WO2004089344A1 - Process for producing tablet - Google Patents

Process for producing tablet 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
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Prior art keywords
drug
tablet
binder
content
weight
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PCT/JP2003/004193
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French (fr)
Japanese (ja)
Inventor
Toshiya Taniguchi
Takao Terai
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Ohara Chmical Industries, Ltd.
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Application filed by Ohara Chmical Industries, Ltd. filed Critical Ohara Chmical Industries, Ltd.
Priority to PCT/JP2003/004193 priority Critical patent/WO2004089344A1/en
Priority to JP2004570538A priority patent/JPWO2004089344A1/en
Priority to AU2003236336A priority patent/AU2003236336A1/en
Publication of WO2004089344A1 publication Critical patent/WO2004089344A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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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Abstract

In a tablet of a drug showing a high pharmacological activity in a small amount, special attention should be paid to the uniformity of its content in the preparation. In such a case, it has been a practice to serially dilute a small amount of the drug with a filler to give a homogeneous mixture or to dissolve the drug in a solvent followed by wet-granulation together with additives. However, the serial dilution method is disadvantageous in production efficiency because of involving many steps, while the wet granulation method frequently suffers from a decrease in the content of the main ingredient in the case of a drug having poor stability to moisture or oxygen. A tablet having a uniform drug content can be produced within a short time without resort to additional steps by uniformly suspending a drug in the form of a fine powder having an average particle size of 1 to 20 μm in a insoluble liquid medium containing a binder, spraying the obtained suspension onto pharmaceutical additive(s) under fluidization to effect fluidized bed granulation, and then compression-molding the grains so as to give a drug content after drying of 0.1 to 10% by weight based on the whole tablet.

Description

明細書 錠剤の製造方法 技術分野  Description Tablet manufacturing method Technical field
本発明は、 少量で薬理活性が高い医薬、 すなわち 1回の投与量が少ない医薬の 含量の均一性と保存性を確保し、 しかも工業的有利に锭剤を製造する方法に関す る。 背景技術  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. Background art
少量で薬理活性が高い医薬の錠剤は、 製剤中の医薬含量が少なく、 その僅かな ばらつきが原因で期待通りの効果が得られなかったり、 不測の副作用が出現する 場合がある。 したがって、 医薬含量が少ない製剤を製造する場合は、 医薬含量の 均一性について特に注意を払う必要があり、 通常、 少量の医薬を賦形剤で倍々希 釈して均一な混合物を得る方法や、 医薬を溶媒に溶解させ、 これを添加剤 （賦形 剤、増量剤などを含む。） に加えて湿式造粒する方法等がとられている。 し力 し、 前記の倍々希釈する方法は、製剤工程数が多く生産効率の点で問題がある。また、 湿気や酸素に対して安定性に問題がある医薬の場合、一旦溶液にして湿式造粒し、 顆粒ないし錠剤とする方法では、 主薬の活性低下が生じ易い。  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. There is a method of dissolving a drug in a solvent, adding it to additives (including excipients, extenders, etc.) and performing wet granulation. However, the above-mentioned double dilution method involves a large number of formulation steps and has a problem in production efficiency. In addition, in the case of a drug having a problem in stability against moisture and oxygen, 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.
本発明の課題は、 製剤中の医薬含量が少ない錠剤を製造するに当たり、 特別に 工程数を増やすことなく医薬含量が均一な錠剤を短時間に製造することができ、 しかも製剤化時及び製造後も医薬を安定に保持できる錠剤の製造方法を提供する ことにある。 発明の開示  It is an object of the present invention to provide a tablet having a low drug content in a pharmaceutical preparation, in which a tablet having a uniform drug content can be manufactured in a short time without increasing the number of steps, and at the time of formulation and after the manufacture. Another object of the present invention is to provide a method for producing a tablet which can stably hold a medicine. Disclosure of the invention
本発明者等は、 前記課題を解決するため鋭意検討した結果、 微粉末状医薬を結 合剤を溶解した不溶性溶媒に懸濁させ、 その懸濁液を流動化させている製剤上の 添加物に噴霧して造粒し、 乾燥後、 圧縮成形すると、 医薬含量の均一性の点、 医 薬の安定保存の点並びに打錠時の医薬の失活抑制の点でも優れた錠剤が得られる ことを見出し、 更に研究を重ねて本発明を完成するに到った。 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.
