WO2018062685A1 - Composite formé d'une seule couche, comprenant du candésartan et de l'amlodipine - Google Patents

Composite formé d'une seule couche, comprenant du candésartan et de l'amlodipine Download PDF

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Publication number
WO2018062685A1
WO2018062685A1 PCT/KR2017/009098 KR2017009098W WO2018062685A1 WO 2018062685 A1 WO2018062685 A1 WO 2018062685A1 KR 2017009098 W KR2017009098 W KR 2017009098W WO 2018062685 A1 WO2018062685 A1 WO 2018062685A1
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WIPO (PCT)
Prior art keywords
candesartan
amlodipine
weight
pharmaceutically acceptable
acid
Prior art date
Application number
PCT/KR2017/009098
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English (en)
Korean (ko)
Inventor
정대영
조민관
박신정
Original Assignee
주식회사 종근당
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Application filed by 주식회사 종근당 filed Critical 주식회사 종근당
Priority to JP2019517006A priority Critical patent/JP6758488B2/ja
Priority to CN201780060226.2A priority patent/CN109789099A/zh
Publication of WO2018062685A1 publication Critical patent/WO2018062685A1/fr
Priority to PH12019500638A priority patent/PH12019500638A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to a composite composed of a single layer containing candesartan and amlodipine, and is prepared by improving the problems that are difficult to develop into a single layer composite due to the inherent properties of the candesartan and amlodipine materials.
  • angiotensin II receptor antagonists and calcium channel blockers are widely used clinically for the treatment and prevention of hypertension, such as a combination of amlodipine besylate and atorvastatin calcium (US Pat. No. 6,455,574), amlodipine besil A combination of latex and valsartan (US Pat. No. 6,395,728), a combination of amlodipine besylate and benazipril hydrochloride (US Pat. No. 6,162,802), a combination of amlodipine camsylate and simvastatin A combination of amlodipine and telmisartan (Korean Patent Publication No. 2007-7012726) and a combination of amlodipine camsylate and rozatan calcium salt (Korean Patent Publication No. 2008-0052852).
  • the inventors of the present invention have attempted to develop a combination of candesartan, an angiotensin II receptor antagonist, and amlodipine, a calcium channel blocker.
  • Candesartan belongs to angiotensin II receptor antagonist (Angiotensin II Receptor Blocker) and has excellent efficacy as a useful therapeutic agent for circulatory diseases such as hypertension, heart disease, seizures, stroke and nephritis.
  • Angiotensin II Receptor Blocker angiotensin II receptor antagonist
  • the prodrug candesartan cilexetil was developed, and during absorption into the gastrointestinal tract, cilexetil was liberated from the candesartan cilexetil and rapidly hydrolyzed to the active candesartan. do.
  • Candesartan cilexetil is a white to off-white powder and hardly soluble in water and methanol.
  • the stability rapidly decreases due to the compression pressure and the exothermic heat generated during the molding into tablets, and thus, the technology for improving the stability and improving the bioavailability of candesartan cilexetil according to physical changes in the tablet molding process is developed. Many studies have been conducted to do this.
  • Korean Patent No. 256633 discloses polymers of hydrocarbons, higher fatty acids, higher alcohols, fatty acid esters of polyhydric alcohols, higher ethers of polyhydric alcohols and alkylene oxides to improve the stability of candesartan cilexetil, or Disclosed is a stabilization method of preparing a mixed oily phase material selected from the group consisting of copolymers.
  • a stabilization method of preparing a mixed oily phase material selected from the group consisting of copolymers is difficult to be constantly controlled under the influence of the oily phase material, and thus, there is a disadvantage in that the variation between individuals is increased during dosing.
  • US Patent 2012 / 516,539 discloses a method of using triethyl citrate as a stabilizer to solve the stability problem of candesartan cilexetil.
  • the soft substance of candesartan cilexetil showed a very low content of 0.48% after 4 weeks at 50 ° C.
  • U.S. Patent No. 2012 / 305,283 also discloses a method of using triethyl citrate as a stabilizer in order to solve the stability problem of candesartan cilexetil, and when using 2.1% by weight of triethyl citrate 50 After 2 weeks, the soft substance of candesartan cilexetil showed a very low content of 0.1%.
  • Republic of Korea Patent No. 256633 shows a flexible material of candesartan 0.9% after 4 weeks at 50 °C when 0.46% by weight of polyethylene glycol 6000 is added in Example 1.
