JP4903900B2 - Pharmaceutical composition comprising levetiracetam - Google Patents
Pharmaceutical composition comprising levetiracetam Download PDFInfo
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- JP4903900B2 JP4903900B2 JP2010549160A JP2010549160A JP4903900B2 JP 4903900 B2 JP4903900 B2 JP 4903900B2 JP 2010549160 A JP2010549160 A JP 2010549160A JP 2010549160 A JP2010549160 A JP 2010549160A JP 4903900 B2 JP4903900 B2 JP 4903900B2
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- MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 claims description 26
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Classifications
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- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
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Description
本発明は、レベチラセタム(levetiracetam)、ブリバラセタム(brivaracetam)又はセレトラセタム(seletracetam)を有効成分として含む医薬組成物に関する。 The present invention relates to a pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam as an active ingredient.
レベチラセタム、即ち(S)−(−)−アルファ−エチル−2−オキソ−1−ピロリジンアセトアミド、左旋性の化合物は、欧州特許第EP0162036Bにおいて、中枢神経系の低酸素型及び虚血性型侵襲の治療及び予防のための保護剤として開示され、下式を有する。 Levetiracetam, ie (S)-(−)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide, a levorotatory compound, is the treatment of hypoxic and ischemic invasion of the central nervous system in European Patent No. EP01662036B. And as a protective agent for prevention, having the following formula:
この化合物はまた、てんかんの治療に効果的であり、その右旋性鏡像体である(R)−(+)−アルファ−エチル−2−オキソ−1−ピロリジンアセトアミドは完全に活性を欠如していることが示された(A.J.Gowerら,Eur.J.Pharmacol.,222,1992,193−203)ことに対する治療指標である。 This compound is also effective in the treatment of epilepsy, and its dextrorotatory enantiomer (R)-(+)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide is completely devoid of activity. (AJ Gower et al., Eur. J. Pharmacol., 222, 1992, 193-203).
公開番号WO01/62726である国際特許出願は、2−オキソ−1−ピロリジン及びその製造方法を開示している。特に、国際的に特定されていない名称であるブリバラセタムとして知られている化合物の(2S)−2−[(4R)−2−オキソ−4−プロピル−ピロリジン−1−イル]ブタンアミドを開示している。 The international patent application with publication number WO 01/62726 discloses 2-oxo-1-pyrrolidine and a process for its preparation. In particular, (2S) -2-[(4R) -2-oxo-4-propyl-pyrrolidin-1-yl] butanamide, a compound known as brivaracetam, an internationally unspecified name, is disclosed. Yes.
公開番号WO2005/121082である国際特許出願は、2−オキソ−1−ピロリジン誘導体の製造方法を記載し、特に、国際的に特定されていない名称であるセレトラセタムとして知られている(2S)−2−[(4S)−4−(2,2−ジフルオロビニル)−2−オキソ−ピロリジン−1−イル]ブタンアミドの製造方法を開示している。 The international patent application with publication number WO 2005/121082 describes a process for the preparation of 2-oxo-1-pyrrolidine derivatives, in particular known as Seretracetum, an internationally unspecified name (2S) -2 Disclosed is a process for producing-[(4S) -4- (2,2-difluorovinyl) -2-oxo-pyrrolidin-1-yl] butanamide.
したがって、2−オキソ−1−ピロリジン誘導体は、製薬産業において特に有用である。 Accordingly, 2-oxo-1-pyrrolidine derivatives are particularly useful in the pharmaceutical industry.
ブリバラセタムは、てんかんの治療に効果的である。フェーズIIの臨床試験は、続発性全身てんかんの有無に関わらず、難治性部分発症発作を有する成人患者(16〜65歳)の補助療法において、ブリバラセタム(5、20及び50mg/日)の有効性及び安全性を評価した。ブリバラセタムはまた、疱疹後神経痛である患者(>18歳)の治療において効果的である。 Brivaracetam is effective in treating epilepsy. Phase II clinical trials show the efficacy of brivaracetam (5, 20 and 50 mg / day) in adjuvant therapy for adult patients (16-65 years old) with refractory partial episodes with or without secondary generalized epilepsy And safety was evaluated. Brivaracetam is also effective in treating patients with postherpetic neuralgia (> 18 years).
セレトラセタムは、てんかんの治療に効果的である。2つのフェーズIIaの服用量調査試験は、てんかんにおいてセレトラセタムを用いて行なわれ、最大3個の同時の抗てんかん薬を現在服用している非常に難治性の成人患者における部分発症発作の補助治療においてセレトラセタムの有効性及び安全性が評価された。 Seletracetam is effective in treating epilepsy. Two phase IIa dose studies were conducted with seletracetam in epilepsy and in the adjunct treatment of partial-onset seizures in very refractory adult patients currently taking up to 3 concurrent antiepileptic drugs The efficacy and safety of seletracetam was evaluated.
経口的に投与することができる医薬組成物の開発において、現在求められている目的の1つは、水に分散されたか又は直接飲み込まれた場合、有効成分の味がしない組成物を有するようにすることである。 In the development of pharmaceutical compositions that can be administered orally, one of the objectives currently sought is to have a composition that does not taste the active ingredient when dispersed in water or swallowed directly. It is to be.
本発明は、有効成分を含む経口投与可能な顆粒、特に、水に分散させた場合に、有効成分の味が実質的にしない、レベチラセタム、ブリバラセタム又はセレトラセタムの経口的に口当たりの良い微粒子形態に関する。 The present invention relates to an orally administrable granule comprising an active ingredient, and particularly to an orally palatable fine particulate form of levetiracetam, brivaracetam or seletracetam, which, when dispersed in water, does not substantially taste the active ingredient.
