WO2004089344A1 - Procede de production de comprime - Google Patents

Procede de production de comprime Download PDF

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Publication number
WO2004089344A1
WO2004089344A1 PCT/JP2003/004193 JP0304193W WO2004089344A1 WO 2004089344 A1 WO2004089344 A1 WO 2004089344A1 JP 0304193 W JP0304193 W JP 0304193W WO 2004089344 A1 WO2004089344 A1 WO 2004089344A1
Authority
WO
WIPO (PCT)
Prior art keywords
drug
tablet
binder
content
weight
Prior art date
Application number
PCT/JP2003/004193
Other languages
English (en)
Japanese (ja)
Inventor
Toshiya Taniguchi
Takao Terai
Original Assignee
Ohara Chmical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ohara Chmical Industries, Ltd. filed Critical Ohara Chmical Industries, Ltd.
Priority to AU2003236336A priority Critical patent/AU2003236336A1/en
Priority to JP2004570538A priority patent/JPWO2004089344A1/ja
Priority to PCT/JP2003/004193 priority patent/WO2004089344A1/fr
Publication of WO2004089344A1 publication Critical patent/WO2004089344A1/fr

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Classifications

    • 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
    • A61K9/2095—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • the present invention relates to a method for producing a medicinal agent that ensures uniformity and preservation of the content of a small amount of a drug having high pharmacological activity, that is, a small amount of a single dose, and is industrially advantageous.
  • Pharmaceutical tablets with a small amount and high pharmacological activity have a low drug content in the formulation, and due to slight variations, the expected effects may not be obtained or unexpected side effects may appear. Therefore, it is necessary to pay special attention to the uniformity of the drug content when manufacturing a drug product with a low drug content, and it is usually necessary to dilute a small amount of the drug twice with an excipient to obtain a uniform mixture.
  • the above-mentioned double dilution method involves a large number of formulation steps and has a problem in production efficiency.
  • a method of once forming a solution and wet granulating it into granules or tablets tends to cause a decrease in the activity of the main drug.
  • the inventors of the present invention have conducted intensive studies to solve the above-mentioned problems. Spray and granulate, dry, and compression-mold to obtain tablets that are excellent in terms of uniformity of drug content, stable storage of drugs, and suppression of drug deactivation during tableting. This led to further studies and completed the present invention.
  • a fine-powder drug having an average particle size of 1 to 20 ⁇ m is uniformly suspended in an insoluble liquid medium, and the resulting suspension is sprayed on a fluidized formulation additive.
  • a method for producing tablets which is subjected to fluidized bed granulation and, after drying, is compression-molded so that the ratio of the drug is 0.1 to 10% by weight based on the whole tablet,
  • the medicament used in the present invention is a solid at room temperature, has high pharmacological activity in a small amount, and therefore exhibits an effect at a small dose, and is poorly soluble in a solvent used in wet granulation.
  • the average particle size of the fine powder of the medicament is from 1 to 20 ⁇ m, preferably from 2 to 15 ⁇ m, more preferably from 3 to 10 ⁇ m.
  • the proportion of the medicament in the tablet is a force S which is between 0.1 and 1 O w / w%, preferably between 0.2 and 5 w / w%.
  • the insoluble solvent examples include organic solvents such as water, ethanol, and methylene chloride that are usually used in the preparation.
  • organic solvents such as water, ethanol, and methylene chloride that are usually used in the preparation.
  • a solvent that does not substantially dissolve the drug is selected. You.
  • the additives in the formulation used in the present invention include excipients, extenders, disintegrants, binders, lubricants and the like.
  • Excipients or fillers include, for example, lactose, sucrose, corn starch, Examples include crystalline cellulose, and among them, lactose and crystalline cellulose are preferable.
  • disintegrant examples include carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropylcellulose, partial alpha imidized starch, and corn starch.
  • binder examples include polyvinylpyrrolidone, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, partially alpha-starched starch, alpha-mono-starch, macro-gloss mono-sodium, and the like. Are also preferably used.
  • lubricant examples include magnesium stearate, calcium stearate, stearic acid, talc, hydrogenated oil, sucrose fatty acid ester and the like.
  • Flavoring, flavoring, coloring and other additives may be added as needed.
  • fluidized bed granulation air is introduced from underneath a packed bed of powder (core particles) in a fluidized bed granulator, and the powder is suspended and dispersed in an air flow, that is, a fluidized bed is formed.
  • This is a method in which a spray liquid containing a binder is sprayed from the spray nozzle onto the fluidized bed, and the particles adhere to each other and aggregate to grow the particles.
  • Fluidized bed granulators are classified into batch type, semi-continuous type, continuous type, etc. according to the operational classification, and fluidized bed type, spouted fluidized bed type, spouted bed type, etc. according to the spray nozzle position and spray direction.
  • a device for misalignment can be used.
  • the core particle powder used in the method of the present invention is usually an excipient, and its average particle size is preferably about 20 to 200 ⁇ m.
  • the volume of the mist liquid is 1 to 10 times the weight of the charged powder, preferably 1/7 to 1 times the weight of the charged powder.
  • the medicament powder is suspended uniformly in the spray liquid.
  • the binder may be dissolved in the spray liquid, may be added to the powder forming the fluidized bed, or both.
  • the proportion of the binder used is 100 to 100% by weight, preferably 200 to 700% by weight, based on the drug.
  • the use ratio of the binder in the spray liquid or the core particle powder is 1 to 30% by weight, preferably 2 to 25% by weight.
