WO2016126012A1 - Comprimé et procédé de préparation associé - Google Patents

Comprimé et procédé de préparation associé Download PDF

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Publication number
WO2016126012A1
WO2016126012A1 PCT/KR2016/000221 KR2016000221W WO2016126012A1 WO 2016126012 A1 WO2016126012 A1 WO 2016126012A1 KR 2016000221 W KR2016000221 W KR 2016000221W WO 2016126012 A1 WO2016126012 A1 WO 2016126012A1
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WIPO (PCT)
Prior art keywords
tablet
active ingredient
particles
diameter
fimasartan
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PCT/KR2016/000221
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English (en)
Inventor
Jayhyuk Myung
Sung Chan Jeong
Yun Sam Kim
Original Assignee
Boryung Pharmaceutical Co., Ltd
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Publication date
Priority claimed from KR1020150018182A external-priority patent/KR101545268B1/ko
Application filed by Boryung Pharmaceutical Co., Ltd filed Critical Boryung Pharmaceutical Co., Ltd
Priority to US15/548,754 priority Critical patent/US10420728B2/en
Priority to RU2017127225A priority patent/RU2697660C2/ru
Priority to MX2017010018A priority patent/MX2017010018A/es
Priority to BR112017016689-5A priority patent/BR112017016689B1/pt
Publication of WO2016126012A1 publication Critical patent/WO2016126012A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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

