JP2023183350A - Lacosamide solid preparation - Google Patents
Lacosamide solid preparation Download PDFInfo
- Publication number
- JP2023183350A JP2023183350A JP2022107370A JP2022107370A JP2023183350A JP 2023183350 A JP2023183350 A JP 2023183350A JP 2022107370 A JP2022107370 A JP 2022107370A JP 2022107370 A JP2022107370 A JP 2022107370A JP 2023183350 A JP2023183350 A JP 2023183350A
- Authority
- JP
- Japan
- Prior art keywords
- lacosamide
- solid preparation
- mass
- methacrylate copolymer
- coating layer
- 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.)
- Pending
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- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 title claims abstract description 47
- 229960002623 lacosamide Drugs 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 239000007787 solid Substances 0.000 title claims abstract description 30
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 claims abstract description 25
- 239000010410 layer Substances 0.000 claims abstract description 24
- 239000007771 core particle Substances 0.000 claims abstract description 23
- 239000011247 coating layer Substances 0.000 claims abstract description 22
- 239000008187 granular material Substances 0.000 claims abstract description 21
- 235000019658 bitter taste Nutrition 0.000 abstract description 7
- 239000003826 tablet Substances 0.000 description 16
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 12
- 239000006188 syrup Substances 0.000 description 11
- 235000020357 syrup Nutrition 0.000 description 11
- 239000000654 additive Substances 0.000 description 10
- 238000005469 granulation Methods 0.000 description 9
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- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- 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
- SWGJCIMEBVHMTA-UHFFFAOYSA-K trisodium;6-oxido-4-sulfo-5-[(4-sulfonatonaphthalen-1-yl)diazenyl]naphthalene-2-sulfonate Chemical compound [Na+].[Na+].[Na+].C1=CC=C2C(N=NC3=C4C(=CC(=CC4=CC=C3O)S([O-])(=O)=O)S([O-])(=O)=O)=CC=C(S([O-])(=O)=O)C2=C1 SWGJCIMEBVHMTA-UHFFFAOYSA-K 0.000 description 1
- 239000008371 vanilla flavor Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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Abstract
Description
本発明は、ラコサミド固形製剤に関する。 The present invention relates to lacosamide solid formulations.
ラコサミド、すなわち、（２Ｒ）－２－アセトアミド－Ｎ－ベンジル－３－メトキシプロパンアミドは抗てんかん薬であり、これを含む錠剤、ドライシロップ剤、注射剤が「ビムパッド（登録商標）」という名称で販売されている。 Lacosamide, i.e. (2R)-2-acetamido-N-benzyl-3-methoxypropanamide, is an antiepileptic drug, and tablets, dry syrups, and injections containing it are sold under the name Vimpad (registered trademark). has been done.
ラコサミドは苦味を有することが知られている。苦味を有する有効成分を製剤化する場合には、患者の服薬アドヒアランスの観点から、苦味をマスキングすることが求められる。有効成分の不快な味をマスキングする方法としては、有効成分を含む顆粒や錠剤を水不溶性高分子でコーティングする方法があり、例えば特許文献１には、有効成分を含むコア粒子の表面に、水不溶性高分子であるエチルセルロースをコーティングする方法が開示されている。 Lacosamide is known to have a bitter taste. When formulating an active ingredient that has a bitter taste, it is required to mask the bitter taste from the viewpoint of patient medication adherence. As a method for masking the unpleasant taste of active ingredients, there is a method of coating granules or tablets containing the active ingredients with a water-insoluble polymer. A method of coating ethylcellulose, an insoluble polymer, is disclosed.
しかしながら、有効成分としてラコサミドを有する固形製剤を製造するにあたり、ラコサミドを含む核粒子をエチルセルロースでコーティングすると、光安定性が低下するという新たな課題が生じることを本発明者は見出した。
本発明は上記事情に鑑みてなされたものであって、苦味が抑制され、光安定性も備えたラコサミド固形製剤の提供を課題とする。However, in producing a solid preparation having lacosamide as an active ingredient, the present inventors have discovered that when core particles containing lacosamide are coated with ethylcellulose, a new problem arises in that photostability is reduced.
The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a solid preparation of lacosamide that has suppressed bitterness and has photostability.
本発明者は、エチルセルロースに代えて、アミノアルキルメタクリレートコポリマーを使用することにより、光安定性が改善されることを見出し、本発明を完成させるに至った。 The present inventors have found that photostability is improved by using an aminoalkyl methacrylate copolymer instead of ethyl cellulose, and have completed the present invention.
