JP7541322B2 - Levetiracetam-containing pharmaceutical composition - Google Patents
Levetiracetam-containing pharmaceutical composition Download PDFInfo
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- JP7541322B2 JP7541322B2 JP2020032632A JP2020032632A JP7541322B2 JP 7541322 B2 JP7541322 B2 JP 7541322B2 JP 2020032632 A JP2020032632 A JP 2020032632A JP 2020032632 A JP2020032632 A JP 2020032632A JP 7541322 B2 JP7541322 B2 JP 7541322B2
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- JP
- Japan
- Prior art keywords
- levetiracetam
- granules
- pharmaceutical composition
- hypromellose
- polyvinyl alcohol
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 45
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- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
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- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000010491 tara gum Nutrition 0.000 description 1
- 239000000213 tara gum Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
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- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、レベチラセタム含有顆粒を含む医薬組成物に関する。 The present invention relates to a pharmaceutical composition comprising levetiracetam-containing granules.
抗てんかん剤のレベチラセタムは、化学名が（２Ｓ）－２－（２－オキソピロリジン－１－イル）ブチラミドであり、下記構造式で表される化合物である。
レベチラセタム含有製剤の市販品として、イーケプラドライシロップとイーケプラ錠（大塚製薬株式会社）が知られている。イーケプラドライシロップは、レベチラセタム、Ｄ－マンニトール、ポビドン、アスパルテーム、及び香料を含む顆粒と軽質無水ケイ酸粉末との混合末である。また、イーケプラ錠は、レベチラセタム、クロスカルメロースナトリウム、マクロゴール６０００ＥＰ、軽質無水ケイ酸、ステアリン酸マグネシウム、部分ケン化ポリビニルアルコール、酸化チタン、マクロゴール４０００、タルク、黄色三二酸化鉄を含むフィルムコーティング錠である（非特許文献１）。 E Keppra dry syrup and E Keppra tablets (Otsuka Pharmaceutical Co., Ltd.) are known as commercially available levetiracetam-containing preparations. E Keppra dry syrup is a mixed powder of granules containing levetiracetam, D-mannitol, povidone, aspartame, and flavoring, and light anhydrous silicic acid powder. E Keppra tablets are film-coated tablets containing levetiracetam, croscarmellose sodium, macrogol 6000EP, light anhydrous silicic acid, magnesium stearate, partially saponified polyvinyl alcohol, titanium oxide, macrogol 4000, talc, and yellow ferric oxide (Non-Patent Document 1).
粉末や顆粒などのレベチラセタム造粒物は、静電付着し易いために、製造装置、計量器具、分包機、包装袋などに付着し易い。このため、製造時、調剤時、分包時、服用時にロスが生じ易い。また、分包量にバラツキが生じたり、頻繁に分包機に詰まるといった難点もある。
また、レベチラセタム造粒物は、保存すると製剤が固まる現象（ブロッキング）が発生し易く、また、塊をほぐしてもサラサラした流動状態になり難い。製剤が固まったり、流動性が低下すると、服用し難く、また吸収した水分により有効成分や添加物が変質する恐れもある。
また、レベチラセタム造粒物は、粒度別のレベチラセタム含有量の均一性が低い、即ち、顆粒の粒度によりレベチラセタムの濃度が異なる場合がある。このため、粒子径が異なることで容器内または分包作業時に顆粒の偏析が起きた場合は、レベチラセタムを均一に分包することができない。
Levetiracetam granules, such as powders and granules, are prone to electrostatic adhesion and therefore tend to adhere to manufacturing equipment, measuring instruments, packaging machines, packaging bags, etc. This leads to losses during manufacturing, dispensing, packaging, and administration. In addition, there are also problems such as variations in the amount of packaging and frequent clogging of packaging machines.
In addition, levetiracetam granules are prone to solidification (blocking) during storage, and even if the lumps are broken down, they are difficult to maintain a smooth flowing state. If the formulation solidifies or its flowability decreases, it becomes difficult to take, and there is also a risk that the absorbed moisture may cause the active ingredients and additives to deteriorate.
In addition, the levetiracetam granules have low uniformity of levetiracetam content by particle size, i.e., the concentration of levetiracetam may vary depending on the particle size of the granules. Therefore, if the granules are segregated in the container or during packaging due to the difference in particle size, levetiracetam cannot be packaged uniformly.
本発明は、レベチラセタム含有顆粒を含む医薬組成物であって、静電付着が抑制された医薬組成物を提供することを課題とする。
また、本発明は、レベチラセタム含有顆粒を含む医薬組成物であって、保存によるブロッキングや流動性の低下が抑制された医薬組成物を提供することを課題とする。
An object of the present invention is to provide a pharmaceutical composition comprising levetiracetam-containing granules, in which electrostatic adhesion is suppressed.
Another object of the present invention is to provide a pharmaceutical composition comprising levetiracetam-containing granules, which is inhibited from blocking or decreasing in fluidity due to storage.
本発明者は、上記課題を解決するために研究を重ね、以下の知見を得た。
(i) レベチラセタム含有顆粒の平均粒子径を２００μｍ以上にすることにより、静電付着が顕著に抑制される。
(ii) レベチラセタム含有顆粒は、コーティング剤として、特に、ヒプロメロース、及び／又はポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体を含む被覆層を備えることにより、保存によるブロッキング及び／又は流動性の低下が抑制される。
(iii) レベチラセタム含有顆粒を押出造粒法で造粒することにより、粒度別のレベチラセタム含有量の均一性が高くなる。
The present inventors have conducted extensive research to solve the above problems and have obtained the following findings.
(i) By making the average particle size of the levetiracetam-containing granules 200 μm or more, electrostatic adhesion is significantly suppressed.
(ii) The levetiracetam-containing granules are provided with a coating layer containing, as a coating agent, in particular, hypromellose and/or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, thereby preventing blocking and/or loss of fluidity due to storage.
(iii) By granulating the levetiracetam-containing granules using an extrusion granulation method, the uniformity of the levetiracetam content by particle size can be increased.
本発明は、上記知見に基づき完成されたものであり、下記の医薬組成物を提供する。
〔１〕 平均粒子径が２００μｍ以上であるレベチラセタム含有顆粒を含む医薬組成物。
〔２〕 レベチラセタム含有顆粒が押出造粒法又は流動層造粒法で製造されている、〔１〕に記載の医薬組成物。
〔３〕 ヒプロメロース、及びポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体からなる群より選ばれる少なくとも１種のコーティング剤を含む被覆層を備える、〔１〕又は〔２〕に記載の医薬組成物。
〔４〕 さらに、スクラロースを含む、〔１〕～〔３〕の何れかに記載の医薬組成物。
〔５〕 ヒプロメロース、及びポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体からなる群より選ばれる少なくとも１種のコーティング剤を含む被覆層を備えるレベチラセタム含有顆粒を含む医薬組成物。
〔６〕 レベチラセタム含有顆粒が押出造粒法又は流動層造粒法で製造されている、〔５〕に記載の医薬組成物。
〔７〕 さらに、スクラロースを含む、〔５〕又は〔６〕に記載の医薬組成物。
The present invention has been completed based on the above findings, and provides the following pharmaceutical composition.
