertical granulator (Paurec Co., Ltd.) or a high-speed mixer (Earth Technica). Further, a powder mixed with amlodipine besylate and excipient is added with a binder dissolved in water, and fluidized bed granulation is performed to produce a granulated product, and a liquid containing a coating agent is added to the granulated product. Spray to produce coated granulate. The uncoated granulated product and the coated granulated product obtained above are dried and sized, then mixed with a disintegrant, a lubricant, and the like, and then compressed into a tablet by a tableting machine.

  EXAMPLES The present invention will be described below with reference to examples and the like, but the present invention is not limited to these examples and the like.

<Manufacture of irbesartan granulated product>
Irbesartan 150.0 g (manufactured by HUAHAI), D-mannitol 50.7 g (mannit k / manufactured by Mitsubishi Corporation Foodtech), corn starch 30.0 g (pharmacopoeia corn starch white / manufactured by Nippon corn starch), crospovidone 13.5 g (CL -SF / BASF) and 15.0 g of sucralose (Sucralose (P) / manufactured by Saneihara FFI) were charged into a high-speed agitation granulator (manufactured by Paulek / VG-01), and PVA copolymer 0 .3 g (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 65.0 g of purified water was added dropwise and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 80 ° C. And dried until the exhaust temperature reached 35 ° C. After drying, the powder was pulverized dry using a screen having a diameter of 1 mm with a pulverizer (Comil QC-197S / Pauleck) to obtain an irbesartan granulated article.

  69.35 g of amlodipine besylate (manufactured by Moehs) and 350.65 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / manufactured by Nippon Cornstarch) were charged into a fluidized bed granulator (manufactured by Paulek / MP-01 type) to prepare a PVA copolymer. A solution obtained by dissolving 12.5 g (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 300 g of purified water was sprayed and granulated at an air supply temperature of 75 ° C. Subsequently, 150.0 g of ethyl cellulose aqueous dispersion (manufactured by Aquacoat ECD / FMC), 11.25 g of D-mannitol (manufactured by Mannit C / Mitsubishi Corporation Foodtech) and 11.25 g of triethyl citrate (Citroflex 2 SC-60 / Morimura) A liquid in which (manufactured by Kogyo) was dispersed was sprayed and coated at a supply air temperature of 75 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature was 35 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 30 mesh. Amlodipine besylate-coated granulated article 100.0 g obtained as described above, irbesartan granulated article 173.0 g obtained in Example 1, D-mannitol 14.0 g (Granitol S / Freund Sangyo), crospovidone Mix with 10.0 g (CL-SF / BASF) and 3.0 g magnesium stearate (Taihei Chemical Industry) and compress with a rotary tableting machine (VIRGO / Kikusui Seisakusho) with a compression pressure of 600 kgf. An orally disintegrating tablet (circular two-stage R tablet) having a tablet mass of 300.0 mg, a diameter of 9.5 mm, a hardness of 31 N, and an oral disintegration time of 40 seconds was obtained.

  166.44 g of amlodipine besylate (manufactured by Moehs) and 236.76 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / manufactured by Nippon Cornstarch) were charged into a fluidized bed granulator (manufactured by Paulek / MP-01 type) to prepare a PVA copolymer. A solution obtained by dissolving 12.0 g (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 290 g of purified water was sprayed and granulated at an air supply temperature of 75 ° C. Subsequently, 144.0 g of an ethyl cellulose aqueous dispersion (manufactured by Aquacoat ECD / FMC), 10.8 g of D-mannitol (mannitk C / manufactured by Mitsubishi Corporation Foodtech) and 10.8 g of triethyl citrate (Citroflex 2 SC-60 / Morimura) A liquid in which (manufactured by Kogyo) was dispersed was sprayed and coated at a supply air temperature of 75 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature was 35 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 30 mesh. 40.0 g of amlodipine besylate-coated granulated article obtained as described above, 173.0 g of irbesartan granulated article obtained in Example 1, 24.5 g of D-mannitol (Granitol S / Freund Sangyo), crospovidone Mixed with 10.0 g (CL-SF / BASF) and 2.5 g magnesium stearate (Taipei Chemical Industry Co., Ltd.) and compressed with a rotary tableting machine (VIRGO type / Kikusui Seisakusho) at a compression pressure of 600 kgf. An orally disintegrating tablet (circular two-stage R tablet) having a mass of 250.0 mg, a diameter of 9.5 mm, a hardness of 36 N, and an oral disintegration time of 37 seconds was obtained.

