JP2021028326A - Tablet comprising levetiracetam - Google Patents
Tablet comprising levetiracetam Download PDFInfo
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- JP2021028326A JP2021028326A JP2020143942A JP2020143942A JP2021028326A JP 2021028326 A JP2021028326 A JP 2021028326A JP 2020143942 A JP2020143942 A JP 2020143942A JP 2020143942 A JP2020143942 A JP 2020143942A JP 2021028326 A JP2021028326 A JP 2021028326A
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- tablet
- levetiracetam
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- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 27
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- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 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
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940071138 stearyl fumarate Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000010698 whale oil Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、溶出性が良好なレベチラセタム含有錠剤に関する。 The present invention relates to a levetiracetam-containing tablet having good dissolution.
レベチラセタムは、化学名：（２Ｓ）−２−（２−Ｏｘｏｐｙｒｒｏｌｉｄｉｎｅ−１−ｙｌ）ｂｕｔｙｒａｍｉｄｅ）で示される化合物である。レベチラセタムは、現在、てんかん患者の部分発作（二次性全般化発作を含む）、他の抗てんかん薬で十分な効果が認められないてんかん患者の強直間代発作に対する抗てんかん薬との併用療法などに用いられることが知られている（非特許文献１）。また、特許文献１には、レベチラセタム、並びに薬剤組成物の全重量に対して崩壊剤２．０〜９．０重量％、滑剤０．０〜３．０重量％、結合剤０．５〜６．０重量％、及び潤滑剤０．０〜１．０重量％を含む薬剤組成物が記載されている。 Levetiracetam is a compound represented by the chemical name: (2S) -2- (2-Oxyrrolidine-1-yl) butyramide). Levetiracetam is currently used in combination with antiepileptic drugs for partial epilepsy in patients with epilepsy (including secondary generalized seizures) and tonic seizures in patients with epilepsy who are not sufficiently effective with other antiepileptic drugs. It is known to be used for (Non-Patent Document 1). Further, Patent Document 1 describes levetyracetam and 2.0 to 9.0% by weight of a disintegrant, 0.0 to 3.0% by weight of a lubricant, and 0.5 to 6% of a binder based on the total weight of the drug composition. Pharmaceutical compositions containing 0.0% by weight and 0.0 to 1.0% by weight of lubricant are described.
また、特許文献２には、レベチラセタムと、フマル酸ステアリルナトリウム及びステアリン酸カルシウムの少なくともいずれかを含むことを特徴とするレベチラセタム含有医薬組成物が記載されている。 Further, Patent Document 2 describes a levetiracetam-containing pharmaceutical composition comprising levetiracetam and at least one of stearyl fumarate and calcium stearate.
しかしながら、レベチラセタム、クロスカルメロースナトリウム、及び硬化油等を含有するレベチラセタム錠剤については、記載されていない。 However, levetiracetam tablets containing levetiracetam, croscarmellose sodium, hydrogenated oil and the like are not described.
本発明の目的は、良好な溶出特性を有するレベチラセタム錠剤を提供することであり、更には、錠剤硬度、崩壊性も良好なレベチラセタム錠剤を提供することである。 An object of the present invention is to provide a levetiracetam tablet having good dissolution characteristics, and further to provide a levetiracetam tablet having good tablet hardness and disintegration property.
本発明は、レベチラセタム、クロスカルメロースナトリウム、並びにショ糖脂肪酸エステル、硬化油、ステアリン酸マグネシウム、及びステアリン酸カルシウムからなる群から選択される１種又は２種以上の添加剤を含有してなる錠剤に関する。 The present invention relates to tablets containing levetiracetam, sodium croscarmellose, and one or more additives selected from the group consisting of sucrose fatty acid esters, hydrogenated oils, magnesium stearate, and calcium stearate. ..
すなわち、本発明は、
（１）レベチラセタム、クロスカルメロースナトリウム、並びにショ糖脂肪酸エステル、硬化油、ステアリン酸マグネシウム、及びステアリン酸カルシウムからなる群から選択される１種又は２種以上の添加剤を含有してなる錠剤、
（２）添加剤がショ糖脂肪酸エステル及び／又は硬化油である前記（１）記載の錠剤、
（３）クロスカルメロースナトリウムの沈降体積が１０〜１８ｍｌである前記（１）〜（２）のいずれかに記載の錠剤、
（４）クロスカルメロースナトリウムを１錠あたり１〜１０重量％含有してなる前記（１）〜（３）のいずれかに記載の錠剤、
（５）硬化油を１錠あたり０．１〜３重量％含有してなる前記（１）〜（４）のいずれかに記載の錠剤、
（６）ショ糖脂肪酸エステルを１錠あたり０．１〜３重量％含有してなる前記（１）〜（４）のいずれかに記載の錠剤、
（７）レベチラセタムを１錠あたり８０〜８９％含有してなる前記（１）〜（６）のいずれかに記載の錠剤、に関する。That is, the present invention
(1) Tablets containing one or more additives selected from the group consisting of levetiracetam, croscarmellose sodium, and sucrose fatty acid ester, hydrogenated oil, magnesium stearate, and calcium stearate.