[1] A pharmaceutical composition comprising levetiracetam-containing granules having an average particle size of 200 μm or more.
[2] The pharmaceutical composition according to [1], wherein the levetiracetam-containing granules are produced by extrusion granulation or fluidized bed granulation.
[3] The pharmaceutical composition according to [1] or [2], which has a coating layer containing at least one coating agent selected from the group consisting of hypromellose and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.
[4] The pharmaceutical composition according to any one of [1] to [3], further comprising sucralose.
[5] A pharmaceutical composition comprising levetiracetam-containing granules having a coating layer containing hypromellose and at least one coating agent selected from the group consisting of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymers.
[6] The pharmaceutical composition according to [5], wherein the levetiracetam-containing granules are produced by extrusion granulation or fluidized bed granulation.
[7] The pharmaceutical composition according to [5] or [6], further comprising sucralose.
本発明の第１の医薬組成物は、レベチラセタム含有顆粒の平均粒子径が２００μｍ以上であることにより、レベチラセタム含有顆粒の静電付着が顕著に抑えられている。このため、製造装置、薬さじなどの計量器具、分包機、包装袋などへの付着が極めて少なく、従来のレベチラセタム含有顆粒を含む製剤（例えば、イーケプラドライシロプ）に見られる、製造時、調剤又は計量時、分包時、服用時の薬剤ロスや、分包量のバラツキ、分包機の詰まりなどが生じ難い。このように、本発明の第１の医薬組成物は、従来のレベチラセタム含有製剤の欠点であるハンドリング性の低さが改善されている。 In the first pharmaceutical composition of the present invention, the average particle size of the levetiracetam-containing granules is 200 μm or more, and thus electrostatic adhesion of the levetiracetam-containing granules is significantly suppressed. As a result, adhesion to manufacturing equipment, measuring instruments such as medicine spoons, packaging machines, packaging bags, etc. is extremely low, and drug loss during manufacturing, dispensing or measuring, packaging, and administration, variation in packaged amount, clogging of packaging machines, etc., which are seen in conventional preparations containing levetiracetam-containing granules (e.g., E Keppra Dry Syrup), are unlikely to occur. In this way, the first pharmaceutical composition of the present invention improves on the poor handleability that is a drawback of conventional levetiracetam-containing preparations.
また、顆粒の造粒方法としては、押出造粒より流動層造粒の方が、生産効率が良いため汎用されている。しかし、後述するように、顆粒の粒度別のレべチラセタム含有量の均一性は押出造粒の方が優れるため、押出造粒を行いたい場合もある。押出造粒で得られたレベチラセタム含有顆粒は、流動層造粒で得られた同じ粒子径のレベチラセタム含有顆粒に比べて、静電付着が多い傾向にあるが、その場合でも、レベチラセタム含有顆粒の平均粒子径が２５０μｍ以上、中でも２６０μｍ以上、中でも２７０μｍ以上、中でも２８０μｍ以上であることにより、静電付着が顕著に抑えられる。 As a method for granulation, fluidized bed granulation is more widely used than extrusion granulation because it has better production efficiency. However, as described below, extrusion granulation is superior in terms of uniformity of levetiracetam content by granule size, so extrusion granulation may be desirable. Levetiracetam-containing granules obtained by extrusion granulation tend to have more electrostatic adhesion than levetiracetam-containing granules of the same particle size obtained by fluidized bed granulation. Even in such cases, electrostatic adhesion is significantly suppressed by setting the average particle size of the levetiracetam-containing granules to 250 μm or more, preferably 260 μm or more, preferably 270 μm or more, and preferably 280 μm or more.
また、本発明の第１の医薬組成物において、顆粒が、ヒプロメロース、及びポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体からなる群より選ばれる少なくとも1種のコーティング剤を含む被覆層を備えるときは、静電付着が一層効果的に抑制される。 In addition, in the first pharmaceutical composition of the present invention, when the granules have a coating layer containing at least one coating agent selected from the group consisting of hypromellose and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, electrostatic adhesion is more effectively suppressed.
また、本発明の第２の医薬組成物は、顆粒が、ヒプロメロース、及びポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体からなる群より選ばれる少なくとも1種のコーティング剤を含む被覆層を備えることにより、無包装状態で保存しても、吸湿によるブロッキング及び／又は流動性の低下が少ない。従って、保存した後も、服用し易い状態が保たれ、また水分による変質が抑制されている。 In addition, the second pharmaceutical composition of the present invention has a coating layer containing at least one coating agent selected from the group consisting of hypromellose and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, so that even when stored unpackaged, there is little blocking and/or loss of fluidity due to moisture absorption. Therefore, even after storage, the composition remains in an easy-to-take state and deterioration due to moisture is suppressed.
以下、本発明を詳細に説明する。
（１）第１の医薬組成物
本発明の第１の医薬組成物は、平均粒子径が２００μｍ以上であるレベチラセタム含有顆粒を含む医薬組成物である。
The present invention will be described in detail below.
(1) First pharmaceutical composition
The first pharmaceutical composition of the present invention is a pharmaceutical composition comprising levetiracetam-containing granules having an average particle size of 200 μm or more.
製剤形態
本発明の第１の医薬組成物の剤型は、レベチラセタム含有顆粒を用いて製造されたものであればよく、顆粒剤、ドライシロップ、カプセル剤（特に、硬カプセル剤）、顆粒を含む成分の打錠により得られる錠剤などが挙げられる。
何れの製剤も、レベチラセタム含有顆粒の他に、添加物を含む粉末及び／又は顆粒を含むことができる。例えば、レベチラセタム及び甘味料を含む顆粒と流動化剤を含むドライシロップが挙げられる。また、レベチラセタム含有顆粒と他の有効成分を含む顆粒との混合末も挙げられる。
Dosage form The dosage form of the first pharmaceutical composition of the present invention may be any dosage form produced using levetiracetam-containing granules, and examples of such dosage forms include granules, dry syrup, capsules (particularly hard capsules), and tablets obtained by compressing ingredients containing granules.
Any of the preparations may contain powder and/or granules containing additives in addition to levetiracetam-containing granules. For example, dry syrup containing granules containing levetiracetam and a sweetener and a flow agent may be used. Also, a mixed powder of levetiracetam-containing granules and granules containing other active ingredients may be used.