錠剤、粉末、顆粒、カプセルなどの医薬製剤の多種のタイプがある。その中でも、ドライシロップ製剤は、日本の薬局方における製造の一般的な規則に従えば、「使用前に溶解させるか又は懸濁させる製剤」を意味する。これは、特に、薬が嫌いなる子供又は嚥下が困難である老齢者のような患者のための製剤であって、このような子供及び/又は老齢者でもそれを容易に摂取することができる。多くの成人及び多くの子供は、丸薬若しくは錠剤を飲み込むことが困難であるか、又はそれらを飲み込めないので、それによって、レベチラセタム、ブリバラセタム又はセレトラセタムから恩恵を受けられない。さらに、この製剤は取扱い易く、非常に簡単に分注し、服用することができる。 There are many types of pharmaceutical formulations such as tablets, powders, granules, capsules. Among them, a dry syrup formulation means “a formulation that is dissolved or suspended before use” according to the general rules of manufacture in the Japanese Pharmacopoeia. This is a formulation especially for patients such as children who dislike drugs or elderly people who have difficulty swallowing, and such children and / or elderly people can easily take it. Many adults and many children have difficulty in swallowing pills or tablets, or cannot swallow them, thereby not benefiting from levetiracetam, brivaracetam or seletracetam. Furthermore, this formulation is easy to handle and can be dispensed and taken very easily.
一局面によれば、本発明は、ドライシロップの形態である経口投与可能な医薬組成物に関し、該医薬組成物は、有効成分としてレベチラセタム、ブリバラセタム又はセレトラセタム、賦形剤として、該組成物の全重量に対して、マンニトール、ソルビトール又はキシリトールの中から選択され、平均粒子径が75〜520μmである、少なくとも10〜90重量%の顆粒希釈剤を含む。 According to one aspect, the present invention relates to an orally administrable pharmaceutical composition in the form of a dry syrup, the pharmaceutical composition comprising levetiracetam, brivaracetam or seletracetam as an active ingredient, and the total weight of the composition as an excipient. In contrast, it comprises at least 10 to 90% by weight of a granular diluent selected from mannitol, sorbitol or xylitol and having an average particle size of 75 to 520 μm.
別の局面によれば、本発明は、ドライシロップの形態である経口投与可能な医薬組成物に関し、該医薬組成物は、有効成分としてレベチラセタム、賦形剤として、該組成物の全重量に対して、平均粒子径が75〜520μmである、希釈剤として少なくとも10〜90重量%の顆粒マンニトールを含む。 According to another aspect, the present invention relates to an orally administrable pharmaceutical composition in the form of a dry syrup, wherein the pharmaceutical composition is levetiracetam as an active ingredient and as an excipient relative to the total weight of the composition. And at least 10 to 90% by weight of granular mannitol as a diluent having an average particle size of 75 to 520 μm.
別の態様によれば、本発明は、てんかん、パーキンソン病、運動障害及び他の神経障害からなる群から選択される疾患を治療するためのドライシロップの形態である経口投与可能な医薬組成物に関し、該医薬組成物は、有効成分としてレベチラセタム、ブリバラセタム又はセレトラセタム、賦形剤として、該組成物の全重量に対して、マンニトール、ソルビトール又はキシリトールの中から選択され、平均粒子径が75〜520μmである、少なくとも10〜90重量%の顆粒希釈剤を含む。 According to another aspect, the present invention relates to an orally administrable pharmaceutical composition in the form of a dry syrup for treating a disease selected from the group consisting of epilepsy, Parkinson's disease, movement disorders and other neurological disorders, The pharmaceutical composition is selected from levetiracetam, brivaracetam or seletracetam as an active ingredient, and as an excipient from mannitol, sorbitol or xylitol with respect to the total weight of the composition, and has an average particle size of 75 to 520 μm At least 10-90% by weight of a granular diluent.
用語「有効成分」とは、本明細書中で使用するとき、治療効果を有する物質として定義される。 The term “active ingredient” as used herein is defined as a substance having a therapeutic effect.
本発明の医薬組成物に存在する有効成分の量は、該組成物が投与される哺乳動物、及び治療されるべき疾患に依存して変更することができる。 The amount of active ingredient present in the pharmaceutical composition of the invention can vary depending on the mammal to which the composition is administered and the disease to be treated.
全てのパーセントは、他に特記される場合を除いて、錠剤コアの全重量に対する重量当たりとして与えられる。 All percentages are given per weight based on the total weight of the tablet core, unless otherwise specified.
用語「ドライシロップ」は、本明細書中で使用するとき、顆粒形態を有する製剤として定義される。本発明の医薬組成物は、投与前には水に分散することができ;好ましくは、次に、透明な溶液が得られる。本発明の医薬組成物はまた、直接的にも、即ち、水を用いないで飲み込むことができる。 The term “dry syrup” as used herein is defined as a formulation having a granular form. The pharmaceutical composition of the invention can be dispersed in water prior to administration; preferably, a clear solution is then obtained. The pharmaceutical composition of the present invention can also be swallowed directly, i.e. without water.
本発明の医薬組成物は、ボトル、サシェ又はカプセルなどのいずれかのタイプの適切なパッケージングに包装することができる。好ましくは、組成物は、包装されたユニットの各々が、1回服用量の有効成分を含むように単位剤形に予め包装されている。単位服用量は、直接舌の上に、又は水若しくは食物中に注ぐことができる。 The pharmaceutical composition of the present invention can be packaged in any type of suitable packaging, such as a bottle, sachet or capsule. Preferably, the composition is prepackaged in unit dosage form so that each packaged unit contains a single dose of the active ingredient. The unit dose can be poured directly on the tongue or in water or food.
希釈剤の例は、マンニトール、ソルビトール及びキシリトールである。より好ましい希釈剤は、マンニトールである。 Examples of diluents are mannitol, sorbitol and xylitol. A more preferred diluent is mannitol.