本発明は以下の態様を有する。
〔１〕ラコサミドとアミノアルキルメタクリレートコポリマーとを含有することを特徴とするラコサミド固形製剤。
〔２〕前記ラコサミドを含有する核粒子に、前記アミノアルキルメタクリレートコポリマーを含有するコーティング層が設けられた顆粒であることを特徴とする〔１〕のラコサミド固形製剤。
〔３〕前記ラコサミドを含有する核粒子に、前記アミノアルキルメタクリレートコポリマーを含有するコーティング層が設けられた顆粒を含む錠剤であることを特徴とする〔１〕のラコサミド固形製剤。
〔４〕前記顆粒は、前記コーティング層の外側にオーバーコート層を有することを特徴とする〔２〕または〔３〕のラコサミド固形製剤。The present invention has the following aspects.
[1] A lacosamide solid preparation containing lacosamide and an aminoalkyl methacrylate copolymer.
[2] The lacosamide solid preparation according to [1], which is a granule in which a coating layer containing the aminoalkyl methacrylate copolymer is provided on the core particle containing the lacosamide.
[3] The lacosamide solid preparation according to [1], which is a tablet comprising granules in which the core particles containing the lacosamide are provided with a coating layer containing the aminoalkyl methacrylate copolymer.
[4] The lacosamide solid preparation according to [2] or [3], wherein the granules have an overcoat layer on the outside of the coating layer.
本発明によれば、苦味が抑制され、光安定性も備えたラコサミド固形製剤を提供できる。 According to the present invention, it is possible to provide a lacosamide solid preparation with suppressed bitterness and photostability.
以下、本発明を詳細に説明する。
本発明のラコサミド固形製剤（以下、単に固形製剤という場合もある。）は、ラコサミドとアミノアルキルメタクリレートコポリマーを含有する。The present invention will be explained in detail below.
The lacosamide solid preparation (hereinafter sometimes simply referred to as solid preparation) of the present invention contains lacosamide and an aminoalkyl methacrylate copolymer.
ラコサミドとしては、特に制限はなく、市場より入手可能なものを使用でき、結晶形態でも、アモルファス形態でもよい。
アミノアルキルメタクリレートコポリマーとしては、市場より医薬品用途として入手可能なアミノアルキルメタクリレートコポリマーＥタイプを使用できる。アミノアルキルメタクリレートコポリマーＥタイプとしては、メタクリル酸メチル、メタクリル酸ブチル及びメタクリル酸ジメチルアミノエチルの共重合体である、市販のオイドラギット（登録商標）Ｅ１００、オイドラギット（登録商標）ＥＰＯ、コリコート（登録商標）スマートシール３０Ｄ、コリコート（登録商標）スマートシール１００Ｐ等を使用できる。Lacosamide is not particularly limited, and any commercially available lacosamide can be used, and may be in crystalline or amorphous form.
As the aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer E type, which is commercially available for pharmaceutical use, can be used. Aminoalkyl methacrylate copolymers E type include the commercially available Eudragit® E100, Eudragit® EPO, and Collicoat®, which are copolymers of methyl methacrylate, butyl methacrylate, and dimethylaminoethyl methacrylate. Smart Seal 30D, Collicoat (registered trademark) Smart Seal 100P, etc. can be used.
本発明の固形製剤は、ラコサミドおよびアミノアルキルメタクリレートコポリマーの他に、医薬品分野で使用可能な賦形剤、結合剤、崩壊剤、界面活性剤、着色剤、甘味剤、香料等の添加剤をいずれも必要に応じて含有することができる。 In addition to lacosamide and the aminoalkyl methacrylate copolymer, the solid preparation of the present invention contains any additives that can be used in the pharmaceutical field, such as excipients, binders, disintegrants, surfactants, colorants, sweeteners, and flavoring agents. may also be included if necessary.
賦形剤としては、例えば、Ｄ－マンニトール、結晶セルロース、乳糖水和物、無水乳糖、精製白糖、バレイショデンプン、アルファー化デンプン等が挙げられ、これらのうちの１種以上を必要に応じて使用できるが、味や造粒等のしやすさの点でＤ－マンニトールを使用することが好ましい。 Examples of excipients include D-mannitol, crystalline cellulose, lactose hydrate, anhydrous lactose, refined white sugar, potato starch, pregelatinized starch, and one or more of these may be used as necessary. However, it is preferable to use D-mannitol in terms of taste and ease of granulation.