(2) The tablet according to (1) above, wherein the additive is a sucrose fatty acid ester and / or a hydrogenated oil.
(3) The tablet according to any one of (1) to (2) above, wherein the sedimentation volume of croscarmellose sodium is 10 to 18 ml.
(4) The tablet according to any one of (1) to (3) above, which contains 1 to 10% by weight of sodium croscarmellose per tablet.
(5) The tablet according to any one of (1) to (4) above, which contains 0.1 to 3% by weight of hydrogenated oil per tablet.
(6) The tablet according to any one of (1) to (4) above, which contains 0.1 to 3% by weight of sucrose fatty acid ester per tablet.
(7) The tablet according to any one of (1) to (6) above, which contains 80 to 89% of levetiracetam per tablet.
本発明によれば、特定の添加剤を選択することにより、レベチラセタムの錠剤からの速やかな溶出挙動を示し、更に、良好な錠剤硬度、崩壊性を有するレベチラセタム錠剤を提供することができる。 According to the present invention, by selecting a specific additive, it is possible to provide a levetiracetam tablet which exhibits rapid dissolution behavior of levetiracetam from a tablet and also has good tablet hardness and disintegration property.
以下に本発明のレベチラセタムを含む錠剤に関して説明する。 The tablet containing levetiracetam of the present invention will be described below.
本発明に用いられるレベチラセタムは、てんかん患者の部分発作（二次性全般化発作を含む）、他の抗てんかん薬で十分な効果が認められないてんかん患者の強直間代発作に対する抗てんかん薬との併用療法に用いられる。 Levetiracetam used in the present invention is used as an antiepileptic drug for partial epilepsy (including secondary generalized seizures) in epilepsy patients and tonic interstitial seizures in epilepsy patients for whom other antiepileptic drugs are not sufficiently effective. Used for combination therapy.
通常、成人にはレベチラセタムとして１日１０００ｍｇを１日２回に分けて経口投与する。なお、症状により１日３０００ｍｇを超えない範囲で適宜増減するが、増量は２週間以上の間隔をあけて１日用量として１０００ｍｇ以下ずつで行う。 In general, for adults, 1000 mg of levetiracetam is orally administered twice daily in divided doses. The dose may be adjusted according to the patient's symptoms within the range not exceeding 3000 mg daily, but the daily dose should be increased by 1000 mg or less at intervals of 2 weeks or more.
また、通常、４歳以上の小児にはレベチラセタムとして１日２０ｍｇ／ｋｇを１日２回に分けて経口投与する。なお、症状により１日６０ｍｇ／ｋｇを超えない範囲で適宜増減するが、増量は２週間以上の間隔をあけて１日用量として２０ｍｇ／ｋｇ以下ずつで行う。ただし、体重５０ｋｇ以上の小児では、成人と同じ用法・用量を用いる。 In addition, usually, for children aged 4 years or older, 20 mg / kg of levetiracetam is orally administered twice a day. The dose may be adjusted according to the patient's symptoms within the range not exceeding 60 mg / kg daily, but the daily dose should be increased by 20 mg / kg or less at intervals of 2 weeks or more. However, for children weighing 50 kg or more, use the same dosage and administration as for adults.
レベチラセタムの配合量は、錠剤全量に対して、８０〜９２％、ある態様として８５〜８９％である。 The blending amount of levetiracetam is 80 to 92%, in some embodiments 85 to 89%, based on the total amount of the tablet.
本明細書において沈降体積とは、１００ｍｌの共栓メスシリンダーに水７５ｍｌを入れ、試料１．５ｇを０．５ｇずつ激しく振り混ぜながら加え、更に水を加えて１００ｍｌとし、均一に分散するまで良く振り混ぜた後、４時間放置したときの、メスシリンダーから読み取った試料の沈降体積を意味する。 In the present specification, the sedimentation volume is defined as 100 ml of water in a 100 ml graduated cylinder, 1.5 g of a sample is added by vigorously shaking 0.5 g each, and water is further added to make 100 ml, which is good until uniformly dispersed. It means the sedimentation volume of the sample read from the measuring cylinder when left for 4 hours after shaking.