すなわち本発明は、  That is, the present invention
1 . 平均粒子径が 1〜 2 0 μ mの微粉末状医薬を不溶性の液体媒体中に均一に懸 濁させ、 得られた懸濁液を流動化している製剤上の添加物に噴霧して流動層造粒 し、 乾燥後医薬の割合が錠剤全体に対し 0 . 1〜 1 0重量％となるように圧縮成 形する錠剤の製造法、  1. A fine-powder drug having an average particle size of 1 to 20 μm 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,
2 . 懸濁液が結合剤を含有する請求項 1記載の製造法、  2. The method according to claim 1, wherein the suspension contains a binder.
3 . 結合剤の懸濁液に対する割合が 1〜 3 0重量％である請求項 1記載の製造法 3. The process according to claim 1, wherein the ratio of the binder to the suspension is 1 to 30% by weight.
4 . 製剤上の添加物が賦形剤と結合剤を含有する請求項 1記載の製造法、4. The method according to claim 1, wherein the additive in the formulation contains an excipient and a binder.
5 . 結合剤の製剤上の添加物に対する割合が 1〜： L 5重量％である請求項 1記載 の製造法、 5. The method according to claim 1, wherein the ratio of the binder to the additive in the preparation is 1 to: L 5% by weight.
6 . 結合剤の医薬に対する割合が 1 0 0〜 1 0 0 0重量％である請求項 1記載の 製造法、 および  6. The method according to claim 1, wherein the ratio of the binder to the drug is from 100 to 100% by weight, and
7 . 医薬が、 トランドラプリル、 ぺリンドプリル、 ェチゾラムまたはブチゾラム であり、 液体媒体が水である請求項 1記載の製造法、  7. The method according to claim 1, wherein the medicament is trandolapril, perindopril, etizolam or butizolam, and the liquid medium is water.
である。 It is.
本発明で用いられる医薬は、 前記のほか、 室温で固体であり、 少量で薬理活性 が高く、 したがって微量の投与量で効果を示し、 湿式造粒の際に使用される溶媒 に難溶であれば、 特に限定されない。 その医薬の微粉末の平均粒子経は、 1〜2 0 μ m であるが、 好ましくは 2〜 1 5 μ m、 より好ましくは 3〜1 0 μ mであ る。  In addition to the above, 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. There is no particular limitation. The average particle size of the fine powder of the medicament is from 1 to 20 µm, preferably from 2 to 15 µm, more preferably from 3 to 10 µm.
錠剤に占める医薬の割合は、 0 . 1〜1 O w/w %である力 S、好ましくは、 0 . 2〜5 w/w %である。  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%.
前記不溶性の溶媒としては、 製剤の際に通常用いられている水やエタノール、 塩化メチレン等の有機溶媒が挙げられるが、 本発明においては医薬を実質的に溶 解しなレ、溶媒が選択される。  Examples of the insoluble solvent include organic solvents such as water, ethanol, and methylene chloride that are usually used in the preparation. In the present invention, a solvent that does not substantially dissolve the drug is selected. You.
本発明に用いられる製剤上の添加剤には、 賦形剤、 増量剤、 崩壊剤、 結合剤、 滑沢剤等が含まれる。  The additives in the formulation used in the present invention include excipients, extenders, disintegrants, binders, lubricants and the like.
賦形剤又は増量剤としては、 たとえば、 乳糖、 白糖、 トウモロコシデンプン、 結晶セルロース等が挙げられ、 中でも乳糖や結晶セルロースが好ましい。 Excipients or fillers include, for example, lactose, sucrose, corn starch, Examples include crystalline cellulose, and among them, lactose and crystalline cellulose are preferable.
崩壊剤としては、 カルボキシメチルセルロース、 カルボキシメチルセルロース カルシウム、 クロスカルメロースナトリウム、 カルポキシメチルスターチナトリ ゥム、 クロスポビドン、 低置換度ヒドロキシプロピルセルロース、 部分アルファ 一化デンプン、 トゥモロコシデンプン等が使用できる。  Examples of the disintegrant include carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropylcellulose, partial alpha imidized starch, and corn starch.