  • triethyl citrate when triethyl citrate is used as a stabilizer, it can be seen that the effect is better in a small amount than polyethylene glycol.
  • polyethylene glycol causes delayed and immediate hypersensitivity (Sapna Shah MD, et al., Hypersensitivity to Polyethylene Glycols, The Journal of Clinical Pharmacology).
  • polyethylene glycol is likely to cause changes in pharmacokinetic behavior due to ABC Phenomenon (accelerated blood clearance), and has the disadvantage of not being a biodegradable polymer (US Schuber et al., Polyethylene glycol in Drug delivery, Angewandte chemie). Therefore, the present inventors considered a method of using triethyl citrate instead of polyethylene glycol as a stabilizer to solve the stability problem of candesartan cilexetil.
  • the inventors of the present invention have shown excellent properties in terms of pharmaceutical properties such as properties, hardness, active ingredients are not decomposed during the manufacturing process and storage, and canesartantan and amlodipine which have a simple dissolution rate and have a simple manufacturing process.
  • a composite comprising a single layer was completed.
  • the present inventors have prepared a monolayer combination containing (i) candesartan, candesartan cilexetil or a pharmaceutically acceptable salt thereof, and (ii) amlodipine or a pharmaceutically acceptable salt thereof.
  • a stabilizer there is provided a single layer composite comprising triethyl citrate as a stabilizer and mannitol as a filler.
  • candesartan used in the present invention is 2-ethoxy-1-[[2 '-(4,5-dihydro-5-oxo-1,2,4-oxadiazole-3- Yl) biphenyl-4-yl] methyl] -1 H-benzimidazole-7-carboxylic acid.
  • candesartan cilexetil is a prodrug of candesartan, and its chemical name is 1- (cyclohexyloxycarbonyloxy) ethyl-2-ethoxy-1-[[2'- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate.
  • the term “pharmaceutically acceptable salts” means salts formed with any inorganic or organic acid, or base, that do not cause serious irritation upon administration to the human body and do not impair the biological activity and properties of the compound.
  • Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbon acids such as citric acid, acetic acid, trichloroacetic acid, trichloroacetic acid, succinic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • pharmaceutically acceptable salts include Is a metal salt formed by lithium, sodium, potassium, calcium, magnesium or the like, an amino acid salt such as alkaline earth metal salt, lysine, arginine, guanidine, dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl Organic salts such as methylamine, diethanolamine, choline and triethylamine, and the like.
  • amlodipine is a calcium channel blocker, the specific chemical name of which is 3-ethyl-5methyl-2- (2-aminoethoxy-methyl) -4- (2-chlorophenyl) -6- Methyl-1,4-dihydro-3,5-pyridine dicarboxylate.
  • amlodipine is a non-toxic acid addition salt form containing a pharmaceutically acceptable anion, for example hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate lactate, tartrate, citrate , Salts such as gluconate, besylate, and the like. More preferably, amlodipine besylate may be used, and amlodipine besylate has superior solubility, stability, non-hygroscopicity, and the like compared to hydrochloride, acetate, mesylate, and the like.
  • a pharmaceutically acceptable anion for example hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate lactate, tartrate, citrate , Salts such as gluconate, besylate, and the like.
  • amlodipine besylate may be used, and amlodipine besylate has superior solubility, stability
  • the candesartan, candesartan cilexetil, or a pharmaceutically acceptable salt thereof may be included in an amount of 0.1 to 30% by weight, more preferably 0.5 to 20% by weight, based on the total weight of the combination. Preferably it may be included in 1 to 10% by weight.
  • amlodipine or a pharmaceutically acceptable salt thereof may be included in an amount of 0.1 to 30% by weight, more preferably 0.5 to 20% by weight, and most preferably 1 to 10% by weight, based on the total weight of the combination. May be included as a%.
  • Triethyl citrate used as a stabilizer in the present invention may be included in 0.1 to 20% by weight, more preferably 0.1 to 10% by weight, most preferably 0.1 to 5% by weight based on the total weight of the composite May be included.
  • Mannitol used as a filler in the present invention may be included in more than 30% by weight, more preferably 40 to 80% by weight, most preferably 50 to 70% by weight based on the total weight of the composite agent Can be.
  • the weight ratio of triethyl citrate and mannitol is 1: 30 to 90, preferably 1: 40 to 80, most preferably 1: 50 to 70.