通常、本発明に係る医薬組成物は、該組成物の全重量に対して、20〜80重量%の希釈剤を含む。 Usually, the pharmaceutical composition according to the present invention comprises 20-80% by weight of diluent with respect to the total weight of the composition.
好ましくは、本発明に係る医薬組成物は、25〜75重量%の希釈剤を含む。 Preferably, the pharmaceutical composition according to the present invention comprises 25-75% by weight diluent.
好ましくは、本発明に係る医薬組成物は、該組成物の全重量に対して、30〜70重量%の希釈剤、より好ましくは35〜65重量の希釈剤、最も好ましくは40〜60重量%の希釈剤を含む。 Preferably, the pharmaceutical composition according to the invention is 30 to 70% by weight diluent, more preferably 35 to 65% by weight diluent, most preferably 40 to 60% by weight relative to the total weight of the composition. Of diluent.
通常、本発明に係る医薬組成物は、平均粒子径が75〜450μmである希釈剤を含む。 Usually, the pharmaceutical composition according to the present invention contains a diluent having an average particle size of 75 to 450 μm.
好ましくは、本発明に係る医薬組成物は、平均粒子径が100〜300μmであり;より好ましくは、平均粒子径が120〜250μmであり;最も好ましくは、平均粒子径が150〜200μmである希釈剤を含む。 Preferably, the pharmaceutical composition according to the present invention has an average particle size of 100 to 300 μm; more preferably an average particle size of 120 to 250 μm; most preferably a dilution with an average particle size of 150 to 200 μm Contains agents.
さらに、顆粒希釈剤に加えて、追加の賦形剤を医薬組成物に添加することができる。通常、本発明の医薬組成物は、少なくとも1つの追加の賦形剤を含む。好ましくは、追加の賦形剤は、室温で水溶性である。 Furthermore, in addition to the granular diluent, additional excipients can be added to the pharmaceutical composition. Usually, the pharmaceutical composition of the invention comprises at least one additional excipient. Preferably, the additional excipient is water soluble at room temperature.
したがって、本発明の医薬組成物はまた、賦形剤として結合剤を含むことができる。 Accordingly, the pharmaceutical composition of the present invention can also include a binder as an excipient.
用語「結合剤」とは、本明細書中で使用するとき、圧縮力だけでは結合することができない粒子を結合することができる試薬として定義される。結合剤は、単一の化合物の形態であるか又は化合物の混合物の形態で存在してもよい。 The term “binder”, as used herein, is defined as a reagent that can bind particles that cannot be bound by compressive force alone. The binder may be present in the form of a single compound or in the form of a mixture of compounds.
結合剤の例は、スターチ、架橋したカルボキシメチルセルロースナトリウムとも呼ばれるクロスカルメロースナトリウム、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、ヒドロキシメチルセルロース、ポリビニルアルコール、アルギン酸塩、及びポリビニルピロリドンである。本発明に係る好ましい結合剤は、ポリビニルピロリドン、スターチグリコール酸ナトリウム、及びクロスカルメロースナトリウムである。より好ましい結合剤は、ポリビニルピロリドンである。 Examples of binders are starch, croscarmellose sodium, also called crosslinked sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, polyvinyl alcohol, alginate, and polyvinylpyrrolidone. Preferred binders according to the invention are polyvinylpyrrolidone, sodium starch glycolate and croscarmellose sodium. A more preferred binder is polyvinylpyrrolidone.
本発明に係る医薬組成物は、該組成物の全重量に対して、0.5〜5.0重量%の結合剤を含む。好ましくは、医薬組成物は、該組成物の全重量に対して、1.0〜4.0重量%の結合剤を含む。より好ましくは、本発明に係る医薬組成物は、該組成物の全重量に対して、1.5〜2.5重量%の結合剤を含む。 The pharmaceutical composition according to the present invention comprises 0.5 to 5.0% by weight of binder with respect to the total weight of the composition. Preferably, the pharmaceutical composition comprises 1.0-4.0% by weight binder based on the total weight of the composition. More preferably, the pharmaceutical composition according to the invention comprises 1.5 to 2.5% by weight of binder, based on the total weight of the composition.
本発明の医薬組成物はまた、賦形剤として、甘味剤を含んでもよい。本発明に従って使用することができる甘味剤の例は、アスパルテーム、カリウムのアセサルフェーム(acesulfame)、シクラメート(人工甘味料)、サッカリンである。好ましくは、組成物は、人工甘味剤を含む。より好ましい甘味剤は、アスパルテームである。 The pharmaceutical composition of the present invention may also contain a sweetening agent as an excipient. Examples of sweeteners that can be used according to the present invention are aspartame, potassium acesulfame, cyclamate (artificial sweetener), saccharin. Preferably, the composition includes an artificial sweetener. A more preferred sweetener is aspartame.
本発明に係る医薬組成物は、該組成物の全重量に対して、1.0〜30重量%の甘味剤を含む。好ましくは、医薬組成物は、2.0〜15重量%の甘味剤を含む。より好ましくは、本発明に係る医薬組成物は、該組成物の全重量に対して、1.0〜7.5重量%の甘味剤を含む。 The pharmaceutical composition according to the present invention comprises 1.0 to 30% by weight of a sweetener relative to the total weight of the composition. Preferably, the pharmaceutical composition comprises 2.0-15% by weight sweetener. More preferably, the pharmaceutical composition according to the present invention comprises 1.0-7.5% by weight of sweetening agent relative to the total weight of the composition.
本発明の医薬組成物はまた、賦形剤として、香味剤を含むことができる。
香味剤の例は、チェリーフレーバー、グレープフルーツフレーバー、テトラロームオレンジ及びハッカ油(oleum aurantii)である。好ましくは、液体の香味剤が用いられる。好ましい香味剤は、テトラロームオレンジである。
The pharmaceutical composition of the present invention may also contain a flavoring agent as an excipient.