結合剤としては、 ポリビュルピロリ ドン、 ェチルセルロース、 ヒドロキシプロ ピルセルロース、 ヒドロキシプロピルメチルセルロース、 プルラン、 部分アルフ ァー化デンプン、 アルファ一化デンプン、 マクロゴ一ノレ 6 0 0 0等が挙げられ、 それらの混合物も好適に使用される。  Examples of the binder include polyvinylpyrrolidone, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, partially alpha-starched starch, alpha-mono-starch, macro-gloss mono-sodium, and the like. Are also preferably used.
滑沢剤としては、 ステアリン酸マグネシウム、 ステアリン酸カルシウム、 ステ アリン酸、 タルク、 硬化油、 ショ糖脂肪酸エステル等が挙げられる。  Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, talc, hydrogenated oil, sucrose fatty acid ester and the like.
必要に応じて矯味、 矯臭、 着色剤、 その他の添加剤を加えてもよい。  Flavoring, flavoring, coloring and other additives may be added as needed.
流動層造粒法は、 流動層造粒装置内の粉末 (核粒子) の充填層の下から空気を 送入し、 粉末が空気流に浮遊、 分散している状態、 つまり流動層を形成させ、 そ の流動層に結合剤を含む噴霧液をスプレーノズルから噴霧して粒子を相互に付着 凝集させて粒子を成長させる方法である。  In 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.
流動層造粒装置には操作上の分類から回分式、 半連続式、 連続式などが、 また スプレーノズルの位置や噴霧方向により、 流動層型、 噴流流動層型、 噴流層型な どに分類されるが、 本発明においてはレ、ずれの装置も使用可能である。  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. However, in the present invention, a device for misalignment can be used.
本発明方法において用いられる核粒子粉末は、 通常賦形剤であり、 その平均粒 子経は 2 0〜 2 0 0 μ m程度のものが好ましい。 嘖霧液量は、 重量割合で仕込粉 末の 1 Z 1 0 ~ 2倍量、 好ましくは 1 / 7〜1倍量である。 医薬粉末は噴霧液中 に均一に懸濁される。  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 μm. 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.
結合剤は、 噴霧液中に溶解させてもよく、 また、 流動層を形成させる粉末の中 に加えてもよく、 その両者でもよい。 結合剤の使用割合は、 医薬に対して 1 0 0 〜 1 0 0 0重量％、 好ましくは 2 0 0〜 7 0 0重量％である。 嘖霧液中または核 粒子粉末中の結合剤の使用割合は、 1〜 3 0重量％、 好ましくは 2〜 2 5重量％ である。  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.
流動層造粒装置の吸気温度は 5 0〜 1 0 0 °C、 好ましくは 6 0〜 9 0 °Cで、 排 気温度が 2 0〜 6 0 °C、 好ましくは 2 5〜 4 0 °Cとなるよう吸気温度、 噴霧液の 嘖霧速度及び送風量を調節するのがよい。 噴霧時間は、 原料粉末の仕込量、 噴霧 速度 （量） によっても異なってくるが、 通常 2 0〜1 2 0分で終了する。 嘖霧が 終了すれば 5〜3 0分程度吸気を続けて乾燥すると乾燥造粒物が得らる。 得られ た造粒物の平均粒子経は 5 0 ~ 5 0 0 μ m程度である。 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 μm.
この造粒物に、 必要によりさらに賦形剤、 崩壊剤や滑沢剤を適宜混合し、 常法 に従って圧縮打錠する。  If necessary, 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.
本発明の錠剤は、 通常の方法、 例えば第十四改正日本薬局方の製剤総則に記載 されている方法により、 容易に製造できる。  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.
なお、 得られた錠剤は、 任意にコーティングされてもよい。 ' 本発明を実施するための最良の形態  In addition, the obtained tablet may be optionally coated. '' Best mode for carrying out the present invention
以下に実施例を挙げて本発明をさらに詳しく説明するが、 本発明はこれらに限 定されるものではない。 実施例 1  Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. Example 1
乳糖 3 1 9 5 g、 ポリビュルピロリ ドン 9 0 gおよび部分アルファ一化デンプ ン 1 5 0 gを混合して流動層造粒機 （F D— 5 S、 バウレック社製) に投入し、 流動層を形成させた。 精製水 6 9 O m Lとポリビュルピロリ ドン 6 0 gからなる 溶液に平均粒子経 8 μ mのトランドラプリル粉末 3 0 gを均一に分散させた懸濁 液を調製し、 この液を 4 0 g /分の速度で流動層中に噴霧した。 造粒機への吸気 温度が 6 0 °C、 排気温度が 2 5〜 3 0 °Cとなるよう空気の温度と送風量を調節し た。 噴霧終了後、 5分間送風乾燥し、 造粒物を得た。  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). Was formed. 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 μm 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.