本発明に用いられるクロスカルメロースナトリウムとしては、製薬学的に許容されるものであれば、特に制限されない。ある態様として、沈降体積が１０〜１８ｍｌであるクロスカルメロースナトリウムであり、沈降体積が１０〜１８ｍｌであるクロスカルメロースナトリウムは、溶媒を水とした場合の沈降体積が１０〜１８ｍｌのクロスカルメロースナトリウムと規定される。具体的には、例えば、ある態様としてＫＩＣＣＯＬＡＴＥ ＮＤ−２００（ニチリン化学工業）、ＶＩＶＡＳＯＬ ＳＦ２００（ＪＲＳ ＰＨＡＲＭＡ）が挙げられる。ある態様としてＫＩＣＣＯＬＡＴＥ ＮＤ−２００（ニチリン化学工業）が挙げられる。 The croscarmellose sodium used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. In one embodiment, croscarmellose sodium having a sedimentation volume of 10 to 18 ml and croscarmellose sodium having a sedimentation volume of 10 to 18 ml have a sedimentation volume of 10 to 18 ml when the solvent is water. Defined as sodium. Specifically, for example, KICCOLATE ND-200 (Nichirin Chemical Industry Co., Ltd.) and VIVASOL SF200 (JRS PHARMA) can be mentioned as certain embodiments. One embodiment is KICCOLATE ND-200 (Nichirin Chemical Industry Co., Ltd.).
クロスカルメロースナトリウムの配合量は、錠剤全量に対して、１〜１０重量％、ある態様として２〜８重量％、ある態様として４〜６重量％である。 The blending amount of croscarmellose sodium is 1 to 10% by weight, 2 to 8% by weight in some embodiments, and 4 to 6 wt% in some embodiments, based on the total amount of the tablets.
本発明に用いられる硬化油としては、製薬学的に許容されているものであれば特に制限されない。硬化油としては、例えば、ヒマシ油、ナタネ油、綿実油、ダイズ油、ヤシ油、パーム核油、パーム油等の硬化植物油、或いは、牛脂、鯨油、魚油などの硬化動物油等が挙げられる。ある態様としては、ヒマシ油、ナタネ油、綿実油、ダイズ油、ヤシ油、パーム核油、パーム油等の硬化植物油が挙げられる。ある態様としては、ヒマシ油が挙げられる。 The hydrogenated oil used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples of the hydrogenated oil include hardened vegetable oils such as castor oil, rapeseed oil, cottonseed oil, soybean oil, palm oil, palm kernel oil and palm oil, and hardened animal oils such as beef fat, whale oil and fish oil. In one embodiment, hardened vegetable oils such as castor oil, rapeseed oil, cottonseed oil, soybean oil, palm oil, palm kernel oil and palm oil can be mentioned. In one embodiment, castor oil is mentioned.
硬化油の配合量は、錠剤全量に対して、０．１〜３重量％、ある態様として０．３〜２重量％、ある態様として０．６〜１．２重量％である。また、ショ糖脂肪酸エステルと合わせて使用してもよい。 The blending amount of the hydrogenated oil is 0.1 to 3% by weight, 0.3 to 2% by weight in some embodiments, and 0.6 to 1.2 wt% in some embodiments, based on the total amount of the tablets. It may also be used in combination with a sucrose fatty acid ester.
本発明に用いられるショ糖脂肪酸エステルとしては、製薬学的に許容されているものであれば特に制限されない。
ショ糖脂肪酸エステルの配合量は、錠剤全量に対して、０．１〜３重量％、ある態様として０．３〜２重量％、ある態様として０．６〜１．２重量％である。また、硬化油と合わせて使用してもよい。The sucrose fatty acid ester used in the present invention is not particularly limited as long as it is pharmaceutically acceptable.
The blending amount of the sucrose fatty acid ester is 0.1 to 3% by weight, 0.3 to 2% by weight in some embodiments, and 0.6 to 1.2 wt% in some embodiments, based on the total amount of the tablets. It may also be used in combination with hydrogenated oil.
本発明における錠剤は、素錠でもコーティング錠でもよく、口腔内崩壊錠であってもよい。 The tablet in the present invention may be an uncoated tablet, a coated tablet, or an orally disintegrating tablet.