Examples of flavoring agents are cherry flavors, grapefruit flavors, tetralome oranges and oleum aurantii. Preferably, a liquid flavoring agent is used. A preferred flavoring agent is tetralome orange.
通常、本発明に係る医薬組成物は、0.01〜2.00重量%の香味剤を含む。好ましくは、本発明に係る医薬組成物は、0.02〜1.50重量%の香味剤、より好ましくは0.04〜1.00重量%の香味剤、最も好ましくは0.08%〜1.2重量%の香味剤を含む。 Usually, the pharmaceutical composition according to the present invention comprises 0.01 to 2.00% by weight of a flavoring agent. Preferably, the pharmaceutical composition according to the present invention comprises 0.02 to 1.50% by weight of flavoring agent, more preferably 0.04 to 1.00% by weight of flavoring agent, most preferably 0.08% to 1%. Contains 2 wt% flavoring agent.
通常、本発明は、有効成分としてレベチラセタム、該組成物の全重量に対して、10〜90重量%の希釈剤、0.5〜5.0重量%の結合剤、1.0〜30重量%の甘味剤、及び0.01〜2.00重量%の香味剤を含む医薬組成物に関する。 Usually, the present invention comprises levetiracetam as an active ingredient, 10 to 90% by weight diluent, 0.5 to 5.0% by weight binder, 1.0 to 30% by weight, based on the total weight of the composition. And a pharmaceutical composition comprising 0.01 to 2.00% by weight of a flavoring agent.
特に、本発明は、有効成分としてレベチラセタム、該組成物の全重量に対して、20〜80重量%の希釈剤、0.5〜5.0重量%の結合剤、1.0〜30重量%の甘味剤、及び0.01〜2.00重量%の香味剤を含む医薬組成物に関する。 In particular, the present invention relates to levetiracetam as an active ingredient, 20 to 80% by weight diluent, 0.5 to 5.0% by weight binder, 1.0 to 30% by weight relative to the total weight of the composition. And a pharmaceutical composition comprising 0.01 to 2.00% by weight of a flavoring agent.
好ましくは、本発明は、有効成分としてレベチラセタム、該組成物の全重量に対して、30〜70重量%の希釈剤、1.0〜4.0重量%の結合剤、2.0〜15重量%の甘味剤、及び0.02〜1.50重量%の香味剤を含む医薬組成物に関する。 Preferably, the present invention comprises levetiracetam as an active ingredient, 30-70% by weight diluent, 1.0-4.0% by weight binder, 2.0-15% by weight relative to the total weight of the composition. % Sweetener, and 0.02-1.50% by weight of a flavoring agent.
より好ましくは、本発明は、有効成分としてレベチラセタム、該組成物の全重量に対して、40〜60重量%の希釈剤、1.5〜2.5重量%の結合剤、1.0〜7.5重量%の甘味剤、及び0.08〜1.2重量%の香味剤を含む医薬組成物に関する。 More preferably, the present invention provides levetiracetam as an active ingredient, 40-60 wt% diluent, 1.5-2.5 wt% binder, 1.0-7, based on the total weight of the composition. It relates to a pharmaceutical composition comprising 5% by weight sweetener and 0.08-1.2% by weight flavoring agent.
通常、本発明は、有効成分としてレベチラセタム、該組成物の全重量に対して、10〜90重量%のマンニトール、0.5〜5.0重量%のポリビニルピロリドン、1.0〜30重量%のアスパルテーム、及び0.01〜2.00重量%のテトラロームオレンジを含む医薬組成物に関する。 Usually, the present invention comprises levetiracetam as an active ingredient, 10 to 90% by weight of mannitol, 0.5 to 5.0% by weight of polyvinylpyrrolidone, 1.0 to 30% by weight of the total weight of the composition. The present invention relates to a pharmaceutical composition comprising aspartame and 0.01 to 2.00% by weight of tetralome orange.
特に、本発明は、有効成分としてレベチラセタム、該組成物の全重量に対して、20〜80重量%のマンニトール、0.5〜5.0重量%のポリビニルピロリドン、1.0〜30重量%のアスパルテーム、及び0.01〜2.00重量%のテトラロームオレンジを含む医薬組成物に関する。 In particular, the present invention relates to levetiracetam as an active ingredient, 20 to 80% by weight mannitol, 0.5 to 5.0% by weight polyvinylpyrrolidone, 1.0 to 30% by weight based on the total weight of the composition. The present invention relates to a pharmaceutical composition comprising aspartame and 0.01 to 2.00% by weight of tetralome orange.
好ましくは、本発明は、有効成分としてレベチラセタム、該組成物の全重量に対して、30〜70重量%のマンニトール、1.0〜4.0重量%のポリビニルピロリドン、2.0〜15重量%のアスパルテーム、及び0.02〜1.50重量%のテトラロームオレンジを含む医薬組成物に関する。 Preferably, the present invention comprises levetiracetam as an active ingredient, 30 to 70% by weight mannitol, 1.0 to 4.0% by weight polyvinylpyrrolidone, 2.0 to 15% by weight, based on the total weight of the composition. Of aspartame and 0.02 to 1.50% by weight of tetralome orange.
より好ましくは、本発明は、有効成分としてレベチラセタム、該組成物の全重量に対して、40〜60重量%のマンニトール、1.5〜2.5重量%のポリビニルピロリドン、1.0〜7.5重量%のアスパルテーム、及び0.08〜1.20重量%のテトラロームオレンジを含む医薬組成物に関する。 More preferably, the present invention relates to levetiracetam as an active ingredient, 40 to 60% by weight of mannitol, 1.5 to 2.5% by weight of polyvinyl pyrrolidone, 1.0 to 7% based on the total weight of the composition. It relates to a pharmaceutical composition comprising 5% by weight of aspartame and 0.08-1.20% by weight of tetralome orange.
