WO2014010008A1 - Composition de candésartan cilexétil destinée à être remplie dans une capsule - Google Patents

Composition de candésartan cilexétil destinée à être remplie dans une capsule Download PDF

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Publication number
WO2014010008A1
WO2014010008A1 PCT/JP2012/067424 JP2012067424W WO2014010008A1 WO 2014010008 A1 WO2014010008 A1 WO 2014010008A1 JP 2012067424 W JP2012067424 W JP 2012067424W WO 2014010008 A1 WO2014010008 A1 WO 2014010008A1
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WO
WIPO (PCT)
Prior art keywords
capsule
fatty acid
polyethylene glycol
composition
candesartan cilexetil
Prior art date
Application number
PCT/JP2012/067424
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English (en)
Japanese (ja)
Inventor
高橋　雅人
後藤　正浩
遠藤　隆浩
愛 吉野
Original Assignee
東洋カプセル株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 東洋カプセル株式会社 filed Critical 東洋カプセル株式会社
Priority to PCT/JP2012/067424 priority Critical patent/WO2014010008A1/fr
Publication of WO2014010008A1 publication Critical patent/WO2014010008A1/fr

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to a capsule filling composition containing candesartan cilexetil as an active ingredient and having an increased elution rate of the active ingredient.
  • Candesartan cilexetil is an antihypertensive agent that exhibits angiotensin II (AII) receptor antagonism.
  • AII angiotensin II
  • Commercially available preparations are tablets for oral administration, but because candesartan cilexetil is extremely poorly soluble in water (solubility of less than 0.05 ⁇ g / ml), it has a low dissolution rate and thus low bioavailability.
  • this compound is polyvinyl pyrrolidone (PVP), or this compound, PVP and nonionic surfactant are dissolved in ethanol, and then the formed component is granulated using this solution as a binder, and then compressed into tablets. Made up of.
  • PVP polyvinyl pyrrolidone
  • Patent Document 2 proposes the use of polyethylene glycol 6000 as a stabilizer that suppresses the degradation of the active ingredient over time in solid preparations such as tablets containing candesartan cilexetil (Compound V). ing.
  • This technique is not concerned with improving dissolution rates related to drug bioavailability.
  • the aforementioned solid dosage form for oral administration comprising candesartan cilexetil in substantially amorphous form and a solubilizer requires a number of steps including the use of organic solvents such as ethanol and is resistant to heat. There has not been sufficient consideration for the manufacturing process and storage stability of formulations of this unstable compound. Furthermore, when compared with the candesartan cilexetil drug substance, it is difficult to say that the dissolution rate is sufficiently improved.
  • the object of the present invention is therefore to provide new formulations for oral administration of candesartan cilexetil in which these drawbacks are at least partly improved, in particular a formulation which is even higher than was possible by the prior art with regard to dissolution rate. That is.
  • a capsule filling composition containing candesartan cilexetil dissolved in polyethylene glycol which is liquid at room temperature and an antioxidant.
  • polyethylene glycol which is liquid at normal temperature (25 ° C.) as a solvent, has functions such as drug dissolution assistance and / or dissolution rate and / or viscosity adjustment of the preparation and / or drug stabilization.
  • PEG polyethylene glycol
  • the present invention also provides a capsule filled with the capsule filling composition described above.
  • capsules include the capsule filling composition of the present invention as a core, and encapsulate an intermediate layer and an intermediate layer composed of a lipophilic surfactant and an oil covering the core. It may be a capsule having a multilayer structure including a covering.
  • the present invention provides a higher drug elution rate than was possible with the prior art. This is because candesartan cilexetil exists in a state dissolved in PEG.
  • candesartan cilexetil is unstable to heat.
  • it when it is dissolved in PEG, it may be heated to 40 to 50 ° C., which is lower than before. Stabilization in the manufacturing process is achieved.
  • the preparation since the preparation contains an antioxidant, storage stability after production is also ensured.
  • PEG has the formula H- (OCH 2 CH 2 ) n -OH And n is 4 or more.
  • PEG is called with a numerical value corresponding to its average molecular weight.
  • PEG having an average molecular weight of 400 is called “polyethylene glycol 400”, and in the pharmaceutical field, it is called “macrogol 400”.
  • PEGs that are liquid at room temperature are PEG200, PEG400, and PEG600.
  • PEG400 mp4-8 ° C
  • PEG 6000 which is solid at room temperature, cannot be used alone, it can be used as an auxiliary agent for adjusting its viscosity and the like by adding it to liquid PEG at room temperature.
  • Candesartan cilexetil dissolves in liquid PEG at room temperature to form a solution.
