WO2024049155A1 - Dual-strength odor-shielding pharmaceutical composition - Google Patents

Dual-strength odor-shielding pharmaceutical composition Download PDF

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Publication number
WO2024049155A1
WO2024049155A1 PCT/KR2023/012762 KR2023012762W WO2024049155A1 WO 2024049155 A1 WO2024049155 A1 WO 2024049155A1 KR 2023012762 W KR2023012762 W KR 2023012762W WO 2024049155 A1 WO2024049155 A1 WO 2024049155A1
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tablet
adsorbent
agent
coating
group
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PCT/KR2023/012762
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French (fr)
Korean (ko)
Inventor
이태윤
이병훈
한은지
정다워
조우형
한성균
홍언표
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(주)셀트리온
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Publication of WO2024049155A1 publication Critical patent/WO2024049155A1/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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • 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
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a pharmaceutical composition in the form of a tablet, characterized by a double odor-masking coating layer comprising an adsorbent and an inclusion agent in the coating agent, and more specifically, to a pharmaceutical composition having a medoxomyl group-containing prodrug and/or a pharmaceutically acceptable form thereof.
  • It is a pharmaceutical composition containing a salt in the inner core layer.
  • the coating layer including a coating agent, an adsorbent, and an encapsulant removes the odor component (diacetyl) generated from the inner core by adsorbing and encapsulating it, and blocks moisture from the outside, thereby protecting the parent drug and medoxomil. It relates to a tablet that has the effect of preventing hydrolysis and suppressing the generation of odor components.
  • Azilsartan medoxomil is a drug of the Angiotensin Receptor Blocker (ARB) class that improves binding and dissociation with the AT1 (Angiotensin 1) receptor, thereby lowering blood pressure and controlling blood pressure at the same time.
  • Substances such as olmesartan medoxomil or azilsartan medoxomil, which are in the form of prodrugs, are easily separated into the active parent drug and medoxomil.
  • the medoxomil isolated through this process is Due to hydrolysis, it is converted to diacetyl, which releases a characteristic unpleasant odor.
  • Methods for reducing the unpleasant odor generated from tablets containing medoxomil include the use of packaging using adsorbents such as silica gel, metal oxides, or zeolites, or the use of inclusion compounds (e.g., beta cyclodextrin, etc.) as additives in the prior art. etc.
  • adsorbents such as silica gel, metal oxides, or zeolites
  • inclusion compounds e.g., beta cyclodextrin, etc.
  • cyclodextrin which is an encapsulating agent, requires high cost in terms of economics and efficiency when used alone, and has the disadvantage of reducing inclusion efficiency or having to use a large amount depending on the molecular weight of the material to be included.
  • Idarbi ® tablets a blood pressure regulator currently used on the market, do not have odor masking technology applied, which has the disadvantage of reducing patients' medication compliance.
  • Idarbiclo ® tablets are applied with a hypromellose (HPMC)-based coating, which blocks odor to some extent, but it still reduces medication compliance in patients with a sensitive sense of smell, so more effective odor masking is needed.
  • HPMC hypromellose
  • the object of the present invention is to provide a pharmaceutical composition containing a prodrug having a medoxoyl group and/or a pharmaceutically acceptable salt thereof to significantly reduce the unpleasant odor caused by the diacetyl substance of the prodrug having a medoxoyl group.
  • a pharmaceutical composition containing a prodrug having a medoxoyl group and/or a pharmaceutically acceptable salt thereof to significantly reduce the unpleasant odor caused by the diacetyl substance of the prodrug having a medoxoyl group.
  • a coating layer comprising a coating agent, an adsorbent, and an encapsulating agent.
  • the present invention provides a prodrug having a medoxoyl group, which is characterized by a coating layer containing a coating agent, an adsorbent, and an encapsulant, and/or a pharmaceutically thereof
  • the aim is to provide tablets with the following characteristics.
  • One aspect of the present invention provides a tablet having a coating layer including a coating agent, an adsorbent, and an inclusion agent as a pharmaceutical composition comprising a prodrug having a medoxoyl group or a pharmaceutically acceptable salt thereof.
  • One aspect of the present invention is a pharmaceutical composition containing azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof, having a coating layer containing hypromellose (HPMC), magnesium aluminometasilicate, and betacyclodextrin. Provides tablets.
  • HPMC hypromellose
  • magnesium aluminometasilicate magnesium aluminometasilicate
  • betacyclodextrin Provides tablets.
  • One aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof, comprising 1 to 10 w/w% of a coating agent and 0.01 to 0.5 w/w% of an adsorbent based on the total tablet content. , and 0.05 to 5 w/w% of an encapsulating agent.
  • One aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof, 5 to 35 w/w% compared to azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof.
  • a tablet having a coating layer comprising a coating agent, 0.05 to 2.0 w/w% of an adsorbent, and 1 to 20 w/w% of an encapsulant is provided.
  • the pharmaceutical composition in the form of a tablet according to the present invention removes the odor component (Diacetyl) generated from the inner core by adsorbing and encapsulating the inner core layer containing a prodrug having a medoxyl group by coating it with a coating layer containing a coating agent, an adsorbent, and an encapsulant. And, by blocking moisture from the outside, it has the effect of improving the odor shielding function that prevents the hydrolysis of the parent drug and Medoxomil and suppresses the generation of odor components.
  • odor component Diacetyl
  • the tablet according to the present invention has the effect of improving patient compliance by suppressing odor components generated from prodrugs having a medoxoyl group and/or pharmaceutically acceptable salts thereof.
  • FIG. 1 is a schematic diagram of an example of a tablet of the present invention featuring a coating layer comprising a coating agent, an adsorbent, and an encapsulating agent.
  • a prodrug having a medoxomil group is a substance containing a medoxomil group in the form of a prodrug, and is a pharmaceutically active ingredient that is easily separated into an active parent drug and medoxomil.
  • prodrugs having a medoxoyl group include olmesartan medoxomil, azilsartan medoxomil, etc.
  • odor masking is defined as removing or reducing the unpleasant odor of a pharmaceutical active ingredient, or reducing the perception of the odor.
  • the present invention adsorbs and encapsulates the odor component (Diacetyl) generated in the inner core by coating the inner core layer containing a prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof with a coating layer containing a coating agent, an adsorbent, and an encapsulant.
  • a tablet with an improved odor-blocking function that prevents the hydrolysis of the parent drug and Medoxomil by contacting and removing it and blocking moisture from the outside, thereby suppressing the generation of odor components.
  • the present invention is a pharmaceutical composition containing a prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof, and is characterized by a coating layer containing a coating agent, an adsorbent, and an inclusion agent.
  • the pharmaceutical composition may be tablets or granules, for example, tablets.
  • the pharmaceutical composition may be a tablet in which the inner core layer is coated with a coating layer, and for example, it may be a film-coated tablet.
  • the film-coated tablet includes a coating agent, an adsorbent, and an inclusion agent in a coating layer that coats the inner core layer containing the pharmaceutically active ingredient.
  • the inner core layer may be a single tablet, a double-layer tablet, or a multi-layer tablet containing an active pharmaceutical ingredient.
  • it may be a single tablet, and for another example, it may be a double-layer tablet.
  • the inner core layer containing azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof and amlodipine and/or a pharmaceutically acceptable salt thereof is formed into a coating layer containing a coating agent, an adsorbent, and an inclusion agent.
  • a tablet with improved odor masking function is provided by coating to adsorb and remove odor components generated from the inner core.
  • a coating layer composition including a coating agent, an adsorbent, and an inclusion agent that has an odor masking function by adsorbing and removing odor components generated from a prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof.
  • composition of the coating layer (coating layer composition) with odor shielding function
  • a coating agent is a material with a specific function that covers the surface of a drug, and can play roles such as shielding drug exposure, blocking moisture, and preventing oxidation.
  • the type of coating agent of the coating layer of the present invention is not particularly limited, and for example, polyvinyl alcohol (PVA), hypromellose (Hydroxypropyl methyl Cellulose), which is a water-soluble coating base in the cellulose ether derivative series, and hyde. Alone or a mixture thereof selected from the group consisting of Hydroxy propyl Cellulose, Hydroxyethyl Cellulose, Methyl Cellulose, Ethyl Cellulose, Carboxy methyl cellulose, etc. It may include a coating agent made of a mixture.
  • hypromellose Hydropropyl methyl Cellulose
  • Opadry coating agent can be used as a hypromellose-based coating base.
  • the content of the coating agent can be appropriately selected depending on the type of pharmaceutical active ingredient and the combination and composition of the adsorbent and inclusion agent.
  • the coating agent may contain 1 to 10 w/w% relative to the total tablet content, for example, 1 to 8 w/w%, and in another example, 1 to 5 w%. /w%, and the coating agent may include hypromellose (HPMC).
  • HPMC hypromellose
  • the coating agent may be included in an amount of 5 to 35 w/w% relative to the prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof, for example, 7 to 28 w/w. %, another example is 10 to 26 w/w%, and the coating agent may include hypromellose (HPMC).
  • HPMC hypromellose
  • An adsorbent is a material that adsorbs adsorbent materials such as liquid and gas, such as odorants and moisture, and can play a role in shielding certain substances and blocking moisture.
  • the type of adsorbent included in the coating layer of the present invention is not particularly limited, and includes, for example, inorganic salts and metal silicate materials, such as Magnesium Aluminosilicate (trade name: Neusilin ® ), Calcium silicate (trade name) : Florite ® R) or colloidal silicon dioxide (trade name: Aerosil ® 200), activated carbon, ion exchange resin, etc. may be included alone or as a mixture of these adsorbents.
  • magnesium metasilicate aluminate (Neusilin ® ) can be used as an adsorbent.
  • the content of the adsorbent may be appropriately selected depending on the combination and composition of the amount of diacetyl, an odor component of the active ingredient, and the inclusion agent.
  • the adsorbent may be equal to the amount of diacetyl produced from the prodrug having a medoxomethyl group in a 1:1 ratio.
  • the adsorbent may contain 0.01 to 0.5 w/w% relative to the total tablet content, for example, 0.01 to 0.3 w/w%, and in another example, 0.01 to 0.3 w/w%. It may contain 0.2 w/w%, and the adsorbent may include magnesium aluminate metasilicate.
  • the adsorbent may contain 0.01 to 0.05 w/w% based on the total tablet content.
  • the molar ratio of the prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof and the adsorbent may be 300:1 to 10:1, and for example, 300:1 to 10:1. It may be 25:1, in another example it may be 300:1 to 50:1, and in another example it may be 300:1 to 100:1.
  • the adsorbent may be included in an amount of 0.05 to 2.0 w/w% relative to the prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof, for example, 0.1 to 2.0 w/w. It may be included in %, and as another example, it may be included in 0.1 to 1.0 w/w%, and the adsorbent may include magnesium aluminate metasilicate.
  • Encapsulants are substances for complexing and encapsulating various guest molecules, and include stabilizing guest molecules against decomposition (e.g., hydrolysis, etc.); Improving or enhancing the taste or odor of commercial products; Either delayed or continuous emission of odor or odor, more than one may be provided.
  • decomposition e.g., hydrolysis, etc.
  • Improving or enhancing the taste or odor of commercial products either delayed or continuous emission of odor or odor, more than one may be provided.
  • inclusion agent included in the coating layer of the present invention is not particularly limited and may include, for example, alphacyclodextrin, betacyclodextrin, and gammacyclodextrin.
  • beta cyclodextrin may be used as the inclusion agent.
  • the content of the inclusion agent may be appropriately selected depending on the amount of diacetyl, which is an odor component of the active ingredient, and the combination and composition of the adsorbent.
  • the inclusion agent may be present in a 1:1 ratio with diacetyl produced in the composition.
  • the inclusion agent may contain 0.05 to 5 w/w% relative to the total tablet content, in one example it may contain 0.1 to 5 w/w%, and in another example, 0.1 w/w%. It may contain to 3 w/w%, and the inclusion agent may include betacyclodextrin.
  • the molar ratio of the prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof and the inclusion agent may be 200:1 to 10:1, and for example, 180:1. It may be from 10:1, in another example it may be 180:1 to 20:1, and in another example it may be 50:1 to 10:1.
  • the inclusion agent may be included in an amount of 1 to 20 w/w% relative to the prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof, for example, 1 to 15 w/w%. It may be included in w%, and in another example, it may be included in 2 to 12 w/w%, and the inclusion agent may include betacyclodextrin.
  • the adsorbent and the inclusion agent may be included in a weight ratio of 1:1 to 1:50, for example, 1:1 to 1:40, and in another example, 1:1. It may be included in a weight ratio of 1:30 to 1:30, and as another example, it may be included in a weight ratio of 1:20 to 1:25.
  • the adsorbent and the coating agent may be included in a weight ratio of 1:5 to 1:150, for example, 1:10 to 1:100, and in another example, 1:30 to 1:100. It may be included at a weight ratio of 1:80, and as another example, it may be included at a weight ratio of 1:25 to 1:62.5.
  • the inclusion agent and the coating agent may be included in a weight ratio of 1:1 to 1:30, for example, 1:1 to 1:15, and in another example, 1:1. It may be included in a weight ratio of 1:5 to 1:5, and as another example, it may be included in a weight ratio of 1:1 to 1:2.5.
  • hypromellose HPMC
  • HPMC hypromellose
  • magnesium aluminometasilicate as an adsorbent
  • a tablet is provided in which an inner core layer containing a prodrug having a medoxoyl group and/or a pharmaceutically acceptable salt thereof is coated with a coating layer containing 0.1 to 3 w/w% of betacyclodextrin as an encapsulating agent.
  • the present invention contains 10 to 26 w/w% of a coating agent relative to the prodrug having a medoxomyl group or a pharmaceutically acceptable salt thereof, and includes 0.1 to 1.0 w/w% of an adsorbent,
  • a tablet is provided in which an inner core layer containing a prodrug having a medoxoyl group and/or a pharmaceutically acceptable salt thereof is coated with a coating layer containing 2 to 12 w/w% of an inclusion agent.
  • the total coating layer composition including the coating agent, adsorbent, and encapsulant may include 1 to 16 w/w% of the total tablet content, for example, 1 to 12 w/w%, and Another example may include 2 to 8 w/w%, and another example may include 3 to 5 w/w%.
  • the pharmaceutically active ingredient of the tablet according to the present invention is contained in the inner core layer coated by the coating layer.
  • the active ingredient of the tablet coated with the coating layer may include a prodrug having a medoxoyl group and/or a pharmaceutically acceptable salt thereof.
  • prodrugs having a medoxoyl group include olmesartan medoxomil and azilsartan medoxomil.
  • azilsartan medoxomil may be included as an active ingredient in tablets coated with a coating layer.
  • the active ingredient of the tablet coated with the coating layer may include 3 to 30 w/w% of azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof based on the total tablet content,
  • One example may include 5 to 30 w/w% of azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof, and another example may include 7 to 30 w/w% of azilsartan medoxomil and/or Or it may include a pharmaceutically acceptable salt thereof, and as another example, it may include 10 to 25 w/w% of azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof.
  • azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof which are the active ingredients of the tablet according to the present invention, are included in an amount of 10 mg to 100 mg, for example, 20 mg to 100 mg, in another example. It may be included in an amount of 30 mg to 95 mg, in another example, 70 mg to 90 mg.
  • the active ingredient azilsartan medoxomil and/or its pharmaceutically acceptable salt may be 40 mg, 80 mg, or 100 mg.
  • the inner core layer of the tablet according to the present invention may be a single drug containing a prodrug having a medoxomyl group, and/or a combined drug containing additional active ingredients.
  • a complex tablet refers to a tablet in which the inner nuclear layer contains additional pharmaceutical active ingredients that exhibit pharmacological effects in addition to the prodrug having a medoxomyl group.
  • the composite tablet may contain a dihydropyridine series active ingredient and/or a pharmaceutically acceptable salt thereof as an additional active ingredient in addition to the prodrug having a medoxoyl group.
  • the combination tablet may contain a statin-based active ingredient and/or a pharmaceutically acceptable salt thereof as an additional active ingredient in addition to the prodrug having a medoxoyl group.
  • the composite tablet may contain a thiazide series active ingredient and/or a pharmaceutically acceptable salt thereof as an additional active ingredient in addition to the prodrug having a medoxoyl group.
  • the above complex tablet may additionally contain an active ingredient for treating hyperlipidemia as an active ingredient.
  • additional active ingredients include atorvastatin, rosuvastatin, ezetimibe, chlorthalidone and/or pharmaceutically acceptable salts thereof, etc. It may contain one or more.
  • the active ingredients of the composite tablet coated with a coating layer may include azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof and amlodipine and/or a pharmaceutically acceptable salt thereof.
  • the active ingredients of the composite tablet coated with a coating layer may include azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof and atorvastatin and/or a pharmaceutically acceptable salt thereof. there is.