本発明の医薬組成物が錠剤である場合、顆粒は錠剤中で粒の形が打錠前と異なっている可能性があるが、このような場合も、本発明では「顆粒を含む」ことを意味する。錠剤は、コーティング剤を含む被覆層を有しない素錠であってもよく、或いは水不溶性ないしは水難溶性のコーティング剤、又は水溶性のコーティング剤を含む被覆層を有していてもよい。 When the pharmaceutical composition of the present invention is a tablet, the shape of the granules in the tablet may be different from that before tableting, but even in such a case, the present invention means that the composition "contains granules." The tablet may be a plain tablet that does not have a coating layer containing a coating agent, or may have a coating layer containing a water-insoluble or poorly water-soluble coating agent, or a water-soluble coating agent.
レベチラセタム
レベチラセタムは、薬学的に許容される塩であってもよい。
また、レベチラセタムは、無水物、半水和物、水和物の何れであってもよい。
Levetiracetam Levetiracetam may be a pharma- ceutically acceptable salt.
Levetiracetam may be in the form of anhydrous, hemihydrate or hydrate.
レベチラセタム含有顆粒の平均粒子径は、２２０μｍ以上、中でも２４０μｍ以上、中でも２６０μｍ以上、中でも２８０μｍ以上が好ましい。特に、２５０μｍ以上、中でも２６０μｍ以上、中でも２７０μｍ以上、中でも２８０μｍ以上であれば、押出造粒法でレベチラセタム含有顆粒を製造した場合も、静電付着が顕著に抑制される。また、レベチラセタム含有顆粒の平均粒子径は、１０００μｍ以下、中でも８５０μｍ以下、中でも６００μｍ以下が好ましい。５００μｍ以下、又は４００μｍ以下とすることもできる。この範囲が顆粒剤として使用し易い。
本発明において、レベチラセタム含有顆粒の平均粒子径は、ふるい分け法で測定した値である。
The average particle size of the levetiracetam-containing granules is preferably 220 μm or more, more preferably 240 μm or more, more preferably 260 μm or more, more preferably 280 μm or more. In particular, if the average particle size is 250 μm or more, more preferably 260 μm or more, more preferably 270 μm or more, more preferably 280 μm or more, electrostatic adhesion is significantly suppressed even when the levetiracetam-containing granules are produced by extrusion granulation. The average particle size of the levetiracetam-containing granules is preferably 1000 μm or less, more preferably 850 μm or less, more preferably 600 μm or less. It can also be 500 μm or less, or 400 μm or less. This range is easy to use as a granule.
In the present invention, the average particle size of the levetiracetam-containing granules is a value measured by a sieving method.
被覆層
本発明の第１の医薬組成物は、レベチラセタム含有顆粒の粒子径の設定により静電付着が抑制されているため、レベチラセタム含有顆粒がコーティングされていなくても、静電付着が抑制されている。但し、顆粒は、水不溶性ないしは水難溶性のコーティング剤、又は水溶性のコーティング剤を含む被覆層を備えていてもよい。
レベチラセタム含有顆粒が、コーティング剤として、特にヒプロメロース、及び／又はポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体を含む被覆層を備えるときは、静電付着が一層効果的に抑制される。また、保存によるブロッキング及び／又は流動性の低下が効果的に抑制される。ヒプロメロースとポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体の両方を含む場合、１層の被覆層に両コーティング剤が含まれていてもよく、各コーティング剤をそれぞれ含む２層の被覆層を備えていてもよい。
Coating layer In the first pharmaceutical composition of the present invention, electrostatic adhesion is suppressed by setting the particle size of the levetiracetam-containing granules, so that electrostatic adhesion is suppressed even if the levetiracetam-containing granules are not coated. However, the granules may have a coating layer containing a water-insoluble or poorly water-soluble coating agent or a water-soluble coating agent.
When the levetiracetam-containing granules have a coating layer containing, in particular, hypromellose and/or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer as a coating agent, electrostatic adhesion is more effectively suppressed. In addition, blocking and/or a decrease in fluidity due to storage are effectively suppressed. When both hypromellose and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer are contained, both coating agents may be contained in one coating layer, or two coating layers each containing one coating agent may be provided.
本発明の第１の医薬組成物において、レベチラセタム含有顆粒が被覆層を備える場合、平均粒子径は、被覆層も含めた顆粒全体について測定した値である。 In the first pharmaceutical composition of the present invention, when the levetiracetam-containing granules have a coating layer, the average particle size is a value measured for the entire granule including the coating layer.
ヒプロメロース、及び／又はポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体の何れを含む場合も、ヒプロメロース、及び／又はポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体の総配合量は、０．１重量％以上、中でも０．２重量％以上、中でも０．２５重量％以上、中でも０．５重量％以上、中でも１重量％以上、中でも１．３重量％以上が好ましい。この範囲であれば、静電付着抑制効果が十分に向上する。また、保存によるブロッキング及び／又は流動性の低下が十分に抑制される。また、コーティング剤の総配合量は、５重量％以下、中でも３重量％以下、中でも２重量％以下が好ましい。この範囲であれば、顆粒として使用し易い。
この総配合量は、顆粒剤又はドライシロップでは、医薬組成物（製剤）の全量に対する比率であり、硬カプセル剤ではカプセル内に収容される成分の全量に対する比率であり、軟カプセル剤ではカプセル基剤と混合される成分の全量に対する比率であり、錠剤では、錠剤製造に供される顆粒の全量に対する比率である。
In the case where either hypromellose and/or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is contained, the total amount of hypromellose and/or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is 0.1% by weight or more, preferably 0.2% by weight or more, more preferably 0.25% by weight or more, more preferably 0.5% by weight or more, more preferably 1% by weight or more, and more preferably 1.3% by weight or more. Within this range, the electrostatic adhesion suppression effect is sufficiently improved. In addition, blocking and/or a decrease in fluidity due to storage is sufficiently suppressed. In addition, the total amount of the coating agent is preferably 5% by weight or less, more preferably 3% by weight or less, and more preferably 2% by weight or less. Within this range, it is easy to use as granules.
For granules or dry syrups, this total blend amount is the ratio to the total amount of the pharmaceutical composition (formulation); for hard capsules, it is the ratio to the total amount of ingredients contained in the capsule; for soft capsules, it is the ratio to the total amount of ingredients mixed with the capsule base; and for tablets, it is the ratio to the total amount of granules used in tablet production.
ヒプロメロース、及び／又はポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体を含む被覆層は、さらに他のコーティング剤を含むことができる。また、レベチラセタム含有顆粒は、ヒプロメロース、及び／又はポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体を含む被覆層の他に、別のコーティング剤を含む被覆層を備えていてもよい。 The coating layer containing hypromellose and/or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer may further contain other coating agents. The levetiracetam-containing granule may also have a coating layer containing another coating agent in addition to the coating layer containing hypromellose and/or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.