更に特定の態様では、本発明は、該組成物の全重量に対して、30.0〜85.0重量%のレベチラセタム、ブリバラセタム又はセレトラセタムを含む医薬組成物に関する。 In a more particular aspect, the invention relates to a pharmaceutical composition comprising 30.0-85.0% by weight of levetiracetam, brivaracetam or seletracetam relative to the total weight of the composition.
通常、この更なる特定の態様では、本発明は、該組成物の全重量に対して、35.0〜83.0重量%のレベチラセタムを含む医薬組成物に関する。 Usually, in this further particular embodiment, the present invention relates to a pharmaceutical composition comprising 35.0-83.0% by weight of levetiracetam, relative to the total weight of the composition.
特に、この更なる特定の態様では、本発明は、該組成物の全重量に対して、36.0〜80.0重量%のレベチラセタムを含む医薬組成物に関する。 In particular, in this further particular embodiment, the invention relates to a pharmaceutical composition comprising 36.0-80.0% by weight of levetiracetam, relative to the total weight of the composition.
好ましくは、この更なる特定の態様では、本発明は、該組成物の全重量に対して、38.0〜78.0重量%のレベチラセタムを含む医薬組成物に関する。 Preferably, in this further particular embodiment, the present invention relates to a pharmaceutical composition comprising 38.0-78.0% by weight of levetiracetam, relative to the total weight of the composition.
より好ましくは、この更なる特定の態様では、本発明は、該組成物の全重量に対して、45.0〜75.0重量%のレベチラセタムを含む医薬組成物に関する。 More preferably, in this further particular embodiment, the present invention relates to a pharmaceutical composition comprising 45.0-75.0% by weight of levetiracetam, relative to the total weight of the composition.
本発明の一態様では、有効成分としてレベチラセタムを含む医薬組成物に存在する甘味剤、香味剤、及び結合剤の全量は、該組成物の全重量に対して、90.0重量%以下、好ましくは80.0重量%以下、より好ましくは30.0重量%以下である。 In one aspect of the present invention, the total amount of sweetener, flavoring agent and binder present in the pharmaceutical composition comprising levetiracetam as an active ingredient is preferably 90.0% by weight or less, preferably 90.0% by weight or less, based on the total weight of the composition. Is 80.0% by weight or less, more preferably 30.0% by weight or less.
本発明に係る医薬組成物は、好ましくは、サシェ中の顆粒の形態、及びボトル中の顆粒の形態である。組成物はまた、チューワブルな錠剤に圧縮されてもよい。 The pharmaceutical composition according to the present invention is preferably in the form of granules in a sachet and in the form of granules in a bottle. The composition may also be compressed into chewable tablets.
場合により、本発明に係る医薬組成物は、味マスキング剤を含んでもよい。
本発明の医薬組成物は、当業者に知られている慣用的な方法に従って、いずれかのプロセスによって製造することができる。プロセスの例は、直接圧縮、乾式造粒、湿式造粒、溶融造粒である。好ましくは、医薬組成物は、湿式造粒によって製造される。
Optionally, the pharmaceutical composition according to the present invention may comprise a taste masking agent.
The pharmaceutical compositions of the invention can be manufactured by any process according to conventional methods known to those skilled in the art. Examples of processes are direct compression, dry granulation, wet granulation, melt granulation. Preferably, the pharmaceutical composition is manufactured by wet granulation.
有効成分、マンニトール及び結合剤は、湿式造粒プロセスによって粒状にされる。次に、乾燥した顆粒上に香味剤を添加する。次いで、甘味剤を添加する。最終混合を行う。 The active ingredient, mannitol and binder are granulated by a wet granulation process. Next, a flavoring agent is added on the dried granules. A sweetener is then added. Perform final mixing.
具体的な製剤は下記の通りである:
・500mgのレベチラセタム、平均粒子径が180μmの451mgの顆粒マンニトール(パーリトール(Pearlitol)(登録商標)SD200)、19mgのポリビニルピロリドン(ポビドン(Povidone)K30)、30mgのアスパルテーム、及び1mgのテトラロームオレンジを含むドライシロップ組成物。
Specific formulations are as follows:
500 mg levetiracetam, 451 mg granule mannitol (Pearlitol® SD200) with an average particle size of 180 μm, 19 mg polyvinylpyrrolidone (Povidone K30), 30 mg aspartame, and 1 mg tetralome orange A dry syrup composition comprising.
・500mgのレベチラセタム、平均粒子径が180μmの451mgの顆粒マンニトール(パーリトール(登録商標)SD200)、19mgのポリビニルピロリドン(ポビドンK30)、30mgのアスパルテーム、及び1mgのハッカ油を含むドライシロップ組成物。 A dry syrup composition comprising 500 mg levetiracetam, 451 mg granular mannitol (Perritol® SD200) with an average particle size of 180 μm, 19 mg polyvinylpyrrolidone (Povidone K30), 30 mg aspartame, and 1 mg mint oil.
別の態様では、本発明は、疾患の治療又は予防に有用なレベチラセタムを含む医薬組成物に関する。 In another aspect, the invention relates to a pharmaceutical composition comprising levetiracetam useful for the treatment or prevention of disease.