  • the present invention is a.
  • It comprises a composite consisting of a single layer containing.
  • combination according to the invention may further comprise a binder, excipient or glidant.
  • the binder is an additive to maintain the form of the formulation, polyvinyl alcohol- polyethylene glycol graft copolymer, polyvinylpyrrolidone vinyl acetate, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose , Methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, gelatin, propylene glycol, sodium alginate and mixtures thereof, but may be any one or more selected from, but is not limited thereto.
  • the excipient is an additive used for dilution or increase, preferably at least one selected from the group consisting of sugars, lactose, cellulose and starch. More preferably, lactose monohydrate, microcrystalline cellulose, microcrystalline cellulose-lactose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose salt (e.g., carboxy cellulose calcium, carboxy cellulose) Sodium), other substituted and unsubstituted cellulose, corn starch, gelatinized starch, lactose, anhydrous sugars, sugar alcohols (e.g.
  • mannitol, sorbitol sucrose, xylitol, acrylate polymers and copolymers, dextrates, dextrins, dextrose, maltose Dextrins, pectins, gelatin, inorganic diluents (eg, calcium carbonate dibasic calcium phosphate dihydrate, tricalcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium chloride) and other excipients known in the art, including but not limited to It is not.
  • inorganic diluents eg, calcium carbonate dibasic calcium phosphate dihydrate, tricalcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium chloride
  • the lubricant is an additive for smoothing the compression operation of the granules, may be any one or more selected from the group consisting of magnesium stearate, sodium stearyl fumarate and glyceryl behenate, but is not limited thereto. .
  • additives that may be incorporated into the formulation may include lubricants, preservatives, surfactants, antioxidants, colorants (eg, red iron oxide), flavors, flavor enhancers, or any other additives commonly used in the art. have.
  • the complex according to the present invention includes candesartan and amlodipine as active ingredients, it may be usefully used for the prevention or treatment of cardiovascular diseases.
  • the combination of the present invention in order to more effectively treat hypertension or related cardiovascular diseases, therapeutically effective amounts of diuretics, beta receptors, alpha blockers, alpha-beta blockers, sympathetic inhibitors, angiotensin converting enzyme inhibitors, calcium channel blockers , Angiotensin receptor blockers, mineralocorticoid receptor antagonists, and the like.
  • the formulations of the invention are tablets, they may be prepared by wet or dry granulation, or by direct compression, preferably in the form of tablets prepared by wet or dry granulation, more preferably by wet granulation.
  • the combination of the present invention can be used in the pharmaceutical use to treat circulatory diseases such as hypertension, heart disease, seizures, stroke and nephritis
  • the method of administration is not particularly limited and appropriate administration methods and administration according to the age, sex and symptoms of the patient It can be administered by route, with oral administration being preferred.
  • the present invention relates to (i) candesartan, candesartan cilexetil or a pharmaceutically acceptable salt thereof, (ii) amlodipine or a pharmaceutically acceptable salt thereof, (iii) triethyl citrate as stabilizer, and (iv)
  • the present invention relates to a composite comprising a single layer containing mannitol as a filler, which improves the stability of the active ingredient during the manufacturing process and storage, has excellent dissolution rate, and is easy to prepare into a formulation such as tablets.
  • Triethyl citrate and hydroxypropyl cellulose are added to water, and the solution which is completely dissolved by stirring is used as a binding solution.
  • the active ingredient candesartan cilexetil, amlodipine besylate, mannitol, and microcrystalline cellulose are put into a mixer and mixed.
  • the granules of 3) are put in a fluidized-bed drier and dried, and then granulated with a comil granulator.
  • the mixture of 4) and mannitol were added to the mixer, followed by primary mixing. Then, magnesium stearate and sodium stearyl fumarate were passed through the mixture to perform secondary mixing.
  • the final mixture of 5) was compressed into tablets using an automatic tablet press (XP1, Korsch, Germany) to give a tablet of 130 mg in total weight.