Definitions

  • the present invention relates to a tablet comprising fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, and a method for preparing the same.
  • the present invention relates to a tablet superior in terms of hardness and friability where an active ingredient particle with a small diameter is used to improve tableting characteristics, and a method for preparing the same.
  • Fimasartan is angiotensin II receptor antagonist used for the treatment of hypertension, and is commercially available in doses of 30mg, 60 mg and 120 mg under the brand name of Kanarb, which is in the form of fimasartan potassium trihydrate.
  • fimasartan can be used in the form of fimasartan potassium trihydrate.
  • the present invention provides a method for preparing a tablet comprising fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, the method comprising milling the active ingredient to allow 50 % (v/v) of the active ingredient based on the total amount of the active ingredient contained in the tablet to have a diameter of 10 ⁇ m or less.
  • the active ingredient is milled such that 50 % (v/v) of the active ingredient based on the total amount of the active ingredient has a diameter of 10 ⁇ m or less.
  • the active ingredient particles can be of high compressibility so that they can be more greatly compressed according to an increase in compression pressure, which makes it possible to easily control the hardness and disintegration time of the tablet and to decrease the friability of the tablet.
  • tablets comprising the active ingredient particles in such a particle size distribution exhibit uniform physical properties.
  • D50 is the value of the diameter of the active ingredient particle at 50 %(v/v) of the active ingredient based on the total amount of the active ingredients in the cumulative distribution
  • D90 is the value of the diameter of the active ingredient particle at 90 % (v/v) of the active ingredient based on the total amount of the active ingredients in the cumulative distribution
  • the present invention provides a method for preparing a tablet, comprising:
  • the milling step may be carried out in such a way that 50 % (v/v) of the active ingredient based on the total amount of the active ingredient contained in the tablet may be milled into the particles having a diameter of 10 ⁇ m or less. In exemplary embodiments of the present invention, the milling step may be carried out in such a way that 90 % (v/v) of the active ingredient based on the total amount of the active ingredient contained in the tablet may be milled into the particles having a diameter of 25 ⁇ m or less.
  • the milling step may be carried out in such a way that 90 % (v/v) of the active ingredient based on the total amount of the active ingredient contained in the tablet may be milled into the particles having a diameter of 25 ⁇ m or less, and 50 % (v/v) of the active ingredient based on the total amount of the active ingredient may be milled into the particles having a diameter of 10 ⁇ m or less.
  • the milling step may be carried out in such a way that 50 % (v/v) of the active ingredient based on the total amount of the active ingredient contained in the tablet may be milled into the particles having a diameter of 6 ⁇ m or less.
  • the milling step may be carried out in such a way that 90 % (v/v) of the active ingredient based on the total amount of the active ingredient contained in the tablet may be milled into the particles having a diameter of 15 ⁇ m or less.
  • the milling step may be carried out in such a way that 90 % (v/v) of the active ingredient based on the total amount of the active ingredient contained in the tablet may be milled into the particles having a diameter of 15 ⁇ m or less, and 50 % (v/v) of the active ingredient based on the total amount of the active ingredient contained in the tablet may be milled into the particles having a diameter of 6 ⁇ m or less.
  • the milling step may be carried out in such a way that the active ingredient fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is milled into the particles having a diameter of 0.5 ⁇ m or more.
  • the milling step may be carried out in such a way that the active ingredient fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is milled into particles having a diameter of 2 ⁇ m or more, preferably 3 ⁇ m or more.
  • the particle of the active ingredients has the above diameter range, the active ingredient particles are easy to handle and prepare into a tablet since static electricity is less prone to occur in that diameter range.
  • the active ingredient fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof amounts to approximately 40 weight % or higher based on the total weight of the tablet.
  • the physical properties of the tablet greatly depend on those of the active ingredient.
  • the active ingredient is milled in the form of particles, it is possible to easily control physical properties of the tablet and to improve uniformity of the physical properties of the tablet.
  • the active ingredient is highly compressible such that they can be more greatly compressed with an increase in compression pressure, which makes it possible to easily control the hardness and disintegration time of the tablet and to decrease the friability of the tablet.
  • tablets containing the active ingredient in such a size distribution exhibit uniform physical properties.
  • the tablet may include the active ingredient fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in an amount of 30 weight % or more, based on the total weight of the tablet, preferably in an amount of 40 weight % to 70 weight %, and more preferably in an amount of 40 weight % to 60 weight %.
  • the active ingredient fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof hardness and disintegration time of the tablet can be easily controlled and friability of the tablet can be decreased because the active ingredient is used in the form of particles having the above particle size distribution.
  • the milling the active ingredient may be achieved using a method or an apparatus that is typically used in the medicinal and pharmaceutical field, for example, a jet mill if it does not degrade the activity of the active ingredient.
  • any pharmaceutically acceptable additive may be used in the present invention without special limitations thereto.
  • the pharmaceutically acceptable additive may be a carrier, an excipient, a diluent, or a mixture thereof.
  • Examples of the carrier, the excipient, or the diluent may include lactose, lactose hydrate, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, corn starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, crospovidone, sodium starch glycolate, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, croscamellose sodium, magnesium stearate, mineral oil, microcrystalline cellulose, or a mixture thereof, with preference for lactose, lactose hydrate, microcrystalline cellulose, croscamellose sodium, magnesium stearate, or a mixture thereof.
  • the forming the tablet may be performed in various manners.
  • the tablet may be manufactured using a direct compression process, or a wet or dry granulation process.
  • the tablet may be prepared by a wet granulation process.
  • the forming the tablet may comprise granulating the mixture.
  • Granules may be prepared from the mixture, and the granules may be mixed with an additional pharmaceutically acceptable additive to give a granule-containing mixture that is then compressed into a tablet.