得られた造粒物を 2 4メッシュの J I S標準篩で篩過して整粒末を得た。 この 整粒末に、 硬化油 7 5 gを加え、 タンブラ一混合機 （TM— 1 5 S、 昭和技研株 式会社製） を用いて均一に混合し、 回転式打錠機で圧縮成型して次の組成を有す る錠剤を得た。  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.
〔成 分〕 〔1錠当たりの重量 （m g )〕 トランドラプリノレ 1. 0 [Component] [Weight per tablet (mg)] Trandra Purinole 1.0
乳糖 106. 5  Lactose 106.5
ポリビエルピロリ ドン 5. 0  Polyvierpyrrolidone 5.0
部分アルファ一化デンプン 5. 0  Partial alpha mono-starch 5.0
硬化油 2. 5  Hardened oil 2.5
合 計 120. 0 実施例 2  Total 120.0 Example 2
実施例 1と同様にして、 乳糖 3300 g、 結晶セルロース 2100 gおよびト ゥモロコシデンプン 600 gを混合して流動層造粒機に投入し、 流動層を形成さ せた。 次いで、 精製水 1800mLとマクロゴール 6000の 1 20 gからなる 溶液に平均粒子径 6 μιηのェチゾラム粉末 60 gを加えて均一に分散させた液を 調製し、 この液を 100 g/分の速度で流動層中に噴霧して、 造粒した。 得られ た造粒物を、 乾燥後、 30メッシュの J I S標準篩で篩過し、 整粒末を得た。 こ の整粒末にカルボキシメチルセルロースカルシウム 300 gおよびステアリン酸 マグネシウム 120 gを加え、 タンブラ一混合機を用いて均一に混合し、 回転式 打錠機で圧縮成形して下記組成の錠剤を得た。  In the same manner as in Example 1, 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. Next, 60 g of etizolam powder with an average particle size of 6 μιη 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.
〔成 分〕 〔1錠当たりの重量 (m g )] [Ingredient] [Weight per tablet (mg)]
ェチゾラム 1. 0  Etizolam 1.0
乳糖 55. 0  Lactose 55. 0
結晶セルロース 35. 0  Microcrystalline cellulose 35.0
トゥモロコシデンプン 10. 0  Tumor starch 10.0
マク口ゴーノレ 6000 2. 0  Mc mouth gonorre 6000 2.0
カノレボキシメチノレセノレロース,カノレシゥム 5. 0  Canoleboximetinoresenorelose, canolesome 5.0
ステアリン酸マグネシゥム 2. 0  Magnesium stearate 2.0
き + 1 10. 0 比較例 1 乳糖 3195 g、 ポリビニルピロリ ドン 150 gおよび部分アルファ一化デン プン 150 gを高速撹拌造粒機 （バーチカルグラ二ユレータ、 FM— VG— 10 パゥレック社製） に投入し、 290/r pmで攪拌混合した。 次いで、 ェチル アルコール 900mLにトランドラプリル粉末 30 gを溶解した液を加えて造粒 した。 得られた造粒物を、 乾燥後、 30メッシュの J I S標準篩で篩過して整粒 末を得た。 +1 10.0 Comparative Example 1 3195 g of lactose, 150 g of polyvinylpyrrolidone and 150 g of partially alpha-starched starch are charged into a high-speed stirring granulator (vertical granulator, FM-VG-10, manufactured by Parec) and mixed at 290 / rpm. did. Next, a solution prepared by dissolving 30 g of trandolapril powder in 900 mL of ethyl alcohol was added and granulated. The obtained granules were dried and sieved with a 30-mesh JIS standard sieve to obtain sized powder.
この整粒末に硬化油 75 gを加え、 タンブラ一混合機を用いて均一に混合し、 回 転打錠機で圧縮成型して下記組成の錠剤を得た。 75 g of hardened oil was 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.