用語「疾患」に関して、本出願人は、てんかん発生、発作性障害、けいれん、パーキンソン病、ドーパミン代償療法によって誘導される運動障害、神経弛緩剤の投与によって誘導される遅発性運動障害、ハンチントン舞踏病、他の神経障害、例えば双極性障害、マニア、うつ病、不安症、注意欠陥過活動性障害(ADHD)、片頭痛、三叉神経痛及び他の神経痛、慢性疼痛、神経因性疼痛、脳虚血、心不整脈、筋緊張症、コカイン中毒、脳梗塞、ミオクローヌス、振戦、本態性振戦、単純及び複雑チック、トゥレット・シンドローム、下肢静止不能症候群及び他の運動障害、新生脳出血、筋萎縮性側索硬化症、痙縮及び変性疾患、気管支喘息、喘息重積状態及びアレルギー性気管支炎、喘息症候群、気管支過敏性及び気管支症候群、並びにアレルギー性及び血管運動神経性鼻炎及び鼻結膜炎からなる群から選択される疾患を了解する。 With respect to the term “disease”, Applicants have identified the following: Disease, other neurological disorders such as bipolar disorder, mania, depression, anxiety, attention deficit hyperactivity disorder (ADHD), migraine, trigeminal neuralgia and other neuralgia, chronic pain, neuropathic pain, cerebral imagination Blood, cardiac arrhythmia, myotonia, ***e addiction, cerebral infarction, myoclonus, tremor, essential tremor, simple and complex tics, Tourette syndrome, restless leg syndrome and other movement disorders, new cerebral hemorrhage, muscle atrophy Lateral sclerosis, spasticity and degenerative diseases, bronchial asthma, asthma status and allergic bronchitis, asthma syndrome, bronchial hypersensitivity and bronchial syndrome, and a To understand a disease selected from the group consisting of Energy resistance and vasomotor rhinitis and rhinoconjunctivitis.
用語「治療(treatment)」は、本明細書中で使用するとき、治療的(curative)処置及び予防的処置が含まれる。 The term “treatment”, as used herein, includes curative treatment and prophylactic treatment.
「治療的(curative)」とは、障害又は状態の現在の症候出現の処置に有効であることを意味する。 “Curative” means effective in treating the current manifestation of a disorder or condition.
「予防的」とは、障害又は状態の発生又は再発予防を意味する。
本発明はまた、医薬組成物の使用によるヒト患者の治療方法に関する。
“Prophylactic” means prevention of occurrence or recurrence of a disorder or condition.
The present invention also relates to a method for treating a human patient through the use of a pharmaceutical composition.
本発明はまた、前記疾患を治療するための薬剤として使用するための医薬組成物に関する。 The present invention also relates to a pharmaceutical composition for use as a medicament for treating said disease.
本発明はまた、前記疾患における治療用途のための薬剤を製造するための医薬組成物の使用に関する。 The invention also relates to the use of a pharmaceutical composition for the manufacture of a medicament for therapeutic use in said diseases.
好ましくは、前記疾患は、てんかん、パーキンソン病、運動障害、片頭痛、振戦、本態性振戦、双極性障害、慢性疼痛、神経因性疼痛、又は気管支、喘息若しくはアレルギー状態から本質的になる群から選択される。より好ましくは、前記疾患はてんかんである。 Preferably, the disease consists essentially of epilepsy, Parkinson's disease, movement disorder, migraine, tremor, essential tremor, bipolar disorder, chronic pain, neuropathic pain, or bronchial, asthma or allergic conditions Selected from the group. More preferably, the disease is epilepsy.
本発明はまた、本発明に係る医薬組成物が使用されることによって特徴付けられる、前記疾患における治療用途に意図された薬剤を製造する方法に関する。 The invention also relates to a method for producing a medicament intended for therapeutic use in said diseases, characterized by the use of a pharmaceutical composition according to the invention.
本発明はまた、医薬組成物の投与による疾患を軽減するためにヒトを治療する方法に指向される。 The present invention is also directed to a method of treating a human to alleviate a disease caused by administration of a pharmaceutical composition.
本発明の医薬組成物は、均質な、フリーフローな、磨耗耐性な、均一サイズの顆粒の形態である。 The pharmaceutical composition of the present invention is in the form of homogeneous, free-flow, abrasion-resistant, uniform-sized granules.
本発明の1つの利点は、香味剤が顆粒表面で十分に分散しているという特徴である。
本発明の別の利点は、医薬組成物が味をマスクした製剤であるということである。組成物は、可溶化したレベチラセタムの味が実質的になく、口当たりの良く、薬剤の味がしない。
One advantage of the present invention is that the flavoring is well dispersed on the granule surface.
Another advantage of the present invention is that the pharmaceutical composition is a taste masked formulation. The composition is substantially free of the solubilized levetiracetam taste, is palatable and does not taste the drug.
本発明の別の利点は、顆粒のより容易な流動性、同時に、良好であり迅速な水への溶解を可能にする少量の結合剤である。 Another advantage of the present invention is the small amount of binder that allows easier flowability of the granules, while at the same time allowing good and rapid dissolution in water.
本発明の組成物は、食物又は水溶液に分散させ、苦味なく飲み込むことができる。
本発明の別の利点は、医薬組成物が、一度、舌の上に置かれると、ザラザラした感じ又は他の目立った残留物なしに、ほとんど即座に分散することである。
The composition of the present invention can be dispersed in food or an aqueous solution and swallowed without bitterness.
Another advantage of the present invention is that once placed on the tongue, the pharmaceutical composition disperses almost instantly without a gritty feel or other noticeable residue.
さらに、本発明の医薬組成物は、賦形剤として、潤滑剤、ステアリン酸マグネシウム、ステアリン酸、ポリエチレングリコール、スクロース、糖を含むことを要しない。外部被覆を必要としない。そのため、製造が容易である。分散剤が必要でない。 Furthermore, the pharmaceutical composition of the present invention does not need to contain a lubricant, magnesium stearate, stearic acid, polyethylene glycol, sucrose, or sugar as an excipient. Does not require external coating. Therefore, manufacture is easy. No dispersant is required.
下記の実施例は、例示のみを目的として提供され、いかなる方法においても本発明を限定するように構築することは意図しておらず、そのように構築されていない。当業者は、下記の実施例の日常的な変更及び修飾が本発明の精神又は範囲を超えることなしに実施され得ることを承認する。 The following examples are provided for purposes of illustration only and are not intended to be constructed to limit the invention in any way, and are not so constructed. Those skilled in the art will appreciate that routine variations and modifications of the following examples can be made without exceeding the spirit or scope of the present invention.