  • the active ingredient of the composite tablet coated with a coating layer is azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof; Atrovastatin and/or a pharmaceutically acceptable salt thereof; It may include ezetimibe and/or a pharmaceutically acceptable salt thereof.
  • the active ingredients of the composite tablet coated with a coating layer may include azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof and rosuvastatin and/or a pharmaceutically acceptable salt thereof. You can.
  • the active ingredients of the composite tablet coated with the coating layer may include azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof and chlorthalidone and/or a pharmaceutically acceptable salt thereof. You can.
  • the active ingredients of the composite tablet coated with a coating layer may include azilsartan medoxomil potassium and amlodipine besylate.
  • the active ingredient of the composite tablet coated with the coating layer may include 0.05 to 7 w/w% of amlodipine and/or a pharmaceutically acceptable salt thereof based on the total tablet content, as an example. May include 1 to 5 w/w% of amlodipine and/or a pharmaceutically acceptable salt thereof, and another example may include 1 to 3 w/w% of amlodipine and/or a pharmaceutically acceptable salt thereof. It can be included.
  • the amount of amlodipine and/or its pharmaceutically acceptable salt may be 5 mg or 10 mg.
  • the tablet of the present invention may contain diluents, disintegrants, binders, stabilizers, lubricants, and colorants as additives in addition to the pharmaceutically effective ingredients.
  • the additive may be one or more selected from the group consisting of diluents, disintegrants, binders, stabilizers, lubricants, and colorants.
  • the pharmaceutical composition according to the present invention may contain a pharmaceutically acceptable diluent, examples of which include lactose hydrate, starch, sucrose, mannitol, sorbitol, powdered cellulose, microcrystalline cellulose, and hydrogen phosphate. It may be one or more selected from the group consisting of calcium, etc.
  • the pharmaceutical composition according to the present invention may contain a pharmaceutically acceptable disintegrant, examples of which include croscarmellose sodium, sodium starch glycolate, gelatinized starch, crospovidone, It may be one or more selected from the group consisting of low-substituted hydroxypropylcellulose, alginic acid, carboxymethyl cellulose calcium or sodium salt, colloidal silicon dioxide, guar gum, magnesium aluminate silicate, methyl cellulose, and sodium alginate.
  • a pharmaceutically acceptable disintegrant examples of which include croscarmellose sodium, sodium starch glycolate, gelatinized starch, crospovidone, It may be one or more selected from the group consisting of low-substituted hydroxypropylcellulose, alginic acid, carboxymethyl cellulose calcium or sodium salt, colloidal silicon dioxide, guar gum, magnesium aluminate silicate, methyl cellulose, and sodium alginate.
  • the pharmaceutical composition according to the present invention may contain a pharmaceutically acceptable binder, examples of which include hydroxypropyl cellulose, low-substituted cellulose, ethyl cellulose, polyvinylpyrrolidone, and lactose hydrate. It may be one or more selected from the group consisting of starch, talc, and gelatin.
  • the pharmaceutical composition according to the present invention may include a pharmaceutically acceptable stabilizer, and the stabilizer may include a buffer, thickener, antioxidant, solubilizer, etc.
  • the pharmaceutical composition according to the present invention may include a pharmaceutically acceptable lubricant, examples of which include fatty acid esters, stearic acid, magnesium stearate, glyceryl behenate, calcium stearate, It may be one or more selected from the group consisting of sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, talc, hydrogenated oil, and carnaubanap.
  • a pharmaceutically acceptable lubricant examples of which include fatty acid esters, stearic acid, magnesium stearate, glyceryl behenate, calcium stearate, It may be one or more selected from the group consisting of sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, talc, hydrogenated oil, and carnaubanap.
  • the pharmaceutical composition according to the present invention may contain a pharmaceutically acceptable colorant, examples of which may include iron oxide, natracol iron oxide, carotenoids, etc.
  • a tablet containing a prodrug having an azilsartan medoxoyl group and/or a pharmaceutically acceptable salt thereof of the present invention may be a tablet prepared by adding and mixing additives commonly used in the art.
  • the odor masking effect generated from the prodrug having a medoxoyl group of the present invention is not affected by the type and content of additives and additional active ingredients other than the prodrug having a medoxoyl group, so the additive can be commonly used in the art. It may be a tablet manufactured by adding and mixing.
  • the inner core layer containing the prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof according to the present invention may be a tablet conventionally manufactured in the art.
  • a tablet having a coating layer including a coating agent, an adsorbent, and an inclusion agent is prepared from a pharmaceutical composition comprising a prodrug having an azilsartan medoxoyl group and/or a pharmaceutically acceptable salt thereof.
  • the uncoated tablet can be used commercially purchased Idalbi Tablet ® (lot no.12127566, Celltrion Pharmaceutical).
  • the pharmaceutical composition may be a tablet in which the inner core layer containing the pharmaceutical active ingredient is coated with a coating layer, and for example, it may be a film-coated tablet.
  • mixing a coating agent, an encapsulant, and an adsorbent can be prepared by coating the mixed coating solution on the inner core layer containing a prodrug having a medoxyl group using a coating machine to obtain a film-coated tablet.
  • the preparation may include the step of obtaining a composite film coated tablet by coating the mixed coating solution on a two-layer tablet prepared by mixing one or more active ingredients.
  • the tablet manufacturing method manufactured in one embodiment of the present invention includes tablet manufacturing methods commonly used in the art, such as mixing, granulation, lubrication, tableting, etc., and can be manufactured by, for example, the method described in the Korean Pharmacopoeia.
  • a pharmaceutical composition comprising azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof, comprising 5 to 30 w/w% of azilsartan medoxomil and/or a pharmaceutical thereof based on the total tablet content.
  • a pharmaceutical composition comprising azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof, comprising 5 to 30 w/w% of azilsartan medoxomil and/or a pharmaceutical thereof based on the total tablet content.
  • An inner core layer containing a scientifically acceptable salt, 0.5 to 7 w/w% of amlodipine and/or a pharmaceutically acceptable salt thereof, and 1 to 10 w/w% of hypromellose (HPMC) relative to the total tablet content. , 0.01 to 0.5 w/w% of magnesium aluminometasilicate, and 0.05 to 5 w/w% of betacyclodextrin.
  • Example 1 Tablets containing azilsartan medoxomil and odor masking effect depending on the type of adsorbent and encapsulant
  • Azilsartan medoxomil tablet uncoated tablet (Idalbi tablet) ® )
  • the experiment was conducted using commercially purchased Idalbee tablets ® (lot no. 12127566, Celltrion Pharmaceuticals).
  • film-coated tablets were obtained by adding an adsorbent and an inclusion agent to the coating agent as shown in Table 1 below.
  • alphacyclodextrin Cavamax W6, Ashland
  • betacyclodextrin Cavamax
  • W7, Ashland and 0.6 g of each type of adsorbent, either calcium silicate (Calcium Silicate; Florite-R, Tomita) or magnesium aluminometasilicate (Fuji Chem.) are sequentially dissolved.
  • Example 1 Manufactured according to the method of Example 1, but containing only a coating layer containing Opadry, a hypromellose-based coating base, as shown in Comparative Example 1-1 according to Table 1 below, 367.8 mg of film-coated tablets were produced per tablet. got it
  • the amount of diacetyl detected over time was measured using a GC-based electronic nose for azilsartan medoxomil tablets having a coating layer containing a mixture of coating agent, adsorbent, and encapsulant obtained in Example 1.
  • the prepared coated tablets were vacuum dried (2.0 mbar, 40°C, 12 hours), sealed in an aluminum bag with 1 g of silica gel, and loaded into a harsh chamber.
  • Diacetyl was measured by unloading at 1 week (1W) according to time after harsh chamber loading.
  • chromatograms were obtained using a GC-based electronic nose (Heracles-II, Alpha-Mos). Five tablets of each example were placed in a 50 mL vial and loaded into the electronic nose. Each vial is incubated at 40°C for 20 minutes, then 5mL of upper gas is collected and injected into the GC. Two columns were used, MXT-1701-FID (slightly polar) and MXT-5-FID (non-polar), and the peak at about 27 to 28.5 seconds (RT) of the MXT-5-FID (non-polar) column was the peak of diacetyl. It was confirmed in the Arochem library in the electronic nose.
  • Example 1 Since all samples of Example 1 showed differences only in the corresponding peak and the remaining peaks were similar, it can be seen that the difference in odor between the examples is due to the difference in the amount of diacetyl detected.
  • the diacetyl detection amount was derived by calculating the corresponding peak area of the chromatogram, and was expressed as a percentage based on the initial diacetyl detection amount of 1-1 for comparison.
  • Example 1 coating agent absorbent inclusion agent Diacetyl detection amount (compared to Comparative Example 1-1 Initial, %) 7.8 mg 0.2mg 2mg Initial 1W
  • Examples 1-1 to 1-4 which included all coating agents, adsorbents, and inclusion agents, showed a lower amount of diacetyl detected than Comparative Example 1-1, and metasilicic acid was used as the type of adsorbent and inclusion agent, respectively.
  • Examples 1-4 which were magnesium aluminate and betacyclodextrin (beta-CD), showed the lowest amount of diacetyl detected.
  • Example 2 a film-coated tablet was manufactured using Idarbi Tablet ® purchased in Example 1. Specifically, first, magnesium aluminometasilicate (Neusilin, Fuji Chem.) and betacyclodextrin (beta-CD; Cavamax W7, Ashland) are sequentially dissolved in purified water according to the amounts of adsorbent and inclusion agent in Table 2. Afterwards, dissolve 10mg of hypromellose-based coating base (Opadry 03A640040 Pink, Colorcon). Thereafter, using the prepared coating solution, 360 mg of the uncoated tablet was coated with a coating machine (KC65FC, Goldstar) so that the total weight was as shown in Table 2. Film-coated tablets of Examples 2-1, 2-2, 2-3, and 2-4 got it
  • Film-coated tablets were prepared according to the method of Example 2, with the contents and combinations of Comparative Examples 2-1, 2-2, 2-3, and 2-4 according to Table 2 below.
  • Comparative Examples 2-4 used Dalbijeong ® purchased as in Example 1 above.
  • Example 2 Composition of azilsartan medoxomil tablets with a coating layer comprising a coating agent, an adsorbent and an encapsulating agent according to Example 2 Azilsartan medoxomil (mg) coating agent (Opadry) (mg) absorbent (Magnesium aluminate metasilicate) (mg) Inclusion agent (betacyclodextrin) (mg) Total tablet weight (mg)
  • Example 2-1 80 10 0.2 2 372.2
  • Example 2-3 80 10 0.2 4 374.2
  • the azilsartan medoxomil tablets having a coating layer mixed with Opadry, magnesium aluminometasilicate, and betacyclodextrin according to Example 2 and Table 2 were analyzed over time using a GC-based electronic nose. The amount of acetyl detected was measured.
  • the film-coated tablets obtained above were vacuum dried (2.0 mbar, 40°C, 12 hours), sealed in an aluminum bag, and loaded into a harsh chamber. Diacetyl was measured by unloading at 1 week (1W) according to time after harsh chamber loading.
  • Example 2 To measure the amount of diacetyl, a GC-based electronic nose was used in the same manner as in Example 1. The measured detection amount of diacetyl was expressed as a percentage compared to the initial detection amount in Comparative Example 2-3. The results are shown in Table 3 below.
  • Example 3 Long-term odor-masking effect of azilsartan medoxomil tablets depending on the content of coating agent, adsorbent, and encapsulant
  • Dalbijeong ® purchased as in Example 1 was used.
  • an adsorbent and an encapsulant were added to the coating agent as shown in Table 4 below to obtain film-coated tablets of Examples 3-1 to 3-11.
  • magnesium aluminometasilicate Nesilin, Fuji Chem.
  • betacyclodextrin Cavamax W7, Ashland
  • hypromellose-based coating base Opadry 03A640040 Pink, Colorcon
  • 360 mg of the uncoated tablet was coated with a coating machine (KC65FC, Goldstar) to obtain a film-coated tablet with a total weight as shown in Table 4.
  • Example 3 Composition of azilsartan medoxomil tablets according to coating agent, adsorbent and encapsulant content according to Example 3 Azilsartan medoxomil (mg) Coating (Opadry) (mg) Adsorbent (magnesium aluminate metasilicate) (mg) Inclusion agent (betacyclodextrin) (mg) Total tablet weight (mg)
  • Example 3-1 80 12.5 0.5 5 378
  • Example 3-2 80 12.5 0.5 One 374
  • Example 3-3 80 12.5 0.2 5 377.7
  • Example 3-4 80 7.5 0.5 5 373
  • Example 3-5 80 12.5 0.2 One 373.7
  • Example 3-6 80 7.5 0.5 One 369
  • Example 3-7 80 7.5 0.2 5 372.7
  • Example 3-8 80 7.5 0.2 One 368.7
  • Example 3-9 80 10 0.35 3 373.4
  • Example 3-10 80 10 0.35 3 373.4
  • Example 3-11 80 10 0.35 3 373.4 Comparative Example 3
  • Experimental Example 3-1 Measurement of diacetyl detection amount of azilsartan medoxomil tablets according to coating agent, adsorbent, and inclusion agent content
  • Azilsartan medoxomil tablets having a coating layer mixed with Opadry, magnesium aluminometasilicate, and betacyclodextrin according to Example 3 and Table 4 were analyzed over time using a GC-based electronic nose. The amount of acetyl detected was measured.
  • the film-coated tablets obtained above were vacuum dried (2.0 mbar, 40°C, 12 hours), sealed in an aluminum bag, and loaded into a harsh chamber. Diacetyl was measured by unloading at the 4th week of long-term harsh conditions according to the time after loading into the harsh chamber.
  • Example 2 To measure the amount of diacetyl, a GC-based electronic nose was used in the same manner as in Example 1. The measured detection amount of diacetyl was expressed as a percentage compared to the initial detection amount in Comparative Example 3-1. The results are shown in Table 5 below.
  • Example 3-1 Diacetyl detection amount (Comparative Example 3-1 Initial, %) Initial 4W
  • Example 3-1 11.50 52.46
  • Example 3-2 19.26 211.04
  • Example 3-3 7.97 50.50
  • Example 3-4 22.10 251.90
  • Example 3-5 22.63 210.74
  • Example 3-6 29.00 601.10
  • Example 3-7 18.12 230.88
  • Example 3-8 37.29 592.79
  • Example 3-9 31.20 360.79
  • the odor intensity of the azilsartan medoxomil tablet according to Example 3 was measured on the four scales shown in Table 6 (1. No odor, 2. Feeling weak, 3. Feeling clearly, 4. Feeling enough to interfere with taking). Based on this, a survey was conducted on 16 adults. Based on the electronic nose-based GC analysis results in Table 5, samples of Examples 3-3, 3-7, and 3-9 with the lowest total coating amount were selected from some of the composition samples in Table 4, and were used together with Comparative Example 3-1. As shown in Table 6, four odor scale surveys were conducted. The results are shown in Table 6 below as a percentage of the total number of people.
  • the odor masking effect according to the coating amount was confirmed to be a significant difference between groups, and a good effect was shown in all examples compared to Comparative Example 3-1. Statistical significance was confirmed to be over 95% confidence interval through the Chi-square test (p-value ⁇ 0.05). The results of Example 3-3 showed a significant effect, with more than 50% not feeling the smell at all, and about 94% not feeling the smell or feeling it very weakly. Therefore, it was confirmed through a survey that the compositions showed excellent odor masking effects.
  • Example 4 Odor masking effect of composite tablets containing azilsartan medoxomil and amlodipine or a pharmaceutically acceptable salt thereof depending on the content of coating agent, adsorbent, and encapsulant
  • amlodipine besylate 1331.11 g of silicified microcrystalline cellulose, 400.00 g of anhydrous calcium phosphate, 20.00 g of colloidal silicon dioxide and 100.00 g of crospovidone are mixed in a mixer (FTMF 50 MCG, Muller). Then add 10.00g of magnesium stearate and lubricate it.
  • Double-layer tablet manufacturing method Double-layer tablet manufacturing method
  • a mixture of azilsartan medoxomil and amlodipine besylate is used to compress tablets using a double-layer tablet press (EP200L, Parle).
  • EP200L double-layer tablet press
  • a film-coated tablet can be obtained by adding an adsorbent and an inclusion agent to the coating agent as in Examples 2 and 3. Thereafter, using the prepared coating solution, the double-layer tablet was coated with a coater (KC65FC, Goldstar) to obtain a film-coated tablet as shown in Table 7 below.
