JP5204976B2 - Fast disintegrating tablets containing iguratimod - Google Patents
Fast disintegrating tablets containing iguratimod Download PDFInfo
- Publication number
- JP5204976B2 JP5204976B2 JP2007016185A JP2007016185A JP5204976B2 JP 5204976 B2 JP5204976 B2 JP 5204976B2 JP 2007016185 A JP2007016185 A JP 2007016185A JP 2007016185 A JP2007016185 A JP 2007016185A JP 5204976 B2 JP5204976 B2 JP 5204976B2
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- JP
- Japan
- Prior art keywords
- iguratimod
- tablet
- disintegrating tablet
- mixed
- powder
- Prior art date
- Legal status (The legal status 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 status listed.)
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- 229950003909 iguratimod Drugs 0.000 title claims description 67
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- 150000001720 carbohydrates Chemical class 0.000 claims description 13
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
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- 239000008274 jelly Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000010501 lemon oil Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
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- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
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- 229940085605 saccharin sodium Drugs 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
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- 239000000892 thaumatin Substances 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
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Images
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- Pyrane Compounds (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、（１）糖類および糖アルコール類から選ばれる物質、（２）崩壊剤ならびに（３）イグラチモドを含有することを特徴とする速崩壊性錠剤に関する。 The present invention relates to a rapidly disintegrating tablet comprising (1) a substance selected from sugars and sugar alcohols, (2) a disintegrant and (3) iguratimod.
これまでに、服用しやすい薬剤形として、口腔内で迅速に崩壊する速崩壊性錠剤の開発が進められている。薬剤を速崩壊性錠剤とすることで、様々なメリットが生まれる。たとえば、嚥下困難な患者、高齢者および小児にとって、速崩壊性錠剤は、容易にかつ安全に服用することができる錠剤である。睡眠導入剤では、横になったままリラックスした状態で、服用することができ、降圧剤では、急に血圧が上がって気分が悪くなった際、すぐに何処でも服用できる（非特許文献１）。 So far, fast-disintegrating tablets that rapidly disintegrate in the oral cavity have been developed as drug forms that are easy to take. Various merit is born by making a medicine into a fast disintegrating tablet. For example, for patients with difficulty swallowing, the elderly and children, fast disintegrating tablets are tablets that can be easily and safely taken. With a sleep-inducing agent, it can be taken in a relaxed state while lying down, and with an antihypertensive agent, when blood pressure suddenly rises and makes you feel sick (Non-Patent Document 1) .
このような速崩壊性錠剤の製造法としては、薬物および糖類を寒天水溶液に懸濁し、予め成型されたＰＴＰ（Press Through Package）のポケットに充填し、ゼリー状に固化させた後、乾燥することにより錠剤を得る製造法が知られている（特許文献１）。しかし、この方法では、特殊な製造設備が必要であり、得られる錠剤の硬度は十分なものではなかった。また、薬物、水溶性結合剤および水溶性賦形剤を含む混合物を低圧力で打錠後、加湿し、乾燥させる方法が知られている（特許文献２）。しかし、この方法は、特殊な製造設備が必要であり、製造工程が煩雑になるなどの欠点があった。
一方、崩壊性に優れるが成形性の低い糖類または糖アルコール類を崩壊性に劣るが成形性の高い糖類または糖アルコール類を用いて造粒後、この造粒物を通常の打錠機で圧縮成形して速崩壊性錠剤を製造する方法が知られている（特許文献３）。しかし、この方法により得られる錠剤の硬度は、通常の経口用医薬錠剤よりも小さく、錠剤硬度をさらに高めることが望まれている。
As a method for producing such a fast disintegrating tablet, a drug and a saccharide are suspended in an agar aqueous solution, filled in a pre-formed PTP (Press Through Package) pocket, solidified in a jelly shape, and then dried. The manufacturing method which obtains a tablet by this is known (patent document 1). However, this method requires special production equipment, and the hardness of the resulting tablet is not sufficient. In addition, a method is known in which a mixture containing a drug, a water-soluble binder, and a water-soluble excipient is tableted at low pressure, and then humidified and dried (Patent Document 2). However, this method has the disadvantages that a special manufacturing facility is required and the manufacturing process becomes complicated.
On the other hand, after granulating saccharides or sugar alcohols with excellent disintegrability but poor moldability but with poor disintegrability but with high moldability, this granulated product is compressed with a normal tablet press. A method for producing a rapidly disintegrating tablet by molding is known (Patent Document 3). However, the hardness of the tablet obtained by this method is smaller than that of a normal oral pharmaceutical tablet, and it is desired to further increase the tablet hardness.
速崩壊性錠剤は、通常の錠剤と異なり、錠剤のサイズを大きくしても服用性が損なわれることがない。錠剤を意図的に大きくすることで、服用性ならびに、たとえばＰＴＰ包装からの取り出し易さおよび錠剤の摘み易さといった取扱性を同時に改善することができる（非特許文献２）。たとえば、関節リウマチ患者に投与される抗関節リウマチ剤および消炎鎮痛剤などは、速崩壊性錠剤のサイズを大きくすることで、優れた服用性を維持しながら、取扱性を改善し、指先が不自由な患者の服薬コンプライアンスを格段に向上させる。 Unlike a normal tablet, a rapidly disintegrating tablet does not impair the ingestibility even if the tablet size is increased. By intentionally increasing the size of the tablet, it is possible to simultaneously improve the ingestibility and handling properties such as ease of taking out from the PTP package and ease of picking the tablet (Non-patent Document 2). For example, anti-rheumatoid arthritis drugs and anti-inflammatory analgesics administered to patients with rheumatoid arthritis increase the size of fast-disintegrating tablets, improving the handleability and improving the fingertips. Significantly improve compliance of free patients.
通常、錠剤の服用性を向上させるためには、速やかな崩壊性が必要である。一方、錠剤には、製造から服用までの間に壊れない程度の硬度が必要である。しかしながら、崩壊性および硬度は、通常相反する。そのため、速やかな崩壊性と取り扱いに十分な硬度を同時に満たす錠剤を通常の製造法で製造することは、困難である。 Usually, rapid disintegration is necessary to improve the dosage of tablets. On the other hand, tablets need to have a hardness that does not break between manufacture and administration. However, disintegration and hardness are usually in conflict. For this reason, it is difficult to produce a tablet that simultaneously satisfies rapid disintegration and hardness sufficient for handling by a normal production method.
イグラチモド（Ｎ−（７−（（メタンスルホニル）アミノ）−４−オキソ−６−フェノキシ−４Ｈ−１−ベンゾピラン−３−イル）ホルムアミド）は、抗リウマチ剤として開発されている薬剤である（特許文献４）。これまで、イグラチモドの速崩壊性錠剤は、知られていない。
口腔内の唾液または少量の水の存在下において、速やかに崩壊する優れた服用性を有し、かつ取り扱いに十分な硬度を有し、さらに、通常の製造設備で製造できるイグラチモドを含有する速崩壊性錠剤が強く望まれている。 Fast disintegration containing iguratimod, which has excellent dosing properties that disintegrate rapidly in the presence of saliva or a small amount of water in the oral cavity, has sufficient hardness for handling, and can be manufactured with ordinary manufacturing equipment Sex tablets are highly desired.