本発明のレベチラセタムを含む錠剤には、本発明の所望の効果が達成される範囲で更に各種医薬品添加物が適宜使用され、製剤化される。かかる医薬品添加物としては、製薬学的に許容され、かつ薬理学的に許容されるものであれば特に制限されない。例えば、賦形剤、結合剤、崩壊剤、酸味料、発泡剤、甘味剤、香料、着色剤、緩衝剤、抗酸化剤、界面活性剤、フィルムコーティング剤等が使用される。 In the tablet containing levetiracetam of the present invention, various pharmaceutical additives are appropriately used and formulated as long as the desired effect of the present invention is achieved. The pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable. For example, excipients, binders, disintegrants, acidulants, foaming agents, sweeteners, fragrances, colorants, buffers, antioxidants, surfactants, film coating agents and the like are used.
賦形剤としては、例えば、乳糖、白糖、Ｄ−マンニトール、Ｄ−ソルビトール、デンプン、α化デンプン、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、カルメロースナトリウム、アラビアゴム、デキストリン、プルラン、軽質無水ケイ酸、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム等が挙げられる。 Excipients include, for example, lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, carmellose sodium, gum arabic, dextrin, pullulan, light anhydrous silicate. Examples thereof include acids, synthetic aluminum silicate, and magnesium aluminometasilicate.
結合剤としては、例えば、アラビアゴム、ヒプロメロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン、ポリビニルアルコール等が挙げられる。 Examples of the binder include gum arabic, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol and the like.
崩壊剤としては、例えば、トウモロコシデンプン、バレイショデンプン、カルメロースカルシウム、カルメロースナトリウム、低置換度ヒドロキシプロピルセルロース等が挙げられる。 Examples of the disintegrant include corn starch, potato starch, carmellose calcium, carmellose sodium, low-substituted hydroxypropyl cellulose and the like.
酸味料としては、例えば、クエン酸、酒石酸、リンゴ酸等が挙げられる。 Examples of the acidulant include citric acid, tartaric acid, malic acid and the like.
発泡剤としては、例えば、重曹等が挙げられる。 Examples of the foaming agent include baking soda and the like.
甘味剤としては、例えば、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、ソーマチン等が挙げられる。 Examples of the sweetener include sodium saccharin, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like.
香料としては、例えば、レモン、レモンライム、オレンジ、メントール等を挙げることができる。 Examples of the fragrance include lemon, lemon lime, orange, menthol and the like.
着色剤としては、例えば、食用黄色４号、食用黄色５号、食用赤色３号、食用赤色１０２号、食用青色３号、食用黄色４号アルミニウムレーキ、食用黄色５号アルミニウムレーキ、食用赤色３号アルミニウムレーキ、食用青色２号アルミニウムレーキ、黄色三二酸化鉄、三二酸化鉄等が挙げられる。着色剤はコーティング層にも使用することができる。 Examples of the colorant include edible yellow No. 4, edible yellow No. 5, edible red No. 3, edible red No. 102, edible blue No. 3, edible yellow No. 4 aluminum lake, edible yellow No. 5 aluminum lake, and edible red No. 3. Examples include aluminum lake, edible blue No. 2 aluminum lake, yellow iron sesquioxide, and iron sesquioxide. The colorant can also be used in the coating layer.
緩衝剤としては、クエン酸、コハク酸、フマル酸、酒石酸、アスコルビン酸又はその塩類、グルタミン酸、グルタミン、グリシン、アスパラギン酸、アラニン、アルギニン又はその塩類、酸化マグネシウム、酸化亜鉛、水酸化マグネシウム、リン酸、ホウ酸又はその塩類等が挙げられる。 As buffers, citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or its salts, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or its salts, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid. , Citric acid or salts thereof and the like.
抗酸化剤としては、例えば、アスコルビン酸、ジブチルヒドロキシトルエン、没食子酸プロピル等が挙げられる。 Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
界面活性剤としては、例えば、ポリソルベート８０、ラウリル硫酸ナトリウム、ポリオキシエチレン硬化ヒマシ油等が挙げられる。 Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil and the like.
フィルムコーティング剤としては、例えば、ヒプロメロース、ヒドロキシプロピルセルロース、ポリビニルアルコール、酸化チタン、タルク、プレミックスコーティング剤等が挙げられる。プレミックスコーティング剤として、ある態様として、オパドライＩＩ、オパドライＱＸ、オパドライａｍｂＩＩ、ある態様として、オパドライＩＩが挙げられる。 Examples of the film coating agent include hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, titanium oxide, talc, premix coating agent and the like. Examples of the premix coating agent include Opadry II, Opadry QX, and Opadry ambII, and some embodiments Opadry II.