結合剤としては、例えば、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、ポリビニルアルコール、ポリビニルピロリドン、ステアリルアルコール、アンモニオメタクリレート・コポリマー、ポリビニルアセタールジエチルアミノアセテート、デキストリン、水アメ等が挙げられ、これらのうちの１種以上を使用できるが、ヒドロキシプロピルセルロースを使用すると、ラコサミド固形製剤の安定性が優れ、類縁物質の生成を抑制できる点で好ましい。 Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, stearyl alcohol, ammoniomethacrylate copolymer, polyvinyl acetal diethylaminoacetate, dextrin, starch syrup, and the like. Although the above can be used, it is preferable to use hydroxypropylcellulose because the stability of the lacosamide solid preparation is excellent and the production of related substances can be suppressed.
崩壊剤としては、クロスカルメロースナトリウム、カルメロースカルシウム、カルメロース、低置換度ヒドロキシプロピルセルロース、クロスポビドン、トウモロコシデンプン、デンプングリコール酸ナトリウム、部分アルファー化デンプン、ヒドロキシプロピルスターチ等が挙げられ、これらのうち１種以上を使用できる。 Examples of disintegrants include croscarmellose sodium, carmellose calcium, carmellose, low-substituted hydroxypropyl cellulose, crospovidone, corn starch, sodium starch glycolate, partially pregelatinized starch, hydroxypropyl starch, etc. One or more types can be used.
界面活性剤としては、ラウリル硫酸ナトリウム、ポリソルベート８０等が挙げられ、これらのうち１種以上を使用できる。
着色剤としては、例えば黄色三二酸化鉄、三二酸化鉄、食用黄色４号、食用黄色５号、食用赤色２号、食用赤色３号、食用赤色１０２号等が挙げられ、これらのうちの１種以上を使用できる。Examples of the surfactant include sodium lauryl sulfate and polysorbate 80, and one or more of these can be used.
Examples of the coloring agent include yellow iron sesquioxide, iron sesquioxide, food yellow No. 4, food yellow No. 5, food red No. 2, food red No. 3, food red No. 102, and one of these. You can use the above.
甘味剤としては、アセスルファムカリウム、アスパルテーム、スクラロース、ソーマチン、スクロース、サッカリン又はその塩、グリチルリチン酸又はその塩、ステビア又はその塩等が挙げられ、これらのうちの１種以上を使用できる。
香料としては、オレンジエッセンス、オレンジ油、カラメル、カンフル、ケイヒ油、スペアミント油、ストロベリーエッセンス、チョコレートエッセンス、チェリーフレーバー、トウヒ油、パインオイル、ハッカ油、バニラフレーバー、ビターエッセンス、フルーツフレーバー、ペパーミントエッセンス、ミックスフレーバー、ミントフレーバー、ｌ－メントール、レモンパウダー、レモン油、ローズ油等が挙げられ、これらのうちの１種以上を使用できる。Examples of sweeteners include acesulfame potassium, aspartame, sucralose, thaumatin, sucrose, saccharin or a salt thereof, glycyrrhizic acid or a salt thereof, stevia or a salt thereof, and one or more of these may be used.
Fragrances include orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, spruce oil, pine oil, peppermint oil, vanilla flavor, bitter essence, fruit flavor, peppermint essence, Examples include mixed flavor, mint flavor, l-menthol, lemon powder, lemon oil, rose oil, etc., and one or more of these can be used.
その他の添加剤としては、滑沢剤（ステアリン酸マグネシウム、ステアリン酸カルシウム等のステアリン酸金属塩、グリセリン脂肪酸エステル、ショ糖脂肪酸エステル等の脂肪酸エステル類、フマル酸ステアリルナトリウム，タルク等）、フィルムコート用基材（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等）、軽質無水ケイ酸、酸化チタン、カルナウバロウ等が挙げられ、これらのうち１種以上を使用できる。 Other additives include lubricants (stearate metal salts such as magnesium stearate and calcium stearate, fatty acid esters such as glycerin fatty acid ester and sucrose fatty acid ester, sodium stearyl fumarate, talc, etc.), and for film coating. Examples include base materials (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc.), light silicic anhydride, titanium oxide, carnauba wax, etc., and one or more of these can be used.