このような状況下において、本発明者らは、関節リウマチ患者に投与される抗リウマチ作用を有する化合物または消炎鎮痛作用を有する化合物を含有する速崩壊性錠剤について鋭意検討した結果、驚くべきことに、糖類および糖アルコール類から選ばれる物質ならびに崩壊剤に抗リウマチ剤であるイグラチモドを組み合わせることにより、活性成分であるイグラチモドが高い成形性向上能力を発揮し、イグラチモドを含まない錠剤に比べて速やかな崩壊性を保つにもかかわらず、硬度が飛躍的に高まることを見出した。さらに、通常の製造設備で、優れた速崩壊性錠剤が製造できることを見出し、本発明を完成した。 Under such circumstances, the present inventors have surprisingly studied as a result of diligent research on a fast disintegrating tablet containing a compound having an anti-rheumatic action or an anti-inflammatory analgesic action administered to a patient with rheumatoid arthritis. By combining igratetimo, an anti-rheumatic agent, with a substance selected from saccharides and sugar alcohols and a disintegrant, the active ingredient iguratimod exhibits a high moldability-improving ability and is quicker than tablets containing no iguratimod. It has been found that the hardness increases dramatically despite maintaining disintegration. Furthermore, the present invention was completed by finding that an excellent quick disintegrating tablet can be produced with ordinary production equipment.
本発明で得られる（１）糖類および糖アルコール類から選ばれる物質、（２）崩壊剤ならびに（３）イグラチモドを含有することを特徴とする速崩壊性錠剤は、通常の製造法で製造でき、しかも取り扱いに十分耐える非常に高い硬度を有する。また、本発明の錠剤は、大きな錠剤に成形しても口腔内で速やかに崩壊し、患者の取扱性および服用性に優れている。本発明の速崩壊性錠剤は、手指の動きが不自由なリウマチ患者、薬剤の嚥下が困難な患者、高齢者および小児にとって、取扱性および服用性を同時に満たす錠剤である。
本発明の錠剤は、一般に用いられる製造設備を用いて製造することができ、特別な工程が不要である。さらに、本発明の錠剤は、長期間の保存、安定性にも優れている。またイグラチモドは、口腔内で苦味などの不快な味を示さず、たとえば、苦味マスキングのためにイグラチモドにコーティングを施すといった必要もない。
A rapidly disintegrating tablet characterized by containing (1) a substance selected from saccharides and sugar alcohols obtained in the present invention, (2) a disintegrant and (3) iguratimod can be produced by an ordinary production method, Moreover, it has a very high hardness enough to withstand handling. Moreover, the tablet of this invention disintegrates rapidly in the oral cavity even if it is formed into a large tablet, and is excellent in patient handling and administration. The rapidly disintegrating tablet of the present invention is a tablet that simultaneously satisfies handling and administration for rheumatic patients who have difficulty in hand movement, patients who have difficulty swallowing drugs, elderly people and children.
The tablet of this invention can be manufactured using the manufacturing equipment generally used, and a special process is unnecessary. Furthermore, the tablet of the present invention is excellent in long-term storage and stability. Also, iguratimod does not show an unpleasant taste such as bitterness in the oral cavity, and it is not necessary to coat iguratimod for bitterness masking, for example.
以下、発明について詳述する。なお、本明細書中の％は、重量％を示す。
本発明は、（１）糖類および糖アルコール類から選ばれる物質、（２）崩壊剤ならびに（３）イグラチモドを含有する速崩壊性錠剤を開示する。本発明の錠剤は、取り扱いやすく、かつ、服用容易な速崩壊性錠剤であり、好ましい形態は、口腔内速崩壊性錠剤である。
本発明における「口腔内速崩壊性錠剤」とは、口腔内で速やかに、たとえば、30秒以内で、好ましくは25秒以内で、より好ましくは20秒以内で崩壊し得るものである。
本発明の錠剤の大きさは、特に限定されないが、たとえば、円形錠であれば錠剤径が8mm以上であることが好ましい。錠剤の硬度は、形状や大きさにより特に限定されないが、たとえば、扱いやすい大きな錠剤とする場合は、50N以上であることが好ましい。錠剤中のイグラチモドの含率は、0.5〜40％であればよく、好ましくは1〜30％、より好ましくは1.7〜17％である。
The invention will be described in detail below. In addition,% in this specification shows weight%.
The present invention discloses a fast disintegrating tablet containing (1) a substance selected from saccharides and sugar alcohols, (2) a disintegrating agent, and (3) iguratimod. The tablet of the present invention is a fast disintegrating tablet that is easy to handle and easy to take, and a preferred form is an intraoral quick disintegrating tablet.
The “orally disintegrating tablet in the oral cavity” in the present invention is capable of disintegrating rapidly in the oral cavity, for example, within 30 seconds, preferably within 25 seconds, more preferably within 20 seconds.
The size of the tablet of the present invention is not particularly limited. For example, in the case of a round tablet, the tablet diameter is preferably 8 mm or more. The hardness of the tablet is not particularly limited depending on the shape and size. For example, in the case of a large tablet that is easy to handle, it is preferably 50 N or more. The content of iguratimod in the tablet may be 0.5 to 40%, preferably 1 to 30%, more preferably 1.7 to 17%.
本発明で用いられる糖類としては、乳糖、ブドウ糖、果糖、ショ糖およびトレハロースなどが挙げられる。好ましい糖類としては、乳糖が挙げられる。本発明で用いられる糖アルコール類としては、Ｄ−マンニトール、エリスリトール、キシリトール、マルチトールおよびＤ−ソルビトールなどが挙げられる。好ましい糖アルコール類としては、Ｄ−マンニトールおよびエリスリトールが挙げられ、Ｄ−マンニトールがさらに好ましい。
糖類および糖アルコール類は、それぞれ１種または２種以上を使用してもよい。その使用量は、錠剤に対して30〜95％、好ましくは40〜90％である。
Examples of the saccharide used in the present invention include lactose, glucose, fructose, sucrose, and trehalose. Preferable sugars include lactose. Examples of sugar alcohols used in the present invention include D-mannitol, erythritol, xylitol, maltitol, D-sorbitol and the like. Preferred sugar alcohols include D-mannitol and erythritol, with D-mannitol being more preferred.
One type or two or more types of saccharides and sugar alcohols may be used. The amount used is 30 to 95%, preferably 40 to 90%, based on the tablet.
崩壊剤としては、カルメロースカルシウム、カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、ヒドロキシプロピルスターチ、クロスポビドン、結晶セルロース、粉末セルロース、低置換度ヒドロキシプロピルセルロースおよびカルメロースなどが挙げられる。崩壊剤は、１種または２種以上を使用してもよい。好ましい崩壊剤としては、クロスカルメロースナトリウム、クロスポビドン、結晶セルロース、低置換度ヒドロキシプロピルセルロースおよびカルメロースが挙げられ、より好ましくはクロスポビドンおよびカルメロースが挙げられ、さらに好ましくはクロスポビドンが挙げられる。
崩壊剤を組み合わせて使用する場合は、好ましくは、結晶セルロースおよび粉末セルロースなどのセルロース系の崩壊剤ならびにクロスポビドンの組み合わせが挙げられ、より好ましくは、クロスポビドンおよび結晶セルロースの組み合わせが挙げられる。
その使用量は、錠剤に対して0.5〜50％、好ましくは1〜40％である。
Examples of the disintegrant include carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, hydroxypropyl starch, crospovidone, crystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, and carmellose. You may use 1 type (s) or 2 or more types for a disintegrating agent. Preferred disintegrants include croscarmellose sodium, crospovidone, crystalline cellulose, low-substituted hydroxypropylcellulose and carmellose, more preferably crospovidone and carmellose, more preferably crospovidone.
In the case of using a combination of disintegrants, a cellulose-based disintegrant such as crystalline cellulose and powdered cellulose and a combination of crospovidone are preferable, and a combination of crospovidone and crystalline cellulose is more preferable.