本発明の錠剤は、粉砕、混合、造粒、乾燥、整粒、成形（打錠）、コーティング等の工程を含む、自体公知の方法により、製造することができる。詳細には、本発明の錠剤は、レベチラセタム、軽質無水ケイ酸、クロスカルメロースナトリウムを混合後、ＨＰＣ−Ｌ又はＨＰＣ−ＳＳＬ水溶液を結合液として流動層造粒し、乾燥、整粒し、クロスカルメロースナトリウム、結晶セルロース、滑沢剤を混合、打錠し、素錠を製した後、該素錠に対して、プレミックスコーティング剤であるオパドライＩＩで被覆されることにより、製造される。更に詳細には、素錠については、例えば、レベチラセタム、賦形剤、軽質無水ケイ酸、クロスカルメロースナトリウムを混合して、該混合物に対して、結合剤を製薬学的に許容される溶媒に溶解及び分散した結合剤溶液を噴霧・乾燥して得られた造粒物に、滑沢剤を配合して、成形（打錠）して素錠を製したり、或いは、レベチラセタム、賦形剤、軽質無水ケイ酸、クロスカルメロースナトリウム、滑沢剤を混合して、該混合物に対して、結合剤を製薬学的に許容される溶媒に溶解及び分散した結合剤溶液を噴霧・乾燥して得られた造粒物に、クロスカルメロースナトリウムを配合して、成形（打錠）して素錠を製したり、或いは、賦形剤、を混合して、該混合物に対して、レベタラセタム、結合剤を製薬学的に許容される溶媒に溶解及び分散した結合剤溶液を噴霧・乾燥して得られた造粒物に、滑沢剤を配合して、成形（打錠）して素錠を製する。また、賦形剤に対して、レベチラセタム、軽質無水ケイ酸、クロスカルメロースナトリウム、結合剤を製薬学的に許容される溶媒に溶解及び分散した結合剤溶液を噴霧・乾燥して得られた造粒物に、滑沢剤を配合して、成形（打錠）して素錠を製する。 The tablet of the present invention can be produced by a method known per se, which includes steps such as pulverization, mixing, granulation, drying, sizing, molding (tableting), and coating. Specifically, the tablet of the present invention is prepared by mixing levetylacetam, light silicic acid anhydride, and sodium croscarmellose, and then using HPC-L or an aqueous solution of HPC-SSL as a binder to form a fluidized bed, dry, sizing, and cloth. It is produced by mixing and tableting carmellose sodium, crystalline cellulose, and a fluidizing agent to prepare an uncoated tablet, and then coating the uncoated tablet with Opadry II, which is a premix coating agent. More specifically, for uncoated tablets, for example, levetylacetam, an excipient, light anhydrous silicic acid, and sodium croscarmellose are mixed, and the binder is used as a pharmaceutically acceptable solvent for the mixture. The granulated product obtained by spraying and drying the dissolved and dispersed binder solution is mixed with a lubricant and molded (tablet) to make an uncoated tablet, or levetylacetam, an excipient. , Light anhydrous silicic acid, croscarmellose sodium, and lubricant are mixed, and a binder solution in which the binder is dissolved and dispersed in a pharmaceutically acceptable solvent is sprayed and dried on the mixture. Croscarmellose sodium is blended with the obtained granules and molded (tablet) to make uncoated tablets, or excipients are mixed, and lebetaracetam, A binder solution dissolved and dispersed in a pharmaceutically acceptable solvent is sprayed and dried to obtain a granulated product, which is mixed with a lubricant, molded (tablet) and uncoated. To make. Further, a product obtained by spraying and drying a binder solution in which levetylacetam, light anhydrous silicic acid, croscarmellose sodium, and a binder are dissolved and dispersed in a pharmaceutically acceptable solvent with respect to the excipient. A lubricant is mixed with the granules and molded (tablet) to make an uncoated tablet.
コーティング錠は、素錠に対して、コーティング層が被覆されることにより、製造される。 A coated lock is manufactured by coating an uncoated lock with a coating layer.
以下に、実施例により本発明をさらに具体的に説明するが、本発明は下記の実施例に何ら限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.