  • the granules may be prepared by the wet granulation process using a liquid binder.
  • the granule may be prepared by using a high shear mixer (HSM) or fluidized bed granulator (FBG).
  • HSM high shear mixer
  • FBG fluidized bed granulator
  • the additional pharmaceutically acceptable additive may be a carrier, an excipient, a diluent, or a mixture thereof.
  • the carrier, the excipient, or the diluent include lactose, lactose hydrate, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, corn starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, crospovidone, sodium starch glycolate, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, croscamellose sodium, magnesium stearate, mineral oil, or a mixture thereof, with preference for lactose
  • the compression pressure when the tablet is formed, may be in the range of approximately 200 kgf to 900kgf, preferably approximately 300 kgf to 800 kgf, and more preferably approximately 400 kgf to 600 kgf.
  • the granules may be manufactured by a wet granulation. That is, a binder may be added to the mixture to prepare the wet granule. No particular limitations are imported on the binder.
  • the binder may be liquid, and preferably, the binder may be a solution of hydroxypropyl cellulose in water, or a solution of hydroxypropylmethyl cellulose in water and preferably the solution of hydroxypropyl cellulose in water.
  • the granules may be manufactured by a dry granulation.
  • the pharmaceutically acceptable salt may be a metal salt of fimasartan, preferably an alkali metal salt, and more preferably fimasartan potassium.
  • the hydrate may be a hydrate of the pharmaceutically acceptable salt of fimasartan.
  • the hydrate may be a hydrate of fimasartan potassium, preferably fimasartan potassium monohydrate or fimasartan potassium trihydrate, and more preferably fimasartan potassium trihydrate.
  • the active ingredient contained in the tablet may be fimasartan potassium monohydrate or fimasartan potassium trihydrate and preferably fimasartan potassium trihydrate.
  • the tablet may be an uncoated tablet, a coated tablet or a double layered tablet.
  • the tablet may be the coated tablet.
  • the present invention provides a tablet comprising fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, and pharmaceutically acceptable additives.
  • 50% (v/v) of the active ingredient based on the total amount of the active ingredient is particles having a diameter of 10 ⁇ m or less.
  • 90 % (v/v) of the active ingredient based on the total amount of the active ingredient, which is fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof contained in the tablet is a particle having a diameter of 25 ⁇ m or less.
  • 90 % (v/v) of the active ingredient based on the total amount of the active ingredient which is fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof contained in the tablet is a particle having a diameter of 25 ⁇ m or less, and 50 % (v/v) of the active ingredient based on the total amount of the active ingredient have diameter of 10 ⁇ m or less.
  • 50 % (v/v) of the active ingredient based on the total amount of the active ingredient, which is fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof contained in the tablet have a diameter of 6 ⁇ m or less.
  • 90 % (v/v) of the active ingredient based on the total amount of the active ingredient, which is fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof contained in the tablet have a diameter of 15 ⁇ m or less.
  • 90 % (v/v) of the active ingredient based on the total amount of the active ingredient which is fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof contained in the tablet have a diameter of 15 ⁇ m or less and 50 % (v/v) of the active ingredient based on the total amount of the active ingredient have diameter of 6 ⁇ m or less.
  • the pharmaceutically acceptable additives may include lactose, lactose hydrate, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, corn starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, ethyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, crospovidone, sodium starch glycolate, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, croscamellose sodium, magnesium stearate, mineral oil, or a mixture thereof, with preference for lactose, lactose hydrate, microcrystalline cellulose, croscamellose sodium, magnesium stearate, or a mixture thereof.
  • the active ingredient which is fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, is the particles having a diameter of 0.5 ⁇ m or more.
  • the active ingredient which is fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is the particle having a diameter of 2 ⁇ m or larger and preferably 3 ⁇ m or more.
  • the active ingredient contained in the tablet may be a hydrate of fimasartan potassium, and preferably fimasartan potassium trihydrate.
  • the tablet may be an uncoated tablet, a coated tablet or a double layered tablet.
  • the tablet may be the coated tablet.
  • the present invention provides the method of preparing the tablet including fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as the active ingredient.
  • the tablet of the present invention is prepared using the particle of the active ingredient having a specific particle size distribution by milling the active ingredient to improve the compressibility of the mixture including the active ingredient.
  • the hardness of the tablet may be increased with an increase in the compression pressure the disintegration time may be easily controlled and friability of the tablet may be decreased.
  • FIG. 1 is a graph of a particle size distribution illustrating definitions of D50 and D90 with regard to particle sizes.
  • a maximum particle diameter was a 37.8 ⁇ m in 50% (v/v) of fimasartan potassium trihydrate based on the total amount of fimasartan potassium trihydrate and a maximum particle diameter was 134.96 ⁇ m in 90% (v/v) of fimasartan potassium trihydrate based on the total amount of fimasartan potassium trihydrate.
  • Particle sizes were measured using a laser diffraction particle size analyzer (Sympatec, HELOS system).
  • a liquid binder was prepared by dissolving 2 mg of hydroxypropyl cellulose in 25 mg of pure water. The liquid binder was sprayed at a rate of 26 g/min over the mixture, followed by manufacturing granules. The granules were dried in the fluidized bed granulator while a compressed air of 85oC was fed at a rate of 3 m 3 /mintothegranulator.
  • the resulting granules were mixed with 1.5 mg of magnesium stearate, and compressed at a compression pressure of 300 kgf to prepare an uncoated tablet.
  • the uncoated tablet was then coated with Opadry to afford a coated tablet.
  • a coated tablet was prepared as the same procedure as in Example 1.
  • a coated tablet was prepared as the same procedure as in Example 1.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used and that the compression was carried out at a compression pressure of 500 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used and that the compression was carried out at a compression pressure of 500 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used and that the compression was carried out at a compression pressure of 500 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used and that the compression was carried out at a compression pressure of 500 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 was used and that the compression was carried out at a compression pressure of 500 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used and that the compression was carried out at a compression pressure of 500 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used and that the compression was carried out at a compression pressure of 500 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that fimasartan potassium trihydrate was not used and 72 mg of lactose monohydrate was used.