実施例1.
ドライシロップAは、本発明に係る湿式造粒プロセスによって製造され、下記の組成を有する(表1)。
Example 1.
Dry syrup A is produced by a wet granulation process according to the present invention and has the following composition (Table 1).
マンニトール(パーリトールSD200)は、平均粒子径が約180μmの顆粒マンニトールである。 Mannitol (Peritol SD200) is a granular mannitol having an average particle size of about 180 μm.
ポビドンK30は、結合剤として用いられるポリビニルピロリドンであるが、脱苦味剤しても作用し、第二に粘性の構築に手助けすることができる。 Povidone K30 is a polyvinylpyrrolidone used as a binder, but it can also act as a debittering agent and secondly help build viscosity.
結合剤のポビドンは、顆粒液(8gのエタノール)に溶解され、混合マンニトール及び有効成分に添加される。 The binding agent povidone is dissolved in granule fluid (8 g ethanol) and added to the mixed mannitol and active ingredients.
湿式顆粒物は乾燥される。乾燥の終わりに、温度が室温に下がったら、液体の香味剤であるテトラロームオレンジをアルコールと混合し、全ての顆粒表面に均質に噴霧される。顆粒は、甘味剤であるアスパルテームの添加前に篩いに掛けられる。最終の混和物が混合される。 The wet granulate is dried. At the end of drying, when the temperature drops to room temperature, a liquid flavoring agent, tetralome orange, is mixed with the alcohol and sprayed homogeneously on all granule surfaces. The granules are sieved before addition of the sweetener aspartame. The final blend is mixed.
粒度分布試験を行う。結果は下記の通りである:
<10%の顆粒フラクションは、75μmを下回る。
>90%の顆粒フラクションは、75μmを上回り、500μmを下回る。
0%の顆粒フラクションは、500μmを上回る。
粒度分布の結果は、その1つが本明細書に記載されるように、製剤に関して理想的である。
Perform a particle size distribution test. The results are as follows:
The <10% granule fraction is below 75 μm.
The> 90% granule fraction is above 75 μm and below 500 μm.
The 0% granule fraction is above 500 μm.
The particle size distribution results are ideal for the formulation, one of which is described herein.
有効成分中の服用量が行われ、アッセイ結果は、95%を上回る割合である。得られた結果は、95.0%〜105.5%の共通の規格内にある。 A dose in the active ingredient is made and the assay results are in excess of 95%. The results obtained are within a common standard of 95.0% to 105.5%.
組成物は、フリーフローであり、乾燥形態ではヒトの舌に置かれた場合、又は水に分散され、その分散の約5分以内に摂取される場合、可溶化したレベチラセタムの味が実質的にない。 The composition is free-flowing and, when placed in a dry form on a human tongue, or when dispersed in water and ingested within about 5 minutes of the dispersion, the solubilized levetiracetam taste is substantially reduced. Absent.
実施例2.
ドライシロップBは、本発明に係る湿式造粒プロセスによって製造され、下記の組成を有する(表2)。
Example 2
Dry syrup B is manufactured by the wet granulation process according to the present invention and has the following composition (Table 2).
この組成物は、満足のいく味を示す。 This composition exhibits a satisfactory taste.
実施例3(比較例)
ドライシロップCは、湿式造粒プロセスによって製造され、下記の組成を有する(表3)。
Example 3 (comparative example)
Dry syrup C is produced by a wet granulation process and has the following composition (Table 3).
この組成物は、苦味があり、したがって、患者による薬物摂取の良好なコンプライアンスは承認されない。 This composition has a bitter taste and therefore is not approved for good compliance of drug intake by the patient.
実施例4(比較例)
ドライシロップDは、湿式造粒プロセスによって製造され、下記の組成を有する(表4)。
Example 4 (comparative example)
Dry syrup D is produced by a wet granulation process and has the following composition (Table 4).
湿式造粒後に得られた顆粒は、フリーフローではなく、均質なサイズでない。 Granules obtained after wet granulation are not free flow and are not of uniform size.
実施例5(比較例)
ドライシロップEは、湿式造粒プロセスによって製造され、下記の組成を有する(表5)。
Example 5 (comparative example)
Dry syrup E is produced by a wet granulation process and has the following composition (Table 5).
湿式造粒後に得られた顆粒は、フリーフローではなく、均質なサイズでない。 Granules obtained after wet granulation are not free flow and are not of uniform size.
実施例6:薬理学的データ
レベチラセタムは、1回の54mg/kg服用後に、試験した全ての種(マウス、ラット、ウサギ及びイヌ)において十分に吸収され、概して、完全に生体に利用可能である。レベチラセタムは、一般に、服用に比例している血漿レベル及び曝露と共に、これらの種において直線的な動力学を示すが、イヌでは、血漿レベル及び曝露の両方は、嘔吐によりいくつかの試験においてより高い服用量で比例以下であった。マウス及びラットでは、血漿レベル及び曝露は、強制飼養と比較して、飼料投与によって与えられた場合により低かったので、食物は吸収を減少させるようであった。毒性学試験で用いた服用量での繰り返し投与後、血漿レベルは、マウスにおいて安定を維持し、ラットでは増加する傾向にあった。マウス、ラット及びイヌでは、より高い服用量での酵素誘導の兆候がいくつかあった。しかしながら、これは、繰り返し投与後のレベチラセタムの感知できるほどの低い曝露に帰着しなかった。
Example 6: Pharmacological data Levetiracetam is well absorbed in all species tested (mouse, rat, rabbit and dog) after a single 54 mg / kg dose and is generally fully bioavailable . Levetiracetam generally shows linear kinetics in these species with plasma levels and exposure proportional to dose, but in dogs both plasma levels and exposure are higher in some studies due to vomiting The dose was less than proportional. In mice and rats, food appeared to reduce absorption because plasma levels and exposure were lower when given by feed administration compared to gavage. After repeated administration at the dose used in the toxicology study, plasma levels tended to remain stable in mice and increased in rats. There were some signs of enzyme induction at higher doses in mice, rats and dogs. However, this did not result in appreciably low exposure to levetiracetam after repeated administration.