レベチラセタム２５０．０ｇ、クロスカルメロースナトリウム（ニチリン化学工業 キッコレート ＮＤ−２００）５．５ｇ、軽質無水ケイ酸（日本アエロジル アエロジル２００）１．０ｇを混合した。次いで、目開き８５０μｍの篩を用いて解砕し、混合粉体とした。ヒドロキシプロピルセルロース（日本曹達 ＨＰＣ−ＳＳＬ）８．２ｇを水１５５．８ｇに溶解させ、結合液とした。混合粉体を流動層造粒機（パウレック ＭＰ−０１）に投入し、流動させながら結合液を噴霧し、造粒した。造粒終了後、流動層造粒機を用いて乾燥した。造粒物をパワーミル（ダルトン Ｐ−０４Ｓ スクリーン径０．５ｍｍ）を用いて整粒した。袋に整粒品とクロスカルメロースナトリウム５．５ｇ、結晶セルロース（旭化成 セオラス ＫＧ−１０００）３．４ｇ、ステアリン酸マグネシウム（太平化学産業植物性）３．４ｇを投入し混合を行い、打錠用顆粒とした。打錠用顆粒を、ロータリー式打錠機（菊水製作所 ＶＥＬ５）と、長径１６．４ｍｍ、短径７．７ｍｍのオーバル形状杵を用い、打錠圧力１０または１２ｋＮで打錠し、素錠を得た。オパドライ（Ｃｏｌｏｒｃｏｎ ＯＰＡＤＲＹ２）１００ｇを水５００ｇに溶解・分散させ、コーティング液とした。コーティング装置（パウレック製 ドリアコーター ＤＲＣ−３００）を用いて所定の質量となるまで素錠にコーティング液を噴霧しフィルムコーティングを行い実施例１の錠剤を得た（１錠あたり５６８．０ ｍｇ）。 250.0 g of levetiracetam, 5.5 g of croscarmellose sodium (Nichirin Kagaku Kogyo Kiccolate ND-200), and 1.0 g of light anhydrous silicic acid (Nihon Aerosil Aerosil 200) were mixed. Then, it was crushed using a sieve having an opening of 850 μm to obtain a mixed powder. 8.2 g of hydroxypropyl cellulose (Nippon Soda HPC-SSL) was dissolved in 155.8 g of water to prepare a binding solution. The mixed powder was put into a fluidized bed granulator (Paurek MP-01), and the binding liquid was sprayed while flowing to granulate. After completion of granulation, it was dried using a fluidized bed granulator. The granulated product was sized using a power mill (Dalton P-04S screen diameter 0.5 mm). Put the sized product, 5.5 g of croscarmellose sodium, 3.4 g of crystalline cellulose (Asahi Kasei Theoras KG-1000), and 3.4 g of magnesium stearate (Taipei Kagaku Sangyo vegetable) into a bag, mix them, and use them for tableting. It was made into granules. Using a rotary type tableting machine (Kikusui Seisakusho VEL5) and an oval-shaped punch with a major axis of 16.4 mm and a minor axis of 7.7 mm, the granules for tableting are locked at a locking pressure of 10 or 12 kN to obtain an uncoated tablet. It was. 100 g of Colorcon OPADRY2 was dissolved and dispersed in 500 g of water to prepare a coating liquid. Using a coating device (Doria coater DRC-300 manufactured by Paulec), a coating solution was sprayed onto the uncoated tablets until the mass reached a predetermined value, and film coating was performed to obtain tablets of Example 1 (568.0 mg per tablet).
ステアリン酸マグネシウム（太平化学産業 植物性）をステアリン酸カルシウム（太平化学産業）に変更した以外は、実施例１と同様の操作により、実施例２の錠剤を得た（１錠あたり５６８．０ ｍｇ）。 The tablets of Example 2 were obtained by the same operation as in Example 1 except that magnesium stearate (Taipei Chemical Industry) was changed to calcium stearate (Taipei Chemical Industry) (568.0 mg per tablet). ..
ステアリン酸マグネシウム（太平化学産業 植物性）を硬化油（フロイント産業 ラブリワックス１０１）に変更した以外は、実施例１と同様の操作により、実施例３の錠剤を得た（１錠あたり５６８．０ ｍｇ）。 The tablets of Example 3 were obtained by the same operation as in Example 1 except that magnesium stearate (Taipei Kagaku Sangyo vegetable) was changed to hydrogenated oil (Freund Sangyo Labrywax 101) (568.0 per tablet). mg).
ステアリン酸マグネシウム（太平化学産業 植物性）３．４ｇを硬化油（フロイント産業 ラブリワックス１０１）１．７ｇ及びショ糖脂肪酸エステル（三菱ケミカルフーズ サーフホープ ＳＥ ＰＨＡＲＭＡ Ｊ−１８１６）１．７ｇに変更した以外は、実施例１と同様の操作により、実施例４の錠剤を得た（１錠あたり５６８．０ ｍｇ）。 Other than changing 3.4 g of magnesium stearate (Taipei Kagaku Sangyo vegetable) to 1.7 g of hydrogenated oil (Freund Sangyo Loveli Wax 101) and 1.7 g of sucrose fatty acid ester (Mitsubishi Chemical Foods Surf Hope SE PHARMA J-1816) Obtained the tablets of Example 4 (568.0 mg per tablet) by the same operation as in Example 1.