  • the fluidized-bed granulator has an intake air temperature of 50 to 100 ° C, preferably 60 to 90 ° C. It is preferable to adjust the intake air temperature, the spray speed of the spray liquid, and the amount of air blow so that the air temperature becomes 20 to 60 ° C, preferably 25 to 40 ° C.
  • the spraying time varies depending on the charged amount of the raw material powder and the spraying speed (amount), but usually ends in 20 to 120 minutes. After the end of the mist, the air is dried for about 5 to 30 minutes to obtain dried granules.
  • the average particle size of the obtained granules is about 50 to 500 ⁇ m.
  • an excipient, a disintegrant and a lubricant are appropriately mixed with the granules, and the mixture is compressed and compressed according to a conventional method.
  • the tablet of the present invention can be easily produced by a usual method, for example, a method described in the general rules for preparations of the Japanese Pharmacopoeia, Fourteenth Edition.
  • the obtained tablet may be optionally coated.
  • Example 1 Example 1
  • Lactose 3195 g, polypyrrolidone 90 g and partially alpha-monostarch starch 150 g are mixed and charged into a fluid bed granulator (FD-5S, manufactured by Baurek).
  • a suspension consisting of 69 g of purified water and 60 g of polyvinylpyrrolidone was prepared by uniformly dispersing 30 g of trandolapril powder having an average particle diameter of 8 ⁇ m in a solution of 60 g of polypyrrolidone. Sprayed into the fluidized bed at a rate of 0 g / min. The air temperature and air flow were adjusted so that the inlet air temperature to the granulator was 60 ° C and the outlet air temperature was 25 to 30 ° C. After the spraying was completed, the mixture was blow-dried for 5 minutes to obtain granules.
  • the obtained granules were sieved with a 24 mesh JIS standard sieve to obtain sized powder.
  • 75 g of hardened oil is added to the sized powder, mixed uniformly using a tumbler mixer (TM-15S, manufactured by Showa Giken Co., Ltd.), and compression-molded by a rotary tableting machine.
  • a tablet having the following composition was obtained.
  • lactose (3300 g), microcrystalline cellulose (2100 g) and corn starch (600 g) were mixed and charged into a fluidized bed granulator to form a fluidized bed.
  • 60 g of etizolam powder with an average particle size of 6 ⁇ was added to a solution consisting of 1800 mL of purified water and 120 g of Macrogol 6000 to prepare a uniformly dispersed liquid. It was sprayed into a fluidized bed and granulated. After the obtained granules were dried, they were sieved through a 30-mesh JIS standard sieve to obtain sized powder.
  • 300 g of calcium carboxymethylcellulose and 120 g of magnesium stearate were added to the sized powder, mixed uniformly using a tumbler mixer, and compression-molded with a rotary tableting machine to obtain tablets having the following composition.
  • Each tablet obtained in Examples 1 and 2 and Comparative Examples 1 and 2 was sealed and stored at a temperature of 60 ° C and a humidity of 75% and kept open in a petri dish. It was measured by a matograph method. The quantification was based on the internal standard method. The results (percentage of the residual value relative to the initial value of the drug) are as follows.
  • Comparative Example 2 96.1% 93.7% From these results, it can be seen that the tablets of Examples 1 and 2 of the present invention are superior to the corresponding Comparative Examples 1 and 2, respectively, in terms of the effect of stabilizing the drug. found.
  • Test Example 2 (Content uniformity test)
  • the test was based on “12. Content uniformity test method” described in the Japanese Pharmacopoeia 14th Edition. That is, the drug content of each of the 10 tablets obtained in Examples 1 and 2 and Comparative Examples 1 and 2 was measured by high performance liquid chromatography, and the uniformity of each drug content was examined. As a result, all the judgment values were appropriate.
  • Industrial applicability described in the Japanese Pharmacopoeia 14th Edition. That is, the drug content of each of the 10 tablets obtained in Examples 1 and 2 and Comparative Examples 1 and 2 was measured by high performance liquid chromatography, and the uniformity of each drug content was examined. As a result, all the judgment values were appropriate.
  • the number of steps is particularly increased for tablets having a low drug content in the preparation.
  • a tablet having a uniform drug content can be produced in a short time without using the same, and a tablet having high storage stability can be produced by suppressing the deactivation of the drug at the time of tableting.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Dans un comprimé contenant un médicament ayant une activité pharmacologique élevée en petite quantité, une attention particulière doit être portée à l'homogénétié de son contenu lors de sa préparation. Dans ce cas, il était d'usage de diluer en série une petite quantité du médicament avec une charge pour produire un mélange homogène ou pour dissoudre le médicament dans un solvant, après quoi une granulation humide était effectuée conjointement avec les additifs. Le procédé de dilution en série est néanmoins désavantageux pour ce qui concerne le rendement de production car il se déroule en de nombreuses étapes, alors que dans le procédé de granulation humide on constate un réduction de la teneur en principe actif si l'on utilise un médicament peu stable à l'humidité ou à l'oxygène. On peut produire un comprimé possédant une teneur en médicament homogène en peu de temps sans étapes supplémentaires par la suspension homogène d'un médicament sous la forme d'une poudre fine possédant une taille particulaire moyenne de 1 à 20 νm dans un milieu liquide insoluble contenant un liant, par pulvérisation de la suspension obtenue sur un ou plusieurs additifs pharmaceutiques en cours de fluidisation en vue de l'obtention d'une granulation à lit fluidisé, et par moulage par compression des grains, pour obtenir une teneur en médicament après séchage de 0,1 à 10 % en poids par rapport au comprimé dans son intégralité.
PCT/JP2003/004193 2003-04-01 2003-04-01 Procede de production de comprime WO2004089344A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU2003236336A AU2003236336A1 (en) 2003-04-01 2003-04-01 Process for producing tablet
JP2004570538A JPWO2004089344A1 (ja) 2003-04-01 2003-04-01 錠剤の製造方法
PCT/JP2003/004193 WO2004089344A1 (fr) 2003-04-01 2003-04-01 Procede de production de comprime