  • KC65FC, Goldstar a coater
  • Example 4-1 80 10 19.774 0.316 7.91 Comparative Example 4-1 80 10 0 0 0 0 Comparative Example 4-2 80 10 19.774 0 0
  • Azilsartan medoxomil tablets having a coating layer mixed with Opadry, magnesium aluminometasilicate, and betacyclodextrin according to Example 4 and Table 7 were analyzed over time using a GC-based electronic nose. The amount of acetyl detected was measured.
  • the film-coated tablets obtained above were vacuum dried (2.0 mbar, 40°C, 12 hours), sealed in an aluminum bag, and loaded into a harsh chamber. Diacetyl was measured by unloading at the 4th week (4W) of harsh conditions according to time after loading into the harsh chamber.
  • Example 8 To measure the amount of diacetyl, a GC-based electronic nose was used in the same manner as in Example 1. The measured detection amount of diacetyl was expressed as a percentage compared to the initial detection amount in Comparative Example 4-2. The results are shown in Table 8 below.
  • Example 4-1 which is a film-coated tablet containing both an adsorbent and an inclusion agent in addition to the coating in the coating layer, compared to Comparative Examples 4-1 and 4-2, can be confirmed.
  • the detection amount was about 5 times lower than the 4th week value of Comparative Example 4-2, in which only the coating agent was coated, so the compositions were combined. It was confirmed that tablets also showed excellent odor masking effect.

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Abstract

The present invention relates to a tablet characterized by a coating layer that includes both an adsorbent and an encapsulating agent in a general coating agent, whereby the tablet significantly improves the odor shielding function caused by medoxomil groups to enhance patient medication compliance.

Description

이중 냄새 차폐 약학 조성물Dual odor masking pharmaceutical composition
본 발명은 코팅제에 흡착제 및 포접제를 같이 포함하는 이중 냄새 차폐 코팅층을 특징으로 가진 정제 형태의 약학 조성물에 관한 것으로, 보다 상세하게는 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염을 내핵층에 함유하는 약학 조성물로 코팅제, 흡착제 및 포접제를 포함한 코팅층이 내핵에서 발생하는 냄새 성분 (디아세틸)을 흡착 및 포접하여 제거하고, 외부로부터 수분을 차단함으로써 모약물과 메독소밀의 가수분해를 막아 냄새 성분의 발생을 억제하는 효과를 가지는 정제에 관한 것이다.The present invention relates to a pharmaceutical composition in the form of a tablet, characterized by a double odor-masking coating layer comprising an adsorbent and an inclusion agent in the coating agent, and more specifically, to a pharmaceutical composition having a medoxomyl group-containing prodrug and/or a pharmaceutically acceptable form thereof. It is a pharmaceutical composition containing a salt in the inner core layer. The coating layer including a coating agent, an adsorbent, and an encapsulant removes the odor component (diacetyl) generated from the inner core by adsorbing and encapsulating it, and blocks moisture from the outside, thereby protecting the parent drug and medoxomil. It relates to a tablet that has the effect of preventing hydrolysis and suppressing the generation of odor components.
아질사르탄 메독소밀은 안지오텐신수용체차단제 (Angiotensin Receptor Blocker;ARB) 계열의 약물로 AT1 (Angiotensin 1) 수용체와의 결합력과 해리력을 개선시켜 혈압강하와 동시에 혈압조절을 가능하게 한다. 전구약물의 형태를 갖는 올메사르탄 메독소밀이나 아질사르탄 메독소밀 같은 물질은 활성의 모약물 (active parent drug)과 메독소밀 (medoxomil)로 용이하게 분리되는데, 이러한 과정을 통해서 분리된 메독소밀은 가수분해로 인해 디아세틸 (diacetyl)로 전환되고, 그로 인해 특유의 불쾌한 냄새를 방출한다. Azilsartan medoxomil is a drug of the Angiotensin Receptor Blocker (ARB) class that improves binding and dissociation with the AT1 (Angiotensin 1) receptor, thereby lowering blood pressure and controlling blood pressure at the same time. Substances such as olmesartan medoxomil or azilsartan medoxomil, which are in the form of prodrugs, are easily separated into the active parent drug and medoxomil. The medoxomil isolated through this process is Due to hydrolysis, it is converted to diacetyl, which releases a characteristic unpleasant odor.
메독소밀을 함유하는 정제에서 발생하는 불쾌한 냄새의 감소 방법으로는 실리카겔, 금속 산화물이나 제올라이트 등과 같은 흡착제를 적용한 포장형태를 이용하거나 포접 화합물 (예를 들면 베타 사이클로덱스트린 등)을 제제 첨가물로서 이용하는 종래 기술 등이 있다. 그러나, 포접제인 사이클로덱스트린 등은 단독으로 사용 시 경제적 및 효율성 측면에서 높은 비용이 요구되며, 포접하고자 하는 물질의 분자량에 따라 포접 효율이 감소되거나 많은 양을 사용해야 하는 단점이 존재한다.Methods for reducing the unpleasant odor generated from tablets containing medoxomil include the use of packaging using adsorbents such as silica gel, metal oxides, or zeolites, or the use of inclusion compounds (e.g., beta cyclodextrin, etc.) as additives in the prior art. etc. However, cyclodextrin, which is an encapsulating agent, requires high cost in terms of economics and efficiency when used alone, and has the disadvantage of reducing inclusion efficiency or having to use a large amount depending on the molecular weight of the material to be included.
현재 시중에서 사용되고 있는 혈압조절제인 이달비®정은 냄새 차폐를 위한 기술이 미 적용되어, 환자의 복약 순응도를 감소시키는 단점을 가지고 있다. 또한, 이달비클로®정은 히프로멜로오스 (HPMC) 기반의 코팅제가 적용되어 냄새가 어느정도 차단은 되나, 여전히 후각이 예민한 환자의 복약 순응도를 감소시켜 더 효과적인 냄새 차폐 개선이 필요한 상황이다.Idarbi ® tablets, a blood pressure regulator currently used on the market, do not have odor masking technology applied, which has the disadvantage of reducing patients' medication compliance. In addition, Idarbiclo ® tablets are applied with a hypromellose (HPMC)-based coating, which blocks odor to some extent, but it still reduces medication compliance in patients with a sensitive sense of smell, so more effective odor masking is needed.
본 발명의 과제는 메독소밀기를 가지는 전구약물의 디아세틸 (diacetyl) 물질에 의한 불쾌한 냄새를 유의하게 감소시키기 위해 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염을 포함한 약학 조성물로 코팅제, 흡착제 및 포접제를 포함한 코팅층을 특징으로 갖는 정제를 제공하는 것이다.The object of the present invention is to provide a pharmaceutical composition containing a prodrug having a medoxoyl group and/or a pharmaceutically acceptable salt thereof to significantly reduce the unpleasant odor caused by the diacetyl substance of the prodrug having a medoxoyl group. To provide a tablet characterized by a coating layer comprising a coating agent, an adsorbent, and an encapsulating agent.
본 발명은 메독소밀기를 가지는 전구약물을 포함하는 약제 투여 시 환자의 복약 순응도를 높이기 위해 코팅제, 흡착제 및 포접제를 포함한 코팅층을 특징으로 갖는 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염을 포함하는 정제 형태의 약학 조성물로, 코팅제, 흡착제 및/또는 포접제를 각자 사용했을 때의 단점 및 효과를 개선시켜 디아세틸 (diacetyl) 물질에 의한 불쾌한 냄새를 유의미하게 감소시키는 코팅층을 특징으로 갖는 정제를 제공하는 것이다. The present invention provides a prodrug having a medoxoyl group, which is characterized by a coating layer containing a coating agent, an adsorbent, and an encapsulant, and/or a pharmaceutically thereof A pharmaceutical composition in the form of a tablet containing an acceptable salt, with a coating layer that significantly reduces the unpleasant odor caused by diacetyl substances by improving the disadvantages and effects of using each coating agent, adsorbent, and/or encapsulant. The aim is to provide tablets with the following characteristics.
본 발명의 일 양상은 메독소밀기를 가지는 전구약물 또는 이의 약제학적으로 허용 가능한 염을 포함하는 약학 조성물로 코팅제, 흡착제 및 포접제를 포함한 코팅층을 특징으로 갖는 정제를 제공한다.One aspect of the present invention provides a tablet having a coating layer including a coating agent, an adsorbent, and an inclusion agent as a pharmaceutical composition comprising a prodrug having a medoxoyl group or a pharmaceutically acceptable salt thereof.
본 발명의 일 양상은 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염을 포함하는 약학 조성물로 히프로멜로오스(HPMC), 메타규산알루민산마그네슘, 및 베타사이클로덱스트린을 포함한 코팅층을 갖는 정제를 제공한다. One aspect of the present invention is a pharmaceutical composition containing azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof, having a coating layer containing hypromellose (HPMC), magnesium aluminometasilicate, and betacyclodextrin. Provides tablets.
본 발명의 일 양상은 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염을 포함하는 약학 조성물로 총 정제 함량 대비 1 내지 10 w/w%의 코팅제, 0.01 내지 0.5 w/w%의 흡착제, 및 0.05 내지 5 w/w%의 포접제를 포함한 코팅층을 갖는 정제를 제공한다. One aspect of the present invention is a pharmaceutical composition comprising azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof, comprising 1 to 10 w/w% of a coating agent and 0.01 to 0.5 w/w% of an adsorbent based on the total tablet content. , and 0.05 to 5 w/w% of an encapsulating agent.
본 발명의 일 양상은 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염을 포함하는 약학 조성물로 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염 대비 5 내지 35 w/w%의 코팅제, 0.05 내지 2.0 w/w%의 흡착제, 및 1 내지 20 w/w%의 포접제를 포함한 코팅층을 갖는 정제를 제공한다. One aspect of the present invention is a pharmaceutical composition comprising azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof, 5 to 35 w/w% compared to azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof. A tablet having a coating layer comprising a coating agent, 0.05 to 2.0 w/w% of an adsorbent, and 1 to 20 w/w% of an encapsulant is provided.
본 발명에 따른 정제 형태의 약학 조성물은 메독소밀기를 가지는 전구약물을 함유하는 내핵층을 코팅제, 흡착제 및 포접제를 포함한 코팅층으로 코팅하여 내핵에서 발생하는 냄새 성분 (Diacetyl)을 흡착 및 포접하여 제거하고, 외부로부터 수분을 차단함으로써 모약물과 메독소밀 (Medoxomil)의 가수분해를 막아 냄새 성분의 발생을 억제하는 냄새 차폐 기능을 개선시키는 효과를 가진다. The pharmaceutical composition in the form of a tablet according to the present invention removes the odor component (Diacetyl) generated from the inner core by adsorbing and encapsulating the inner core layer containing a prodrug having a medoxyl group by coating it with a coating layer containing a coating agent, an adsorbent, and an encapsulant. And, by blocking moisture from the outside, it has the effect of improving the odor shielding function that prevents the hydrolysis of the parent drug and Medoxomil and suppresses the generation of odor components.
본 발명에 따른 정제는 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염에서 발생하는 냄새 성분을 억제하여, 환자의 복약 순응도를 개선시키는 효과를 가진다.The tablet according to the present invention has the effect of improving patient compliance by suppressing odor components generated from prodrugs having a medoxoyl group and/or pharmaceutically acceptable salts thereof.
도 1은 코팅제, 흡착제 및 포접제를 포함한 코팅층을 특징으로 갖는 본 발명 정제의 일 예의 도식화1 is a schematic diagram of an example of a tablet of the present invention featuring a coating layer comprising a coating agent, an adsorbent, and an encapsulating agent.
본 발명에서 사용되는 모든 용어는, 달리 정의 되지 않는 이상, 본 발명의 관련 분야의 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한, 본 명세서에는 바람직한 방법이나 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 발명의 범주에 포함된다.All terms used in the present invention, unless otherwise defined, are used with the same meaning as commonly understood by a person skilled in the art. In addition, although preferred methods and samples are described in this specification, similar or equivalent methods are also included in the scope of the present invention.
본 발명에서 메독소밀기를 가지는 전구약물이란, 전구약물의 형태를 갖는 메독소밀기 (Medoxomil)를 포함한 물질로, 활성 모약물 (active parent drug)과 메독소밀로 용이하게 분리되는 약학적 유효성분 물질을 의미하며, 메독소밀기를 가지는 전구약물의 예로는 올메사르탄 메독소밀, 아질사르탄 메독소밀 등이 있다. In the present invention, a prodrug having a medoxomil group is a substance containing a medoxomil group in the form of a prodrug, and is a pharmaceutically active ingredient that is easily separated into an active parent drug and medoxomil. Means, examples of prodrugs having a medoxoyl group include olmesartan medoxomil, azilsartan medoxomil, etc.
본 명세서에서 용어 “냄새 차폐 (odor masking)”는 약학적 유효성분의 불쾌한 냄새를 제거 또는 감소시키거나, 상기 냄새의 인지를 감소시키는 것으로 정의된다. As used herein, the term “odor masking” is defined as removing or reducing the unpleasant odor of a pharmaceutical active ingredient, or reducing the perception of the odor.
본 발명은 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염을 포함한 내핵층을 코팅제, 흡착제 및 포접제를 포함한 코팅층으로 코팅하여 내핵에서 발생하는 냄새 성분 (Diacetyl)을 흡착 및 포접하여 제거하고, 외부로부터 수분을 차단함으로써 모약물과 메독소밀 (Medoxomil)의 가수분해를 막아 냄새 성분의 발생을 억제하는 냄새 차폐 기능을 개선시킨 정제를 제공한다. The present invention adsorbs and encapsulates the odor component (Diacetyl) generated in the inner core by coating the inner core layer containing a prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof with a coating layer containing a coating agent, an adsorbent, and an encapsulant. Provided is a tablet with an improved odor-blocking function that prevents the hydrolysis of the parent drug and Medoxomil by contacting and removing it and blocking moisture from the outside, thereby suppressing the generation of odor components.
본 발명은 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염을 포함하는 약학 조성물로 코팅제, 흡착제 및 포접제를 포함한 코팅층을 특징으로 갖는다.The present invention is a pharmaceutical composition containing a prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof, and is characterized by a coating layer containing a coating agent, an adsorbent, and an inclusion agent.
본 발명의 일 구현예에서, 상기 약학 조성물은 정제, 또는 과립 일 수 있으며, 일 예로는 정제일 수 있다.In one embodiment of the present invention, the pharmaceutical composition may be tablets or granules, for example, tablets.
상기 약학 조성물은 내핵층을 코팅층으로 코팅한 정제일 수 있으며, 일 예로는 필름 코팅정 일 수 있다. The pharmaceutical composition may be a tablet in which the inner core layer is coated with a coating layer, and for example, it may be a film-coated tablet.
상기 필름 코팅정은 약학적 유효성분이 포함된 내핵층을 코팅하는 코팅층에 코팅제, 흡착제 및 포접제를 포함한다. The film-coated tablet includes a coating agent, an adsorbent, and an inclusion agent in a coating layer that coats the inner core layer containing the pharmaceutically active ingredient.
상기 내핵층은 약학적 유효성분을 포함한 단일정, 이층정 또는 다층정 일 수 있으며, 일 예로는 단일정일 수 있으며, 다른 예로는 이층정 일 수 있다.The inner core layer may be a single tablet, a double-layer tablet, or a multi-layer tablet containing an active pharmaceutical ingredient. For example, it may be a single tablet, and for another example, it may be a double-layer tablet.
본 발명의 일 구현예에서, 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염과 암로디핀 및/또는 이의 약제학적으로 허용 가능한 염을 포함한 내핵층을 코팅제, 흡착제 및 포접제를 포함한 코팅층으로 코팅하여 내핵에서 발생하는 냄새 성분을 흡착 및 제거하여 냄새 차폐 기능을 개선시킨 정제를 제공한다. In one embodiment of the present invention, the inner core layer containing azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof and amlodipine and/or a pharmaceutically acceptable salt thereof is formed into a coating layer containing a coating agent, an adsorbent, and an inclusion agent. A tablet with improved odor masking function is provided by coating to adsorb and remove odor components generated from the inner core.
본 발명의 일 구현예에서, 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염에서 발생하는 냄새 성분을 흡착 및 제거하여 냄새 차폐 기능을 가진 코팅제, 흡착제 및 포접제를 포함한 코팅층 조성물을 제공한다. In one embodiment of the present invention, a coating layer composition including a coating agent, an adsorbent, and an inclusion agent that has an odor masking function by adsorbing and removing odor components generated from a prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof. provides.
냄새 차폐 기능의 코팅층 (코팅층 조성물)의 구성Composition of the coating layer (coating layer composition) with odor shielding function
코팅제coating agent
코팅제는 약물의 표면을 감싸는 특정 기능을 갖는 물질로, 약물 노출에 대한 차폐, 수분 차단, 산화 방지 등의 역할을 할 수 있다.A coating agent is a material with a specific function that covers the surface of a drug, and can play roles such as shielding drug exposure, blocking moisture, and preventing oxidation.