添加物
何れの剤型の場合も、本発明の医薬組成物は、賦形剤、結合剤、崩壊剤、滑沢剤、流動化剤、着色剤、矯味剤、甘味剤、香料、保存剤又は防腐剤などの添加物を含むことができる。添加物は、１種を単独で、又は２種以上を組み合わせて使用できる。
Regardless of the dosage form, the pharmaceutical composition of the present invention may contain additives such as excipients, binders, disintegrants, lubricants, flow agents, colorants, flavorings, sweeteners, flavorings, preservatives, or antiseptics. The additives may be used alone or in combination of two or more.
賦形剤としては、例えば、乳糖水和物、白糖、マルトース、果糖、ブドウ糖（デキストロース）、トレハロースのような糖類；マンニトール（特に、Ｄ－マンニトール）、マルチトール、ソルビトール、キシリトール、エリスリトール、ラクチトールのような糖アルコール；デンプン、アルファー化デンプン、部分アルファー化デンプンのようなデンプン類；結晶セルロースのようなセルロース類；デキストリンなどが挙げられる。 Examples of excipients include sugars such as lactose hydrate, sucrose, maltose, fructose, glucose (dextrose), and trehalose; sugar alcohols such as mannitol (especially D-mannitol), maltitol, sorbitol, xylitol, erythritol, and lactitol; starches such as starch, pregelatinized starch, and partially pregelatinized starch; celluloses such as crystalline cellulose; and dextrin.
結合剤としては、例えば、メチルセルロース、エチルセルロース、カルボキシメチルセルロース、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（ヒプロメロース）、クロスカルメロースナトリウムのようなセルロース類；ポビドン；デンプン；ゼラチン；トラガントゴム；ポリビニルアルコール；塩基性（メタ）アクリレートコポリマーなどが挙げられる。 Binders include, for example, celluloses such as methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), and croscarmellose sodium; povidone; starch; gelatin; tragacanth gum; polyvinyl alcohol; and basic (meth)acrylate copolymers.
崩壊剤としては、例えば、クロスポビドン；カルボキシメチルセルロース（カルメロース）、カルメロースナトリウム、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウムのようなセルロース類；デンプン、アルファー化デンプン、部分アルファー化デンプン、カルボキシメチルスターチナトリウム（デンプングリコール酸ナトリウム）のようなデンプン類；デキストリン；ケイ酸カルシウムなどが挙げられる。 Examples of disintegrants include crospovidone; celluloses such as carboxymethylcellulose (carmellose), carmellose sodium, carmellose calcium, low-substituted hydroxypropylcellulose, and croscarmellose sodium; starches such as starch, pregelatinized starch, partially pregelatinized starch, and sodium carboxymethyl starch (sodium starch glycolate); dextrin; and calcium silicate.
滑沢剤としては、例えば、ステアリン酸、ステアリン酸塩（ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸アルミニウム、ステアリン酸亜鉛など）、ステアリン酸塩エステル（フマル酸ステアリルナトリウム、モノステアリン酸グリセリン、パルミトステアリン酸グリセリンなど）、ラウリル硫酸ナトリウム、ポリエチレングリコール、タルク、ショ糖脂肪酸エステル、酒石酸ナトリウムカリウム、含水二酸化ケイ素などが挙げられる。 Examples of lubricants include stearic acid, stearates (magnesium stearate, calcium stearate, aluminum stearate, zinc stearate, etc.), stearate esters (sodium stearyl fumarate, glyceryl monostearate, glyceryl palmitostearate, etc.), sodium lauryl sulfate, polyethylene glycol, talc, sucrose fatty acid esters, sodium potassium tartrate, and hydrated silicon dioxide.
流動化剤としては、例えば、メタケイ酸アルミン酸マグネシウム、軽質無水ケイ酸などが挙げられる。 Examples of flow agents include magnesium aluminometasilicate and light anhydrous silicic acid.
着色剤としては、例えば、黄色三二酸化鉄、三二酸化鉄、酸化チタン、食用タール色素、天然色素などが挙げられる。 Coloring agents include, for example, yellow ferric oxide, ferric oxide, titanium oxide, edible tar dyes, and natural dyes.
矯味剤としては、例えば、シクロデキストリン、クエン酸、クエン酸ナトリウム、アスコルビン酸、酒石酸、リンゴ酸、グリシン、アラニン、テルペン類（リモネン、ピネン、ゲラニオール、メントール、ボルネオール、メントン、カンフル、オイゲノールなど）、テルペンを含有する精油（オレンジ油、ハッカ油、ユーカリ油、レモン油、ケイヒ油、ラベンダー油、スペアミントなど）などが挙げられる。 Examples of flavoring agents include cyclodextrin, citric acid, sodium citrate, ascorbic acid, tartaric acid, malic acid, glycine, alanine, terpenes (limonene, pinene, geraniol, menthol, borneol, menthone, camphor, eugenol, etc.), and essential oils containing terpenes (orange oil, peppermint oil, eucalyptus oil, lemon oil, cinnamon oil, lavender oil, spearmint, etc.).
甘味剤としては、例えば、マンニトール、ショ糖、スクラロース、アスパルテーム、ステビア、アセスルファムカリウム、還元麦芽糖水あめ、ソルビット、果糖、乳糖水和物、キシリトール、エリスリトール、ソルビトール、甘草およびその抽出物、グリチルリチン酸、甘茶、ソーマチンなどが挙げられる。中でも、本発明の効果を得る上で、スクラロースが好ましい。 Examples of sweeteners include mannitol, sucrose, sucralose, aspartame, stevia, acesulfame potassium, reduced maltose syrup, sorbitol, fructose, lactose hydrate, xylitol, erythritol, sorbitol, licorice and its extracts, glycyrrhizic acid, sweet tea, and thaumatin. Among these, sucralose is preferred for achieving the effects of the present invention.
保存剤又は防腐剤としては、例えば、パラオキシ安息香酸メチル、パラオキシ安息香酸エチルのようなパラベン類、安息香酸、エタノール、エデト酸四ナトリウム、サリチル酸、ソルビトール、ソルビン酸、グリセリン、クロロブタノール、フェノール、プロピレングリコール、ベンジルアルコールなどが挙げられる。 Examples of preservatives or antiseptics include parabens such as methyl parahydroxybenzoate and ethyl parahydroxybenzoate, benzoic acid, ethanol, tetrasodium edetate, salicylic acid, sorbitol, sorbic acid, glycerin, chlorobutanol, phenol, propylene glycol, and benzyl alcohol.