The amount used is 0.5 to 50%, preferably 1 to 40%, based on the tablet.
その他、本発明の錠剤は、通常の製剤の製造に用いられる種々の添加剤を適量含んでもよい。このような添加剤としては、たとえば、賦形剤、結合剤、酸味剤、発泡剤、甘味料、香料、流動化剤、滑沢剤および着色剤などが挙げられる。 In addition, the tablet of the present invention may contain appropriate amounts of various additives used in the production of ordinary preparations. Examples of such additives include excipients, binders, sour agents, foaming agents, sweeteners, fragrances, fluidizing agents, lubricants, and coloring agents.
賦形剤としては、有機の賦形剤および無機の賦形剤が挙げられる。有機の賦形剤としては、たとえば、トウモロコシデンプン、馬鈴薯デンプン、コムギデンプン、コメデンプン、部分アルファー化デンプン、アルファー化デンプンおよび有孔デンプンなどのデンプン類などが挙げられる。無機の賦形剤としては、たとえば、無水リン酸カルシウム、沈降炭酸カルシウムおよびケイ酸カルシウムなどが挙げられる。結合剤としては、たとえば、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、ポリビニルピロリドン、アラビアゴム末、ゼラチンおよびプルランなどが挙げられる。酸味剤としては、たとえば、クエン酸、酒石酸およびリンゴ酸などが挙げられる。発泡剤としては、たとえば、炭酸水素ナトリウムおよび炭酸ナトリウムなどが挙げられる。甘味料としては、たとえば、サッカリンナトリウム、グリチルリチン二カリウム、アスパルテーム、ステビアおよびソーマチンなどが挙げられる。香料としては、たとえば、レモン油、オレンジ油およびメントールなどが挙げられる。流動化剤としては、たとえば、含水二酸化ケイ素、軽質無水ケイ酸、合成ケイ酸アルミニウム、合成ヒドロタルサイト、乾燥水酸化アルミニウムゲル、カオリン、ケイ酸カルシウムおよびメタケイ酸アルミン酸マグネシウムなどが挙げられる。滑沢剤としては、たとえば、ステアリン酸マグネシウム、ステアリン酸カルシウム、ショ糖脂肪酸エステル、ポリエチレングリコール、タルク、ステアリン酸およびフマル酸ステアリルナトリウムなどが挙げられる。着色剤としては、たとえば、食用黄色５号および食用赤色２号などの食用色素、食用レーキ色素、三二酸化鉄ならびに黄色三二酸化鉄などが挙げられる。これらに用いられる粒子径は、特に限定されないが、口腔内でザラツキ感を生じにくい粒子径500μm以下が好ましい。また、これらの添加剤は、いずれか１種または２種以上を組み合わせて用いてもよく、配合量は、通常当業者が製薬的に使用する範囲内であれば、特に限定されない。 Excipients include organic excipients and inorganic excipients. Examples of the organic excipient include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch. Examples of inorganic excipients include anhydrous calcium phosphate, precipitated calcium carbonate, and calcium silicate. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic powder, gelatin and pullulan. Examples of sour agents include citric acid, tartaric acid and malic acid. Examples of the foaming agent include sodium bicarbonate and sodium carbonate. Examples of the sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin. Examples of the fragrance include lemon oil, orange oil and menthol. Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, synthetic hydrotalcite, dry aluminum hydroxide gel, kaolin, calcium silicate, and magnesium metasilicate aluminate. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and sodium stearyl fumarate. Examples of the colorant include edible pigments such as edible yellow No. 5 and edible red No. 2, edible lake pigments, iron sesquioxide and yellow sesquioxide. The particle size used in these is not particularly limited, but a particle size of 500 μm or less that is less likely to cause roughness in the oral cavity is preferable. In addition, these additives may be used alone or in combination of two or more, and the blending amount is not particularly limited as long as it is within a range that is usually used by a person skilled in the art.
本発明の錠剤は、たとえば、（１）糖類および糖アルコール類から選ばれる物質、（２）崩壊剤ならびに（３）イグラチモドの混合物を圧縮成形することにより、製造することができる。 The tablet of the present invention can be produced, for example, by compression molding a mixture of (1) a substance selected from saccharides and sugar alcohols, (2) a disintegrant and (3) iguratimod.
具体的な製造法としては、たとえば、（１）イグラチモドおよび適宜製剤原料を混合粉砕した後、必要に応じ添加剤を加え、混合機で混合し、打錠して製造する方法ならびに（２）イグラチモドおよび適宜製剤原料を混合粉砕した後、造粒後、打錠して製造する方法が挙げられる。
上記の混合粉砕は、常法により、行えばよい。
上記の造粒は、常法により行えばよいが、たとえば、スラッグ法、ローラーコンパクター法および湿式造粒法などにより行うことができる。スラッグ法またはローラーコンパクター法は、乾式で圧縮し、造粒する方法である。湿式造粒法は、溶媒を用いる造粒方法であり、たとえば、結合剤を含む製剤原料に溶媒を加える方法および製剤原料に結合剤を含む溶液を加える方法である。造粒に使用される溶媒としては、たとえば、水、アセトン、エチルアルコールおよびプロピルアルコールなどが挙げられ、これらを１種または２種以上混合して使用してもよい。
また、特開２００１−２４０５４０号公報記載の方法などにより、粉砕および造粒を同時に行うこともできる。
粉砕末または造粒末を打錠し、錠剤を製造する際には、必要に応じて、糖および糖アルコール、崩壊剤、流動化剤、滑沢剤、甘味料などを混合してもよい。
Specific production methods include, for example, (1) a method of mixing and pulverizing iguratimod and appropriate preparation raw materials, adding additives as necessary, mixing with a mixer, tableting, and (2) iguratimod In addition, there may be mentioned a method in which the raw materials for preparation are mixed and pulverized as appropriate, granulated, and then tableted for production.
The above mixing and pulverization may be performed by a conventional method.
The above granulation may be performed by a conventional method, and for example, it can be performed by a slug method, a roller compactor method, a wet granulation method, or the like. The slug method or the roller compactor method is a method of compressing and granulating by a dry method. The wet granulation method is a granulation method using a solvent, for example, a method of adding a solvent to a preparation raw material containing a binder and a method of adding a solution containing a binder to the preparation raw material. Examples of the solvent used for granulation include water, acetone, ethyl alcohol and propyl alcohol. These may be used alone or in combination.
Further, pulverization and granulation can be performed simultaneously by the method described in JP-A-2001-240540.
When tableting the pulverized powder or granulated powder to produce a tablet, sugar and sugar alcohol, a disintegrant, a fluidizing agent, a lubricant, a sweetener and the like may be mixed as necessary.
錠剤は、たとえば、単発打錠機またはロータリー式打錠機などを用いて成型される。打錠の際の圧力は、通常1.5〜30kN/cm2である。本発明の錠剤の形状は、特に限定されないが、丸形、キャップレット形もしくはオブロング形などの形状、積層錠または有核錠などが挙げられる。本発明の錠剤は、必要に応じて、コーティングすることもでき、また、必要に応じて、識別性のためマーク、文字、分割用の割線などを付すこともできる。 Tablets are molded using, for example, a single tableting machine or a rotary tableting machine. The pressure during tableting is usually 1.5 to 30 kN / cm 2 . Although the shape of the tablet of this invention is not specifically limited, Shapes, such as a round shape, a caplet shape, or an oblong shape, a laminated tablet, or a dry-coated tablet are mentioned. The tablet of the present invention can be coated as necessary, and can be provided with marks, characters, dividing lines for identification, and the like as necessary.