본 발명의 코팅층이 가지는 코팅제의 종류는 특별히 제한되지 않으며, 예를 들어 폴리비닐알코올 (PVA), 셀룰로오스 에테르 유도체 (Cellulose ether derivative) 계열 중 수용성 코팅 기제인 히프로멜로오스 (Hydroxypropyl methyl Cellulose), 히드록시프로필셀룰로오스 (Hydroxy propyl Cellulose), 히드록시에틸셀룰로오스 (Hydroxyethyl Cellulose), 메틸셀룰로오스 (Methyl Cellulose), 에틸셀룰로오스(Ethyl Cellulose), 카르복시메틸셀룰로오스 (Carboxy methyl cellulose) 등으로 이루어진 군에서 선택된 단독 또는 이들의 혼합물로 이루어진 코팅제를 포함할 수 있다. 일 예로는 상기 코팅제로 히프로멜로오스 (Hydroxypropyl methyl Cellulose)를 사용할 수 있다. 일 예로는 히프로멜로오스 기반 코팅기제로 오파드라이 (Opadry) 코팅제를 사용할 수 있다. The type of coating agent of the coating layer of the present invention is not particularly limited, and for example, polyvinyl alcohol (PVA), hypromellose (Hydroxypropyl methyl Cellulose), which is a water-soluble coating base in the cellulose ether derivative series, and hyde. Alone or a mixture thereof selected from the group consisting of Hydroxy propyl Cellulose, Hydroxyethyl Cellulose, Methyl Cellulose, Ethyl Cellulose, Carboxy methyl cellulose, etc. It may include a coating agent made of a mixture. As an example, hypromellose (Hydroxypropyl methyl Cellulose) can be used as the coating agent. As an example, Opadry coating agent can be used as a hypromellose-based coating base.
상기 코팅제의 함량은 약학적 유효성분의 종류와 흡착제 및 포접제의 조합 및 구성에 따라 적절하게 선택될 수 있다.The content of the coating agent can be appropriately selected depending on the type of pharmaceutical active ingredient and the combination and composition of the adsorbent and inclusion agent.
본 발명의 일 구현예에서, 상기 코팅제는 총 정제 함량 대비 1 내지 10 w/w% 를 포함할 수 있으며, 일 예로 1 내지 8 w/w%로 포함 될 수 있으며, 또 다른 예로 1 내지 5 w/w%로 포함될 수 있으며, 코팅제로는 히프로멜로오스 (HPMC)를 포함할 수 있다. In one embodiment of the present invention, the coating agent may contain 1 to 10 w/w% relative to the total tablet content, for example, 1 to 8 w/w%, and in another example, 1 to 5 w%. /w%, and the coating agent may include hypromellose (HPMC).
본 발명의 일 구현예에서, 상기 코팅제는 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염 대비 5 내지 35 w/w%로 포함될 수 있으며, 일 예로는 7 내지 28 w/w%로 포함될 수 있으며, 또 다른 예로는 10 내지 26 w/w%로 포함될 수 있으며, 코팅제로는 히프로멜로오스 (HPMC)를 포함할 수 있다. In one embodiment of the present invention, the coating agent may be included in an amount of 5 to 35 w/w% relative to the prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof, for example, 7 to 28 w/w. %, another example is 10 to 26 w/w%, and the coating agent may include hypromellose (HPMC).
흡착제absorbent
흡착제는 냄새 물질, 수분 등 액체와 가스인 피흡착제 물질을 흡착하는 물질로, 특정 물질에 대한 차폐, 수분 차단 등의 역할을 할 수 있다. An adsorbent is a material that adsorbs adsorbent materials such as liquid and gas, such as odorants and moisture, and can play a role in shielding certain substances and blocking moisture.
본 발명의 코팅층에 포함되는 흡착제로의 종류는 특별히 제한되지 않으며, 예를 들어 무기 염 및 금속 실리케이트 물질, 예컨대 메타규산알루민산마그네슘 (Magnesium Aluminosilicate, 상품명: Neusilin®), 규산칼슘 (Calcium silicate; 상품명: Florite® R) 또는 콜로이드성이산화규소 (Colloidal silicon dioxide; 상품명: Aerosil® 200), 활성탄소, 이온교환 수지 등으로 이루어진 군에서 선택된 단독 또는 이들의 혼합물로 이루어진 흡착제를 포함할 수 있다. 일 예로는 흡착제로 메타규산알루민산마그네슘 (Neusilin®)을 사용할 수 있다. The type of adsorbent included in the coating layer of the present invention is not particularly limited, and includes, for example, inorganic salts and metal silicate materials, such as Magnesium Aluminosilicate (trade name: Neusilin ® ), Calcium silicate (trade name) : Florite ® R) or colloidal silicon dioxide (trade name: Aerosil ® 200), activated carbon, ion exchange resin, etc. may be included alone or as a mixture of these adsorbents. For example, magnesium metasilicate aluminate (Neusilin ® ) can be used as an adsorbent.
상기 흡착제의 함량은 유효성분의 냄새 성분인 디아세틸 (diacetyl)의 양과 포접제의 조합 및 구성에 따라 적절하게 선택될 수 있다. 상기 흡착제는 메독소밀기를 가지는 전구약물에서 생성되는 디아세틸 (diacetyl)의 양과 1:1비율로 동일할 수 있다. The content of the adsorbent may be appropriately selected depending on the combination and composition of the amount of diacetyl, an odor component of the active ingredient, and the inclusion agent. The adsorbent may be equal to the amount of diacetyl produced from the prodrug having a medoxomethyl group in a 1:1 ratio.
본 발명의 일 구현예에서, 상기 흡착제는 총 정제 함량 대비 0.01 내지 0.5 w/w%를 포함할 수 있으며, 일 예로는 0.01 내지 0.3 w/w%를 포함할 수 있으며, 또 다른 예로는 0.01 내지 0.2 w/w%를 포함할 수 있으며, 흡착제로는 메타규산알루민산마그네슘을 포함할 수 있다. In one embodiment of the present invention, the adsorbent may contain 0.01 to 0.5 w/w% relative to the total tablet content, for example, 0.01 to 0.3 w/w%, and in another example, 0.01 to 0.3 w/w%. It may contain 0.2 w/w%, and the adsorbent may include magnesium aluminate metasilicate.
본 발명의 일 구현예에서, 상기 흡착제는 총 정제 함량 대비 0.01 내지 0.05 w/w%를 포함할 수 있다.In one embodiment of the present invention, the adsorbent may contain 0.01 to 0.05 w/w% based on the total tablet content.
본 발명의 일 구현예에서, 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염과 상기 흡착제의 몰비율은 300:1 내지 10:1 일 수 있고, 일 예로는 300:1 내지 25:1 일 수 있고, 또 다른 예로는 300:1 내지 50:1 일 수 있고, 또 다른 예로는 300:1 내지 100:1 일 수 있다.In one embodiment of the present invention, the molar ratio of the prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof and the adsorbent may be 300:1 to 10:1, and for example, 300:1 to 10:1. It may be 25:1, in another example it may be 300:1 to 50:1, and in another example it may be 300:1 to 100:1.
본 발명의 일 구현예에서, 상기 흡착제는 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염 대비 0.05 내지 2.0 w/w%로 포함될 수 있으며, 일 예로는 0.1 내지 2.0 w/w%로 포함될 수 있으며, 또 다른 예로는 0.1 내지 1.0 w/w%로 포함될 수 있으며, 흡착제로는 메타규산알루민산마그네슘을 포함할 수 있다. In one embodiment of the present invention, the adsorbent may be included in an amount of 0.05 to 2.0 w/w% relative to the prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof, for example, 0.1 to 2.0 w/w. It may be included in %, and as another example, it may be included in 0.1 to 1.0 w/w%, and the adsorbent may include magnesium aluminate metasilicate.
포접제inclusion agent
포접제는 다양한 게스트 (guest) 분자를 착화 및 포접하기 위한 물질로 게스트 분자의 분해 (예를 들면, 가수 분해 등)에 대한 안정화; 시판 제품의 맛 또는 냄새 개선 또는 증진; 냄새 또는 냄새의 지연되거나 지속적인 배출 중, 하나 이상을 제공 할 수 있다. Encapsulants are substances for complexing and encapsulating various guest molecules, and include stabilizing guest molecules against decomposition (e.g., hydrolysis, etc.); Improving or enhancing the taste or odor of commercial products; Either delayed or continuous emission of odor or odor, more than one may be provided.
본 발명의 코팅층에 포함되는 포접제의 종류는 특별히 제한되지 않으며, 예를 들어 알파사이클로덱스트린, 베타사이클로덱스트린, 감마사이클로덱스트린 등을 포함할 수 있다. 일 예로는 상기 포접제로 베타사이클덱스트린을 사용할 수 있다.The type of inclusion agent included in the coating layer of the present invention is not particularly limited and may include, for example, alphacyclodextrin, betacyclodextrin, and gammacyclodextrin. For example, beta cyclodextrin may be used as the inclusion agent.
상기 포접제의 함량은 유효성분의 냄새 성분인 디아세틸 (diacetyl)의 양과 흡착제의 조합 및 구성에 따라 적절하게 선택될 수 있다. 포접제는 상기 조성물에서 생성되는 디아세틸 (diacetyl)과 1:1 비율로 존재 할 수 있다. The content of the inclusion agent may be appropriately selected depending on the amount of diacetyl, which is an odor component of the active ingredient, and the combination and composition of the adsorbent. The inclusion agent may be present in a 1:1 ratio with diacetyl produced in the composition.
본 발명의 일 구현예에서, 상기 포접제는 총 정제 함량 대비 0.05 내지 5 w/w%를 포함할 수 있으며, 일 예로는 0.1 내지 5 w/w%를 포함할 수 있으며, 또 다른 예로는 0.1 내지 3 w/w%를 포함할 수 있으며, 포접제로는 베타사이클로덱스트린을 포함할 수 있다. In one embodiment of the present invention, the inclusion agent may contain 0.05 to 5 w/w% relative to the total tablet content, in one example it may contain 0.1 to 5 w/w%, and in another example, 0.1 w/w%. It may contain to 3 w/w%, and the inclusion agent may include betacyclodextrin.
본 발명의 일 구현예에서, 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염과 상기 포접제의 몰비율은 200:1 내지 10:1 일 수 있고, 일 예로는 180:1 내지 10:1 일 수 있고, 또 다른 예로는 180:1 내지 20:1 일 수 있고, 또 다른 예로는 50:1 내지 10:1 일 수 있다.In one embodiment of the present invention, the molar ratio of the prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof and the inclusion agent may be 200:1 to 10:1, and for example, 180:1. It may be from 10:1, in another example it may be 180:1 to 20:1, and in another example it may be 50:1 to 10:1.
본 발명의 일 구현예에서, 상기 포접제는 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염 대비 1 내지 20 w/w%로 포함될 수 있으며, 일 예로는 1 내지 15 w/w%로 포함될 수 있으며, 또 다른 예로는 2 내지 12 w/w%로 포함될 수 있으며, 포접제로는 베타사이클로덱스트린을 포함할 수 있다. In one embodiment of the present invention, the inclusion agent may be included in an amount of 1 to 20 w/w% relative to the prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof, for example, 1 to 15 w/w%. It may be included in w%, and in another example, it may be included in 2 to 12 w/w%, and the inclusion agent may include betacyclodextrin.
본 발명의 일 구현예에서, 상기 흡착제와 포접제는 1:1 내지 1:50 중량비로 포함될 수 있으며, 일 예로는 1:1 내지 1:40 중량비로 포함될 수 있으며, 또 다른 예로는 1:1 내지 1:30 중량비로 포함될 수 있으며, 또 다른 예로는 1:20 내지 1:25 중량비로 포함 될 수 있다. In one embodiment of the present invention, the adsorbent and the inclusion agent may be included in a weight ratio of 1:1 to 1:50, for example, 1:1 to 1:40, and in another example, 1:1. It may be included in a weight ratio of 1:30 to 1:30, and as another example, it may be included in a weight ratio of 1:20 to 1:25.
본 발명의 일 구현예에서, 상기 흡착제와 코팅제는 1:5 내지 1: 150 중량비로 포함될 수 있으며, 일 예로는 1:10 내지 1:100 중량비로 포함될 수 있고, 또 다른 예로는 1:30 내지 1: 80 중량비로 포함 될 수 있으며, 또 다른 예로는 1:25 내지 1:62.5 중량비로 포함 될 수 있다. In one embodiment of the present invention, the adsorbent and the coating agent may be included in a weight ratio of 1:5 to 1:150, for example, 1:10 to 1:100, and in another example, 1:30 to 1:100. It may be included at a weight ratio of 1:80, and as another example, it may be included at a weight ratio of 1:25 to 1:62.5.
본 발명의 일 구현예에서, 상기 포접제와 코팅제는 1:1 내지 1:30 중량비로 포함될 수 있으며, 일 예로는 1:1 내지 1:15 중량비로 포함될 수 있으며, 또 다른 예로는 1:1 내지 1:5 중량비로 포함될 수 있으며, 또 다른 예로는 1:1 내지 1:2.5 중량비로 포함될 수 있다. In one embodiment of the present invention, the inclusion agent and the coating agent may be included in a weight ratio of 1:1 to 1:30, for example, 1:1 to 1:15, and in another example, 1:1. It may be included in a weight ratio of 1:5 to 1:5, and as another example, it may be included in a weight ratio of 1:1 to 1:2.5.
본 발명의 일 구현예에서, 총 정제 함량 대비 코팅제로 1 내지 5 w/w%의 히프로멜로오스 (HPMC); 흡착제로 0.01 내지 0.2 w/w%의 메타규산알루민산마그네슘 및; 포접제로 0.1 내지 3 w/w%의 베타사이클로덱스트린을 포함한 코팅층으로 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염을 포함한 내핵층을 코팅한 정제를 제공한다.In one embodiment of the present invention, 1 to 5 w/w% of hypromellose (HPMC) as a coating agent relative to the total tablet content; 0.01 to 0.2 w/w% of magnesium aluminometasilicate as an adsorbent; A tablet is provided in which an inner core layer containing a prodrug having a medoxoyl group and/or a pharmaceutically acceptable salt thereof is coated with a coating layer containing 0.1 to 3 w/w% of betacyclodextrin as an encapsulating agent.
본 발명의 일 구현예에서, 메독소밀기를 가지는 전구약물 또는 이의 약제학적으로 허용 가능한 염 대비 10 내지 26 w/w%의 코팅제를 포함하고, 0.1 내지 1.0 w/w%의 흡착제를 포함하고, 2 내지 12 w/w%의 포접제를 포함한 코팅층으로 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염을 포함한 내핵층을 코팅한 정제를 제공한다. 본 발명에서, 코팅제, 흡착제 및 포접제를 포함한 총 코팅층 조성물은 총 정제 함량 대비 1 내지 16 w/w%를 포함할 수 있으며, 일 예로는 1 내지 12 w/w%를 포함할 수 있으며, 또 다른 예로는 2 내지 8 w/w%를 포함할 수 있으며, 또 다른 예로는 3 내지 5 w/w%를 포함할 수 있다. In one embodiment of the present invention, it contains 10 to 26 w/w% of a coating agent relative to the prodrug having a medoxomyl group or a pharmaceutically acceptable salt thereof, and includes 0.1 to 1.0 w/w% of an adsorbent, A tablet is provided in which an inner core layer containing a prodrug having a medoxoyl group and/or a pharmaceutically acceptable salt thereof is coated with a coating layer containing 2 to 12 w/w% of an inclusion agent. In the present invention, the total coating layer composition including the coating agent, adsorbent, and encapsulant may include 1 to 16 w/w% of the total tablet content, for example, 1 to 12 w/w%, and Another example may include 2 to 8 w/w%, and another example may include 3 to 5 w/w%.
유효성분active ingredient
본 발명에 따른 정제의 약학적 유효성분은 코팅층이 코팅하는 내핵층에 포함된다.The pharmaceutically active ingredient of the tablet according to the present invention is contained in the inner core layer coated by the coating layer.
본 발명의 일 구현예에서, 코팅층으로 코팅된 정제의 유효성분으로 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있다. 메독소밀기를 가지는 전구약물의 예로는 올메사르탄 메독소밀, 아질사르탄 메독소밀 등이 있다. In one embodiment of the present invention, the active ingredient of the tablet coated with the coating layer may include a prodrug having a medoxoyl group and/or a pharmaceutically acceptable salt thereof. Examples of prodrugs having a medoxoyl group include olmesartan medoxomil and azilsartan medoxomil.
본 발명의 일 구현예에서, 코팅층으로 코팅된 정제의 유효성분으로 아질사르탄 메독소밀을 포함할 수 있다.In one embodiment of the present invention, azilsartan medoxomil may be included as an active ingredient in tablets coated with a coating layer.