  • the heating temperature at this time is preferably up to 50 ° C. in order to avoid thermal decomposition.
  • Candesartan cilexetil dissolves well in liquid PEG.
  • the dose per dose is 2 to 12 mg, it is difficult to fill the capsule with a solution dissolved up to or near its maximum solubility because the amount of the solution per dose is too small. . Therefore, the drug may be dissolved in liquid PEG so that the amount of liquid administered at one time is at least 80 mg.
  • the dose per dose of candesartan cilexetil is subdivided up to a maximum of 12 mg. Therefore, the drug concentration in the PEG can be increased in proportion to the dose of the drug so that the liquid volume per one dose, and hence the number of capsules, is equal in all doses.
  • a plurality of capsules filled with solutions having different concentrations depending on the number of drug administration levels must be prepared, and there is a risk of under- or over-administration of the drug if selected incorrectly. Therefore, it is preferable to prepare only one type of capsule having a constant drug concentration in the capsule filling solution, and the dose of the drug can be selected according to the number of capsules. For this reason, it is not necessary to dissolve the drug in PEG at a high concentration above a certain concentration, and a drug concentration expressed by the drug / PEG weight ratio may be 1/20.
  • the amount of liquid suitable for filling the capsule can be adjusted by adding an auxiliary agent.
  • the adjuvant must be miscible with PEG and a pharmaceutically acceptable ingredient.
  • the auxiliary agent can also have other functions such as drug dissolution assistance, viscosity adjustment, drug stabilization, and drug elution rate control. Examples of adjuvants that can be used include:
  • PEG solid at normal temperature such as PEG6000; polyalcohol fatty acid ester such as prolene glycol fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, polyethylene glycol fatty acid ester; medium chain fatty acid triglyceride, saturated polyglycolation Nonionic surfactants containing polyoxyethylene chains such as glycerides (transesterification reaction product of hydrogenated vegetable oil and PEG); polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and the like.
  • polyalcohol fatty acid ester such as prolene glycol fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, polyethylene glycol fatty acid ester
  • Nonionic surfactants containing polyoxyethylene chains such as glycerides (transesterification
  • Adjuvants can be added from 5% to 150%, preferably 100% of the liquid PEG by weight, and can be pre-mixed with PEG prior to warming, as with other components.
  • the capsule filling composition of the present invention must contain an antioxidant.
  • antioxidants that are approved as pharmaceutical or food additives. Examples are tocopherol, ascorbic acid and its salts, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate, sodium edetate, citric acid, soy lecithin and the like. Dibutylhydroxytoluene or butylhydroxyanisole is preferred. The amount depends on the antioxidant power of the specific antioxidant, but in the case of dibutylhydroxytoluene, 0.05 to 0.5 parts by weight per 1 part by weight of candesartan cilexetil is appropriate. Antioxidants can be mixed into PEG prior to warming as well as other ingredients.
  • the pharmaceutical composition of the present invention is a capsule and may be a soft capsule or a hard capsule.
  • the soft capsule can be produced by filling a soft capsule film such as gelatin by any one of a seamless method, a flat plate method, and a rotary die method.
  • a hard capsule can be manufactured by enclosing in a hard capsule such as gelatin by a method of filling a liquid or paste-like content.
  • the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is used as a seamless capsule, an intermediate layer that is difficult to mix with water can be interposed between the film and the contents.
  • the polyethylene glycol used in the present invention is a hydrophilic substance
  • the capsule may be softened due to the compatibility with the film at the time of capsule filling or the moisture transfer after the capsule filling, and may not be able to be encapsulated in a stable state.
  • Such a three-layer seamless capsule uses a concentric triple nozzle to simultaneously extrude the contents from the center, the intermediate layer from the inner annular nozzle, and the capsule film from the outer annular nozzle to form a three-layer droplet. And can be obtained by solidification.
  • Examples of the lipophilic surfactant constituting the intermediate layer include glycerin fatty acid ester, polyhydric alcohol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, saturated polyglycolized glyceride, polyoxyethylene Polyoxypropylene glycol, acetyl glycerin fatty acid ester, polyglycerin fatty acid ester, lecithin, polyoxyethylene hydrogenated castor oil and the like, or a mixture thereof can be used.
  • condensed ricinoleic acid ester Preferably, condensed ricinoleic acid ester, propylene glycol fatty acid ester, palmitic acid ester, isostearic acid ester, linoleic acid ester, stearic acid ester, oleic acid ester, sucrose acetate isobutyric acid, or a mixture thereof can be used.