  • Example 2 To the components and contents of the following Table 2, was prepared in the same manner as in Example 1 to prepare a composite formulation of candesartan and amlodipine. At this time, sorbitol was used instead of mannitol as an excipient.
  • Example 3 To the components and contents of the following Table 3, was prepared in the same manner as in Example 1 to prepare a composite formulation of candesartan and amlodipine. At this time, Isomalt was used instead of mannitol as an excipient.
  • Example 4 To the ingredients and contents of the following Table 4, was prepared in the same manner as in Example 1 to prepare a complex formulation of candesartan and amlodipine. At this time, sugar was used instead of mannitol as an excipient.
  • Mobile phase A solution adjusted to pH 7.1 with glacial acetic acid in a mixture (300: 420: 280) of acetonitrile, methanol, and 0.1 mol / L ammonium acetate.
  • Example 1 and Comparative Examples 1 to 3 according to the present invention were subjected to a dissolution test according to the Dissolution Test Method 2 (paddle method) of the General Test Method of the eleventh revised Korean Pharmacopoeia.
  • Mobile phase B 0.0 100 0 9.0 100 0 9.1 10 90 13.0 10 90 13.1 100 0 24.0 100 0
  • Mobile phase B 0 100 0 15 100 0 25 80 20 90 0 100 130 0 100 135 100 0 150 100 0
  • Example 1 using mannitol showed the best dissolution rate
  • Comparative Example 2 using isomalt and Comparative Example 3 using white sugar showed low dissolution rates of both candesartan and amlodipine.
  • Comparative Example 1 exhibited an unsuitable property due to the rough surface
  • Comparative Example 2 produced the most flexible material.
  • Tablets prepared according to Example 1 and Comparative Examples 1-3 were stored for 1 week in harsh conditions (packaged Duma ® bottle at 60 ° C), and then the hardness, thickness, candesartan and amlodipine content, dissolution rate and softening material of the tablets. The results of measuring the amount of are shown in Table 8 below.
  • Comparative Example 1 using sorbitol produced the least amount of the flexible material, but the hardness was lowered and the tablets swelled to show an inappropriate property.
  • Comparative Example 2 using isomalt produced the most flexible material from the first time, showing the highest amount of flexible material.
  • Example 1 using mannitol and comparative example 3 using sucrose showed similar results.
  • Example 1 The tablets prepared according to Example 1 and Comparative Examples 1-3 were stored for 1 week under accelerated conditions (40 ° C., Duma® bottle packaging at RH 75%), and then the hardness, thickness, candesartan and amlodipine content of the tablets, The results of measuring the dissolution rate and the amount of lead substance are shown in Table 9 below.
  • Example 1 As shown in the experimental results of Table 9 confirming the effect of the sugar and sugar alcohol filler, Example 1, Comparative Example 2, Comparative Example 3 showed a test result similar to the initial test results. However, Comparative Example 1 using the isomalt showed a decrease in hardness, and the color was changed to pale gray, indicating an inadequate property.
  • Tablets prepared according to Example 1 and Comparative Examples 1-3 were stored for 1 week under accelerated conditions (opened at 40 ° C., RH 75%) for one week, then the hardness, thickness, candesartan and amlodipine content, dissolution rate and softness of the tablets. The results of measuring the amount of the substance are shown in Table 10 below.
  • Example 1 As shown in the experimental results of Table 10 confirming the effect of the sugar and sugar alcohol filler, Example 1, Comparative Example 2, Comparative Example 3 showed the test results similar to the initial test results. However, Comparative Example 1 using isomalt showed a severe hardness decrease that is impossible to measure, and the tablet swelled severely and showed inadequate properties.
  • mannitol has a very good pharmaceutical formulation in all aspects of properties, hardness, thickness, dissolution rate and stability under all conditions.
  • sorbitol when used, it has a disadvantage in that the surface property is very rough after tableting and the dissolution rate of candesartan is low, and it cannot be manufactured as a tablet due to severe swelling under severe and open acceleration conditions.
  • the dissolution rate of candesartan and amlodipine when used, the dissolution rate of candesartan and amlodipine is very low, and in all conditions, the total amount of the flexible compound is relatively high, which is not suitable for use in the manufacture of tablets.
  • the dissolution rate was so low that it could not be used to prepare tablets.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