コーティング剤
ヒプロメロース及びポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体以外のコーティング剤としては、水溶性のものでは、例えば、キサンタンガム、カラヤガム、ローカストビーンガム、トラガントガム、グァーガム、アカシアガム、タマリンドガム、タラガム、アラビアゴム、カルナウバロウ、アルギン酸、アルギン酸ナトリウム、アルファー化デンプン、カゼインナトリウム、カラギーナン、カルボキシビニルポリマー、カルボキシメチルスターチナトリウム、ショ糖脂肪酸エステル、デキストラン、デキストリン、プルラン、キチン、キトサン、ガラクトマンナン、カゼイン、ゼラチン、水溶性プルランエーテル（プルランメチルエーテル、プルランエチルエーテル、プルランプロピルエーテルなど）、水溶性プルランエステル（プルランアセテート、プルランブチレートなど）、寒天、ビニル樹脂（ポビドン、コポリビドン、酢酸ポリビニル、ポリビニルアルコール－ポリエチレングリコールコポリマーなど）、ポリオキシエチレン－ポリオキシプロピレングリコール、マクロゴール、グリチルリチン酸、糖類（白糖、果糖、乳糖、マルトース、ブドウ糖、シクロデキストリンなど）、糖アルコール（マンニトール、キシリトール、マルチトール、ソルビトールなど）、オパドライ（登録商標）などが挙げられる。
Coating agents other than hypromellose and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer include, for example, water-soluble coating agents such as xanthan gum, karaya gum, locust bean gum, tragacanth gum, guar gum, acacia gum, tamarind gum, tara gum, gum arabic, carnauba wax, alginic acid, sodium alginate, pregelatinized starch, sodium caseinate, carrageenan, carboxyvinyl polymer, sodium carboxymethyl starch, sucrose fatty acid ester, dextran, dextrin, pullulan, chitin, chitosan, galactomannan, casein, gelatin, Examples of the water-soluble pullulan ethers include water-soluble pullulan ethers (pullulan methyl ether, pullulan ethyl ether, pullulan propyl ether, etc.), water-soluble pullulan esters (pullulan acetate, pullulan butyrate, etc.), agar, vinyl resins (povidone, copolyvidone, polyvinyl acetate, polyvinyl alcohol-polyethylene glycol copolymer, etc.), polyoxyethylene-polyoxypropylene glycol, macrogol, glycyrrhizic acid, sugars (sucrose, fructose, lactose, maltose, glucose, cyclodextrin, etc.), sugar alcohols (mannitol, xylitol, maltitol, sorbitol, etc.), and Opadry (registered trademark).
また、水不溶性又は水難溶性のコーティング剤としては、例えば、セルロース系コーティング剤（メチルセルロース、エチルセルロース、ヒドロキシエチルセルロース、ヒドロキプロピルセルロース、ヒドロキプロピルセルロースフタル酸エステル、カルボキシメチルエチルセルロース、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ナトリウム、フタル酸ヒプロメロース、酢酸コハク酸ヒプロメロース、酢酸セルロース、酢酸フタル酸セルロースなど）、ビニル樹脂（クロスポビドン、ポリビニルアルコール、ポリビニルアセタールジエチルアミノアセテート、酢酸フタル酸ポリビニルなど）、メタクリレートポリマー又はメタクリル酸ポリマー、ポリシロキサン系コーティング剤（ジメチルポリシロキサン、ジメチルポリシロキサン・二酸化ケイ素混合物など）などが挙げられる。 Examples of water-insoluble or poorly water-soluble coating agents include cellulose-based coating agents (methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylcellulose phthalate, carboxymethylethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hypromellose phthalate, hypromellose acetate succinate, cellulose acetate, cellulose acetate phthalate, etc.), vinyl resins (crospovidone, polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, polyvinyl acetate phthalate, etc.), methacrylate polymers or methacrylic acid polymers, polysiloxane-based coating agents (dimethylpolysiloxane, dimethylpolysiloxane-silicon dioxide mixture, etc.), etc.
メタクリレートポリマー又はメタクリル酸ポリマーとしては、レーム社のアミノアルキルメタクリレートコポリマーＥ（オイドラギットＥ１００、ＥＰＯなど）、メタクリル酸コポリマーＬＤ（オイドラギットＬ３０Ｄ－５５、Ｌ１００－５５など）、メタクリル酸コポリマーＬ（オイドラギットＬ１００など）、メタクリル酸コポリマーＳ（オイドラギットＳ１００など）、アンモニオアルキルメタクリレートコポリマー（オイドラギットＲＬ１００、ＲＬＰＯ、ＲＳ１００、ＲＳＰＯ、ＲＬ３０Ｄ、ＲＳ３０Ｄなど）、アクリル酸エチル・メタクリル酸メチルコポリマー（オイドラギットＮＥ３０Ｄなど）などが挙げられる。 Examples of methacrylate polymers or methacrylic acid polymers include Rehm's aminoalkyl methacrylate copolymer E (Eudragit E100, EPO, etc.), methacrylic acid copolymer LD (Eudragit L30D-55, L100-55, etc.), methacrylic acid copolymer L (Eudragit L100, etc.), methacrylic acid copolymer S (Eudragit S100, etc.), ammonioalkyl methacrylate copolymer (Eudragit RL100, RLPO, RS100, RSPO, RL30D, RS30D, etc.), and ethyl acrylate-methyl methacrylate copolymer (Eudragit NE30D, etc.).
コーティング層には可塑剤などの添加物を配合することができる。可塑剤としては、ポリエチレングリコール、プロピレングリコール、グリセリン、トリアセチン（グリセリン三酢酸）のようなグリセリン脂肪酸エステル、流動パラフィン、ソルビタンモノラウレート、モノステアリン、クエン酸トリエチル、クエン酸トリブチル、フタル酸ジエチル、フタル酸ジブチル、セバシン酸ジエチル、セバシン酸ジブチル、ポロキサマー、ポリオキシエチレン硬化ヒマシ油などが挙げられる。 Additives such as plasticizers can be blended into the coating layer. Examples of plasticizers include polyethylene glycol, propylene glycol, glycerin, glycerin fatty acid esters such as triacetin (glycerin triacetate), liquid paraffin, sorbitan monolaurate, monostearin, triethyl citrate, tributyl citrate, diethyl phthalate, dibutyl phthalate, diethyl sebacate, dibutyl sebacate, poloxamer, and polyoxyethylene hydrogenated castor oil.