以下に、実施例、比較例および試験例を挙げて本発明を説明するが、これらは本発明を限定するものではない。なお、比較例２〜５では、イグラチモドを一般的に成形性がよいとされる結晶セルロースに置き換えた製剤を用いた。また、比較例６〜７では、イグラチモドを関節リウマチ患者に利用される薬剤であるアセトアミノフェンおよびイブプロフェンに置き換えた製剤を用いた。 Hereinafter, the present invention will be described with reference to Examples, Comparative Examples and Test Examples, but these do not limit the present invention. In Comparative Examples 2 to 5, preparations were used in which iguratimod was replaced with crystalline cellulose, which is generally considered to have good moldability. In Comparative Examples 6 to 7, preparations in which iguratimod was replaced with acetaminophen and ibuprofen, which are drugs used for rheumatoid arthritis patients, were used.
試験例１ 口腔内崩壊時間の測定
３人の被験者（健康な成人男性）の口腔内に錠剤を入れてから完全に崩壊するまでの時間を測定し、その平均値を口腔内崩壊時間とした。なお、試験後、直ちに薬物を吐き出し、口腔内を十分に水ですすいだ。
Test Example 1 Measurement of Oral Disintegration Time The time from when a tablet was put into the oral cavity of three subjects (healthy adult males) until complete disintegration was measured, and the average value was taken as the oral disintegration time. After the test, the drug was discharged immediately and the oral cavity was thoroughly rinsed with water.
試験例２ 錠剤の硬度測定
錠剤硬度計（シュロイニゲル、Tablet Tester 8M）を用いて測定した。試験はｎ＝６で行い、その平均値を錠剤の硬度とした。
Test Example 2 Tablet Hardness Measurement Measured using a tablet hardness tester (Schleunigel, Tablet Tester 8M). The test was performed at n = 6, and the average value was taken as the hardness of the tablet.
試験例３ 錠剤の重量
電子天秤（メトラートレド、HX-400）を用いて測定した。試験はｎ＝６で行い、その平均値を錠剤の重量とした。
Test Example 3 Tablet Weight Measured using an electronic balance (Mettler Toledo, HX-400). The test was performed at n = 6, and the average value was taken as the weight of the tablet.
実施例１〜４および比較例１〜７の処方を表１に示す。また、得られた錠剤を上記試験例によって測定した結果を表２に示す。実施例において、活性成分をイグラチモドとした錠剤は、迅速な口腔内崩壊性を維持したまま、高い錠剤硬度を維持した。一方、比較例において、活性成分をアセトアミノフェンまたはイブプロフェンとした錠剤は、錠剤硬度が低かった。なお、いずれの処方でも、バインディングおよびステッキングなどの打錠障害を認めなかった。 Table 1 shows formulations of Examples 1 to 4 and Comparative Examples 1 to 7. Table 2 shows the results obtained by measuring the obtained tablets according to the above test examples. In Examples, tablets with iguratimod as the active ingredient maintained high tablet hardness while maintaining rapid oral disintegration. On the other hand, in the comparative examples, tablets with active ingredient acetaminophen or ibuprofen had low tablet hardness. In any prescription, no tableting troubles such as binding and sticking were observed.
実施例１〜４および比較例１〜５の錠剤硬度の測定結果を該処方中のイグラチモドの含率またはイグラチモドと置き換えた結晶セルロースの含率に対してプロットした結果を図１に示す。イグラチモドの含率が高まるに伴い、錠剤硬度が明らかに上昇した。 FIG. 1 shows the results of plotting the tablet hardness measurement results of Examples 1 to 4 and Comparative Examples 1 to 5 against the content of iguratimod or the content of crystalline cellulose replaced with iguratimod in the formulation. As the content of iguratimod increased, the tablet hardness clearly increased.
実施例７〜１２および１５〜１７の処方を表３に示す。また、得られた錠剤を上記試験例によって測定した結果を表４に示す。糖および糖アルコール類や崩壊剤の種類を変更しても、高い成形性および速やかな崩壊性を有する錠剤が得られた。なお、いずれの処方でも、バインディングおよびステッキングなどの打錠障害を認めなかった。 The formulations for Examples 7-12 and 15-17 are shown in Table 3. Table 4 shows the results obtained by measuring the obtained tablets according to the above test examples. Even if the types of sugar, sugar alcohols and disintegrant were changed, a tablet having high moldability and rapid disintegration was obtained. In any prescription, no tableting troubles such as binding and sticking were observed.
実施例１
イグラチモド（富山化学工業）6.0g、結晶セルロース（旭化成ケミカルズ：セオラスPH101）36.0gおよび軽質無水ケイ酸（ワイ・ケイ・エフ：サイリシア350）6.0gを混合し、粉砕機（パウレック：コントラプレックス63C）により粉砕し、粉砕末を得た。得られた粉砕末のうちの40.0g、Ｄ−マンニトール（東和化成工業：マンニットP）211.0g、クロスポビドン（ISP：ポリプラスドンXL-10）12.5g、黄色三二酸化鉄（癸巳化成：黄色三二酸化鉄）0.9gおよびヒドロキシプロピルセルロース（日本曹達：HPC-L）0.8gを攪拌造粒機（パウレック：VG-01）に仕込み、混合し、水を添加して造粒後、流動層乾燥機（パウレック：MP-01）により乾燥し、造粒末を得た。得られた造粒末のうちの176.8gに結晶セルロース（旭化成ケミカルズ：セオラスKG802）20.0g、アスパルテーム（味の素：アスパルテーム）0.8gおよびステアリン酸マグネシウム（メルク：ステアリン酸マグネシウム）2.4gを加え、混合し、混合末を得た。この混合末を錠剤径9.5mmでダブルアール面の杵を用い、打錠速度30rpmで1錠重量300mgとなるように打錠（畑鐵工所：HT-P18A）し、イグラチモド5mgを含有する円形の速崩壊性錠剤を得た。
Example 1
Iguratimod (Toyama Chemical Co., Ltd.) 6.0g, crystalline cellulose (Asahi Kasei Chemicals: Theolas PH101) 36.0g, and light anhydrous silicic acid (Way K. F .: Silicia 350) 6.0g are mixed and pulverized (Paurek: Contraplex 63C) To obtain a pulverized powder. Of the obtained pulverized powder, 40.0 g, D-mannitol (Towa Kasei Kogyo: Mannit P) 211.0 g, Crospovidone (ISP: Polyplastidone XL-10) 12.5 g, Yellow iron sesquioxide (Hana Kasei: Yellow) 0.9g of iron sesquioxide and 0.8g of hydroxypropylcellulose (Nippon Soda: HPC-L) were added to a stirring granulator (Paurek: VG-01), mixed, water added and granulated, then fluidized bed dried It was dried with a machine (Pauleck: MP-01) to obtain a granulated powder. Add 170.0 g of the resulting granulated powder to 20.0 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas KG802), 0.8 g of aspartame (Ajinomoto: Aspartame) and 2.4 g of magnesium stearate (Merck: magnesium stearate) and mix. A mixed powder was obtained. This mixed powder was tableted with a tablet diameter of 9.5mm and a double areal side, and tableted at a tableting speed of 30rpm so that the weight of one tablet was 300mg (Hatabe Factory: HT-P18A), and a circle containing 5mg of iguratimod A fast disintegrating tablet was obtained.