本発明の固形製剤の形態には特に制限はなく、顆粒状製剤（顆粒剤、ドライシロップ剤、細粒剤等）、錠剤（即放錠、口腔内崩壊錠等）等が挙げられる。 The form of the solid preparation of the present invention is not particularly limited, and examples include granular preparations (granules, dry syrup, fine granules, etc.), tablets (immediate release tablets, orally disintegrating tablets, etc.), and the like.
＜顆粒状製剤＞
本発明の固形製剤が顆粒状製剤である場合には、ラコサミドを含有する核粒子に、アミノアルキルメタクリレートコポリマーを含有するコーティング層が設けられた顆粒であることが好ましい。コーティング層の外側には、目的に応じたオーバーコート層を設けてもよい。オーバーコート層を設けることにより、例えば顆粒同士の固着を防止する等、特定の機能を付与することができる。
核粒子の形態としては、ラコサミドと添加物を含む造粒物、添加物粒子の表面にラコサミドを含む原薬層が形成されたレイヤリング粒子等が挙げられ、ラコサミドを含有する粒子状物であればよい。<Granular preparation>
When the solid preparation of the present invention is a granular preparation, it is preferably a granule in which a coating layer containing an aminoalkyl methacrylate copolymer is provided on a core particle containing lacosamide. An overcoat layer may be provided on the outside of the coating layer depending on the purpose. By providing an overcoat layer, a specific function can be imparted, such as preventing granules from sticking to each other.
Examples of the form of core particles include granules containing lacosamide and additives, layered particles in which a drug substance layer containing lacosamide is formed on the surface of additive particles, and even particulates containing lacosamide. Bye.
本発明の固形製剤中のラコサミドの含有量は適宜設定できるが、固形製剤が顆粒状製剤である場合には、顆粒状製剤を１００質量％とした場合、例えば１～３０質量％とすることができ、好ましくは２～２０質量％、より好ましくは５～１５質量％である。
また、核粒子を１００質量％とした場合、核粒子中のラコサミドの含有量は例えば５～３５質量％とすることができ、好ましくは８～２５質量％、１０～２０質量％である。The content of lacosamide in the solid preparation of the present invention can be set as appropriate, but when the solid preparation is a granular preparation, it may be set to, for example, 1 to 30% by mass when the granular preparation is 100% by mass. The amount is preferably 2 to 20% by weight, more preferably 5 to 15% by weight.
Further, when the core particle is 100% by mass, the content of lacosamide in the core particle can be, for example, 5 to 35% by mass, preferably 8 to 25% by mass, and 10 to 20% by mass.
核粒子は、ラコサミド以外に、先に例示したような添加物を必要に応じて含むことができ、Ｄ－マンニトールのような賦形剤と、ヒドロキシプロピルセルロースのような結合剤を少なくとも含むことが好ましい。
顆粒状製剤を１００質量％とした場合、賦形剤の含有量は例えば４０～７０質量％とすることができ、好ましくは４５～６５質量％、より好ましくは５０～６０質量％である。
核粒子を１００質量％とした場合、核粒子中の賦形剤の含有量は例えば６０～９０質量％とすることができ、好ましくは７０～９０質量％、より好ましくは７５～８５質量％である。
顆粒状製剤を１００質量％とした場合、結合剤の含有量は例えば１～１５質量％とすることができ、好ましくは２～１０質量％、より好ましくは３～８質量％である。
核粒子を１００質量％とした場合、核粒子中の結合剤の含有量は例えば３～２０質量％とすることができ、好ましくは４～１５質量％、より好ましくは５～１０質量％である。In addition to lacosamide, the core particles may optionally contain additives such as those exemplified above, and may contain at least an excipient such as D-mannitol and a binder such as hydroxypropyl cellulose. preferable.
When the granular preparation is 100% by mass, the content of excipients can be, for example, 40 to 70% by mass, preferably 45 to 65% by mass, and more preferably 50 to 60% by mass.
When the core particle is 100% by mass, the content of the excipient in the core particle can be, for example, 60 to 90% by mass, preferably 70 to 90% by mass, more preferably 75 to 85% by mass. be.
When the granular preparation is 100% by mass, the content of the binder can be, for example, 1 to 15% by mass, preferably 2 to 10% by mass, and more preferably 3 to 8% by mass.