본 발명의 일 구현예에서, 코팅층으로 코팅된 정제의 유효성분은 총 정제 함량 대비 3 내지 30 w/w% 의 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있으며, 일 예로는 5 내지 30 w/w%의 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있으며, 다른 예로는 7 내지 30 w/w%의 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있으며, 또 다른 예로는 10 내지 25 w/w%의 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있다.In one embodiment of the present invention, the active ingredient of the tablet coated with the coating layer may include 3 to 30 w/w% of azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof based on the total tablet content, One example may include 5 to 30 w/w% of azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof, and another example may include 7 to 30 w/w% of azilsartan medoxomil and/or Or it may include a pharmaceutically acceptable salt thereof, and as another example, it may include 10 to 25 w/w% of azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof.
본 발명의 일 구현예에서, 본 발명에 따르는 정제의 유효성분인 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염은 10mg 내지 100mg으로 포함되며, 일 예로는 20mg 내지 100mg, 다른 예로는 30mg 내지 95mg, 다른 예로는 70mg 내지 90mg으로 포함될 수 있다.In one embodiment of the present invention, azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof, which are the active ingredients of the tablet according to the present invention, are included in an amount of 10 mg to 100 mg, for example, 20 mg to 100 mg, in another example. It may be included in an amount of 30 mg to 95 mg, in another example, 70 mg to 90 mg.
본 발명의 일 구현예에서 유효성분인 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염은 40mg, 80mg, 100mg 일 수 있다.In one embodiment of the present invention, the active ingredient azilsartan medoxomil and/or its pharmaceutically acceptable salt may be 40 mg, 80 mg, or 100 mg.
본 발명의 일 구현예에서, 본 발명에 따르는 정제의 내핵층은 메독소밀기를 가지는 전구약물을 포함하는 단일제, 및/또는 추가 유효성분을 포함하는 복합제 일 수 있다. 복합정제란 메독소밀기를 가지는 전구약물 외 약리효과를 나타내는 추가 약학적 유효성분이 내핵층에 포함된 정제를 의미한다.In one embodiment of the present invention, the inner core layer of the tablet according to the present invention may be a single drug containing a prodrug having a medoxomyl group, and/or a combined drug containing additional active ingredients. A complex tablet refers to a tablet in which the inner nuclear layer contains additional pharmaceutical active ingredients that exhibit pharmacological effects in addition to the prodrug having a medoxomyl group.
본 발명의 일 구현예에서, 상기 복합정제에서 메독소밀기를 가지는 전구약물 외에 추가 유효성분으로 디히드로피리딘 계열의 유효성분 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있다. In one embodiment of the present invention, the composite tablet may contain a dihydropyridine series active ingredient and/or a pharmaceutically acceptable salt thereof as an additional active ingredient in addition to the prodrug having a medoxoyl group.
본 발명의 일 구현예에서, 상기 복합정제에서 메독소밀기를 가지는 전구약물 외에 추가 유효성분으로 스타틴 계열의 유효성분 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있다. In one embodiment of the present invention, the combination tablet may contain a statin-based active ingredient and/or a pharmaceutically acceptable salt thereof as an additional active ingredient in addition to the prodrug having a medoxoyl group.
본 발명의 일 구현예에서, 상기 복합정제에서 메독소밀기를 가지는 전구약물 외에 추가 유효성분으로 티아지드 계열의 유효성분 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있다. In one embodiment of the present invention, the composite tablet may contain a thiazide series active ingredient and/or a pharmaceutically acceptable salt thereof as an additional active ingredient in addition to the prodrug having a medoxoyl group.
상기 복합정제에서 유효성분으로 고지혈증 치료제 유효성분을 추가 포함할 수 있다.The above complex tablet may additionally contain an active ingredient for treating hyperlipidemia as an active ingredient.
본 발명의 일 구현예에서, 상기 복합정제에서 메독소밀기를 가지는 전구약물 외에 추가 유효성분으로 아트로바스타틴, 로수바스타틴, 에제티미브, 클로르탈리돈 및/또는 이의 약제학적으로 허용 가능한 염 등이 하나 또는 그 이상으로 포함할 수 있다.In one embodiment of the present invention, in the composite tablet, in addition to the prodrug having a medoxomyl group, additional active ingredients include atorvastatin, rosuvastatin, ezetimibe, chlorthalidone and/or pharmaceutically acceptable salts thereof, etc. It may contain one or more.
본 발명의 일 구현예에서, 코팅층으로 코팅된 복합정제의 유효성분으로 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염 및 암로디핀 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있다. In one embodiment of the present invention, the active ingredients of the composite tablet coated with a coating layer may include azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof and amlodipine and/or a pharmaceutically acceptable salt thereof. .
본 발명의 일 구현예에서, 코팅층으로 코팅된 복합정제의 유효성분으로 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염 및 아트로바스타틴 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있다.In one embodiment of the present invention, the active ingredients of the composite tablet coated with a coating layer may include azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof and atorvastatin and/or a pharmaceutically acceptable salt thereof. there is.
본 발명의 일 구현예에서, 코팅층으로 코팅된 복합정제의 유효성분으로 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염; 아트로바스타틴 및/또는 이의 약제학적으로 허용 가능한 염; 에제티미브 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있다.In one embodiment of the present invention, the active ingredient of the composite tablet coated with a coating layer is azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof; Atrovastatin and/or a pharmaceutically acceptable salt thereof; It may include ezetimibe and/or a pharmaceutically acceptable salt thereof.
본 발명의 일 구현예에서, 코팅층으로 코팅된 복합정제의 유효성분으로 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염 및 로수바스타틴 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있다.In one embodiment of the present invention, the active ingredients of the composite tablet coated with a coating layer may include azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof and rosuvastatin and/or a pharmaceutically acceptable salt thereof. You can.
본 발명의 일 구현예에서, 코팅층으로 코팅된 복합정제의 유효성분으로 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염 및 클로르탈리돈 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있다.In one embodiment of the present invention, the active ingredients of the composite tablet coated with the coating layer may include azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof and chlorthalidone and/or a pharmaceutically acceptable salt thereof. You can.
본 발명의 일 구현예에서, 코팅층으로 코팅된 복합정제의 유효성분으로 아질사르탄 메독소밀 칼륨 및 암로디핀 베실레이트를 포함할 수 있다. In one embodiment of the present invention, the active ingredients of the composite tablet coated with a coating layer may include azilsartan medoxomil potassium and amlodipine besylate.
본 발명의 일 구현예에서, 상기 코팅층으로 코팅된 복합정제의 유효성분 중 총 정제 함량 대비 0.05 내지 7 w/w%의 암로디핀 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있으며, 일 예로는 1 내지 5 w/w%의 암로디핀 및/또는 이의 약제학적으로 허용 가능한 염을 포함할 수 있으며, 또 다른 예로는 1 내지 3 w/w%의 암로디핀 및/또는 이의 약제학적으로 허용 가능한 염을 포함 할 수 있다. In one embodiment of the present invention, the active ingredient of the composite tablet coated with the coating layer may include 0.05 to 7 w/w% of amlodipine and/or a pharmaceutically acceptable salt thereof based on the total tablet content, as an example. May include 1 to 5 w/w% of amlodipine and/or a pharmaceutically acceptable salt thereof, and another example may include 1 to 3 w/w% of amlodipine and/or a pharmaceutically acceptable salt thereof. It can be included.
본 발명의 일 구현예에서, 상기 암로디핀 및/또는 이의 약제학적으로 허용 가능한 염은 5mg 또는 10mg 일 수 있다.In one embodiment of the present invention, the amount of amlodipine and/or its pharmaceutically acceptable salt may be 5 mg or 10 mg.
첨가제additive
본 발명의 정제는 약학적 유효성분 외 첨가제로 희석제, 붕해제, 결합제, 안정화제, 활택제 및 착색제 등을 포함할 수 있다. 첨가제는 희석제, 붕해제, 결합제, 안정화제, 활택제 및 착색제로 이루어지는 군으로부터 선택되는 하나 이상일 수 있다. The tablet of the present invention may contain diluents, disintegrants, binders, stabilizers, lubricants, and colorants as additives in addition to the pharmaceutically effective ingredients. The additive may be one or more selected from the group consisting of diluents, disintegrants, binders, stabilizers, lubricants, and colorants.
본 발명의 일 구현예에서, 본 발명에 따른 약학 조성물은 약제학적으로 허용 가능한 희석제를 포함 할 수 있으며, 예시로는 유당수화물, 전분, 수크로스, 만니톨, 소르비톨, 분말 셀룰로오스, 미결정 셀룰로오스 및 인산수소칼슘 등으로 이루어진 군에서 선택된 하나 이상일 수 있다. In one embodiment of the present invention, the pharmaceutical composition according to the present invention may contain a pharmaceutically acceptable diluent, examples of which include lactose hydrate, starch, sucrose, mannitol, sorbitol, powdered cellulose, microcrystalline cellulose, and hydrogen phosphate. It may be one or more selected from the group consisting of calcium, etc.
본 발명의 일 구현예에서, 본 발명에 따른 약학 조성물은 약제학적으로 허용 가능한 붕해제를 포함 할 수 있으며, 예시로는 크로스카르멜로오스 나트륨, 전분글리콘산 나트륨, 젤라틴화 전분, 크로스포비돈, 저치환 히드록시 프로필셀룰로오스, 알긴산, 카르복시메틸 셀룰로오스 칼슘염 또는 나트륨염, 콜로이드성 이산화규소, 구아검, 규산알루민산 마그네슘, 메틸 셀룰로오스 및 알긴산나트륨으로 이루어진 군에서 선택되는 하나 이상일 수 있다. In one embodiment of the present invention, the pharmaceutical composition according to the present invention may contain a pharmaceutically acceptable disintegrant, examples of which include croscarmellose sodium, sodium starch glycolate, gelatinized starch, crospovidone, It may be one or more selected from the group consisting of low-substituted hydroxypropylcellulose, alginic acid, carboxymethyl cellulose calcium or sodium salt, colloidal silicon dioxide, guar gum, magnesium aluminate silicate, methyl cellulose, and sodium alginate.
본 발명의 일 구현예에서, 본 발명에 따른 약학 조성물은 약제학적으로 허용 가능한 결합제를 포함할 수 있으며, 예시로는 히드록시프로필셀룰로오스, 저치환도 셀룰로오스, 에틸 셀룰로스 폴리비닐피롤리돈, 유당수화물, 전분, 탤크, 젤라틴으로 이루어진 군에서 선택되는 하나 이상일 수 있다. In one embodiment of the present invention, the pharmaceutical composition according to the present invention may contain a pharmaceutically acceptable binder, examples of which include hydroxypropyl cellulose, low-substituted cellulose, ethyl cellulose, polyvinylpyrrolidone, and lactose hydrate. It may be one or more selected from the group consisting of starch, talc, and gelatin.
본 발명의 일 구현예에서, 본 발명에 따른 약학 조성물은 약제학적으로 허용 가능한 안정화제를 포함할 수 있으며, 안정화제로서 완충제, 점증제, 산화방지제, 가용화제 등이 포함될 수 있다. In one embodiment of the present invention, the pharmaceutical composition according to the present invention may include a pharmaceutically acceptable stabilizer, and the stabilizer may include a buffer, thickener, antioxidant, solubilizer, etc.
본 발명의 일 구현예에서, 본 발명에 따른 약학 조성물은 약제학적으로 허용 가능한 활택제를 포함할 수 있으며, 예시로는 지방산 에스테르, 스테아르산, 스테아르산마그네슘, 글리세릴 베헤네이트, 스테아르산칼슘, 스테아릴 푸마르산 나트륨, 라우릴 황산 나트륨, 라우릴 황산 마그네슘, 벤조산나트륨, 탤크, 수소첨가유, 카르나우바납으로 이루어진 군에서 선택된 하나 이상일 수 있다. In one embodiment of the present invention, the pharmaceutical composition according to the present invention may include a pharmaceutically acceptable lubricant, examples of which include fatty acid esters, stearic acid, magnesium stearate, glyceryl behenate, calcium stearate, It may be one or more selected from the group consisting of sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, talc, hydrogenated oil, and carnaubanap.
본 발명의 일 구현예에서, 본 발명에 따른 약학 조성물은 약제학적으로 허용 가능한 착색제를 포함할 수 있으며, 예시로는 산화철, 나트라콜 산화철, 카로테노이드 등이 포함 될 수 있다. In one embodiment of the present invention, the pharmaceutical composition according to the present invention may contain a pharmaceutically acceptable colorant, examples of which may include iron oxide, natracol iron oxide, carotenoids, etc.
본 발명의 아질사르탄 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염을 포함한 정제는 당해 기술분야에서 통상적으로 사용될 수 있는 첨가제를 추가 및 혼합하여 제조한 정제일 수 있다.A tablet containing a prodrug having an azilsartan medoxoyl group and/or a pharmaceutically acceptable salt thereof of the present invention may be a tablet prepared by adding and mixing additives commonly used in the art.
본 발명의 메독소밀기를 가지는 전구약물에서 발생하는 냄새 차폐 효과는 메독소밀기를 가지는 전구약물 외 첨가제 및 추가 유효성분의 종류 및 함량에는 영향을 받지 않으므로, 당해 기술분야에서 통상적으로 사용될 수 있는 첨가제를 추가 및 혼합하여 제조한 정제일 수 있다.The odor masking effect generated from the prodrug having a medoxoyl group of the present invention is not affected by the type and content of additives and additional active ingredients other than the prodrug having a medoxoyl group, so the additive can be commonly used in the art. It may be a tablet manufactured by adding and mixing.
필름 코팅정film coated tablets
본 발명에 따른 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염을 포함한 내핵층은 당해 기술분야에서 통상적으로 제조된 정제일 수 있다.The inner core layer containing the prodrug having a medoxomyl group and/or a pharmaceutically acceptable salt thereof according to the present invention may be a tablet conventionally manufactured in the art.
본 발명의 일 구현예에서, 아질사르탄 메독소밀기를 가지는 전구약물 및/또는 이의 약제학적으로 허용 가능한 염을 포함하는 약학 조성물로 코팅제, 흡착제 및 포접제를 포함한 코팅층을 특징으로 갖는 정제를 제조하기 위해 나정은 시중에서 구입한 이달비정® (lot no.12127566, 셀트리온제약)을 사용할 수 있다. In one embodiment of the present invention, a tablet having a coating layer including a coating agent, an adsorbent, and an inclusion agent is prepared from a pharmaceutical composition comprising a prodrug having an azilsartan medoxoyl group and/or a pharmaceutically acceptable salt thereof. For this purpose, the uncoated tablet can be used commercially purchased Idalbi Tablet ® (lot no.12127566, Celltrion Pharmaceutical).
본 발명의 일 구현예에서, 상기 약학 조성물은 약학적 유효성분을 포함한 내핵층을 코팅층으로 코팅한 정제일 수 있으며, 일 예로는 필름 코팅정 일 수 있다. In one embodiment of the present invention, the pharmaceutical composition may be a tablet in which the inner core layer containing the pharmaceutical active ingredient is coated with a coating layer, and for example, it may be a film-coated tablet.
본 발명의 일 구현예에서, 코팅제, 포접제 및 흡착제를 혼합하는 단계; 혼합된 코팅액을 코팅기를 이용해 메독소밀기를 가지는 전구약물이 함유된 내핵층에 코팅하여 필름 코팅정을 얻는 단계를 포함하여 제조할 수 있다. In one embodiment of the present invention, mixing a coating agent, an encapsulant, and an adsorbent; It can be prepared by coating the mixed coating solution on the inner core layer containing a prodrug having a medoxyl group using a coating machine to obtain a film-coated tablet.
본 발명의 일 구현예에서, 하나 또는 그 이상의 유효성분을 각각 혼합하여 제조한 이층정제에 혼합된 코팅액을 코팅하여 복합 필름 코팅정을 얻는 단계를 포함하여 제조할 수 있다. In one embodiment of the present invention, the preparation may include the step of obtaining a composite film coated tablet by coating the mixed coating solution on a two-layer tablet prepared by mixing one or more active ingredients.
본 발명의 일 구현예에서 제조하는 정제 제조 방법은 당해 기술분야에서 통상적으로 사용되는 정제 제조 방법인 혼합, 과립, 활택, 타정 등을 포함하며, 예컨대 한국 약전에 기재된 방법 등으로 제조할 수 있다. The tablet manufacturing method manufactured in one embodiment of the present invention includes tablet manufacturing methods commonly used in the art, such as mixing, granulation, lubrication, tableting, etc., and can be manufactured by, for example, the method described in the Korean Pharmacopoeia.