  • Tablets prepared in the Examples 1 to 15 and the Comparative Examples 1 to 9 were assayed for hardness, disintegration time, and friability. Hardness was measured according to Chapter 1217 (Tablet Breaking Force) of the United States Pharmacopeia (USP). For the analysis procedure of disintegration time, reference was made to Chapter 701 (Disintegration), USP. Friability was calculated according to the following equation after a friability test was performed according to Chapter 1216 (Tablet Friability), USP.
  • Friability (%) ⁇ (Weight (mg) of 20 initial tablets Weight (mg) of 20 tablets post friability test)/ Weight (mg) of 20 initial tablets ⁇ ⁇ 100 (%)
  • the tablets tended to increase in hardness with an increase in compression pressure when the active ingredient particles had a D50 of 10 ⁇ m or less (a maximum particle diameter of 10 ⁇ m or less in 50% (v/v) of the active ingredient based on the total amount of the active ingredient) and a D90 of 25 ⁇ m or less (a maximum particle diameter of 25 ⁇ m or less in 90 % (v/v) of the active ingredient based on the total amount of the active ingredient).
  • the tablets of the Comparative Examples did not significantly increase in hardness although compressed at increased compression pressures.
  • the tablets of the Comparative Examples were found to have a hardness of approximately 7 kp or less, which was similar to the hardness of the tablets of Examples compressed at a compression pressure of 300 kgf.
  • the fimasartan potassium trihydrate particles can be of high compressibility so that they can be more greatly compressed with an increase in compression pressure, which makes it possible to easily control the hardness and disintegration time of the tablet and to decrease the friability of the tablet to 1 % or less.
  • the method of the present invention allows tablets to be homogeneous in physical properties even in mass production.
  • Granules prepared in the Examples and the Comparative Examples were assayed for density and Carr’s index.
  • Density was measured according to Chapter 616 in General Chapter (Bulk density and Tapped density of powders) of the United States Pharmacopeia (USP).
  • Carr’s index was calculated according to the following equation:
  • the granules has higher Carr’s index when the active ingredient particles had a D50 of 10 ⁇ m or less (a maximum particle diameter of 10 ⁇ m or less in 50% (v/v) of the active ingredient based on the total amount of the active ingredient) and a D90 of 25 ⁇ m or less (a maximum particle diameter of 25 ⁇ m or less in 90 % (v/v) of the active ingredient based on the total amount of the active ingredient) compared to those of the active ingredients having the D50 value of exceeds 10 ⁇ m.
  • the compressibility is increased.
  • the granules including the fimasartan potassium hydrate having a D50 of 10 ⁇ m or less and a D90 of 25 ⁇ m or less superior compressibility.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that 29 mg of D mannitol was used instead of lactose monohydrate and that the compression was carried out at a compression pressure of 500 kgf.
  • a coated tablet was prepared as the same procedure as in Example 16.
  • a tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 16, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • Tablets prepared in the Examples 16 to 25 and the Comparative Examples 11 to 16 were assayed for hardness, disintegration time, and friability the same as those of TEST EXAMPLE 1.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that 29 mg of corn starch was used instead of lactose monohydrate and that the compression was carried out at a compression pressure of 500 kgf.
  • a coated tablet was prepared as the same procedure as in Example 26.
  • a tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 26, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • Tablets prepared in the Examples 26 to 35 and the Comparative Examples 17 to 22 were assayed for hardness, disintegration time, and friability the same as those of TEST EXAMPLE 1.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that 2.0mg of hydroxypropylmethyl cellulose was used instead of hydroxypropyl cellulose and that the compression was carried out at a compression pressure of 500 kgf.
  • a coated tablet was prepared as the same procedure as in Example 36.
  • a tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 2 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 3 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 4 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 5 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 6 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 7 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • a tablet was prepared in the same procedure as in Example 36, with the exception that the fimasartan potassium trihydrate particles of Preparation Example 8 were used and that the compression was carried out at a compression pressure of 800 kgf.
  • Tablets prepared in the Examples 36 to 45 and the Comparative Examples 23 to 28 were assayed for hardness, disintegration time, and friability the same as those of TEST EXAMPLE 1.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate was not used, 72 mg of lactose monohydrate was used and the compression was carried out at a compression pressure of 500 kgf.
  • a tablet was prepared in the same procedure as in Example 1, with the exception that the fimasartan potassium trihydrate was not used, 72 mg of lactose monohydrate was used and the compression was carried out at a compression pressure of 800 kgf.
  • the tablets according to Examples 16 to 45 exhibited superior hardness, disintegration time, and friability to those of comparative Examples 11 to 28 although the additives included in the tablet is changed from lactose monohydrate and hydroxypropyl cellulose into D mannitol (Examples 16 to 25), corn starch (Examples 26 to 35) and hydroxypropylmethyl cellulose (Examples 36 to 45), respectively.
  • the properties of the tablet are not greatly affected by the addictives when the amount of the active ingredients of fimasartan potassium trihydrate is high in the tablet.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un comprimé. Le procédé peut améliorer la compressibilité des principes actifs et produire des comprimés de qualité uniforme, donnant l'avantage d'augmenter la dureté du comprimé avec une augmentation de la pression de compression, de contrôler facilement le temps de délitement, et de réduire la friabilité du comprimé en utilisant le principe actif fimasartan, un sel ou un hydrate ou un solvate pharmaceutiquement acceptable de celui-ci ayant une distribution granulométrique spécifique.
PCT/KR2016/000221 2015-02-05 2016-01-11 Comprimé et procédé de préparation associé WO2016126012A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US15/548,754 US10420728B2 (en) 2015-02-05 2016-01-11 Tablet and method of preparing the same
RU2017127225A RU2697660C2 (ru) 2015-02-05 2016-01-11 Таблетка и способ ее получения
MX2017010018A MX2017010018A (es) 2015-02-05 2016-01-11 Comprimido y metodo para preparar el mismo.
BR112017016689-5A BR112017016689B1 (pt) 2015-02-05 2016-01-11 Comprimido e método para preparar o mesmo