〔成 分〕 錠当たりの重量 （mg)〕 [Ingredient] Weight per tablet (mg)]
1. 0  Ten
乳糖 106. 5  Lactose 106.5
ポリビュルピロリ ドン 5. 0  Polypyrrolidone 5.0
部分アルファ 5. 0  Partial Alpha 5.0
硬化油 2. 5  Hardened oil 2.5
π PI- 比較例 2  π PI- Comparative Example 2
比較例 1と同様の方法により、 乳糖 1650 g、 結晶セルロース 1050 gお よびトウモロコシデンプン 300 gを高速攪拌造粒機に投入し、 攪拌混合した。 次いで、 エチルアルコール 90 OmLにェチゾラム 30 gを溶解した液を加えて 造粒した。 得られた造粒物を、 乾燥後、 30メッシュの J I S標準篩で篩過し、 整粒末を得た。 この整粒末にカルボキシメチルセルロースカルシウム 1 50 gお よびステアリン酸マグネシウム 60 gを加え、 タンブラー混合機を用いて均一に 混合し、 回転式打錠機で圧縮成形して下記組成の錠剤を得た。
Figure imgf000007_0001
錠当たりの重量 （mg)〕 In the same manner as in Comparative Example 1, l650 g of lactose, 1050 g of crystalline cellulose, and 300 g of corn starch were charged into a high-speed stirring granulator and mixed by stirring. Next, a solution prepared by dissolving 30 g of etizolam in 90 OmL of ethyl alcohol was added and granulated. After the obtained granules were dried, they were sieved with a 30-mesh JIS standard sieve to obtain sized powder. 150 g of carboxymethylcellulose calcium and 60 g of magnesium stearate were added to the sized powder, uniformly mixed using a tumbler mixer, and compression-molded with a rotary tableting machine to obtain tablets having the following composition.
Figure imgf000007_0001
Weight per tablet (mg)]
ェ 1. 0  1.0
55. 0 結晶セルロース 35. 0 55. 0 Microcrystalline cellulose 35.0
トウモロコシデンプン 1 0. 0  Corn starch 1 0.0
マク口ゴーノレ 6000 2. 0  Mc mouth gonorre 6000 2.0
カノレポキシメチノレセノレロースカノ 1ハンゥム 5. 0  Canolepoxy methino-reseno-reroscano 1 hand 5.0
ステアリン酸マグネシウム 2. 0  Magnesium stearate 2.0
σ p I- 11 0. 0 試験例 1 (苛酷試験による製剤の保存安定性比較）  σ p I- 11 0.0 Test Example 1 (Comparison of storage stability of drug product by severe test)
実施例 1および 2並びに比較例 1および 2で得た各錠剤を、 温度 60 °C、 湿度 75%で密封保存およびシャーレ中開放保存し、 10 S後に各錠剤の医薬残存量 を高速液体ク口マトグラフ法により測定した。 なお、 定量は内標準法によつた。 結果 （医薬の初期値に対する残存値の百分率） は下記のとおりである。  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.
密封保存 シャーレ中開放保存  Sealed storage Open storage in petri dish
実施例 1 97. 0% 95. 7%  Example 1 97.0% 95.7%
比較例 1 91. 5% 80. 5%  Comparative Example 1 91.5% 80.5%
実施例 2 98. 6% 97. 2%  Example 2 98.6% 97.2%
比較例 2 96. 1 % 93. 7% この結果から、 本発明の実施例 1および 2の錠剤は、 医薬の安定化効果の点で 対応する比較例 1および 2より、 それぞれ優れていることが判明した。 試験例 2 (含量均一性試験）  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)
試験は、 第十四改正日本薬局方に記載の 「12. 含量均一性試験法」 に準拠し た。 すなわち、 実施例 1および 2並びに比較例 1および 2で得た各錠剤 10個づ つについて医薬含量を高速液体クロマトグラフ法により測定し、 各医薬含量の均 一性を調べた。 その結果、 判定値は何れも適合であった。 産業上の利用可能性  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
： 本発明によれば、 製剤中の医薬含量が少ない錠剤に関し、 特別に工程数を増や すことなく且つ短時間で医薬含量が均一な錠剤を製造することができ、 しかも打 錠時の医薬の失活を抑制し、 高い保存安定性を有する錠剤が製造できる。 According to the present invention, 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.