본 발명의 일 구현예에서 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염을 포함하는 약학 조성물로 총 정제 함량 대비 5 내지 30 w/w%의 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염을 포함한 내핵층, 총 정제 함량 대비 1 내지 10 w/w%의 히프로멜로오스 (HPMC), 0.01 내지 0.5 w/w%의 메타규산알루민산마그네슘, 및 0.05 내지 5 w/w%의 베타사이클로덱스트린을 포함한 코팅층을 갖는 정제를 포함할 수 있다.In one embodiment of the present invention, a pharmaceutical composition comprising azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof, comprising 5 to 30 w/w% of azilsartan medoxomil and/or a pharmaceutical thereof based on the total tablet content. An inner core layer containing a scientifically acceptable salt, 1 to 10 w/w% of hypromellose (HPMC), 0.01 to 0.5 w/w% of magnesium aluminometasilicate, and 0.05 to 5 w/w/% of the total tablet content. It may include a tablet having a coating layer containing w% betacyclodextrin.
본 발명의 일 구현예에서 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염을 포함하는 약학 조성물로 총 정제 함량 대비 5 내지 30 w/w%의 아질사르탄 메독소밀 및/또는 이의 약제학적으로 허용 가능한 염을 포함하는 내핵층, 총 정제 함량 대비 0.5 내지 7 w/w%의 암로디핀 및/또는 이의 약제학적으로 허용 가능한 염, 1 내지 10 w/w%의 히프로멜로오스 (HPMC), 0.01 내지 0.5 w/w%의 메타규산알루민산마그네슘, 및 0.05 내지 5 w/w%의 베타사이클로덱스트린을 포함한 코팅층을 갖는 정제를 포함할 수 있다.In one embodiment of the present invention, a pharmaceutical composition comprising azilsartan medoxomil and/or a pharmaceutically acceptable salt thereof, comprising 5 to 30 w/w% of azilsartan medoxomil and/or a pharmaceutical thereof based on the total tablet content. An inner core layer containing a scientifically acceptable salt, 0.5 to 7 w/w% of amlodipine and/or a pharmaceutically acceptable salt thereof, and 1 to 10 w/w% of hypromellose (HPMC) relative to the total tablet content. , 0.01 to 0.5 w/w% of magnesium aluminometasilicate, and 0.05 to 5 w/w% of betacyclodextrin.
이하, 본 발명을 하기 실시예 및 실험예에 의거하여 상세하게 설명하고자 한다. 단, 하기 실시예 및 실험예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이에 한정되는 것은 아니다. Hereinafter, the present invention will be described in detail based on the following examples and experimental examples. However, the following examples and experimental examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.
실시예 1. 흡착제 및 포접제 종류에 따른 아질사르탄 메독소밀을 함유하는 정제 및 냄새 차폐 효과 Example 1 . Tablets containing azilsartan medoxomil and odor masking effect depending on the type of adsorbent and encapsulant
아질사르탄 메독소밀 정제 나정 (이달비정Azilsartan medoxomil tablet uncoated tablet (Idalbi tablet) ®® ))
시중에서 구입한 이달비정® (lot no. 12127566, 셀트리온제약)을 사용하여 실험을 진행하였다. The experiment was conducted using commercially purchased Idalbee tablets ® (lot no. 12127566, Celltrion Pharmaceuticals).
실시예 1-1 내지 1-4Examples 1-1 to 1-4
구매한 이달비정®을 사용하여 하기 표1과 같이 코팅제에 흡착제와 포접제를 첨가하여 필름 코팅정을 얻었다. 먼저 정제수 270g에 하기 표 1에 따른 실시예 1-1, 1-2, 1-3 및 1-4 조합과 같이 포접제의 종류로 각각 알파사이클로덱스트린 (Cavamax W6, Ashland) 또는 베타사이클로덱스트린 (Cavamax W7, Ashland) 6g과 흡착제의 종류로 각각 규산칼슘 (Calcium Silicate; Florite-R, Tomita) 또는 메타규산알루민산마그네슘 (메타규산알루민산마그네슘, Fuji Chem.) 0.6g을 차례로 녹인다. 이후, 히프로멜로오스 기반 코팅기제 (Opadry 03A640040 Pink, Colorcon, 히프로멜로오스 78% 함량)를 녹인다. 이후, 제조된 코팅액을 사용하여 상기 나정 360mg에 코팅기 (KC65FC, 금성)로 코팅하여 1정당 370mg의 필름 코팅정을 얻었다.Using purchased Idalbee tablets ® , film-coated tablets were obtained by adding an adsorbent and an inclusion agent to the coating agent as shown in Table 1 below. First, in 270 g of purified water, alphacyclodextrin (Cavamax W6, Ashland) or betacyclodextrin (Cavamax) was added as an encapsulating agent, as in Examples 1-1, 1-2, 1-3, and 1-4 according to Table 1 below. W7, Ashland) and 0.6 g of each type of adsorbent, either calcium silicate (Calcium Silicate; Florite-R, Tomita) or magnesium aluminometasilicate (Fuji Chem.) are sequentially dissolved. Afterwards, dissolve the hypromellose-based coating base (Opadry 03A640040 Pink, Colorcon, 78% hypromellose content). Thereafter, using the prepared coating solution, 360 mg of the uncoated tablet was coated with a coating machine (KC65FC, Goldstar) to obtain 370 mg of film-coated tablet per tablet.
비교예 1Comparative Example 1
실시예 1의 방법에 따라 제조하되, 하기 표 1에 따른 비교예 1-1과 같이 히프로멜로오스 기반 코팅기제인 오파드라이 (Opadry)만 포함한 코팅층만 포함하도록 하여 1정당 367.8mg의 필름 코팅정을 얻었다. Manufactured according to the method of Example 1, but containing only a coating layer containing Opadry, a hypromellose-based coating base, as shown in Comparative Example 1-1 according to Table 1 below, 367.8 mg of film-coated tablets were produced per tablet. got it
실험예 1. 흡착제 및 포접제 종류 선정을 위한 코팅제, 흡착제 및 포접제를 포함한 아질사르탄 메독소밀 정제의 디아세틸 검출량 측정Experimental Example 1. Measurement of diacetyl detection amount of azilsartan medoxomil tablets containing coating agent, adsorbent, and inclusion agent for selection of adsorbent and encapsulant type
상기 실시예 1에서 얻어진 코팅제, 흡착제 및 포접제를 혼합한 코팅층을 가진 아질사르탄 메독소밀 정제에 대해 GC기반 전자코를 이용하여 시간 경과에 따른 디아세틸 검출량을 측정하였다. 제조된 코팅정은 진공 건조(2.0mbar, 40℃, 12시간)하여 실리카겔 1g과 함께 알루미늄 백에 실링하고 가혹 챔버에 로딩하였다. 가혹 챔버 로딩 이후 시간에 따라 1주차 (1W)에 언로딩하여 디아세틸 측정하였다. The amount of diacetyl detected over time was measured using a GC-based electronic nose for azilsartan medoxomil tablets having a coating layer containing a mixture of coating agent, adsorbent, and encapsulant obtained in Example 1. The prepared coated tablets were vacuum dried (2.0 mbar, 40°C, 12 hours), sealed in an aluminum bag with 1 g of silica gel, and loaded into a harsh chamber. Diacetyl was measured by unloading at 1 week (1W) according to time after harsh chamber loading.
전자코를 이용한 디아세틸 검출 방법Diacetyl detection method using an electronic nose
디아세틸 검출을 위하여 GC 기반 전자코(Heracles-II, Alpha-Mos)를 사용하여 크로마토그램을 얻었다. 각 실시예의 정제 5정을 50mL 바이알에 담아 전자코에 로딩한다. 각 바이알은 40 ℃에서 20분간 인큐베이션 후, 5mL의 상부 기체를 채집하여 GC에 주입한다. MXT-1701-FID(약간 극성), MXT-5-FID(비극성) 두가지 컬럼을 사용했고, MXT-5-FID(비극성) 컬럼의 약 27~28.5초(RT)의 피크가 디아세틸의 피크임을 전자코 내의 Arochem library에서 확인하였다. 실시예1의 모든 샘플이 해당 피크에서만 차이를 보이며 나머지 피크는 유사한 것을 보아, 실시예 간의 냄새 차이는 디아세틸의 검출량 차이에서 기인한 것임을 알 수 있다. 디아세틸 검출량은 크로마토그램의 해당 피크 area를 계산하여 도출했으며, 비교에 1-1의 Initial 디아세틸 검출량을 기준으로 백분율로 표시하였다. For diacetyl detection, chromatograms were obtained using a GC-based electronic nose (Heracles-II, Alpha-Mos). Five tablets of each example were placed in a 50 mL vial and loaded into the electronic nose. Each vial is incubated at 40°C for 20 minutes, then 5mL of upper gas is collected and injected into the GC. Two columns were used, MXT-1701-FID (slightly polar) and MXT-5-FID (non-polar), and the peak at about 27 to 28.5 seconds (RT) of the MXT-5-FID (non-polar) column was the peak of diacetyl. It was confirmed in the Arochem library in the electronic nose. Since all samples of Example 1 showed differences only in the corresponding peak and the remaining peaks were similar, it can be seen that the difference in odor between the examples is due to the difference in the amount of diacetyl detected. The diacetyl detection amount was derived by calculating the corresponding peak area of the chromatogram, and was expressed as a percentage based on the initial diacetyl detection amount of 1-1 for comparison.
흡착제 및 포접제 종류에 따른 아질사르탄 메독소밀 정제의 디아세틸 검출량 Amount of diacetyl detected in azilsartan medoxomil tablets depending on the type of adsorbent and encapsulant
실험예 1Experimental Example 1 코팅제coating agent 흡착제absorbent 포접제inclusion agent 디아세틸 검출량 Diacetyl detection amount
(비교예 1-1 Initial 대비, %)(compared to Comparative Example 1-1 Initial, %)
7.8mg7.8 mg 0.2mg0.2mg 2mg2mg InitialInitial 1W1W
실시예 1-1Example 1-1 OpadryOpadry Florite-RFlorite-R alpha-CDalpha-CD 63.563.5 108.1108.1
실시예 1-2Example 1-2 OpadryOpadry NeusilinNeusilin alpha-CDalpha-CD 45.045.0 149.3149.3
실시예 1-3Example 1-3 OpadryOpadry Florite-RFlorite-R beta-CDbeta-CD 44.144.1 120.9120.9
실시예 1-4Example 1-4 OpadryOpadry NeusilinNeusilin beta-CDbeta-CD 29.529.5 72.172.1
비교예 1-1Comparative Example 1-1 OpadryOpadry -- -- 100.0100.0 155.5155.5
상기 실험예 1 결과에 따르면 코팅제, 흡착제 및 포접제를 모두 포함한 실시예 1-1 내지 1-4가 비교예 1-1 대비 낮은 디아세틸 검출량을 보여주었으며, 흡착제와 포접제의 종류로 각각 메타규산알루민산마그네슘 및 베타사이클로덱스트린 (beta - CD)인 실시예 1-4가 가장 낮은 디아세틸 검출량을 보여주었다. According to the results of Experimental Example 1, Examples 1-1 to 1-4, which included all coating agents, adsorbents, and inclusion agents, showed a lower amount of diacetyl detected than Comparative Example 1-1, and metasilicic acid was used as the type of adsorbent and inclusion agent, respectively. Examples 1-4, which were magnesium aluminate and betacyclodextrin (beta-CD), showed the lowest amount of diacetyl detected.
실시예 2. 흡착제 및 포접제 함량에 따른 아질사르탄 메독소밀 정제의 냄새 차폐 효과Example 2. Odor-masking effect of azilsartan medoxomil tablets according to adsorbent and inclusion agent content
상기 실시예 1 및 실험예 1 결과에 따라 선정된 코팅제, 흡착제 및 포접제 종류의 최적 함량 및 이의 냄새 차폐 효과를 찾아내기 위해 하기와 같이 실험을 진행했다. An experiment was conducted as follows to find the optimal content and odor-masking effect of the coating agent, adsorbent, and encapsulant type selected according to the results of Example 1 and Experiment 1 above.
실시예 2-1 내지 2-5Examples 2-1 to 2-5
실시예 2에서도 실시예 1에서 구매한 이달비정®을 사용하여 필름 코팅정을 제조하였다. 구체적으로 먼저 정제수에 메타규산알루민산마그네슘 (Neusilin, Fuji Chem.)과 베타사이클로덱스트린 (beta-CD; Cavamax W7, Ashland) 을 표2의 흡착제, 포접제의 양에 맞게 차례로 녹인다. 이후, 히프로멜로오스 기반 코팅기제 (Opadry 03A640040 Pink, Colorcon)를 10mg녹인다. 이후, 제조된 코팅액을 사용하여 상기 나정 360mg에 코팅기 (KC65FC, 금성)로 코팅하여 총 중량이 표2와 같이 되도록 실시예 2-1, 2-2, 2-3, 2-4의 필름 코팅정을 얻었다.In Example 2, a film-coated tablet was manufactured using Idarbi Tablet ® purchased in Example 1. Specifically, first, magnesium aluminometasilicate (Neusilin, Fuji Chem.) and betacyclodextrin (beta-CD; Cavamax W7, Ashland) are sequentially dissolved in purified water according to the amounts of adsorbent and inclusion agent in Table 2. Afterwards, dissolve 10mg of hypromellose-based coating base (Opadry 03A640040 Pink, Colorcon). Thereafter, using the prepared coating solution, 360 mg of the uncoated tablet was coated with a coating machine (KC65FC, Goldstar) so that the total weight was as shown in Table 2. Film-coated tablets of Examples 2-1, 2-2, 2-3, and 2-4 got it
비교예 2-1 내지 2-4Comparative Examples 2-1 to 2-4
실시예 2의 방법에 따라 제조하되, 하기 표 2에 따른 비교예 2-1, 2-2, 2-3 및 2-4의 함량 및 조합과 같이 필름 코팅정을 얻었다. 비교예 2-4는 상기 실시예 1과 같이 구매한 이달비정®을 사용했다. Film-coated tablets were prepared according to the method of Example 2, with the contents and combinations of Comparative Examples 2-1, 2-2, 2-3, and 2-4 according to Table 2 below. Comparative Examples 2-4 used Dalbijeong ® purchased as in Example 1 above.
실시예 2에 따른 코팅제, 흡착제 및 포접제를 포함한 코팅층을 가진 아질사르탄 메독소밀 정제의 조성물Composition of azilsartan medoxomil tablets with a coating layer comprising a coating agent, an adsorbent and an encapsulating agent according to Example 2
아질사르탄 메독소밀 (mg)Azilsartan medoxomil (mg) 코팅제 coating agent
(Opadry)(Opadry)
(mg)(mg) 		흡착제absorbent
(메타규산알루민산마그네슘)(Magnesium aluminate metasilicate)
(mg)(mg) 		포접제 (베타사이클로덱스트린)Inclusion agent (betacyclodextrin)
(mg)(mg) 		총 정제 중량 (mg)Total tablet weight (mg)
실시예 2-1Example 2-1 8080 1010 0.20.2 22 372.2372.2
실시예 2-2Example 2-2 8080 1010 0.40.4 22 372.4372.4
실시예 2-3Example 2-3 8080 1010 0.20.2 44 374.2374.2
실시예 2-4Example 2-4 8080 1010 0.40.4 44 374.4374.4
비교예 2-1Comparative Example 2-1 8080 1010 00 22 372372
비교예 2-2Comparative Example 2-2 8080 1010 0.20.2 00 370.2370.2
비교예 2-3Comparative Example 2-3 8080 1010 00 00 370370
비교예 2-4Comparative Example 2-4 8080 00 00 00 360360
실험예 2-1: 흡착제 및 포접제 함량에 따른 아질사르탄 메독소밀 정제의 디아세틸 검출량 측정Experimental Example 2-1: Measurement of diacetyl detection amount of azilsartan medoxomil tablets according to adsorbent and inclusion agent content
상기 실시예 2 및 표2에 따른 오파드라이(Opadry), 메타규산알루민산마그네슘 및 베타사이클로덱스트린을 혼합한 코팅층을 가진 아질사르탄 메독소밀 정제에 대해 GC기반 전자코를 이용하여 시간 경과에 따른 디아세틸 검출량을 측정하였다. The azilsartan medoxomil tablets having a coating layer mixed with Opadry, magnesium aluminometasilicate, and betacyclodextrin according to Example 2 and Table 2 were analyzed over time using a GC-based electronic nose. The amount of acetyl detected was measured.
위에서 얻은 필름 코팅정은 진공 건조(2.0mbar, 40℃, 12시간)하여 알루미늄 백에 실링하고 가혹 챔버에 로딩하였다. 가혹 챔버 로딩 이후 시간에 따라 1주차 (1W)에 언로딩하여 디아세틸을 측정하였다. The film-coated tablets obtained above were vacuum dried (2.0 mbar, 40°C, 12 hours), sealed in an aluminum bag, and loaded into a harsh chamber. Diacetyl was measured by unloading at 1 week (1W) according to time after harsh chamber loading.