製造方法
顆粒は、レベチラセタムと添加物を含む組成物を、常法に従い、湿式又は乾式で造粒し、必要に応じて乾燥、整粒することにより製造することができる。湿式造粒法としては、流動層造粒法、撹拌造粒法、転動造粒法、押出造粒法、破砕造粒法、練合造粒法などが挙げられ、乾式造粒法としては、圧片造粒法、ブリケット造粒法、溶融造粒法などが挙げられる。
中でも、湿式造粒法が好ましく、流動層造粒法又は押出造粒法がより好ましく、粒度別のレベチラセタム含有量の均一性が高い顆粒が得られる点で、押出造粒法が特に好ましい。押出造粒法により得られる顆粒は、球状ではなく円柱状又は長球状をしている。本発明は、レベチラセタムを含む平均粒子径２００μｍ以上の顆粒を押出造粒法で製造する工程を含むレベチラセタム含有医薬組成物の製造方法を包含する。
Granules can be produced by wet or dry granulating a composition containing levetiracetam and additives according to a conventional method, and drying and sieving the granules as necessary. Examples of wet granulation methods include fluidized bed granulation, stirring granulation, rolling granulation, extrusion granulation, crushing granulation, and kneading granulation, while examples of dry granulation methods include flake granulation, briquette granulation, and melt granulation.
Among them, wet granulation is preferred, fluidized bed granulation or extrusion granulation is more preferred, and extrusion granulation is particularly preferred since it can produce granules with high uniformity of levetiracetam content by particle size. Granules obtained by extrusion granulation are cylindrical or spheroidal rather than spherical. The present invention encompasses a method for producing a pharmaceutical composition containing levetiracetam, comprising the step of producing granules containing levetiracetam and having an average particle size of 200 μm or more by extrusion granulation.
錠剤は、上記のようにして得られた造粒物を打錠するか、又は得られた造粒物と１種以上の添加物とを混合して打錠する方法により製造することができる。また、錠剤は口腔内崩壊錠とすることができる。口腔内崩壊錠は、添加物の種類や配合量、打錠圧などを適宜設定することにより、当業者であれば製造できる。
硬カプセル剤は、ゼラチン、ヒドロキシプロピルメチルセルロースのような硬カプセル内に顆粒を充填することにより製造することができる。
The tablets can be produced by compressing the granulated product obtained as described above, or by mixing the granulated product obtained with one or more additives and compressing the mixture. The tablets can be orally disintegrating tablets. Those skilled in the art can produce orally disintegrating tablets by appropriately setting the type and amount of additives, tableting pressure, etc.
Hard capsules can be prepared by filling the granules into a hard capsule material such as gelatin, hydroxypropylmethylcellulose, etc.
（２）第２の医薬組成物
本発明の第２の医薬組成物は、ヒプロメロース、及びポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体からなる群より選ばれる少なくとも１種のコーティング剤を含む被覆層を備えるレベチラセタム含有顆粒を含む医薬組成物である。
(2) Second Pharmaceutical Composition The second pharmaceutical composition of the present invention is a pharmaceutical composition comprising levetiracetam-containing granules having a coating layer comprising hypromellose and at least one coating agent selected from the group consisting of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.
製剤形態
本発明の第２の医薬組成物の剤型は、上記説明した本発明の第１の医薬組成物と同じである。
但し、本発明の第２の医薬組成物において、「顆粒」は平均粒子径２００μｍ未満の粒子も含む。従って、一般に細粒剤、散剤と称されるものも、ここでは「顆粒」に含まれる。
Dosage Form The dosage form of the second pharmaceutical composition of the present invention is the same as that of the first pharmaceutical composition of the present invention described above.
However, in the second pharmaceutical composition of the present invention, the term "granules" also includes particles having an average particle size of less than 200 μm. Therefore, what are generally called fine granules or powders are also included in the term "granules" herein.
被覆層
本発明の第２の医薬組成物は、コーティング剤として、特に、ヒプロメロース、及び／又はポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体を含む被覆層を備えるため、吸湿によるブロッキングや流動性低下が抑制されている。
ヒプロメロースとポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体の両方を含む場合、１層の被覆層に両コーティング剤が含まれていてもよく、各コーティング剤をそれぞれ含む２層の被覆層を備えていてもよい。
Coating Layer The second pharmaceutical composition of the present invention has a coating layer containing, in particular, hypromellose and/or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer as a coating agent, thereby suppressing blocking and loss of fluidity due to moisture absorption.
When both hypromellose and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer are contained, both coating agents may be contained in one coating layer, or two coating layers each containing one coating agent may be provided.
ヒプロメロース、及び／又はポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体の総配合量は、０．１重量％以上、中でも０．２重量％以上、中でも０．２５重量％以上、中でも０．５重量％以上、中でも１重量％以上、中でも１．３重量％以上が好ましい。この範囲であれば、吸湿によるブロッキングや流動性を十分に抑制できる。また、このコーティング剤の総配合量は、５重量％以下、中でも３重量％以下、中でも２重量％以下が好ましい。この範囲であれば、顆粒として使用し易い。
この総配合量は、顆粒剤又はドライシロップでは、医薬組成物（製剤）の全量に対する比率であり、硬カプセル剤ではカプセル内に収容される成分の全量に対する比率であり、軟カプセル剤ではカプセル基剤と混合される成分の全量に対する比率であり、錠剤では、錠剤製造に供される顆粒の全量に対する比率である。
The total amount of hypromellose and/or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer is preferably 0.1% by weight or more, more preferably 0.2% by weight or more, more preferably 0.25% by weight or more, more preferably 0.5% by weight or more, more preferably 1% by weight or more, and more preferably 1.3% by weight or more. Within this range, blocking and fluidity due to moisture absorption can be sufficiently suppressed. In addition, the total amount of the coating agent is preferably 5% by weight or less, more preferably 3% by weight or less, and more preferably 2% by weight or less. Within this range, it is easy to use as granules.
For granules or dry syrups, this total blend amount is the ratio to the total amount of the pharmaceutical composition (formulation); for hard capsules, it is the ratio to the total amount of ingredients contained in the capsule; for soft capsules, it is the ratio to the total amount of ingredients mixed with the capsule base; and for tablets, it is the ratio to the total amount of granules used in tablet production.
ヒプロメロース、及び／又はポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体を含む被覆層は、さらに他のコーティング剤を含むことができる。また、レベチラセタム含有顆粒は、ヒプロメロース、及び／又はポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体を含む被覆層の他に、別のコーティング剤を含む被覆層を備えていてもよい。 The coating layer containing hypromellose and/or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer may further contain other coating agents. The levetiracetam-containing granule may also have a coating layer containing another coating agent in addition to the coating layer containing hypromellose and/or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.
レベチラセタム含有顆粒の大きさは、平均粒子径２００～６００μｍとすることができる。 The size of the levetiracetam-containing granules can be an average particle size of 200 to 600 μm.