実施例２
イグラチモド（富山化学工業）15.1g、結晶セルロース（旭化成ケミカルズ：セオラスPH101）36.0gおよび軽質無水ケイ酸（ワイ・ケイ・エフ：サイリシア350）6.0gを混合し、粉砕機（パウレック：コントラプレックス63C）により粉砕し、粉砕末を得た。得られた粉砕末のうちの47.5g、Ｄ−マンニトール（東和化成工業：マンニットP）203.5g、クロスポビドン（ISP：ポリプラスドンXL-10）12.5g、黄色三二酸化鉄（癸巳化成：黄色三二酸化鉄）0.9gおよびヒドロキシプロピルセルロース（日本曹達：HPC-L）0.8gを攪拌造粒機（パウレック：VG-01）に仕込み、混合し、水を添加して造粒後、流動層乾燥機（パウレック：MP-01）により乾燥し、造粒末を得た。得られた造粒末のうちの176.8gに結晶セルロース（旭化成ケミカルズ：セオラスKG802）20.1g、アスパルテーム（味の素：アスパルテーム）0.8gおよびステアリン酸マグネシウム（メルク：ステアリン酸マグネシウム）2.4gを加え、混合し、混合末を得た。この混合末を実施例１と同様な操作で打錠し、イグラチモド12.5mgを含有する円形の速崩壊性錠剤を得た。
Example 2
Iguratimod (Toyama Chemical Co., Ltd.) 15.1g, crystalline cellulose (Asahi Kasei Chemicals: Theolas PH101) 36.0g, and light anhydrous silicic acid (Way K. F .: Silicia 350) 6.0g are mixed, and the pulverizer (Paurek: Contraplex 63C) To obtain a pulverized powder. Of the obtained pulverized powder, 47.5 g, D-mannitol (Towa Kasei Kogyo: Mannit P) 203.5 g, Crospovidone (ISP: Polyplastidone XL-10) 12.5 g, Yellow iron sesquioxide (Hotkasei: Yellow 0.9g of iron sesquioxide and 0.8g of hydroxypropylcellulose (Nippon Soda: HPC-L) were added to a stirring granulator (Paurek: VG-01), mixed, water added and granulated, then fluidized bed dried It was dried with a machine (Pauleck: MP-01) to obtain a granulated powder. 176.8g of the resulting granulated powder is mixed with 20.1g of crystalline cellulose (Asahi Kasei Chemicals: Theolas KG802), 0.8g of aspartame (Ajinomoto: Aspartame) and 2.4g of magnesium stearate (Merck: magnesium stearate) and mixed. A mixed powder was obtained. This mixed powder was tableted in the same manner as in Example 1 to obtain a circular quick disintegrating tablet containing 12.5 mg of iguratimod.
実施例３
イグラチモド（富山化学工業）30.0g、結晶セルロース（旭化成ケミカルズ：セオラスPH101）36.0gおよび軽質無水ケイ酸（ワイ・ケイ・エフ：サイリシア350）6.0gを混合し、粉砕機（パウレック：コントラプレックス63C）により粉砕し、粉砕末を得た。得られた粉砕末のうちの60.0g、Ｄ−マンニトール（東和化成工業：マンニットP）191.0g、クロスポビドン（ISP：ポリプラスドンXL-10）12.5g、黄色三二酸化鉄（癸巳化成：黄色三二酸化鉄）0.9gおよびヒドロキシプロピルセルロース（日本曹達：HPC-L）0.8gを攪拌造粒機（パウレック：VG-01）に仕込み、混合し、水を添加して造粒後、流動層乾燥機（パウレック：MP-01）により乾燥し、造粒末を得た。得られた造粒末のうちの176.8gに結晶セルロース（旭化成ケミカルズ：セオラスKG802）20.0g、アスパルテーム（味の素：アスパルテーム）0.8gおよびステアリン酸マグネシウム（メルク：ステアリン酸マグネシウム）2.4gを加え、混合し、混合末を得た。この混合末を実施例１と同様な操作で打錠し、イグラチモド25mgを含有する円形の速崩壊性錠剤を得た。
Example 3
Iguratimod (Toyama Chemical Co., Ltd.) 30.0g, crystalline cellulose (Asahi Kasei Chemicals: Theolas PH101) 36.0g, and light anhydrous silicic acid (Way K. F .: Silicia 350) 6.0g are mixed and pulverized (Paurek: Contraplex 63C) To obtain a pulverized powder. Of the obtained pulverized powder, 60.0 g, D-mannitol (Towa Kasei Kogyo: Mannite P) 191.0 g, Crospovidone (ISP: Polyplastidone XL-10) 12.5 g, Yellow iron sesquioxide (Hana Kasei: Yellow) 0.9g of iron sesquioxide and 0.8g of hydroxypropylcellulose (Nippon Soda: HPC-L) were added to a stirring granulator (Paurek: VG-01), mixed, water added and granulated, then fluidized bed dried It was dried with a machine (Pauleck: MP-01) to obtain a granulated powder. Add 170.0 g of the resulting granulated powder to 20.0 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas KG802), 0.8 g of aspartame (Ajinomoto: Aspartame) and 2.4 g of magnesium stearate (Merck: magnesium stearate) and mix. A mixed powder was obtained. This mixed powder was tableted in the same manner as in Example 1 to obtain a circular quick disintegrating tablet containing 25 mg of iguratimod.
実施例４
イグラチモド（富山化学工業）60.1g、結晶セルロース（旭化成ケミカルズ：セオラスPH101）36.0gおよび軽質無水ケイ酸（ワイ・ケイ・エフ：サイリシア350）6.0gを混合し、粉砕機（パウレック：コントラプレックス63C）により粉砕し、粉砕末を得た。得られた粉砕末のうちの85.1g、Ｄ−マンニトール（東和化成工業：マンニットP）166.0g、クロスポビドン（ISP：ポリプラスドンXL-10）12.5g、黄色三二酸化鉄（癸巳化成：黄色三二酸化鉄）0.9gおよびヒドロキシプロピルセルロース（日本曹達：HPC-L）0.8gを攪拌造粒機（パウレック：VG-01）に仕込み、混合し、水を添加して造粒後、流動層乾燥機（パウレック：MP-01）により乾燥し、造粒末を得た。得られた造粒末のうちの176.8gに結晶セルロース（旭化成ケミカルズ：セオラスKG802）20.0g、アスパルテーム（味の素：アスパルテーム）0.8gおよびステアリン酸マグネシウム（メルク：ステアリン酸マグネシウム）2.4gを加え、混合し、混合末を得た。この混合末を実施例１と同様な操作で打錠し、イグラチモド50mgを含有する円形の速崩壊性錠剤を得た。
Example 4
Mixing 60.1 g of iguratimod (Toyama Chemical Co., Ltd.), 36.0 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas PH101) and 6.0 g of light anhydrous silicic acid (Way K. F .: Silicia 350), crusher (Paurek: Contraplex 63C) To obtain a pulverized powder. Of the obtained pulverized powder, 85.1 g, D-mannitol (Towa Kasei Kogyo: Mannit P) 166.0 g, Crospovidone (ISP: Polyplastidone XL-10) 12.5 g, Yellow iron sesquioxide (Hana Kasei: Yellow) 0.9g of iron sesquioxide and 0.8g of hydroxypropylcellulose (Nippon Soda: HPC-L) were added to a stirring granulator (Paurek: VG-01), mixed, water added and granulated, then fluidized bed dried It was dried with a machine (Pauleck: MP-01) to obtain a granulated powder. Add 170.0 g of the resulting granulated powder to 20.0 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas KG802), 0.8 g of aspartame (Ajinomoto: Aspartame) and 2.4 g of magnesium stearate (Merck: magnesium stearate) and mix. A mixed powder was obtained. This mixed powder was tableted in the same manner as in Example 1 to obtain a circular quick disintegrating tablet containing 50 mg of iguratimod.