  • the fats and oils constituting the intermediate layer include fatty acids, vegetable oils, and synthetic oils. Preferred is a medium chain fatty acid triglyceride.
  • the mixing ratio of the lipophilic surfactant to the fat is preferably 19: 1 to 1: 1, more preferably 9: 1 to 7: 3, by weight.
  • Candesartan cilexetil contains only a small amount of one pharmaceutical unit, and the dosage is finely adjusted between 2 mg and 12 mg. Since seamless capsules can be filled with a small amount of contents with high accuracy, capsules with a small amount of active ingredient in one preparation unit can be accurately prepared.
  • packaging and packaging this for each dose it is possible to provide a preparation capable of accurately administering a minute amount and a fine dose. Providing a preparation in which a single dose of a patient is packaged is advantageous from the viewpoint of prevention of mistakes in dosage and ease of administration.
  • the packaging is not particularly limited, but a shape considering ease of taking is desirable, and stick-shaped packaging is preferable.
  • Test example 1 First, in order to examine the solubility and storage stability of candesartan cilexetil (hereinafter simply referred to as “drug”) in various additives, the following accelerated stability test was conducted. 30 mg of the drug and 0.9 g of various additive components were weighed in a transparent glass container, heated at about 80 ° C. for several minutes, and visually observed whether the drug was dissolved in these components. Next, the liquid was transferred to a glass bottle, sealed, and stored for 1 week in an environment of temperature 50 ° C. and humidity 75% RH, and the drug content after storage was quantified by HPLC to calculate the residual rate. The results are shown in Table 1.
  • Test example 2 Next, in order to investigate the stability of drugs in various additives in the presence of an antioxidant, the same accelerated stability test as in Test Example 1 was performed.
  • the test method is the same as the test method of Test Example 1 except that the sample contains an antioxidant.
  • the amount of antioxidant was set to about 10 mg of dibutylhydroxytoluene, 24 mg of tocopherol, and 10 mg of citric acid in consideration of the maximum daily dose of each component. When two kinds of antioxidants were used in combination, the total amount shown above was added. The results are shown in Table 2.
  • Test example 3 The effect on drug dissolution was observed.
  • the formulation shown in Table 3 was filled into hard capsules and subjected to a dissolution test.
  • the dissolution test was conducted by the Japanese Pharmacopoeia, General Test, and dissolution test paddle method.
  • the test solution was 20% 1.0% polysorbate solution, 900 mL, and the rotation speed was 50 rpm.
  • a sinker was used since the hard capsule floats in the test solution, a sinker was used. 20 mL was sampled at a specified time, and the content of candesartan cilexetil was measured by HPLC.
  • Formulations 1 and 2 were tested at an active ingredient amount of 2 mg, and the control was tested at 10 mg for convenience of collection. About each result, it converted into the elution rate with respect to the amount of active ingredients, and the elution property was compared.
  • composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.
  • composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.
  • composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.
  • composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.
  • composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.
  • composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.
  • composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.
  • compositions of Formulation Examples 1 to 7 and Formulation Examples 8 and 9 are filled in soft capsules or hard capsules according to a conventional method in such an amount that the content of the drug per capsule is 2 mg, for example.
  • the seamless capsules containing the compositions of Formulation Examples 10 and 11 were produced by the operation described above so that the active ingredient per capsule was 1 mg or 0.5 mg.
  • the produced capsules containing 1 mg and 0.5 mg of active ingredient per capsule are packaged in the number corresponding to the single dose shown in Table 4, for example, in a stick-shaped package.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Physiology (AREA)
  • Nutrition Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une préparation de candésartan cilexétil administrée par voie orale dans une nouvelle forme galénique ayant un taux de dissolution du médicament jamais atteint jusqu'à présent. La présente invention concerne en outre une composition destinée à être remplie dans une capsule comprenant une solution d'un antioxydant et de candésartan cilexétil dissous dans un polyéthylène glycol qui est liquide à des températures normales.
PCT/JP2012/067424 2012-07-09 2012-07-09 Composition de candésartan cilexétil destinée à être remplie dans une capsule WO2014010008A1 (fr)