レベチラセタム５０００ｇ、クロスカルメロースナトリウム（ニチリン化学工業 キッコレート ＮＤ−２００）１１０ｇ、軽質無水ケイ酸（日本アエロジル アエロジル２００）２０ｇを混合した。次いで、パワーミル（ダルトン Ｐ−３Ｓ スクリーン径０．５ｍｍ）を用いて解砕し、混合粉体とした。ヒドロキシプロピルセルロース（日本曹達 ＨＰＣ−ＳＳＬ）１６４ｇを水３１１６ｇに溶解させ、結合液とした。混合粉体を流動層造粒機（フロイント ＮＦＬＯ−５）に投入し、流動させながら結合液を噴霧し、造粒した。造粒終了後、流動層造粒機を用いて乾燥した。造粒物をパワーミル（ダルトン Ｐ−３Ｓ スクリーン径０．５ｍｍ）を用いて整粒した。袋に整粒品２６４．７ｇとクロスカルメロースナトリウム５．５ｇ、結晶セルロース（旭化成 セオラス ＫＧ−１０００）３．４ｇ、ショ糖脂肪酸エステル（三菱ケミカルフーズ サーフホープ ＳＥ ＰＨＡＲＭＡ Ｊ−１８１６）３．４ｇを投入し混合を行い、打錠用顆粒とした。打錠用顆粒を、ロータリー式打錠機（菊水製作所 ＶＥＬ５）と、長径１６．４ｍｍ、短径７．７ｍｍのオーバル形状杵を用い、打錠圧力１０ｋＮで打錠し、素錠を得た。オパドライ（Ｃｏｌｏｒｃｏｎ ＯＰＡＤＲＹ２）５０ｇを水２５０ｇに溶解・分散させ、コーティング液とした。コーティング装置（パウレック製 ドリアコーター ＤＲＣ−３００）を用いて所定の質量となるまで素錠にコーティング液を噴霧しフィルムコーティングを行い実施例５の錠剤を得た（１錠あたり５６８．０ ｍｇ）。 Levetiracetam 5000 g, croscarmellose sodium (Nichirin Chemical Industry Kiccolate ND-200) 110 g, and light anhydrous silicic acid (Japan Aerosil Aerosil 200) 20 g were mixed. Then, it was crushed using a power mill (Dalton P-3S screen diameter 0.5 mm) to obtain a mixed powder. 164 g of hydroxypropyl cellulose (Nippon Soda HPC-SSL) was dissolved in 3116 g of water to prepare a binding solution. The mixed powder was put into a fluidized bed granulator (Freund NFLO-5), and the binding liquid was sprayed while flowing to granulate. After completion of granulation, it was dried using a fluidized bed granulator. The granulated product was sized using a power mill (Dalton P-3S screen diameter 0.5 mm). 264.7 g of sized product, 5.5 g of croscarmellose sodium, 3.4 g of crystalline cellulose (Asahi Kasei Theoras KG-1000), and 3.4 g of sucrose fatty acid ester (Mitsubishi Chemical Foods Surf Hope SE PHARMA J-1816) in a bag. It was added and mixed to obtain granules for tableting. The granules for tableting were tableted with a rotary tableting machine (Kikusui Seisakusho VEL5) and an oval-shaped punch having a major axis of 16.4 mm and a minor axis of 7.7 mm at a locking pressure of 10 kN to obtain an uncoated tablet. 50 g of Colorcon OPADRY2 was dissolved and dispersed in 250 g of water to prepare a coating liquid. Using a coating device (Doria coater DRC-300 manufactured by Paulec), a coating solution was sprayed onto the uncoated tablets until the mass reached a predetermined value, and film coating was performed to obtain tablets of Example 5 (568.0 mg per tablet).
実施例１〜５で得られた錠剤の配合量を表１に示す。 The compounding amounts of the tablets obtained in Examples 1 to 5 are shown in Table 1.
《試験例１：溶出試験》
実施例１〜５で得られた錠剤について、溶出試験液として水を用い、第１７改正日本薬局方一般試験法の溶出試験法（パドル法）により試験を行なった。更に実施例３、４、５で得られた錠剤については、無包装、２５℃７５％ＲＨで１０日間保存後についても、溶出試験液として水を用い、第１７改正日本薬局方一般試験法の溶出試験法（パドル法）により試験を行なった。<< Test Example 1: Dissolution test >>
The tablets obtained in Examples 1 to 5 were tested by the dissolution test method (paddle method) of the 17th revised Japanese Pharmacopoeia general test method using water as the dissolution test solution. Furthermore, the tablets obtained in Examples 3, 4 and 5 were unpacked and stored at 25 ° C. 75% RH for 10 days, but water was used as the dissolution test solution, and the 17th revised Japanese Pharmacopoeia general test method was used. The test was carried out by the dissolution test method (paddle method).