  346.75 g of amlodipine besylate (from Moehs) and 73.25 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / manufactured by Nippon Cornstarch) were charged into a fluidized bed granulator (manufactured by Paulek / MP-01 type) to obtain a PVA copolymer. A solution obtained by dissolving 12.5 g (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 300 g of purified water was sprayed and granulated at an air supply temperature of 75 ° C. Subsequently, 150.0 g of ethyl cellulose aqueous dispersion (manufactured by Aquacoat ECD / FMC), 11.25 g of D-mannitol (manufactured by Mannit C / Mitsubishi Corporation Foodtech) and 11.25 g of triethyl citrate (Citroflex 2 SC-60 / Morimura) A liquid in which (manufactured by Kogyo) was dispersed was sprayed and coated at a supply air temperature of 75 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature was 35 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 30 mesh. Amlodipine besylate-coated granulated article 20.0 g obtained in the above, irbesartan granulated article 173.0 g obtained in Example 1, D-mannitol 25.0 g (Granitol S / Freund Sangyo), crospovidone It is mixed with 10.0 g (CL-SF / BASF) and 2.0 g magnesium stearate (Taihei Chemical Industry) and compressed with a rotary tableting machine (VIRGO / Kikusui Seisakusho) with a compression pressure of 600 kgf. An orally disintegrating tablet (circular two-stage R tablet) having a mass of 230.0 mg, a diameter of 9.5 mm, a hardness of 41 N, and an oral disintegration time of 33 seconds was obtained.

[Comparative Example 1]
69.35 g of amlodipine besylate (manufactured by Moehs) and 350.65 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / manufactured by Nippon Cornstarch) were charged into a fluidized bed granulator (manufactured by Paulek / MP-01 type) to prepare a PVA copolymer. A solution obtained by dissolving 12.5 g (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 300 g of purified water was sprayed and granulated at an air supply temperature of 75 ° C. Subsequently, 150.0 g of ammonio alkyl methacrylate copolymer dispersion (Eudragid RL-30D / Evonik), 11.25 g of D-mannitol (Mannit K / manufactured by Mitsubishi Corporation Foodtech) and 11.25 g of triethyl citrate (Citroflex 2 SC) −60 / Morimura Sangyo Co., Ltd.) was sprayed and coated at a supply air temperature of 75 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature was 35 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 30 mesh. Amlodipine besylate-coated granulated article 100.0 g obtained as described above, irbesartan granulated article 173.0 g obtained in Example 1, D-mannitol 14.0 g (Granitol S / Freund Sangyo), crospovidone Mix with 10.0 g (CL-SF / BASF) and 3.0 g magnesium stearate (Taihei Chemical Industry) and compress with a rotary tableting machine (VIRGO / Kikusui Seisakusho) with a compression pressure of 600 kgf. 1 tablet mass 300.0 mg, diameter 9.5 mm, hardness 35 N, oral disintegration tablet (circular two-stage R tablet) having an oral disintegration time of 37 seconds was obtained.