Applications Claiming Priority (4)

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KR1020150018182A KR101545268B1 (ko) 2015-02-05 2015-02-05 정제 및 이의 제조방법
KR10-2015-0018182 2015-02-05
CN201510426945.4 2015-07-20
CN201510426945.4A CN106176641B (zh) 2015-02-05 2015-07-20 片剂及其制备方法

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WO2016126012A1 true WO2016126012A1 (fr) 2016-08-11

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040097996A (ko) * 2002-02-14 2004-11-18 글락소 그룹 리미티드 Ｎ-((1-Ｎ-부틸-4-피페리디닐)메틸)-3,4-디하이드로-2Ｈ-(1,3)옥사지노(3,2-ａ)인돌-10-카복스아미드 또는 그의 염을포함하는 제약 조성물, 및 건식 과립화를 포함하는 그의제조 방법
KR20050062467A (ko) * 2002-06-10 2005-06-23 비타 사이엔티피카, 에스.엘. 경구 붕해형 정제 및 이를 수득하는 방법
JP2012153631A (ja) * 2011-01-25 2012-08-16 Ohara Yakuhin Kogyo Kk 錠剤の製造方法
KR20130100237A (ko) * 2010-04-30 2013-09-10 브리스톨-마이어스 스큅 컴퍼니 Ｎ－（４－（２－아미노－３－클로로피리딘－４－일옥시）－３－플루오로페닐）－４－에톡시－１－（４－플루오로페닐）－２－옥소－１，２－디히드로피리딘－３－카르복스아미드를 포함하는 제약 조성물
KR20130130028A (ko) * 2010-12-20 2013-11-29 글락소스미스클라인 인털렉츄얼 프로퍼티 (넘버 2) 리미티드 신규 제약 조성물
KR20150008513A (ko) * 2007-05-03 2015-01-22 글락소스미스클라인 엘엘씨 신규 제약 조성물

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040097996A (ko) * 2002-02-14 2004-11-18 글락소 그룹 리미티드 Ｎ-((1-Ｎ-부틸-4-피페리디닐)메틸)-3,4-디하이드로-2Ｈ-(1,3)옥사지노(3,2-ａ)인돌-10-카복스아미드 또는 그의 염을포함하는 제약 조성물, 및 건식 과립화를 포함하는 그의제조 방법
KR20050062467A (ko) * 2002-06-10 2005-06-23 비타 사이엔티피카, 에스.엘. 경구 붕해형 정제 및 이를 수득하는 방법
KR20150008513A (ko) * 2007-05-03 2015-01-22 글락소스미스클라인 엘엘씨 신규 제약 조성물
KR20130100237A (ko) * 2010-04-30 2013-09-10 브리스톨-마이어스 스큅 컴퍼니 Ｎ－（４－（２－아미노－３－클로로피리딘－４－일옥시）－３－플루오로페닐）－４－에톡시－１－（４－플루오로페닐）－２－옥소－１，２－디히드로피리딘－３－카르복스아미드를 포함하는 제약 조성물
KR20130130028A (ko) * 2010-12-20 2013-11-29 글락소스미스클라인 인털렉츄얼 프로퍼티 (넘버 2) 리미티드 신규 제약 조성물
JP2012153631A (ja) * 2011-01-25 2012-08-16 Ohara Yakuhin Kogyo Kk 錠剤の製造方法

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