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2003/004193 WO2004089344A1 (fr) 2003-04-01 2003-04-01 Procede de production de comprime

Publications (1)

Publication Number Publication Date
WO2004089344A1 true WO2004089344A1 (fr) 2004-10-21

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PCT/JP2003/004193 WO2004089344A1 (fr) 2003-04-01 2003-04-01 Procede de production de comprime

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JP (1) JPWO2004089344A1 (fr)
AU (1) AU2003236336A1 (fr)
WO (1) WO2004089344A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012025683A (ja) * 2010-07-21 2012-02-09 Ohara Yakuhin Kogyo Kk 苦味を有する生理活性物質含有粒子の製造方法
CN102949362A (zh) * 2012-11-27 2013-03-06 西安泰科迈医药科技有限公司 一种含有群多普利的口服固体药物组合物及其制备方法
JP2014129343A (ja) * 2012-11-30 2014-07-10 Ohara Yakuhin Kogyo Kk アリピプラゾール無水物を含有する固形製剤の製造方法
US10188637B2 (en) 2016-03-29 2019-01-29 Hoffmann-La Roche Inc. Granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone and method of making the same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0839526A2 (fr) * 1996-10-31 1998-05-06 Takeda Chemical Industries, Ltd. Préparation pharmaceutique solide à dissolution ou désintégration buccale rapide
EP0914822A1 (fr) * 1996-03-14 1999-05-12 Bayer Aktiengesellschaft Preparation d'ecadotril a microdispersion et liberation rapides
JP2002138034A (ja) * 2000-10-27 2002-05-14 Kyoto Pharmaceutical Industries Ltd 苦味マスキングチュアブル錠およびその製造方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0914822A1 (fr) * 1996-03-14 1999-05-12 Bayer Aktiengesellschaft Preparation d'ecadotril a microdispersion et liberation rapides
EP0839526A2 (fr) * 1996-10-31 1998-05-06 Takeda Chemical Industries, Ltd. Préparation pharmaceutique solide à dissolution ou désintégration buccale rapide
JP2002138034A (ja) * 2000-10-27 2002-05-14 Kyoto Pharmaceutical Industries Ltd 苦味マスキングチュアブル錠およびその製造方法

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012025683A (ja) * 2010-07-21 2012-02-09 Ohara Yakuhin Kogyo Kk 苦味を有する生理活性物質含有粒子の製造方法
CN102949362A (zh) * 2012-11-27 2013-03-06 西安泰科迈医药科技有限公司 一种含有群多普利的口服固体药物组合物及其制备方法
JP2014129343A (ja) * 2012-11-30 2014-07-10 Ohara Yakuhin Kogyo Kk アリピプラゾール無水物を含有する固形製剤の製造方法
JP2016204393A (ja) * 2012-11-30 2016-12-08 大原薬品工業株式会社 アリピプラゾール無水物を含有する固形製剤の製造方法
US10188637B2 (en) 2016-03-29 2019-01-29 Hoffmann-La Roche Inc. Granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone and method of making the same

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Publication number Publication date
JPWO2004089344A1 (ja) 2006-07-06
AU2003236336A1 (en) 2004-11-01

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