La présente invention concerne un composite formé d'une seule couche, comprenant : (i) du candésartan ou du candésartan cilexétil ou un sel pharmaceutiquement acceptable de celui-ci ; (ii) de l'amlodipine ou un sel pharmaceutiquement acceptable de celle-ci ; (iii) du citrate de triéthyle en tant que stabilisant ; et (iv) du mannitol en tant que charge. Le composite de la présente invention présente une stabilité améliorée du candésartan pendant la préparation, le traitement et la conservation, présente un excellent taux de dissolution, et a un effet de facilitation de la préparation dans une formulation telle qu'un comprimé.
PCT/KR2017/009098 2016-09-30 2017-08-21 Composite formé d'une seule couche, comprenant du candésartan et de l'amlodipine WO2018062685A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2019517006A JP6758488B2 (ja) 2016-09-30 2017-08-21 カンデサルタンおよびアムロジピンを含む単一層からなる複合製剤
CN201780060226.2A CN109789099A (zh) 2016-09-30 2017-08-21 包含坎地沙坦和氨氯地平的形成单层的复合物
PH12019500638A PH12019500638A1 (en) 2016-09-30 2019-03-22 Composite formed into single layer, comprising candesartan and amlodipine

Applications Claiming Priority (2)

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KR10-2016-0126879 2016-09-30
KR1020160126879A KR101769293B1 (ko) 2016-09-30 2016-09-30 칸데사르탄 및 암로디핀을 포함하는 단일층으로 이루어진 복합제

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JP (1) JP6758488B2 (fr)
KR (1) KR101769293B1 (fr)
CN (1) CN109789099A (fr)
PH (1) PH12019500638A1 (fr)
WO (1) WO2018062685A1 (fr)

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CN110638764A (zh) * 2019-09-23 2020-01-03 珠海润都制药股份有限公司 一种坎地沙坦酯速释小丸
KR102304910B1 (ko) 2021-01-11 2021-09-27 알리코제약(주) 칸데사르탄을 함유하는 안정한 약학적 조성물
CN117538461B (zh) * 2024-01-10 2024-03-26 地奥集团成都药业股份有限公司 一种盐酸贝那普利片有关物质的检测方法
CN117538462B (zh) * 2024-01-10 2024-03-26 地奥集团成都药业股份有限公司 一种氨氯地平贝那普利胶囊有关物质的检测方法

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JP2013014547A (ja) * 2011-07-05 2013-01-24 Elmed Eisai Kk カンデサルタンシレキセチルを安定化した組成物及びその製造方法
CN102688236B (zh) * 2012-06-06 2014-03-26 石药集团中诺药业（石家庄）有限公司 一种坎地沙坦酯氨氯地平片剂组合物及其制备方法

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US20090208583A1 (en) * 2006-06-20 2009-08-20 Siegfried Generics International Ag Tablets comprising candesartan cilexetil
US20100041644A1 (en) * 2006-11-28 2010-02-18 Laboratorios Liconsa, S. A. Stabilized solid pharmaceutical composition of candesartan cilexetil
KR20150068993A (ko) * 2012-10-12 2015-06-22 아지노모토 가부시키가이샤 칼슘 길항약／안지오텐신 ｉｉ 수용체 길항약 함유 의약 제제
KR20160105543A (ko) * 2012-10-12 2016-09-06 이에이 파마 가부시키가이샤 칼슘 길항약／안지오텐신 ｉｉ 수용체 길항약 함유 의약 제제의 제조 방법
KR20160094869A (ko) * 2015-01-30 2016-08-10 씨제이헬스케어 주식회사 칸데사르탄 및 암로디핀을 포함하는 약제학적 조성물

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JP6758488B2 (ja) 2020-09-23
PH12019500638A1 (en) 2019-11-04
KR101769293B1 (ko) 2017-08-30
CN109789099A (zh) 2019-05-21
JP2019529486A (ja) 2019-10-17

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