[Comparative Example 2]
69.35 g of amlodipine besylate (manufactured by Moehs) and 350.65 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / manufactured by Nippon Cornstarch) were charged into a fluidized bed granulator (manufactured by Paulek / MP-01 type) to prepare a PVA copolymer. A solution obtained by dissolving 12.5 g (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 300 g of purified water was sprayed and granulated at an air supply temperature of 75 ° C. Subsequently, 150.0 g of ammonio alkyl methacrylate copolymer dispersion (Eudragid RS-30D / Evonik), 11.25 g of D-mannitol (Mannit C / Mitsubishi Foodtech) and 11.25 g of triethyl citrate (Citroflex 2 SC) −60 / Morimura Sangyo Co., Ltd.) was sprayed and coated at a supply air temperature of 75 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature was 35 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 30 mesh. Amlodipine besylate-coated granulated article 100.0 g obtained as described above, irbesartan granulated article 173.0 g obtained in Example 1, D-mannitol 14.0 g (Granitol S / Freund Sangyo), crospovidone Mix with 10.0 g (CL-SF / BASF) and 3.0 g magnesium stearate (Taihei Chemical Industry) and compress with a rotary tableting machine (VIRGO / Kikusui Seisakusho) with a compression pressure of 600 kgf. 1 tablet mass 300.0 mg, diameter 9.5 mm, hardness 37 N, oral disintegration tablet (round two-stage R tablet) having an oral disintegration time of 39 seconds was obtained.

  The formulations of each tablet obtained in Examples 2-4 are listed in Table 1 below. In the formulations of Comparative Examples 1 and 2, ethyl cellulose (solid content) in the tablet formulation of Example 1 was replaced with the same amount of ammonioalkyl methacrylate copolymer (solid content).

(Test Example 1)
About each tablet obtained in Comparative Examples 1 and 2 and Examples 2 to 4, the temperature was 60 ° C. immediately after production and in an opened vial (under open conditions) or in a sealed vial (under sealed conditions). After storage for 1 week in an environment with a relative humidity of 75%, the amount of the oxidant-related substance derived from amlodipine was measured by HPLC (quantitative method was area percentage method). The measured results are shown in Table 2 below. The sealing condition is mainly suitable for evaluating the influence of the temperature condition on the drug substance, and the opening condition is mainly suitable for evaluating the influence of the temperature and humidity condition on the drug substance.

By comparing the test results of Example 2 and Comparative Examples 1 and 2 and covering the granulated product containing amlodipine besylate with a coating agent that is ethyl cellulose, the related substance after storage under high temperature and high humidity open conditions It was shown that the generation amount of was significantly suppressed and the stability was greatly improved. In addition, by comparing the test results of Examples 2 to 4, the content ratio of amlodipine besylate in the coated granulated product is decreased to reduce the amount ratio of the coating agent to amlodipine besylate. It was shown that the stability can be further improved.
Therefore, it was shown that the blended orally disintegrating tablet containing irbesartan / amlodipine besylate obtained by the present invention is a preparation with excellent stability of the drug substance under severe storage conditions.

  According to the present invention, a high quality combination orally disintegrating tablet containing irbesartan / amlodipine besylate having an improved effect on chemical stability of the drug substance under storage conditions is provided to the medical field. Make it possible.

Claims (6)

An orally disintegrating tablet comprising irbesartan and amlodipine besylate, wherein a granulated product containing amlodipine besylate is coated with a coating agent, and the coating agent is a pH-independent water-insoluble polymer. The orally disintegrating tablet according to claim 1, wherein the pH-independent water-insoluble polymer is ethyl cellulose or an aqueous dispersion of ethyl cellulose. The coated granule containing amlodipine besylate coated with a coating agent, the coating agent is contained in the range of 5.0 to 40.0 parts by weight with respect to 100.0 parts by weight of amlodipine besylate. Item 3. The orally disintegrating tablet according to Item 1 or 2. In the coated granule containing amlodipine besylate coated with a coating agent, the coating agent is contained in the range of 8.0 to 20.0 parts by weight with respect to 100.0 parts by weight of amlodipine besylate. The orally disintegrating tablet according to any one of Items 1 to 3. The orally disintegrating tablet according to any one of claims 1 to 4, wherein a pharmaceutical additive not contained in the granulated product is contained in an amount of 8.0 to 20.0% by weight based on the total weight of the uncoated tablet. The method comprises physically mixing an uncoated granule comprising irbesartan that is not coated with a coating agent and a coated granule comprising amlodipine besylate coated with a coating agent. 6. A method for producing an orally disintegrating tablet according to any one of 5 above.