溶出試験結果を表２に示す。 The dissolution test results are shown in Table 2.
結果、クロスカルメロースナトリウム（キッコレート ＮＤ−２００（沈降体積１０〜１８ｍｌ））を含有する実施例１〜５は、良好な溶出性を示した。更に実施例３、４、５については無包装、２５℃７５％ＲＨで１０日間保存後であっても、良好な溶出性が保たれていた。 As a result, Examples 1 to 5 containing croscarmellose sodium (Kiccolate ND-200 (precipitation volume 10 to 18 ml)) showed good elution. Further, in Examples 3, 4 and 5, good dissolution property was maintained even after storage at 25 ° C. and 75% RH for 10 days without packaging.
《試験例２：崩壊試験》
試験液として水を用い、第１７改正日本薬局方一般試験法の崩壊試験法により試験を実施した。試験は実施例１〜５で得られた錠剤の各々６錠で実施し、ストップウォッチを用いて崩壊時間を計測した。<< Test Example 2: Collapse test >>
Water was used as the test solution, and the test was carried out by the disintegration test method of the 17th revised Japanese Pharmacopoeia general test method. The test was carried out with 6 tablets each of the tablets obtained in Examples 1 to 5, and the disintegration time was measured using a stopwatch.
《試験例３：錠剤硬度測定》
シュロイニゲル錠剤硬度計を使用し、実施例１〜５で得られた錠剤の各々１０錠を測定した。<< Test Example 3: Tablet hardness measurement >>
Using a Schleunigel tablet hardness tester, 10 tablets of each of the tablets obtained in Examples 1 to 5 were measured.
《試験例４：摩損度試験》
第１７改正日本薬局方参考情報の錠剤の摩損度試験法により試験を実施した。試験は実施例１〜５で得られた錠剤のうち、６．５ｇにできるだけ近い量を試料として実施した。<< Test Example 4: Abrasion Degree Test >>
The test was carried out by the tablet abrasion degree test method of the 17th revised Japanese Pharmacopoeia reference information. The test was carried out using the tablets obtained in Examples 1 to 5 in an amount as close as possible to 6.5 g as a sample.
崩壊試験、錠剤硬度測定及び摩損度試験の結果を表３に示す。 Table 3 shows the results of the disintegration test, tablet hardness measurement and abrasion degree test.
結果、クロスカルメロースナトリウム（キッコレート ＮＤ−２００（沈降体積１０〜１８ｍｌ））とステアリン酸マグネシウム、ステアリン酸カルシウム、硬化油、ショ糖脂肪酸エステルを使用した実施例１〜５の錠剤では、錠剤硬度が７０Ｎ以上で、崩壊時間が６分３０秒以内であった。特に、硬化油、ショ糖脂肪酸エステルを使用した実施例３、４、５の錠剤では錠剤硬度が１００Ｎ以上で、崩壊時間が４分３０秒以内であった。 As a result, the tablets of Examples 1 to 5 using croscarmellose sodium (Kiccolate ND-200 (precipitation volume 10-18 ml)), magnesium stearate, calcium stearate, hydrogenated oil, and sucrose fatty acid ester had a tablet hardness of 70 N. As mentioned above, the collapse time was within 6 minutes and 30 seconds. In particular, the tablets of Examples 3, 4 and 5 using hydrogenated oil and sucrose fatty acid ester had a tablet hardness of 100 N or more and a disintegration time of 4 minutes and 30 seconds or less.
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| CN113398084A (en) * | 2021-07-02 | 2021-09-17 | 安徽省先锋制药有限公司 | Levetiracetam sustained release tablet and preparation method thereof |
| CN115350178A (en) * | 2022-08-24 | 2022-11-18 | 浙江京新药业股份有限公司 | Pharmaceutical composition containing levetiracetam |
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| CN113398084A (en) * | 2021-07-02 | 2021-09-17 | 安徽省先锋制药有限公司 | Levetiracetam sustained release tablet and preparation method thereof |
| CN115350178A (en) * | 2022-08-24 | 2022-11-18 | 浙江京新药业股份有限公司 | Pharmaceutical composition containing levetiracetam |
| CN115350178B (en) * | 2022-08-24 | 2024-04-26 | 浙江京新药业股份有限公司 | Pharmaceutical composition containing levetiracetam |
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Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20240416 |