実施例５
イグラチモド（富山化学工業）262.6g、Ｄ−マンニトール（東和化成工業：マンニットP）315.0gおよび軽質無水ケイ酸（フロイント産業：アドソリダー101）52.5gを混合し、粉砕機（不二電機工業：サンプルミルKIIW-1）により粉砕し、粉砕末を得た。
Example 5
Iguratimod (Toyama Chemical Co., Ltd.) 262.6g, D-mannitol (Towa Kasei Kogyo: Mannit P) 315.0g and light anhydrous silicic acid (Freund Sangyo: Adsolider 101) 52.5g are mixed and pulverizer (Fuji Electric Industry: Sample) Milled with a mill KIIW-1) to obtain a ground powder.
実施例６
イグラチモド（富山化学工業）212.5g、結晶セルロース（旭化成ケミカルズ：セオラスPH101）255.0gおよび軽質無水ケイ酸（フロイント産業：アドソリダー101）42.5gを混合し、粉砕機（不二電機工業：サンプルミルKIIW-1）により粉砕し、粉砕末を得た。
Example 6
Iguratimod (Toyama Chemical Co., Ltd.) 212.5g, crystalline cellulose (Asahi Kasei Chemicals: Theolas PH101) 255.0g and light anhydrous silicic acid (Freund Sangyo: Adsolider 101) 42.5g were mixed and pulverizer (Fuji Electric Industry: Sample Mill KIIW- The powder was pulverized by 1) to obtain a pulverized powder.
実施例７
実施例５で得られた粉砕末のうちの60.0g、Ｄ−マンニトール（東和化成工業：マンニットP）175.6g、カルメロース（五徳薬品：NS-300）30.0gおよびヒドロキシプロピルセルロース（日本曹達：HPC-L）0.8gを攪拌造粒機（パウレック：VG-01）に仕込み、混合し、水を添加して造粒後、流動層乾燥機（パウレック：MP-01）により乾燥し、造粒末を得た。得られた造粒末のうちの177.6gに結晶セルロース（旭化成ケミカルズ：セオラスKG802）20.0gおよびステアリン酸マグネシウム（メルク：ステアリン酸マグネシウム）2.4gを加え、混合し、混合末を得た。この混合末を実施例１と同様な操作で打錠し、イグラチモド25mgを含有する円形の速崩壊性錠剤を得た。
Example 7
60.0 g of the pulverized powder obtained in Example 5, 175.6 g of D-mannitol (Towa Kasei Kogyo: Mannit K), 30.0 g of carmellose (NS-300) and hydroxypropyl cellulose (Nippon Soda: HPC) -L) Charge 0.8g into a stirring granulator (Paurec: VG-01), mix, add water, granulate, dry with fluid bed dryer (Paurec: MP-01), and granulate powder Got. To 177.6 g of the obtained granulated powder, 20.0 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas KG802) and 2.4 g of magnesium stearate (Merck: magnesium stearate) were added and mixed to obtain a mixed powder. This mixed powder was tableted in the same manner as in Example 1 to obtain a circular quick disintegrating tablet containing 25 mg of iguratimod.
実施例８
実施例６で得られた粉砕末のうちの60.0g、Ｄ−マンニトール（東和化成工業：マンニットP）206.2gおよびヒドロキシプロピルセルロース（日本曹達：HPC-L）0.8gを攪拌造粒機（パウレック：VG-01）に仕込み、混合し、水を添加して造粒後、流動層乾燥機（パウレック：MP-01）により乾燥し、造粒末を得た。得られた造粒末のうちの178.0gにクロスカルメロースナトリウム（旭化成ケミカルズ：キッコレートND-200）10.0g、結晶セルロース（旭化成ケミカルズ：セオラスKG802）10.0gおよびステアリン酸マグネシウム（メルク：ステアリン酸マグネシウム）2.0gを加え、混合し、混合末を得た。この混合末を実施例１と同様な操作で打錠し、イグラチモド25mgを含有する円形の速崩壊性錠剤を得た。
Example 8
60.0 g of the pulverized powder obtained in Example 6, 206.2 g of D-mannitol (Towa Kasei Kogyo: Mannit P) and 0.8 g of hydroxypropyl cellulose (Nippon Soda: HPC-L) were mixed with a stirring granulator (Paurec) : VG-01), mixed, added water and granulated, and then dried by a fluidized bed dryer (Paurek: MP-01) to obtain a granulated powder. Of the obtained granulated powder, 178.0 g is croscarmellose sodium (Asahi Kasei Chemicals: Kikkolate ND-200) 10.0 g, crystalline cellulose (Asahi Kasei Chemicals: Theolas KG802) 10.0 g and magnesium stearate (Merck: magnesium stearate) 2.0 g was added and mixed to obtain a mixed powder. This mixed powder was tableted in the same manner as in Example 1 to obtain a circular quick disintegrating tablet containing 25 mg of iguratimod.
実施例９
実施例６で得られた粉砕末のうちの60.0g、Ｄ−マンニトール（東和化成工業：マンニットP）206.2gおよびヒドロキシプロピルセルロース（日本曹達：HPC-L）0.8gを攪拌造粒機（パウレック：VG-01）に仕込み、混合し、水を添加して造粒後、流動層乾燥機（パウレック：MP-01）により乾燥し、造粒末を得た。得られた造粒末のうちの178.0gに低置換度ヒドロキシプロピルセルロース（信越化学工業：L-HPC LH-11）20.0g、結晶セルロース（旭化成ケミカルズ：セオラスKG802）20.0gおよびステアリン酸マグネシウム（メルク：ステアリン酸マグネシウム）2.0gを加え、混合し、混合末を得た。この混合末を実施例１と同様な操作で1錠重量330mgとなるように打錠し、イグラチモド25mgを含有する円形の速崩壊性錠剤を得た。
Example 9
60.0 g of the pulverized powder obtained in Example 6, 206.2 g of D-mannitol (Towa Kasei Kogyo: Mannit P) and 0.8 g of hydroxypropyl cellulose (Nippon Soda: HPC-L) were mixed with a stirring granulator (Paurec) : VG-01), mixed, added water and granulated, and then dried by a fluidized bed dryer (Paurek: MP-01) to obtain a granulated powder. Of the resulting granulated powder, 178.0 g was low substituted hydroxypropylcellulose (Shin-Etsu Chemical: L-HPC LH-11) 20.0 g, crystalline cellulose (Asahi Kasei Chemicals: Theolas KG802) 20.0 g and magnesium stearate (Merck) : Magnesium stearate) was added and mixed to obtain a mixed powder. This mixed powder was tableted by the same operation as in Example 1 so that the weight of one tablet was 330 mg, to obtain a circular quick disintegrating tablet containing 25 mg of iguratimod.
実施例１０
実施例６で得られた粉砕末のうちの60.0g、乳糖（DMV：乳糖200M）193.7g、クロスポビドン（ISP：ポリプラスドンXL-10）12.5gおよびヒドロキシプロピルセルロース（日本曹達：HPC-L）0.8gを攪拌造粒機（パウレック：VG-01）に仕込み、混合し、水を添加して造粒後、流動層乾燥機（パウレック：MP-01）により乾燥し、造粒末を得た。得られた造粒末のうちの178.0gに結晶セルロース（旭化成ケミカルズ：セオラスKG802）20.0gおよびステアリン酸マグネシウム（メルク：ステアリン酸マグネシウム）2.0gを加え、混合し、混合末を得た。この混合末を実施例１と同様な操作で打錠し、イグラチモド25mgを含有する円形の速崩壊性錠剤を得た。
Example 10
Of the pulverized powder obtained in Example 6, 60.0 g, lactose (DMV: lactose 200M) 193.7 g, crospovidone (ISP: polyplastidone XL-10) 12.5 g and hydroxypropyl cellulose (Nippon Soda: HPC-L) ) Charge 0.8g into a stirring granulator (Paurek: VG-01), mix, add water, granulate, and dry with a fluid bed dryer (Paurec: MP-01) to obtain a granulated powder It was. To 178.0 g of the obtained granulated powder, 20.0 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas KG802) and 2.0 g of magnesium stearate (Merck: magnesium stearate) were added and mixed to obtain a mixed powder. This mixed powder was tableted in the same manner as in Example 1 to obtain a circular quick disintegrating tablet containing 25 mg of iguratimod.