When the core particle is 100% by mass, the content of the binder in the core particle can be, for example, 3 to 20% by mass, preferably 4 to 15% by mass, more preferably 5 to 10% by mass. .
本発明の固形製剤中のアミノアルキルメタクリレートコポリマーの含有量は適宜設定できるが、固形製剤が顆粒状製剤である場合には、顆粒状製剤を１００質量％とした場合、例えば１～３０質量％とすることができ、好ましくは２～２０質量％、より好ましくは５～１５質量％である。
また、コーティング層を１００質量％とした場合、コーティング層中のアミノアルキルメタクリレートコポリマーの含有量は少なくとも８０質量％であることが好ましく、９０質量％以上がより好ましく、さらに好ましくは１００質量％である。
コーティング層には、アミノアルキルメタクリレートコポリマー以外に、必要に応じて先に例示したような添加物や、アミノアルキルメタクリレートコポリマー以外の水不溶性高分子を含んでもよい。The content of the aminoalkyl methacrylate copolymer in the solid preparation of the present invention can be set as appropriate, but when the solid preparation is a granular preparation, the content of the aminoalkyl methacrylate copolymer can be set, for example, from 1 to 30% by mass when the granular preparation is 100% by mass. It is preferably 2 to 20% by weight, more preferably 5 to 15% by weight.
Further, when the coating layer is 100% by mass, the content of the aminoalkyl methacrylate copolymer in the coating layer is preferably at least 80% by mass, more preferably 90% by mass or more, and even more preferably 100% by mass. .
In addition to the aminoalkyl methacrylate copolymer, the coating layer may optionally contain additives such as those exemplified above and water-insoluble polymers other than the aminoalkyl methacrylate copolymer.
コーティング層の外側にオーバーコート層を設ける場合、オーバーコート層を構成する成分は目的に応じて選択できるが、例えば顆粒同士の固着を防止する目的の場合には、Ｄ－マンニトール、ソルビトール、キシリトール、マルチトール等の糖アルコール等からなるオーバーコート層を設けることが好ましい。また、服用感を高める目的の場合には甘味剤、光安定性を付与する目的の場合には酸化チタン、着色剤等をオーバーコート層に用いることができる。オーバーコート層は、層を形成するための基材として、ヒドロキシプロピルメチルセルロースや、ヒプロメロース等の水溶性高分子を含んでいてもよい。 When providing an overcoat layer on the outside of the coating layer, the components constituting the overcoat layer can be selected depending on the purpose. For example, when the purpose is to prevent granules from sticking to each other, D-mannitol, sorbitol, xylitol, It is preferable to provide an overcoat layer made of sugar alcohol such as maltitol. In addition, sweeteners may be used in the overcoat layer for the purpose of enhancing the feeling of taking the drug, and titanium oxide, coloring agents, etc. may be used for the purpose of imparting photostability. The overcoat layer may contain a water-soluble polymer such as hydroxypropyl methylcellulose or hypromellose as a base material for forming the layer.
核粒子とコーティング層の質量割合は、核粒子を１００質量部とした場合に、例えば１～５０質量部であり、好ましくは５～３０質量部、より好ましくは１０～２０質量部である。
オーバーコート層を設ける場合、オーバーコート層の質量割合はその目的に応じて適宜設定できるが、核粒子を１００質量部とした場合に、例えば２～１００質量部であり、好ましくは１０～６０質量部、より好ましくは２０～４０質量部である。The mass ratio of the core particles to the coating layer is, for example, 1 to 50 parts by mass, preferably 5 to 30 parts by mass, and more preferably 10 to 20 parts by mass, based on 100 parts by mass of the core particles.
When providing an overcoat layer, the mass proportion of the overcoat layer can be appropriately set depending on the purpose, but it is, for example, 2 to 100 parts by mass, preferably 10 to 60 parts by mass, when the core particles are 100 parts by mass. parts, more preferably 20 to 40 parts by weight.
顆粒状製剤は、上述したとおり、添加剤を適宜含有することができるが、核粒子、コーティング層、オーバーコート層の少なくともいずれかに甘味剤を含有することが好ましい。 As mentioned above, the granular preparation can contain additives as appropriate, but preferably contains a sweetener in at least one of the core particles, the coating layer, and the overcoat layer.