디아세틸의 양을 측정하기 위해 실시예 1과 같은 방법으로 GC 기반 전자코를 사용하였다. 측정된 디아세틸의 검출량은 비교예2-3의 Initial 검출량 대비 백분율로 나타내었다. 그 결과를 하기 표 3에 나타내었다.To measure the amount of diacetyl, a GC-based electronic nose was used in the same manner as in Example 1. The measured detection amount of diacetyl was expressed as a percentage compared to the initial detection amount in Comparative Example 2-3. The results are shown in Table 3 below.
흡착제 및 포접제 함량에 따른 아질사르탄 메독소밀 정제의 디아세틸 검출량 측정Measurement of diacetyl detection amount in azilsartan medoxomil tablets according to adsorbent and inclusion agent content
실험예 2-1Experimental Example 2-1 디아세틸 검출량 (비교예 2-3 Initial 대비, %))Diacetyl detection amount (compared to Initial of Comparative Example 2-3, %))
InitialInitial 1W1W
실시예 2-1Example 2-1 5151 121121
실시예 2-2Example 2-2 4141 427427
실시예 2-3Example 2-3 4242 6060
실시예 2-4Example 2-4 3131 413413
비교예 2-1Comparative Example 2-1 5959 541541
비교예 2-2Comparative Example 2-2 6969 13311331
비교예 2-3Comparative Example 2-3 100100 2,1352,135
비교예 2-4Comparative Example 2-4 316316 12,50812,508
상기 표 3 의 결과에 따르면, 함량 변화에 관계없이 코팅제 외 흡착제와 포접제를 동시 포함한 실시예 2-1 내지 2-4 에서 모두 비교예 대비 디아세틸 검출량이 현저히 줄어든 효과를 확인 할 수 있다. 본 실험을 통해 코팅제에 흡착제와 포접제를 동시에 포함한 성분 조합에 대해 우수한 효과가 있음을 알 수 있고, 디아세틸 검출량을 유의미하게 감소시키기 위해서는 세 가지 성분의 조합의 적정량이 조절되어야 한다는 것을 알 수 있다. According to the results in Table 3, it can be confirmed that the amount of diacetyl detected was significantly reduced in Examples 2-1 to 2-4, which simultaneously included an adsorbent and an encapsulant in addition to the coating, regardless of the change in content, compared to the comparative example. Through this experiment, it can be seen that there is an excellent effect for the combination of components that include both an adsorbent and an inclusion agent in the coating agent, and that the appropriate amount of the combination of the three components must be adjusted to significantly reduce the amount of diacetyl detected. .
실시예 3. 코팅제, 흡착제 및 포접제의 함량에 따른 아질사르탄 메독소밀 정제의 장기 냄새 차폐 효과 Example 3. Long-term odor-masking effect of azilsartan medoxomil tablets depending on the content of coating agent, adsorbent, and encapsulant
실시예 3-1 내지 3-11Examples 3-1 to 3-11
실시예 1과 같이 구입한 이달비정®을 사용하였다. 이달비정®을 사용하여 하기 표4와 같이 코팅제에 흡착제와 포접제를 첨가하여 실시예 3-1 내지 3-11의 필름 코팅정을 얻었다. 구체적으로, 먼저 정제수에 메타규산알루민산마그네슘 (Neusilin, Fuji Chem.)과 베타사이클로덱스트린 (Cavamax W7, Ashland)을 표4의 코팅제, 흡착제, 포접제의 양에 맞게 차례로 녹인다. 이후, 히프로멜로오스 기반 코팅기제 (Opadry 03A640040 Pink, Colorcon)을 하기 표4의 코팅제 함량과 같이 녹인다. 이후, 제조된 코팅액을 사용하여 상기 나정 360mg에 코팅기 (KC65FC, 금성)로 코팅하여 총 중량이 표4와 같이 되도록 필름 코팅정을 얻었다.Dalbijeong ® purchased as in Example 1 was used. Using Dalbi Tablet ® , an adsorbent and an encapsulant were added to the coating agent as shown in Table 4 below to obtain film-coated tablets of Examples 3-1 to 3-11. Specifically, first, magnesium aluminometasilicate (Neusilin, Fuji Chem.) and betacyclodextrin (Cavamax W7, Ashland) are sequentially dissolved in purified water according to the amounts of coating agent, adsorbent, and inclusion agent in Table 4. Afterwards, hypromellose-based coating base (Opadry 03A640040 Pink, Colorcon) is dissolved according to the coating agent content in Table 4 below. Thereafter, using the prepared coating solution, 360 mg of the uncoated tablet was coated with a coating machine (KC65FC, Goldstar) to obtain a film-coated tablet with a total weight as shown in Table 4.
비교예 3-1Comparative Example 3-1
비교예 3-1은 상기 실시예 1과 같이 구매한 이달비정®을 사용하였다. In Comparative Example 3-1, Dalbijeong ® purchased as in Example 1 above was used.
실시예 3에 따른 코팅제, 흡착제 및 포접제 함량에 따른 아질사르탄 메독소밀 정제의 조성물Composition of azilsartan medoxomil tablets according to coating agent, adsorbent and encapsulant content according to Example 3
아질사르탄 메독소밀 (mg)Azilsartan medoxomil (mg) 코팅제 (Opadry) (mg)Coating (Opadry) (mg) 흡착제 (메타규산알루민산마그네슘) (mg)Adsorbent (magnesium aluminate metasilicate) (mg) 포접제 (베타사이클로덱스트린) (mg)Inclusion agent (betacyclodextrin) (mg) 총 정제 중량 (mg)Total tablet weight (mg)
실시예 3-1Example 3-1 8080 12.512.5 0.50.5 55 378378
실시예 3-2Example 3-2 8080 12.512.5 0.50.5 1One 374374
실시예 3-3Example 3-3 8080 12.512.5 0.20.2 55 377.7377.7
실시예 3-4Example 3-4 8080 7.57.5 0.50.5 55 373373
실시예 3-5Example 3-5 8080 12.512.5 0.20.2 1One 373.7373.7
실시예 3-6Example 3-6 8080 7.57.5 0.50.5 1One 369369
실시예 3-7Example 3-7 8080 7.57.5 0.20.2 55 372.7372.7
실시예 3-8Example 3-8 8080 7.57.5 0.20.2 1One 368.7368.7
실시예 3-9Example 3-9 8080 1010 0.350.35 33 373.4373.4
실시예 3-10Example 3-10 8080 1010 0.350.35 33 373.4373.4
실시예 3-11Example 3-11 8080 1010 0.350.35 33 373.4373.4
비교예 3-1Comparative Example 3-1 8080 00 00 00 360360
실험예 3-1: 코팅제, 흡착제 및 포접제 함량에 따른 아질사르탄 메독소밀 정제의 디아세틸 검출량 측정Experimental Example 3-1: Measurement of diacetyl detection amount of azilsartan medoxomil tablets according to coating agent, adsorbent, and inclusion agent content
상기 실시예 3 및 표4에 따른 오파드라이(Opadry), 메타규산알루민산마그네슘 및 베타사이클로덱스트린을 혼합한 코팅층을 가진 아질사르탄 메독소밀 정제의 대해 GC기반 전자코를 이용하여 시간 경과에 따른 디아세틸 검출량을 측정하였다. 위에서 얻은 필름 코팅정은 진공 건조(2.0mbar, 40℃, 12시간)하여 알루미늄 백에 실링하고 가혹 챔버에 로딩하였다. 가혹 챔버 로딩 이후 시간에 따라 장기 가혹 조건 4주차에 언로딩하여 디아세틸 측정하였다.Azilsartan medoxomil tablets having a coating layer mixed with Opadry, magnesium aluminometasilicate, and betacyclodextrin according to Example 3 and Table 4 were analyzed over time using a GC-based electronic nose. The amount of acetyl detected was measured. The film-coated tablets obtained above were vacuum dried (2.0 mbar, 40°C, 12 hours), sealed in an aluminum bag, and loaded into a harsh chamber. Diacetyl was measured by unloading at the 4th week of long-term harsh conditions according to the time after loading into the harsh chamber.
디아세틸의 양을 측정하기 위해 실시예 1과 같은 방법으로 GC 기반 전자코를 사용하였다. 측정된 디아세틸의 검출량은 비교예3-1의 Initial 검출량 대비 백분율로 나타내었다. 그 결과를 하기 표 5에 나타내었다.To measure the amount of diacetyl, a GC-based electronic nose was used in the same manner as in Example 1. The measured detection amount of diacetyl was expressed as a percentage compared to the initial detection amount in Comparative Example 3-1. The results are shown in Table 5 below.
코팅제, 흡착제 및 포접제 함량에 따른 아질사르탄 메독소밀 정제의 디아세틸 검출량 측정Measurement of diacetyl detection in azilsartan medoxomil tablets according to coating agent, adsorbent, and encapsulant content
실험예 3-1Experimental Example 3-1 디아세틸 검출량Diacetyl detection amount
(비교예 3-1 Initial 대비, %) (Comparative Example 3-1 Initial, %)
InitialInitial 4W4W
실시예 3-1Example 3-1 11.5011.50 52.4652.46
실시예 3-2Example 3-2 19.2619.26 211.04211.04
실시예 3-3Example 3-3 7.977.97 50.5050.50
실시예 3-4Example 3-4 22.1022.10 251.90251.90
실시예 3-5Example 3-5 22.6322.63 210.74210.74
실시예 3-6Example 3-6 29.0029.00 601.10601.10
실시예 3-7Example 3-7 18.1218.12 230.88230.88
실시예 3-8Example 3-8 37.2937.29 592.79592.79
실시예 3-9Example 3-9 31.2031.20 360.79360.79
실시예 3-10Example 3-10 22.6222.62 365.30365.30
실시예 3-11Example 3-11 24.0524.05 324.93324.93
비교예 3-1Comparative Example 3-1 100.00100.00 1,651.771,651.77
상기 표 5의 결과에 따르면, 함량 변화에 관계 없이, 코팅제 외 흡착제와 포접제를 동시 포함한 실시예 3-1 내지 3-11에서 모두 비교예 3-1 대비 디아세틸 검출량이 현저히 줄어든 효과를 확인 할 수 있다. 특히, 상기 표 5의 실험예 3-1와 3-3의 경우 장기 가혹 조건 4주동안 로딩되어 있었음에도 불구하고 코팅을 하지 않은 비교예 3-1의 4주차 값 대비 약 33배 정도 낮은 검출량을 보였으므로, 해당 조성들이 우수한 냄새차폐 효과를 보이는 것을 확인하였다.According to the results in Table 5 above, regardless of the change in content, it can be seen that the amount of diacetyl detected is significantly reduced compared to Comparative Example 3-1 in all Examples 3-1 to 3-11, which simultaneously contain an adsorbent and an encapsulant in addition to the coating agent. You can. In particular, in the case of Experimental Examples 3-1 and 3-3 in Table 5, despite being loaded under long-term harsh conditions for 4 weeks, the detection amount was about 33 times lower than the 4th week value of Comparative Example 3-1 without coating. Therefore, it was confirmed that the compositions showed excellent odor masking effect.
실험예 3-2. 코팅제, 흡착제 및 포접제 함량에 따른 아질사르탄 메독소밀 정제의 설문조사를 통한 냄새 강도 측정 결과Experimental Example 3-2. Odor intensity measurement results through a survey of azilsartan medoxomil tablets according to the content of coating agent, adsorbent, and encapsulant
상기 실시예 3에 따른 아질사르탄 메독소밀 정제의 냄새 강도를 표6에 기재된 4가지 척도 (1. 냄새없음, 2. 약하게 느껴짐, 3. 확연히 느껴짐, 4. 복용에 지장이 있을 정도로 느껴짐)에 기초하여 성인 16명 에게 설문 조사를 실시하였다. 상기 표5의 전자코 기반 GC 분석 결과를 토대로 표 4의 일부 조성물 샘플에서 총 코팅량이 가장 적은 실시예 3-3, 3-7, 3-9 샘플을 선정하여, 비교예3-1과 함께 하기 표 6와 같이 4가지 냄새 척도 설문조사를 실시했다. 결과는 전체 인원 대비 백분율로 하기 표 6와 같이 나타내었다. The odor intensity of the azilsartan medoxomil tablet according to Example 3 was measured on the four scales shown in Table 6 (1. No odor, 2. Feeling weak, 3. Feeling clearly, 4. Feeling enough to interfere with taking). Based on this, a survey was conducted on 16 adults. Based on the electronic nose-based GC analysis results in Table 5, samples of Examples 3-3, 3-7, and 3-9 with the lowest total coating amount were selected from some of the composition samples in Table 4, and were used together with Comparative Example 3-1. As shown in Table 6, four odor scale surveys were conducted. The results are shown in Table 6 below as a percentage of the total number of people.
코팅제, 흡착제 및 포접제 함량에 따른 정제의 냄새 강도 설문조사 점수표Depending on the content of coating agent, adsorbent and encapsulant Tablet Odor Intensity Survey Scorecard
실험예 3-2 Experimental Example 3-2 냄새 강도 설문조사 점수 (인원 대비 백분율 %) Odor intensity survey score (% of population)
냄새 없음No smell 약하게 느껴짐feeling weak 확연히 느껴짐I can clearly feel it 복용에 지장이 있을 정도로 느껴짐It feels like it would interfere with taking it. p-valuep-value
실시예 3-3Example 3-3 50.0 50.0 43.8 43.8 6.3 6.3 0.0 0.0 0.006 0.006
실시예 3-7Example 3-7 6.3 6.3 56.3 56.3 37.5 37.5 0.0 0.0 0.004 0.004
실시예 3-9Example 3-9 6.3 6.3 31.3 31.3 62.5 62.5 0.0 0.0 0.001 0.001
비교예 3-1Comparative Example 3-1 0.0 0.0 25.0 25.0 75.0 75.0 0.0 0.0 0.000 0.000
코팅량에 따른 냄새 차폐 효과가 그룹 간의 유의한 차이로 확인되었고, 비교예 3-1 대비 모든 실시예에서 좋은 효과를 나타내었다. 통계적 유의성은 Chi-square 검정을 통해 신뢰구간 95% 이상인 것으로 확인했다 (p-value<0.05). 실시예 3-3의 결과에서 50% 이상이 냄새를 전혀 느끼지 못하였고, 약 94%가 냄새를 느끼지 못하거나 아주 약하게 느낄 정도로 현저한 효과를 보였다. 따라서, 해당 조성들이 우수한 냄새 차폐 효과를 보이는 것을 설문조사를 통해서도 확인하였다. The odor masking effect according to the coating amount was confirmed to be a significant difference between groups, and a good effect was shown in all examples compared to Comparative Example 3-1. Statistical significance was confirmed to be over 95% confidence interval through the Chi-square test (p-value<0.05). The results of Example 3-3 showed a significant effect, with more than 50% not feeling the smell at all, and about 94% not feeling the smell or feeling it very weakly. Therefore, it was confirmed through a survey that the compositions showed excellent odor masking effects.
실시예 4. 코팅제, 흡착제 및 포접제의 함량에 따른 아질사르탄 메독소밀 및 암로디핀 또는 이의 약제학적으로 허용 가능한 염을 함유하는 복합정제의 냄새 차폐 효과 Example 4 . Odor masking effect of composite tablets containing azilsartan medoxomil and amlodipine or a pharmaceutically acceptable salt thereof depending on the content of coating agent, adsorbent, and encapsulant
아질사르탄 메독소밀 층 제조방법Azilsartan medoxomil layer manufacturing method
아질사르탄 메독소밀 칼륨 853.6g, 만니톨 1058.2g, 미결정 셀룰로오스 1058.2g, 크로스카르멜로오스 나트륨 360.0g, 푸마르산 36.0g, 수산화 나트륨 18.0g, 히드록시프로필셀룰로오스 180.0g을 유동층 과립기(Unilab L, Bosch)를 사용하여 과립화한다. 스테아르산 마그네슘 36.0g을 추가하여 혼합기(FTMF 50 MCG, Muller)에서 혼합 및 활택을 진행한다.853.6 g of azilsartan medoxomil potassium, 1058.2 g of mannitol, 1058.2 g of microcrystalline cellulose, 360.0 g of croscarmellose sodium, 36.0 g of fumaric acid, 18.0 g of sodium hydroxide, and 180.0 g of hydroxypropyl cellulose were placed in a fluidized bed granulator (Unilab L, Bosch). ) is used to granulate. Add 36.0 g of magnesium stearate and proceed with mixing and lubrication in a mixer (FTMF 50 MCG, Muller).