実施例１１
イグラチモド（富山化学工業）25.0g、結晶セルロース（旭化成ケミカルズ：セオラスPH101）30.0g、Ｄ−マンニトール（東和化成工業：マンニットP）198.1gおよびクロスポビドン（ISP：ポリプラスドンXL-10）12.5g、ヒドロキシプロピルセルロース（日本曹達：HPC-L）0.8gを攪拌造粒機（パウレック：VG-01）に仕込み、混合した後、粉末が湿る程度に水を添加して約30分間湿式混合し、さらに水を加えて造粒後、流動層乾燥機（パウレック：MP-01）により乾燥し、造粒末を得た。得られた造粒末のうちの177.6gに結晶セルロース（旭化成ケミカルズ：セオラスKG802）20.0gおよびステアリン酸マグネシウム（メルク：ステアリン酸マグネシウム）2.4gを加え、混合し、混合末を得た。この混合末を実施例１と同様な操作で打錠し、イグラチモド25mgを含有する円形の速崩壊性錠剤を得た。
Example 11
Iguratimod (Toyama Chemical) 25.0g, crystalline cellulose (Asahi Kasei Chemicals: Theolas PH101) 30.0g, D-mannitol (Towa Kasei Kogyo: Mannit P) 198.1g and crospovidone (ISP: Polyplusdon XL-10) 12.5g , 0.8g of hydroxypropyl cellulose (Nippon Soda: HPC-L) was charged into a stirring granulator (Paurek: VG-01) and mixed, then water was added to the extent that the powder was moistened and wet mixed for about 30 minutes. Further, after adding water and granulating, it was dried by a fluid bed dryer (Paurek: MP-01) to obtain a granulated powder. To 177.6 g of the obtained granulated powder, 20.0 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas KG802) and 2.4 g of magnesium stearate (Merck: magnesium stearate) were added and mixed to obtain a mixed powder. This mixed powder was tableted in the same manner as in Example 1 to obtain a circular quick disintegrating tablet containing 25 mg of iguratimod.
実施例１２
イグラチモド（富山化学工業）25.0g、乳糖（DMV：乳糖200M）260.2gおよびクロスポビドン（ISP：ポリプラスドンXL-10）12.5gを攪拌造粒機（パウレック：VG-01）に仕込み、混合した後、粉末が湿る程度に水を添加して約30分間湿式混合し、さらに水を加えて造粒後、流動層乾燥機（パウレック：MP-01）により乾燥し、造粒末を得た。得られた造粒末のうちの198.5gにステアリン酸マグネシウム（メルク：ステアリン酸マグネシウム）1.5gを加え、混合し、混合末を得た。この混合末を実施例１と同様な操作で打錠し、イグラチモド25mgを含有する円形の速崩壊性錠剤を得た。
Example 12
25.0g of iguratimod (Toyama Chemical), 260.2g of lactose (DMV: lactose 200M) and 12.5g of crospovidone (ISP: polyplastidone XL-10) were charged into a stirring granulator (Paurek: VG-01) and mixed. Then, water was added to the extent that the powder was moistened and wet-mixed for about 30 minutes. Further, water was added and granulated, followed by drying with a fluid bed dryer (Paurek: MP-01) to obtain a granulated powder. . To 198.5 g of the obtained granulated powder, 1.5 g of magnesium stearate (Merck: magnesium stearate) was added and mixed to obtain a mixed powder. This mixed powder was tableted in the same manner as in Example 1 to obtain a circular quick disintegrating tablet containing 25 mg of iguratimod.
実施例１３
イグラチモド（富山化学工業）180.0g、結晶セルロース（旭化成ケミカルズ：セオラスPH101）216.0gおよび軽質無水ケイ酸（フロイント産業：アドソリダー101）36.0gを混合し、粉砕機（パウレック：コントラプレックス63C）により粉砕し、粉砕末を得た。
Example 13
Mix 18g of iguratimod (Toyama Chemical Co., Ltd.), 216.0g of crystalline cellulose (Asahi Kasei Chemicals: Theolas PH101) and 36.0g of light anhydrous silicic acid (Freund Industries: Adsolider 101) A pulverized powder was obtained.
実施例１４
実施例１３で得られた粉砕末のうちの420.0g、Ｄ−マンニトール（東和化成工業：マンニットP）1131.4g、クロスポビドン（ISP：ポリプラスドンINF-10）87.5g、ヒドロキシプロピルセルロース（日本曹達：HPC-L）5.6gおよび黄色三二酸化鉄（癸巳化成）1.68gを攪拌造粒機（パウレック：VG-10）に仕込み、混合し、水を添加して造粒後、流動層乾燥機（パウレック：MP-01）により乾燥し、造粒末を得た。
Example 14
420.0 g of the pulverized powder obtained in Example 13, D-mannitol (Towa Kasei Kogyo: Mannit P) 1131.4 g, Crospovidone (ISP: Polyplastidone INF-10) 87.5 g, Hydroxypropyl cellulose (Japan) Soda: 5.6g of HPC-L) and 1.68g of yellow ferric oxide (Chemical Kasei) were charged into a stirring granulator (Paurek: VG-10), mixed, added water, granulated, and fluidized bed dryer. (Pauleck: MP-01) to obtain a granulated powder.
実施例１５
実施例１４で得られた造粒末のうちの156.8gに結晶セルロース（旭化成ケミカルズ：セオラスKG802）20.0g、Ｄ−マンニトール（メルク：パーテックＭ100）20.0g、アスパルテーム（味の素：アスパルテーム）0.8gおよびステアリン酸マグネシウム（メルク：ステアリン酸マグネシウム）2.4gを加え、混合し、混合末を得た。この混合末を実施例１と同様な操作で打錠し、イグラチモド25mgを含有する円形の速崩壊性錠剤を得た。
Example 15
156.8 g of the granulated powder obtained in Example 14 was 20.0 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas KG802), 20.0 g of D-mannitol (Merck: Pertec M100), 0.8 g of aspartame (Ajinomoto: Aspartame) and stearin. 2.4 g of magnesium acid (Merck: magnesium stearate) was added and mixed to obtain a mixed powder. This mixed powder was tableted in the same manner as in Example 1 to obtain a circular quick disintegrating tablet containing 25 mg of iguratimod.
実施例１６
実施例１４で得られた造粒末のうちの156.8gに結晶セルロース（旭化成ケミカルズ：セオラスKG802）20.0g、結晶セルロース（旭化成ケミカルズ：セオラスPH302）20.0g、アスパルテーム（味の素：アスパルテーム）0.8gおよびステアリン酸マグネシウム（メルク：ステアリン酸マグネシウム）2.4gを加え、混合し、混合末を得た。この混合末を実施例１と同様な操作で打錠し、イグラチモド25mgを含有する円形の速崩壊性錠剤を得た。
Example 16
156.8 g of the granulated powder obtained in Example 14 was 20.0 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas KG802), 20.0 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas PH302), 0.8 g of aspartame (Ajinomoto: Aspartame) and stearin 2.4 g of magnesium acid (Merck: magnesium stearate) was added and mixed to obtain a mixed powder. This mixed powder was tableted in the same manner as in Example 1 to obtain a circular quick disintegrating tablet containing 25 mg of iguratimod.