固形製剤が顆粒状製剤である場合には、次のような方法で製造できる。
まず、ラコサミドと賦形剤などの添加剤とを混合して造粒用組成物とし、結合剤を水等の溶媒に溶解した液を造粒用組成物に加え、流動層造粒、攪拌造粒等の公知方法で造粒する。ついで、得られた造粒物（核粒子）に対して、アミノアルキルメタクリレートコポリマーをエタノール等の溶媒に溶解した液を噴霧、乾燥し、造粒物の外側にコーティング層を形成する。ついで、必要に応じて、Ｄ－マンニトール等を水に溶解した液を噴霧、乾燥し、オーバーコート層を形成する。
また、Ｄ－マンニトール、乳糖水和物等の賦形剤からなる粒子を用意し、その表面にラコサミドを含む液を噴霧して原薬層を形成し、得られたレイヤリング粒子を核粒子として用いてもよい。
以上のような方法により、顆粒状製剤である本発明の固形製剤を製造することができる。
なお、オーバーコート層の外側に、目的に応じた層をさらに１層以上形成してもよい。When the solid preparation is a granular preparation, it can be manufactured by the following method.
First, lacosamide and additives such as excipients are mixed to make a granulation composition, and a solution of a binder dissolved in a solvent such as water is added to the granulation composition, followed by fluidized bed granulation, stirring granulation, etc. It is granulated by a known method such as granulation. Next, a solution prepared by dissolving an aminoalkyl methacrylate copolymer in a solvent such as ethanol is sprayed onto the obtained granules (core particles) and dried to form a coating layer on the outside of the granules. Then, if necessary, a solution prepared by dissolving D-mannitol or the like in water is sprayed and dried to form an overcoat layer.
In addition, particles made of excipients such as D-mannitol and lactose hydrate are prepared, and a liquid containing lacosamide is sprayed onto the surface of the particles to form a drug substance layer, and the resulting layering particles are used as core particles. May be used.
The solid preparation of the present invention, which is a granular preparation, can be produced by the method described above.
Note that one or more layers may be further formed outside the overcoat layer depending on the purpose.
＜錠剤＞
本発明の固形製剤が錠剤（即放錠、口腔内崩壊錠等）である場合には、ラコサミドを含有する核粒子に、アミノアルキルメタクリレートコポリマーを含有するコーティング層が設けられた顆粒を含む錠剤であることが好ましい。この場合もコーティング層の外側には、目的に応じたオーバーコート層を設けてもよいし、さらにその外側に目的に応じた層を１層以上形成してもよい。
このような錠剤は、顆粒に対して必要に応じて添加剤を加え、打錠することにより製造できる。
また、錠剤の他の形態としては、ラコサミドと必要に応じて添加剤を含有する素錠を得て、その外側にアミノアルキルメタクリレートコポリマーを含有するフィルムコーティング層が形成された形態も好ましく例示できる。
錠剤の形態は、錠剤が即放錠であるか口腔内崩壊錠であるか等に応じて、適宜決定できる。<Tablets>
When the solid preparation of the present invention is a tablet (immediate release tablet, orally disintegrating tablet, etc.), it is a tablet containing granules in which a coating layer containing an aminoalkyl methacrylate copolymer is provided on a core particle containing lacosamide. It is preferable that there be. In this case as well, an overcoat layer depending on the purpose may be provided on the outside of the coating layer, and one or more layers depending on the purpose may be further formed on the outside of the overcoat layer.
Such tablets can be manufactured by adding additives to granules as needed and then tableting.
Another preferred form of the tablet is a form in which a plain tablet containing lacosamide and optionally additives is obtained, and a film coating layer containing an aminoalkyl methacrylate copolymer is formed on the outside of the plain tablet.
The form of the tablet can be determined as appropriate depending on whether the tablet is an immediate release tablet or an orally disintegrating tablet.
以上説明したように、本発明の固形製剤は、ラコサミドとアミノアルキルメタクリレートコポリマーとを含有するため、苦味が抑制され、光安定性も備える。 As explained above, since the solid preparation of the present invention contains lacosamide and an aminoalkyl methacrylate copolymer, bitterness is suppressed and it also has photostability.