암로디핀 층 제조방법Amlodipine layer manufacturing method
암로디핀 베실레이트 138.89g, 규화 미결정 셀룰로오스 1331.11g, 무수인산칼슘 400.00g, 콜로이드성 이산화규소 20.00g과 크로스포비돈 100.00g을 혼합기(FTMF 50 MCG, Muller)에서 혼합한다. 그리고 스테아르산 마그네슘 10.00g을 추가하여 활택한다.138.89 g of amlodipine besylate, 1331.11 g of silicified microcrystalline cellulose, 400.00 g of anhydrous calcium phosphate, 20.00 g of colloidal silicon dioxide and 100.00 g of crospovidone are mixed in a mixer (FTMF 50 MCG, Muller). Then add 10.00g of magnesium stearate and lubricate it.
이층정 제조방법Double-layer tablet manufacturing method
아질사르탄 메독소밀 혼합물과 암로디핀 베실레이트 혼합물을 사용하여 이층정 타정기(EP200L, Parle)로 타정한다. 타정 시 14.5x8.0mm 장방형 펀치를 사용해 1정당 각각 아질사르탄 메독소밀 층 360mg, 암로디핀 층 200mg로 총 560mg가 되도록 타정한다. A mixture of azilsartan medoxomil and amlodipine besylate is used to compress tablets using a double-layer tablet press (EP200L, Parle). When compressing tablets, use a 14.5x8.0mm rectangular punch to make a total of 560mg, with 360mg of azilsartan medoxomil layer and 200mg of amlodipine layer per tablet.
이층정 필름 코팅정 제조 방법Method for manufacturing two-layer film coated tablets
상기 제조된 이층정제를 사용하여 실시예 2 및 3과 같이 코팅제에 흡착제와 포접제를 첨가하여 필름 코팅정을 얻을 수 있다. 이후, 제조된 코팅액을 사용하여 상기 이층정에 코팅기(KC65FC, 금성)로 코팅하여 하기 표7과 같이 필름 코팅정을 얻었다. Using the double-layer tablet prepared above, a film-coated tablet can be obtained by adding an adsorbent and an inclusion agent to the coating agent as in Examples 2 and 3. Thereafter, using the prepared coating solution, the double-layer tablet was coated with a coater (KC65FC, Goldstar) to obtain a film-coated tablet as shown in Table 7 below.
실시예 4-1Example 4-1
구체적으로 먼저 정제수에 베타사이클로덱스트린 (Cavamax W7, Ashland) 0.632g 과 마그네슘 메타규산알루민산마그네슘 (Neusilin, Fuji Chem.) 15.820g을 차례로 녹인다. 이후, 히프로멜로오스 기반 코팅기제 (Opadry 03A640040 Pink, Colorcon)를 39.548g 녹인다. 이후, 제조된 코팅액을 사용하여 실시예 4와 같이 제조한 560mg의 이층정(나정)에 코팅기(KC65FC, 금성)로 코팅하여 하기 표7과 같이 1정당 588mg의 필름 코팅정을 얻었다.Specifically, first, dissolve 0.632 g of betacyclodextrin (Cavamax W7, Ashland) and 15.820 g of magnesium metasilicate aluminate (Neusilin, Fuji Chem.) in purified water. Afterwards, melt 39.548g of hypromellose-based coating base (Opadry 03A640040 Pink, Colorcon). Thereafter, using the prepared coating solution, 560 mg of double-layer tablets (uncoated tablets) prepared in Example 4 were coated with a coating machine (KC65FC, Geumseong) to obtain 588 mg of film-coated tablets per tablet as shown in Table 7 below.
비교예 4-1 내지 4-2Comparative Examples 4-1 to 4-2
실시예 4의 방법에 따라 제조하되, 하기 표 7에 따른 비교예 4-1, 4-2의 함량 및 조합과 같이 나정과 필름 코팅정을 얻었다.Prepared according to the method of Example 4, uncoated tablets and film-coated tablets were obtained with the contents and combinations of Comparative Examples 4-1 and 4-2 according to Table 7 below.
아질사르탄 메독소밀 (mg)Azilsartan medoxomil (mg) 암로디핀amlodipine
(mg)(mg) 		코팅제 (Opadry) (mg)Coating (Opadry) (mg) 흡착제 (메타규산알루민산마그네슘) (mg)Adsorbent (magnesium aluminate metasilicate) (mg) 포접제 (베타사이클로덱스트린) (mg)Inclusion agent (betacyclodextrin) (mg)
실시예 4-1Example 4-1 8080 1010 19.77419.774 0.3160.316 7.917.91
비교예 4-1Comparative Example 4-1 8080 1010 00 00 00
비교예 4-2Comparative Example 4-2 8080 1010 19.77419.774 00 00
실험예 4. 코팅제, 흡착제 및 포접제 함량에 따른 아질사르탄 메독소밀 및 암로디핀 복합정제의 디아세틸 검출량 측정Experimental Example 4. Measurement of diacetyl detection amount of azilsartan medoxomil and amlodipine complex tablet according to coating agent, adsorbent, and inclusion agent content
상기 실시예 4 및 표7에 따른 오파드라이(Opadry), 메타규산알루민산마그네슘 및 베타사이클로덱스트린을 혼합한 코팅층을 가진 아질사르탄 메독소밀 정제의 대해 GC기반 전자코를 이용하여 시간 경과에 따른 디아세틸 검출량을 측정하였다. Azilsartan medoxomil tablets having a coating layer mixed with Opadry, magnesium aluminometasilicate, and betacyclodextrin according to Example 4 and Table 7 were analyzed over time using a GC-based electronic nose. The amount of acetyl detected was measured.
위에서 얻은 필름 코팅정은 진공 건조(2.0mbar, 40℃, 12시간)하여 알루미늄 백에 실링하고 가혹 챔버에 로딩하였다. 가혹 챔버 로딩 이후 시간에 따라 가혹 조건 4주차(4W)에 언로딩하여 디아세틸을 측정하였다.The film-coated tablets obtained above were vacuum dried (2.0 mbar, 40°C, 12 hours), sealed in an aluminum bag, and loaded into a harsh chamber. Diacetyl was measured by unloading at the 4th week (4W) of harsh conditions according to time after loading into the harsh chamber.
디아세틸의 양을 측정하기 위해 실시예 1과 같은 방법으로 GC 기반 전자코를 사용하였다. 측정된 디아세틸의 검출량은 비교예4-2의 Initial 검출량 대비 백분율로 나타내었다. 그 결과를 하기 표 8에 나타내었다.To measure the amount of diacetyl, a GC-based electronic nose was used in the same manner as in Example 1. The measured detection amount of diacetyl was expressed as a percentage compared to the initial detection amount in Comparative Example 4-2. The results are shown in Table 8 below.
디아세틸 검출량Diacetyl detection amount
(비교예 4-2 Initial 대비, %)(Comparative Example 4-2 Initial, %)
InitialInitial 4W4W
실시예 4-1Example 4-1 5353 160160
비교예 4-1Comparative Example 4-1 228228 7,2107,210
비교예 4-2Comparative Example 4-2 100100 762762
상기 표 8의 결과에 따르면, 비교예 4-1 및 4-2 대비 코팅층에 코팅제 외 흡착제와 포접제를 동시 포함한 필름 코팅정인 실시예 4-1 에서 디아세틸 검출량이 현저히 줄어든 효과를 확인할 수 있다.특히, 상기 실시예 4-1의 경우 장기 가혹 조건 4주동안 로딩되어 있었음에도 불구하고 코팅제만 코팅된 비교예 4-2 의 4주차 값 대비 약 5배 정도 낮은 검출량을 보였으므로, 해당 조성들이 복합정제에서도 우수한 냄새 차폐 효과를 보이는 것을 확인하였다.According to the results in Table 8, the effect of significantly reducing the amount of diacetyl detected in Example 4-1, which is a film-coated tablet containing both an adsorbent and an inclusion agent in addition to the coating in the coating layer, compared to Comparative Examples 4-1 and 4-2, can be confirmed. In particular, in the case of Example 4-1, despite being loaded under long-term harsh conditions for 4 weeks, the detection amount was about 5 times lower than the 4th week value of Comparative Example 4-2, in which only the coating agent was coated, so the compositions were combined. It was confirmed that tablets also showed excellent odor masking effect.

Claims (18)

  1. 메독소밀기를 가지는 전구약물 또는 이의 약제학적으로 허용 가능한 염을 포함하는 약학 조성물로 코팅제, 흡착제 및 포접제를 포함한 코팅층을 특징으로 갖는 정제.A pharmaceutical composition containing a prodrug having a medoxomyl group or a pharmaceutically acceptable salt thereof, and having a coating layer including a coating agent, an adsorbent, and an inclusion agent.
  2. 제 1항에 있어서, According to clause 1,
    상기 코팅층의 코팅제로 총 정제 함량 대비 1 내지 10 w/w%를 포함하는 정제.A tablet containing 1 to 10 w/w% of the coating agent of the coating layer based on the total tablet content.
  3. 제 1항에 있어서, According to clause 1,
    상기 코팅층의 흡착제로 총 정제 함량 대비 0.01 내지 0.5 w/w%를 포함하는 정제.A tablet containing 0.01 to 0.5 w/w% of the total tablet content as an adsorbent in the coating layer.
  4. 제 1항에 있어서,According to clause 1,
    상기 코팅층의 포접제로 총 정제 함량 대비 0.05 내지 5 w/w%를 포함하는 정제.A tablet containing 0.05 to 5 w/w% of the total tablet content as an inclusion agent in the coating layer.
  5. 제 1항에 있어서, According to clause 1,
    상기 코팅층은 메독소밀기를 가지는 전구약물 또는 이의 약제학적으로 허용 가능한 염 대비 5 내지 35 w/w%의 코팅제, 0.05 내지 2.0 w/w%의 흡착제, 1 내지 20 w/w%의 포접제를 포함하는 정제.The coating layer contains 5 to 35 w/w% of a coating agent, 0.05 to 2.0 w/w% of an adsorbent, and 1 to 20 w/w% of an encapsulant relative to the prodrug having a medoxomyl group or a pharmaceutically acceptable salt thereof. Tablets containing.
  6. 제1항에 있어서, According to paragraph 1,
    흡착제와 포접제는 1:1 내지 1:50 중량비인 정제Tablets where the adsorbent and encapsulant are in a weight ratio of 1:1 to 1:50.
  7. 제1항에 있어서, According to paragraph 1,
    흡착제와 코팅제는 1:5 내지 1:150 중량비인 정제.Tablets where the adsorbent and coating agent are in a weight ratio of 1:5 to 1:150.
  8. 제1항에 있어서, According to paragraph 1,
    포접제와 코팅제는 1: 1 내지 1:30 중량비인 정제Tablets where the inclusion agent and coating agent are in a weight ratio of 1:1 to 1:30.
  9. 제1항에 있어서, According to paragraph 1,
    메독소밀기를 가지는 전구약물 또는 이의 약제학적으로 허용 가능한 염과 흡착제의 몰비율은 300:1 내지 10:1 정제.The molar ratio of the prodrug having a medoxomyl group or a pharmaceutically acceptable salt thereof and the adsorbent is 300:1 to 10:1.
  10. 제1항에 있어서, According to paragraph 1,
    메독소밀기를 가지는 전구약물 또는 이의 약제학적으로 허용 가능한 염과 포접제의 몰비율은 200:1 내지 10:1인 정제.A tablet in which the molar ratio of the prodrug or a pharmaceutically acceptable salt thereof having a medoxomyl group and the inclusion agent is 200:1 to 10:1.
  11. 제 1항에 있어서,According to clause 1,
    상기 코팅제는 히프로멜로오스 (Hydroxypropyl methyl Cellulose), 히드록시프로필셀룰로오스 (Hydroxy propyl Cellulose), 히드록시에틸셀룰로오스 (Hydroxyethyl Cellulose), 메틸셀룰로오스 (Methyl Cellulose), 에틸셀룰로오스 (Ethyl Cellulose), 카르복시메틸셀룰로오스 (Carboxy methyl cellulose) 으로 이루어진 군에서 선택된 단독 또는 이들의 혼합물로 포함되는 정제.The coating agent is hypromellose (Hydroxypropyl methyl Cellulose), Hydroxypropyl Cellulose (Hydroxyethyl Cellulose), Methyl Cellulose (Methyl Cellulose), Ethyl Cellulose (Ethyl Cellulose), Carboxymethyl Cellulose ( Carboxy methyl cellulose) Tablets selected from the group consisting of either alone or a mixture thereof.
  12. 제 1항에 있어서,According to clause 1,
    상기 흡착제는 메타규산알루민산마그네슘, 규산칼슘 또는 콜로이드성이산화규소, 활성탄소, 이온교환 수지로 이루어진 군에서 선택된 단독 또는 이들의 혼합물로 포함되는 정제.The adsorbent is a tablet selected from the group consisting of magnesium aluminometasilicate, calcium silicate, colloidal silicon oxide, activated carbon, and ion exchange resin, or a mixture thereof.
  13. 제 1항에 있어서,According to clause 1,
    상기 포접제는 알파사이클로덱스트린, 베타사이클로덱스트린, 감마사이클로덱스트린으로 이루어진 군에서 선택된 단독 또는 이들의 혼합물로 포함되는 정제.A tablet comprising the inclusion agent alone or a mixture thereof selected from the group consisting of alphacyclodextrin, betacyclodextrin, and gammacyclodextrin.
  14. 제 1항에 있어서, According to clause 1,
    상기 코팅층은 코팅제로 히프로멜로오스를 포함하고,The coating layer includes hypromellose as a coating agent,
    흡착제로 메타규산알루민산마그네슘을 포함하고,Contains magnesium aluminate metasilicate as an adsorbent,
    포접제로 베타사이클로덱스트린을 포함한 정제.Tablets containing betacyclodextrin as an inclusion agent.
  15. 제 1항에 있어서, According to clause 1,
    총 정제 함량 대비 코팅제, 흡착제 및 포접제가 혼합된 코팅층 1 내지 16 w/w%를 포함하는 정제.A tablet containing 1 to 16 w/w% of a coating layer mixed with a coating agent, an adsorbent, and an encapsulant, relative to the total tablet content.
  16. 제 1항에 있어서,According to clause 1,
    상기 메독소밀기를 가지는 전구약물은 아질사르탄 메독소밀인 정제.A tablet wherein the prodrug having a medoxomil group is azilsartan medoxomil.
  17. 제 1항에 있어서,According to clause 1,
    상기 정제는 메독소밀기를 가지는 전구약물 외에 추가로 약학적 유효성분을 포함하는 복합정제. The tablet is a complex tablet containing an additional pharmaceutical active ingredient in addition to a prodrug having a medoxomyl group.
  18. 제 17항에 있어서,According to clause 17,
    상기 유효성분으로 암로디핀, 아트로바스타틴, 로수바스타틴, 에제티미브, 클로르탈리돈 또는 이의 약제학적으로 허용 가능한 염을 하나 또는 그 이상 포함하는 복합정제.A composite tablet containing one or more of amlodipine, atorvastatin, rosuvastatin, ezetimibe, chlorthalidone, or a pharmaceutically acceptable salt thereof as the active ingredients.
PCT/KR2023/012762 2022-08-31 2023-08-29 Dual-strength odor-shielding pharmaceutical composition WO2024049155A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20130020966A (en) * 2010-08-31 2013-03-04 도레이 카부시키가이샤 Coating agent for pharmaceutical solid preparation, pharmaceutical film formulation, and coated pharmaceutical solid preparation
WO2014188728A1 (en) * 2013-05-24 2014-11-27 持田製薬株式会社 Film-coating composition
JP2014224099A (en) * 2013-04-15 2014-12-04 株式会社三和化学研究所 Olmesartan medoxomil-containing pharmaceutical composition
JP2015017136A (en) * 2008-08-11 2015-01-29 第一三共株式会社 Method for decreasing odor
JP2017119714A (en) * 2015-01-15 2017-07-06 大原薬品工業株式会社 Film coating formulation containing prodrug having medoxomil group

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0612032A2 (en) 2005-06-13 2010-10-13 Cargill Inc cyclodextrin inclusion complexes and methods for preparing them

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Publication number Priority date Publication date Assignee Title
JP2015017136A (en) * 2008-08-11 2015-01-29 第一三共株式会社 Method for decreasing odor
KR20130020966A (en) * 2010-08-31 2013-03-04 도레이 카부시키가이샤 Coating agent for pharmaceutical solid preparation, pharmaceutical film formulation, and coated pharmaceutical solid preparation
JP2014224099A (en) * 2013-04-15 2014-12-04 株式会社三和化学研究所 Olmesartan medoxomil-containing pharmaceutical composition
WO2014188728A1 (en) * 2013-05-24 2014-11-27 持田製薬株式会社 Film-coating composition
JP2017119714A (en) * 2015-01-15 2017-07-06 大原薬品工業株式会社 Film coating formulation containing prodrug having medoxomil group

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