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PCT/JP2012/067424 WO2014010008A1 (fr) 2012-07-09 2012-07-09 Composition de candésartan cilexétil destinée à être remplie dans une capsule

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PCT/JP2012/067424 WO2014010008A1 (fr) 2012-07-09 2012-07-09 Composition de candésartan cilexétil destinée à être remplie dans une capsule

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05229947A (ja) * 1991-03-26 1993-09-07 Tokai Capsule Kk 塩酸アゼラスチン軟カプセル剤
JPH07228531A (ja) * 1994-02-17 1995-08-29 Toyo Capsule Kk ニコランジルカプセル剤
JPH09501150A (ja) * 1993-06-30 1997-02-04 藤沢薬品工業株式会社 カプセル製剤
JPH11502838A (ja) * 1995-03-29 1999-03-09 ザ、プロクター、エンド、ギャンブル、カンパニー キサンチン誘導体を含むゼラチン外殻を有するソフトゼラチンカプセル
JP2008150298A (ja) * 2006-12-15 2008-07-03 Toyo Capsule Kk 溶解性を改善したジフェンヒドラミン含有医薬組成物
JP2008543728A (ja) * 2005-06-27 2008-12-04 第一三共株式会社 アンジオテンシンｉｉ受容体拮抗剤及びカルシウム拮抗剤含有医薬組成物
JP2010502698A (ja) * 2006-09-05 2010-01-28 アストラゼネカ アクチボラグ カンデサルタンシレキセチルを含む医薬組成物
JP2011084521A (ja) * 2009-10-16 2011-04-28 Toyo Capsule Kk アゼラスチン塩酸塩含有カプセル剤
JP2012025715A (ja) * 2010-07-27 2012-02-09 Ohara Yakuhin Kogyo Kk カンデサルタンシレキセチル含有錠剤
JP2012180287A (ja) * 2011-02-28 2012-09-20 Toyo Capsule Kk カンデサルタンシレキセチルのカプセル充填用組成物

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05229947A (ja) * 1991-03-26 1993-09-07 Tokai Capsule Kk 塩酸アゼラスチン軟カプセル剤
JPH09501150A (ja) * 1993-06-30 1997-02-04 藤沢薬品工業株式会社 カプセル製剤
JPH07228531A (ja) * 1994-02-17 1995-08-29 Toyo Capsule Kk ニコランジルカプセル剤
JPH11502838A (ja) * 1995-03-29 1999-03-09 ザ、プロクター、エンド、ギャンブル、カンパニー キサンチン誘導体を含むゼラチン外殻を有するソフトゼラチンカプセル
JP2008543728A (ja) * 2005-06-27 2008-12-04 第一三共株式会社 アンジオテンシンｉｉ受容体拮抗剤及びカルシウム拮抗剤含有医薬組成物
JP2010502698A (ja) * 2006-09-05 2010-01-28 アストラゼネカ アクチボラグ カンデサルタンシレキセチルを含む医薬組成物
JP2008150298A (ja) * 2006-12-15 2008-07-03 Toyo Capsule Kk 溶解性を改善したジフェンヒドラミン含有医薬組成物
JP2011084521A (ja) * 2009-10-16 2011-04-28 Toyo Capsule Kk アゼラスチン塩酸塩含有カプセル剤
JP2012025715A (ja) * 2010-07-27 2012-02-09 Ohara Yakuhin Kogyo Kk カンデサルタンシレキセチル含有錠剤
JP2012180287A (ja) * 2011-02-28 2012-09-20 Toyo Capsule Kk カンデサルタンシレキセチルのカプセル充填用組成物

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