レベチラセタムは、塩であってもよく、無水物、半水和物、水和物の何れであってもよいことは本発明の第１の医薬組成物と同じである。
また、配合できる添加物、ヒプロメロース及びポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体以外の使用できるコーティング剤、並びに医薬組成物の製造方法も、本発明の第１の医薬組成物について述べたとおりである。本発明は、レベチラセタム含有顆粒を押出造粒法で製造する工程と、得られた顆粒に、ヒプロメロース及び／又はポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体を含む被覆層を施す工程を含む、レベチラセタム含有医薬組成物の製造方法を包含する。
As in the first pharmaceutical composition of the present invention, levetiracetam may be in the form of a salt, anhydrous, hemihydrate or hydrate.
In addition, additives that can be blended, coating agents that can be used other than hypromellose and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and a method for producing the pharmaceutical composition are also the same as those described for the first pharmaceutical composition of the present invention. The present invention encompasses a method for producing a pharmaceutical composition containing levetiracetam, comprising the steps of producing levetiracetam-containing granules by extrusion granulation and providing the obtained granules with a coating layer containing hypromellose and/or polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.
以下、実施例を挙げて、本発明をより詳細に説明するが、本発明はこれらに限定されない。
（１）顆粒の製造
実施例１
流動化剤及び香料以外の成分を流動層造粒装置（フロイント産業株式会社製，FLO-LABO）を用いて造粒及び乾燥し、篩を用いて整粒した。そこに流動化剤及び香料を加え混合した。
The present invention will be described in more detail below by way of examples, but the present invention is not limited to these.
(1) Production of granules
Example 1
The ingredients other than the fluidizing agent and the flavoring were granulated and dried using a fluidized bed granulator (FLO-LABO, manufactured by Freund Corporation), and the granules were sized using a sieve. The fluidizing agent and the flavoring were then added and mixed.
実施例２、３、比較例１～３
流動化剤及び香料以外の成分を押出造粒装置（株式会社アーステクニカ製，ハイスピードミキサFS-GS-40J）により混錬し、得られた混練物を、押出造粒装置（株式会社ダルトン社製，押出造粒機 バスケットリューザー BR-150）で造粒し、乾燥機で乾燥させ、篩で整粒した。そこに流動化剤及び香料を加え混合した。
Examples 2 and 3, Comparative Examples 1 to 3
The ingredients other than the flow agent and the flavoring were mixed using an extrusion granulator (High Speed Mixer FS-GS-40J, manufactured by Earth Technica Co., Ltd.), and the resulting mixture was granulated using an extrusion granulator (Basket Granulator BR-150, manufactured by Dalton Co., Ltd.), dried in a dryer, and sized using a sieve. The flow agent and flavoring were then added and mixed.
実施例４～６
流動層造粒装置（フロイント産業株式会社製，流動層造粒乾燥機NFL (O) -15SJまたはFLO-LABO）を用いて、実施例２の顆粒にヒプロメロースを含むコーティングを施した。そこに流動化剤及び香料を加え混合した。製剤の全量に対するヒプロメロースの使用量は、それぞれ、０．２５重量％、１．５重量％、３．０重量％とした。
Examples 4 to 6
Using a fluidized bed granulator (fluidized bed granulator dryer NFL (O)-15SJ or FLO-LABO, manufactured by Freund Corporation), the granules of Example 2 were coated with a coating containing hypromellose. A flow agent and a flavor were added and mixed thereto. The amounts of hypromellose used relative to the total amount of the preparation were 0.25 wt%, 1.5 wt%, and 3.0 wt%, respectively.
実施例７
流動層造粒装置（フロイント産業株式会社製，流動層造粒乾燥機NFL(O)-15SJまたはFLO-LABO）を用いて、実施例２の顆粒にポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体を含むコーティングを施した。そこに流動化剤及び香料を加え混合した。製剤の全量に対するポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体の使用量は、１．５重量％とした。
Example 7
Using a fluidized bed granulator (fluidized bed granulator dryer NFL(O)-15SJ or FLO-LABO, manufactured by Freund Corporation), the granules of Example 2 were coated with a coating containing polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. A fluidizer and a flavor were added and mixed thereto. The amount of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer used relative to the total amount of the preparation was 1.5% by weight.
実施例８
押出造粒装置（株式会社アーステクニカ製，ハイスピードミキサFS-GS-40J）により製した混練物を、押出造粒装置（株式会社ダルトン社製，押出造粒機 バスケットリューザー BR-150）で造粒、乾燥機で乾燥、篩で整粒し、レベチラセタム含有顆粒を得た。そこに流動化剤及び香料を加え混合した。
Example 8
The kneaded material produced by an extrusion granulator (High-speed mixer FS-GS-40J, manufactured by Earth Technica Co., Ltd.) was granulated by an extrusion granulator (Basket granulator BR-150, manufactured by Dalton Co., Ltd.), dried in a dryer, and sized by a sieve to obtain levetiracetam-containing granules. A flow agent and flavor were added and mixed thereto.
実施例１～８、及び比較例１～３の顆粒の組成を表１に示す。
（２）静電付着の抑制の評価
帯電後付着量の測定
実施例１～５、比較例１～３の各顆粒と、イーケプラドライシロップ５０％を、それぞれ５０ｍｌ容量のガラス瓶に２０ｍｇづつ入れ、キムワイプで５０往復擦ったスパーテルを顆粒に差し込み、引き抜いて、付着量を測定した。
(2) Evaluation of electrostatic adhesion suppression
Measurement of adhesion amount after charging Each of the granules of Examples 1 to 5 and Comparative Examples 1 to 3 and 50% E-Kepler dry syrup was placed in a 50 ml glass bottle in an amount of 20 mg each, and a spatula that had been rubbed back and forth with a Kimwipe 50 times was inserted into the granules and then pulled out to measure the adhesion amount.
平均粒子径の測定
実施例１～５、比較例１～３の各顆粒の平均粒子径を、ふるい分け法で測定した。また、イーケプラドライシロップ５０％についても、同様にして、平均粒子径を測定した。
Measurement of average particle size The average particle size of each granule of Examples 1 to 5 and Comparative Examples 1 to 3 was measured by a sieving method. The average particle size of E Keppra Dry Syrup 50% was also measured in the same manner.
評価結果
実施例１～３、比較例１～３の各顆粒の平均粒子径と帯電後付着量を表２に示す。
また、実施例２、４、５の各顆粒について、ヒプロメロース量、平均粒子径、及び帯電後付着量を表３に示す。
ヒプロメロースを含む被覆層を備えることで、静電付着が顕著に抑制された。
Furthermore, for each of the granules of Examples 2, 4, and 5, the amount of hypromellose, the average particle size, and the amount of adhesion after charging are shown in Table 3.