Claims

請求の範囲 The scope of the claims
1 . 平均粒子径が 1〜 2 0 mの微粉末状医薬を不溶性の液体媒体中に均一に懸 濁させ、 得られた懸濁液を流動化している製剤上の添加物に噴霧して流動層造粒 し、 乾燥後医薬の割合が錠剤全体に対し 0 . 1〜1 0重量％となるように圧縮成 形する錠剤の製造法。 1. A fine powdered drug having an average particle size of 1 to 20 m is uniformly suspended in an insoluble liquid medium, and the obtained suspension is sprayed onto a fluidized formulation additive to flow. A method for producing tablets, which comprises layer granulation and, after drying, compression-molding so that the ratio of the drug is 0.1 to 10% by weight based on the whole tablet.
2 . 懸濁液が結合剤を含有する請求の範囲第 1項記載の製造法。  2. The method according to claim 1, wherein the suspension contains a binder.
3 . 結合剤の懸濁液に対する割合が 1〜 1 5重量％である請求の範囲第 1項記載 の製造法。  3. The process according to claim 1, wherein the ratio of the binder to the suspension is 1 to 15% by weight.
4 .製剤上の添加物が賦形剤と結合剤を含有する請求の範囲第 1項記載の製造法。 4. The production method according to claim 1, wherein the additive in the formulation contains an excipient and a binder.
5 . 結合剤の製剤上の添加物に対する割合が 1〜 1 5重量％である請求の範囲第 1項記載の製造法。 5. The method according to claim 1, wherein the ratio of the binder to the additive in the preparation is 1 to 15% by weight.
6 . 結合剤の医薬に対する割合が 1 0 0〜1 0 0 0重量％である請求の範囲第 1 項記載の製造法。  6. The method according to claim 1, wherein the ratio of the binder to the drug is from 100 to 100% by weight.
7 . 医薬が、 トランドラプリル、 ぺリンドプリル、 ェチゾラムまたはプチゾラム であり、 液体媒体が水である請求の範囲第 1項請求の範囲第 1項記載の製造法。  7. The method according to claim 1, wherein the medicament is trandolapril, perindopril, etizolam, or petizolam, and the liquid medium is water.
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JP2012025683A (en) * 2010-07-21 2012-02-09 Ohara Yakuhin Kogyo Kk Method for producing physiologically active substance-containing particle having bitterness
CN102949362A (en) * 2012-11-27 2013-03-06 西安泰科迈医药科技有限公司 Orally-taken solid medicinal composition containing trandolapril and preparation method thereof
JP2014129343A (en) * 2012-11-30 2014-07-10 Ohara Yakuhin Kogyo Kk Production method of solid preparation comprising aripiprazole anhydride
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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EP0839526A2 (en) * 1996-10-31 1998-05-06 Takeda Chemical Industries, Ltd. Solid pharmaceutical preparation with fast buccal disintegration or dissolution
EP0914822A1 (en) * 1996-03-14 1999-05-12 Bayer Aktiengesellschaft Rapid-release microdispersible ecadotril preparation
JP2002138034A (en) * 2000-10-27 2002-05-14 Kyoto Pharmaceutical Industries Ltd Bitter taste masked chewable tablet and preparation method of the same

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EP0914822A1 (en) * 1996-03-14 1999-05-12 Bayer Aktiengesellschaft Rapid-release microdispersible ecadotril preparation
EP0839526A2 (en) * 1996-10-31 1998-05-06 Takeda Chemical Industries, Ltd. Solid pharmaceutical preparation with fast buccal disintegration or dissolution
JP2002138034A (en) * 2000-10-27 2002-05-14 Kyoto Pharmaceutical Industries Ltd Bitter taste masked chewable tablet and preparation method of the same

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012025683A (en) * 2010-07-21 2012-02-09 Ohara Yakuhin Kogyo Kk Method for producing physiologically active substance-containing particle having bitterness
CN102949362A (en) * 2012-11-27 2013-03-06 西安泰科迈医药科技有限公司 Orally-taken solid medicinal composition containing trandolapril and preparation method thereof
JP2014129343A (en) * 2012-11-30 2014-07-10 Ohara Yakuhin Kogyo Kk Production method of solid preparation comprising aripiprazole anhydride
JP2016204393A (en) * 2012-11-30 2016-12-08 大原薬品工業株式会社 Production method of solid preparation comprising aripiprazole anhydride
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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