以下本発明を実施例により具体的に説明する。
［例１、例２］
下記の表１の処方に従い、顆粒状製剤であるドライシロップ剤を製造した。
具体的には、まず、表１の造粒物の欄に記載の各成分のうち、ヒドロキシプロピルセルロース以外の成分を混合して造粒用組成物とし、ヒドロキシプロピルセルロースを水に溶解させた液を造粒用組成物に噴霧して流動層造粒し、造粒物（核粒子）を得た。ついで、得られた造粒物に対して、表１のコーティング層の欄に記載の成分をエタノールに溶解させた液を噴霧、乾燥してコーティング層を形成し、さらに表１のオーバーコート層の欄に記載の成分を水に溶解させた液を噴霧、乾燥してオーバーコート層を形成した。
その後、１８メッシュのスクリーンを通過させて整粒し、表１に示す割合で各成分を含有する例１、例２のドライシロップ剤を得た。
得られた各ドライシロップ剤について、以下の方法により、純度試験（光安定性の評価）を行った。
結果を表２に示す。The present invention will be specifically explained below using examples.
[Example 1, Example 2]
A dry syrup, which is a granular preparation, was produced according to the formulation shown in Table 1 below.
Specifically, first, among the components listed in the granulated product column of Table 1, components other than hydroxypropylcellulose are mixed to prepare a granulation composition, and a solution in which hydroxypropylcellulose is dissolved in water is prepared. was sprayed onto the granulation composition and subjected to fluidized bed granulation to obtain granules (core particles). Next, a solution prepared by dissolving the components listed in the coating layer column of Table 1 in ethanol was sprayed onto the obtained granules and dried to form a coating layer. An overcoat layer was formed by spraying and drying a solution in which the components listed in the column were dissolved in water.
Thereafter, the mixture was sized by passing through an 18 mesh screen to obtain dry syrup formulations of Examples 1 and 2 containing each component in the proportions shown in Table 1.
A purity test (evaluation of photostability) was conducted on each of the obtained dry syrups by the following method.
The results are shown in Table 2.
＜純度試験（光安定性の評価）＞
開放系において、各ドライシロップ剤に３０００ｌｘの光を連続照射し、照射開始から４００時間（積算照射量１２０万ｌｘ・ｈｒ）経過した後の総類縁物質量と、照射前の総類縁物質量を測定することにより、純度試験を実施した。具体的には、水とメタノールとの９：１混液１０ｍＬにドライシロップ剤５００ｍｇを溶解し、得られた溶解液を３０００ｒｐｍで５分間遠心して上澄み液を採取して試料溶液とし、これを高速液体クロマトグラフィーを用いた自動分析法で分析した。
表２に記載の総類縁物質量の数値は、ラコサミド由来のピーク面積に対する、観測された複数の類縁物質によるピーク面積の総和の割合を百分率で示したものである。<Purity test (light stability evaluation)>
In an open system, each dry syrup agent was continuously irradiated with 3000 lx of light, and the total amount of related substances after 400 hours (total irradiation amount: 1.2 million lx/hr) from the start of irradiation and the total amount of related substances before irradiation were measured. A purity test was conducted by: Specifically, 500 mg of dry syrup is dissolved in 10 mL of a 9:1 mixture of water and methanol, the resulting solution is centrifuged at 3000 rpm for 5 minutes, the supernatant is collected and used as a sample solution, and this is subjected to high-performance liquid chromatography. The analysis was carried out using an automatic analysis method using graphography.
The numerical value of the total amount of related substances listed in Table 2 is the ratio of the sum of peak areas due to a plurality of observed related substances to the peak area derived from lacosamide, expressed as a percentage.
表２に示すように、コーティング層にアミノアルキルメタクリレートコポリマーＥを用いた例１のドライシロップ剤は、エチルセルロースを用いた例２のドライシロップ剤に比べて、光照射による総類縁物質量の増加が抑制されており、光安定性に優れていた。
また、例１および例２のドライシロップ剤は、５０℃および６０℃の開放系で１週間保存した後も固着が認められなかった。As shown in Table 2, the dry syrup of Example 1 using aminoalkyl methacrylate copolymer E in the coating layer suppressed the increase in the total amount of related substances due to light irradiation compared to the dry syrup of Example 2 using ethyl cellulose. It had excellent photostability.
In addition, no sticking was observed in the dry syrups of Examples 1 and 2 even after they were stored in an open system at 50°C and 60°C for one week.
Claims (4)
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| JP2022107370A JP2023183350A (en) | 2022-06-15 | 2022-06-15 | Lacosamide solid preparation |
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| JP2022107370A JP2023183350A (en) | 2022-06-15 | 2022-06-15 | Lacosamide solid preparation |
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