By providing a coating layer containing hypromellose, electrostatic adhesion was significantly suppressed.
（３）ブロッキング抑制の評価
流動性低下・ブロッキングの測定
実施例２、４～６の顆粒を、それぞれ、５０ｍｌ容量のガラス容器に２０ｇづつ入れ、温度２５±２℃、湿度７５±５％ＲＨの下、解放状態で、７日間静置した。１２メッシュの篩に検体を５ｇ載せ、パウダーテスターで１０秒間振動した後、篩上に残った検体量を測定し、秤取量（約５ｇ）に対する篩上残存量の比率（％）を算出した（ブロッキング量比）。１２メッシュの篩上に残った検体は顆粒がブロッキングしたものである。
また、静置後の実施例２、７の顆粒について、目視でブロッキングの有無を判定した。塊がない場合を〇、容器を傾けても顆粒が動かない場合を×と判定した。
(3) Evaluation of blocking inhibition
Measurement of fluidity reduction and blocking Granules of Examples 2 and 4 to 6 were each placed in a 50 ml glass container in an amount of 20 g, and left to stand for 7 days in an open state at a temperature of 25±2°C and a humidity of 75±5% RH. 5 g of a specimen was placed on a 12 mesh sieve, and after vibrating for 10 seconds with a powder tester, the amount of specimen remaining on the sieve was measured, and the ratio (%) of the amount remaining on the sieve to the weighed amount (about 5 g) was calculated (blocking amount ratio). The specimens remaining on the 12 mesh sieve were granules that had been blocked.
After standing, the granules of Examples 2 and 7 were visually inspected for the presence or absence of blocking. The absence of lumps was evaluated as ◯, and the absence of movement of the granules even when the container was tilted was evaluated as ×.
評価結果
実施例２、４～６の各顆粒について、ヒプロメロース量、平均粒子径、及びブロッキング量比を表４に示す。
ヒプロメロースを含む被覆層を備えることで、ブロッキングが顕著に抑制された。
Evaluation Results The amount of hypromellose, average particle size, and blocking ratio for each of the granules of Examples 2 and 4 to 6 are shown in Table 4.
By providing a coating layer containing hypromellose, blocking was significantly suppressed.
実施例２、７の各顆粒について、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体量、平均粒子径、及びブロッキングの有無を表５に示す。
被覆層を備えない顆粒はブロッキングが生じたが、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合を含む被覆層を備えることで、流動性の低下はなくなり、ブロッキングも顕著に抑制された。
For each of the granules of Examples 2 and 7, the amount of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, the average particle size, and the presence or absence of blocking are shown in Table 5.
Granules without a coating layer caused blocking, but by providing a coating layer containing a polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, the decrease in fluidity was eliminated and blocking was significantly suppressed.
（４）粒度別の成分含有量の偏りの評価
実施例８の顆粒をスクリーン径３５５μｍ篩で分級し、篩上に残った検体、及び篩を通過した検体のぞれぞれのレベチラセタム濃度を高速液体クロマトグラフィー（ＨＰＬＣ）で測定した。
（ＨＰＬＣ条件）
検出器：紫外吸光光度計（測定波長：２０５ｎｍ）
カラム：内径４．６ｍｍ、長さ１５ｃｍのステンレス管に５μｍの液体クロマトグラフィー用オクチルシリル化シリカゲルを充填する。
カラム温度：３０℃付近の一定温度
移動相：無水リン酸水素二ナトリウム１．４２ｇを水１０００ｍＬに溶かし、薄めたリン酸（１→５）又はトリエチルアミン溶液を加えてｐＨ３．５±０．０５に調整する。この液９００ｍＬにアセトニトリル１００ｍＬを加える。
流量：レベチラセタムの保持時間が約３分になるように調整する。
(4) Evaluation of bias in component content by particle size The granules of Example 8 were classified using a sieve with a screen diameter of 355 μm, and the levetiracetam concentration of each of the samples remaining on the sieve and the samples passing through the sieve was measured by high performance liquid chromatography (HPLC).
(HPLC conditions)
Detector: ultraviolet spectrophotometer (measurement wavelength: 205 nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm is packed with 5 μm octylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 30°C Mobile phase: dissolve 1.42 g of anhydrous disodium hydrogen phosphate in 1000 mL of water, and add diluted phosphoric acid (1→5) or triethylamine solution to adjust to pH 3.5±0.05. Add 100 mL of acetonitrile to 900 mL of this solution.
Flow rate: Adjust so that the retention time of levetiracetam is approximately 3 minutes.
実施例８の顆粒は、１ｇ中にレベチラセタム５００ｍｇを含有する製剤である。この含量を表示量とするときの表示量に対する含量の比率（％）を、実施例８の顆粒（３２８．２μｍ）、篩上に残った検体、及び篩を通過した検体について測定した。結果を表６に示す。
本発明の第１の医薬組成物は、製造蔵置、薬さじ、分包機、包装袋などへの静電付着が抑制されているため、製造時、調剤時、分包時、服用時のハンドリング性が良く、薬剤ロスも回避される。また、本発明の第２の医薬組成物は、吸湿の影響が抑えられているため、保存してもブロッキングを生じたり、流動性が低下したりし難い。従って、これらの医薬組成物は、商品価値が高い。
The first pharmaceutical composition of the present invention is suppressed from electrostatically adhering to storage, medicine spoons, packaging machines, packaging bags, etc., and therefore has good handling properties during production, preparation, packaging, and administration, and drug loss is also avoided. In addition, the second pharmaceutical composition of the present invention is suppressed from being affected by moisture absorption, and therefore is unlikely to cause blocking or decrease in fluidity even during storage. Therefore, these pharmaceutical compositions have high commercial value.
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| CN101647789A (en) | 2009-09-01 | 2010-02-17 | 天津药物研究院药业有限责任公司 | Levetiracetam slow release pellet capsule preparation and preparation method thereof |
| WO2011027728A1 (en) | 2009-09-02 | 2011-03-10 | 日本曹達株式会社 | Coating agent comprising hydroxyalkyl cellulose |
| JP2018177657A (en) | 2017-04-05 | 2018-11-15 | 東和薬品株式会社 | Levetiracetam-containing pharmaceutical composition and method for producing the same |
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| CN101647789A (en) | 2009-09-01 | 2010-02-17 | 天津药物研究院药业有限责任公司 | Levetiracetam slow release pellet capsule preparation and preparation method thereof |
| WO2011027728A1 (en) | 2009-09-02 | 2011-03-10 | 日本曹達株式会社 | Coating agent comprising hydroxyalkyl cellulose |
| JP2018177657A (en) | 2017-04-05 | 2018-11-15 | 東和薬品株式会社 | Levetiracetam-containing pharmaceutical composition and method for producing the same |
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