実施例１７
実施例１４で得られた造粒末のうちの156.8gに結晶セルロース（旭化成ケミカルズ：セオラスKG802）20.0g、トウモロコシデンプン（日本食品加工：コーンスターチ）20.0g、アスパルテーム（味の素：アスパルテーム）0.8gおよびステアリン酸マグネシウム（メルク：ステアリン酸マグネシウム）2.4gを加え、混合し、混合末を得た。この混合末を実施例１と同様な操作で打錠し、イグラチモド25mgを含有する円形の速崩壊性錠剤を得た。
Example 17
156.8 g of the granulated powder obtained in Example 14 was 20.0 g of crystalline cellulose (Asahi Kasei Chemicals: Theolas KG802), 20.0 g of corn starch (Japanese food processing: corn starch), 0.8 g of aspartame (Ajinomoto: Aspartame) and stearin. 2.4 g of magnesium acid (Merck: magnesium stearate) was added and mixed to obtain a mixed powder. This mixed powder was tableted in the same manner as in Example 1 to obtain a circular quick disintegrating tablet containing 25 mg of iguratimod.
比較例１
実施例１の処方中のイグラチモドをＤ−マンニトール（東和化成工業：マンニットP）に置き換えて、実施例１の方法に従い、錠剤を得た。なお、イグラチモドを含まないため粉砕は行わなかった。
Comparative Example 1
According to the method of Example 1, tablets were obtained by replacing iguratimod in the formulation of Example 1 with D-mannitol (Towa Kasei Kogyo: Mannit P). Since no iguratimod was contained, pulverization was not performed.
比較例２
実施例１の処方中のイグラチモドを結晶セルロース（旭化成ケミカルズ：セオラスPH101）に置き換えて、実施例１の方法に従い、イグラチモド5mgを含有する速崩壊性錠剤に対応する錠剤を得た。なお、イグラチモドを含まないため粉砕は行わなかった。
Comparative Example 2
In accordance with the method of Example 1 by replacing iguratimod in the formulation of Example 1 with crystalline cellulose (Asahi Kasei Chemicals: Theolas PH101), a tablet corresponding to a rapidly disintegrating tablet containing 5 mg of iguratimod was obtained. Since no iguratimod was contained, pulverization was not performed.
比較例３
実施例２の処方中のイグラチモドを結晶セルロース（旭化成ケミカルズ：セオラスPH101）に置き換えて、実施例２の方法に従い、イグラチモド12.5mgを含有する速崩壊性錠剤に対応する錠剤を得た。なお、イグラチモドを含まないため粉砕は行わなかった。
Comparative Example 3
In accordance with the method of Example 2 by replacing iguratimod in the formulation of Example 2 with crystalline cellulose (Asahi Kasei Chemicals: Theolas PH101), a tablet corresponding to a rapidly disintegrating tablet containing 12.5 mg of iguratimod was obtained. Since no iguratimod was contained, pulverization was not performed.
比較例４
実施例３の処方中のイグラチモドを結晶セルロース（旭化成ケミカルズ：セオラスPH101）に置き換えて、実施例３の方法に従い、イグラチモド25mgを含有する速崩壊性錠剤に対応する錠剤を得た。なお、イグラチモドを含まないため粉砕は行わなかった。
Comparative Example 4
By replacing iguratimod in the formulation of Example 3 with crystalline cellulose (Asahi Kasei Chemicals: Theolas PH101), a tablet corresponding to a rapidly disintegrating tablet containing 25 mg of iguratimod was obtained according to the method of Example 3. Since no iguratimod was contained, pulverization was not performed.
比較例５
実施例４の処方中のイグラチモドを結晶セルロース（旭化成ケミカルズ：セオラスPH101）に置き換えて、実施例４の方法に従い、イグラチモド50mgを含有する速崩壊性錠剤に対応する錠剤を得た。なお、イグラチモドを含まないため粉砕は行わなかった。
Comparative Example 5
According to the method of Example 4 except that iguratimod in the formulation of Example 4 was replaced with crystalline cellulose (Asahi Kasei Chemicals: Theolas PH101), a tablet corresponding to a rapidly disintegrating tablet containing 50 mg of iguratimod was obtained. Since no iguratimod was contained, pulverization was not performed.
比較例６
実施例３の処方中の活性成分をイグラチモドからアセトアミノフェン（岩城製薬）に置き換えて、実施例３の方法に従い、イグラチモド25mgを含有する速崩壊性錠剤に対応するアセトアミノフェンを含有する錠剤を得た。なお、イグラチモドを含まないため粉砕は行わなかった。
Comparative Example 6
A tablet containing acetaminophen corresponding to a rapidly disintegrating tablet containing 25 mg of iguratimod according to the method of Example 3, substituting the active ingredient in the formulation of Example 3 from iguratimod to acetaminophen (Iwaki Pharmaceutical). Obtained. Since no iguratimod was contained, pulverization was not performed.
比較例７
実施例３の処方中の活性成分をイグラチモドからイブプロフェン（セクサリアケミカルズ（SEKHSARIA CHEMICALS））に置き換えて、実施例３の方法に従い、イグラチモド25mgを含有する速崩壊性錠剤に対応するイブプロフェン含有錠剤を得た。なお、イグラチモドを含まないため粉砕は行わなかった。
Comparative Example 7
The active ingredient in the formulation of Example 3 was replaced by ibuprofen (SEKHSARIA CHEMICALS) from iguratimod to obtain an ibuprofen-containing tablet corresponding to the fast disintegrating tablet containing 25 mg of iguratimod according to the method of Example 3. It was. Since no iguratimod was contained, pulverization was not performed.
Claims (8)
イグラチモドが、錠剤中に、1〜30％含まれ、速崩壊性錠剤の口腔内崩壊時間が、30秒以内である速崩壊性錠剤。 (1) a rapidly disintegrating tablet characterized by containing a substance selected from saccharides and sugar alcohols, (2) a disintegrant and (3) iguratimod, wherein the substance selected from saccharides and sugar alcohols is 30 to 95% contained in the tablet, disintegrant contained 0.5 to 50% in the tablet,
A fast disintegrating tablet comprising 1-30% of iguratimod and having an orally disintegrating time of 30 seconds or less.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2021146523A1 (en) * | 2020-01-17 | 2021-07-22 | Evelo Biosciences, Inc. | Solid dosage forms with improved disintegration profiles |
| WO2022061123A1 (en) * | 2020-09-21 | 2022-03-24 | Evelo Biosciences, Inc. | Solid dosage forms with improved disintegration profiles |
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| JP2008127320A (en) * | 2006-11-20 | 2008-06-05 | Zensei Yakuhin Kogyo Kk | Solid preparation quickly disintegrating in oral cavity |
| US8829019B2 (en) | 2008-10-24 | 2014-09-09 | Toray Industries, Inc. | Stable tablet containing 4,5-epoxymorphinan derivative |
| JP6045238B2 (en) * | 2012-07-27 | 2016-12-14 | 旭化成株式会社 | Tablet containing thickening polysaccharide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2021146523A1 (en) * | 2020-01-17 | 2021-07-22 | Evelo Biosciences, Inc. | Solid dosage forms with improved disintegration profiles |
| WO2022061123A1 (en) * | 2020-09-21 | 2022-03-24 | Evelo Biosciences, Inc. | Solid dosage forms with improved disintegration profiles |
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