レベチラセタムは、マウス、ラット、ウサギ及びイヌに投与後、組織に均質に分布し、主な例外は、腎臓(高濃度)、及び脂肪組織(非常に低濃度)であった。血漿と中枢神経系との間の交換の速度は、ほとんど他の組織に対するものよりも遅かった。 Levetiracetam was distributed homogeneously in tissues after administration to mice, rats, rabbits and dogs, with the main exception being kidney (high concentration) and adipose tissue (very low concentration). The rate of exchange between plasma and the central nervous system was almost slower than for other tissues.
レベチラセタムは、胎盤関門を通過するが、羊水に蓄積されない。
組織分布試験からの見解と一致して、レベチラセタムは、細胞内及び細胞外の水の体積に対応して0.5〜0.7L/kgの分布体積を有する。レベチラセタムは、血漿タンパク質に結合せず、血液と血漿との間に等しく分布する。
Levetiracetam crosses the placental barrier but does not accumulate in amniotic fluid.
Consistent with observations from tissue distribution studies, levetiracetam has a distribution volume of 0.5-0.7 L / kg corresponding to the volume of intracellular and extracellular water. Levetiracetam does not bind to plasma proteins and is equally distributed between blood and plasma.
全ての種において、レベチラセタム及びその代謝物は、他の重要な***経路を伴わないで、尿中に大部分が排出される。生体では、レベチラセタムの保持及び蓄積はなく、1%未満の放射線活性が、マウス及びラットへの[14C]−レベチラセタムの投与後に死体に残存していた。 In all species, levetiracetam and its metabolites are largely excreted in the urine without other important excretion routes. In vivo, there was no retention and accumulation of levetiracetam and less than 1% radioactivity remained in the cadaver after administration of [ 14 C] -levetiracetam to mice and rats.
実施例7:全ての実験は、地方の動物実験に関する倫理委員会のガイドラインに従って行った。 Example 7: All experiments were performed according to the guidelines of the Ethics Committee for local animal experiments.
海馬スライスにおけるてんかん応答:レベチラセタムは、還流液中の高いK+/低いCa2+濃度によるラットの海馬スライスにおいて誘導され、ビククリンによって誘導されるてんかん応答を減少させる。高いK+/低いCa2+濃度によるか又はビククリンによって誘導されるてんかん応答に対するブリバラセタムの効果は、従来報告された標準的な手法に従って、Sprague−Dawleyから調製した横位海馬スライスにおいて試験された。てんかん応答は、人工的な脳脊髄液(ACSF)(K+3mM;Ca2+2.4mM)の通常の還流から、高いK+/低いCa2+液(HKLCF)(K+7.5mM;Ca2+0.5mM)に又は5Mビククリンメチオダイド(BMI)含有ACSFに通過させることによって誘導した。 Epilepsy Response in Hippocampal Slices: Levetiracetam is induced in rat hippocampal slices by high K + / low Ca 2+ concentrations in the reflux and reduces the epileptic response induced by bicuculline. The effect of brivaracetam on epilepsy responses induced by high K + / low Ca 2+ concentration or by bicuculline was tested in lateral hippocampal slices prepared from Sprague-Dawley, according to previously reported standard procedures. The epilepsy response is from normal reflux of artificial cerebrospinal fluid (ACSF) (K + 3 mM; Ca 2+ 2.4 mM) to high K + / low Ca 2+ fluid (HKLCF) (K + 7.5 mM; Ca2 + 0.5 mM) or by passing through 5M bicuculline methiodide (BMI) -containing ACSF.
細胞外のフィールド電位(FP)は、2MのNaClを満たしたガラス微小電極を用いて、スライスのCA3領域において記録された。誘発されたFPは、スライスがACSFにある場合に最大振幅の50〜75%の1つのポピュレーションスパイク(PS)を発揮する定電流方形パルスを用いて、線毛刺激に応答して、10分の間隔で記録した。HKLCFモデルでは、2分の自発的な活動も、誘発された応答の記録間の各10分の間隔の中間で記録された。 Extracellular field potential (FP) was recorded in the CA3 region of the slice using a glass microelectrode filled with 2M NaCl. The induced FP is 10 minutes in response to ciliary stimulation using a constant current square pulse that exerts one population spike (PS) of 50-75% of maximum amplitude when the slice is in ACSF. Recorded at intervals. In the HKLCF model, 2 minutes of spontaneous activity was also recorded in the middle of each 10 minute interval between the recordings of evoked responses.
ブリバラセタム又はレベチラセタムのいずれかは、ACSFからHKLCF又は5M BMI含有ACSFに移す20分前に、スライスの浴液に添加し、実験を通じて、還流液に維持された。 Either brivaracetam or levetiracetam was added to the slicing bath solution 20 minutes prior to transfer from ACSF to HKLCF or 5 M BMI-containing ACSF and maintained at reflux throughout the experiment.
マウスにおける聴原発作:音刺激に対して野生的なランニング、間代性及び緊張性けいれんを伴って反応する遺伝的に音に感受性の雄性マウス(16〜28g;n=10匹/群)を用いた。聴原発作は、30秒間与えられた音刺激(90dB、10〜20kHz)によって誘導した。マウスは、生理食塩水、ブリバラセタム(i.p.,30分)又はレベチラセタム(i.p.,60分)のいずれかで用意され、慢性けいれんに対して保護されたマウスの割合は、抗けいれん作用を評価するために端点として用いた。 Auditory seizures in mice: genetically sound-sensitive male mice (16-28 g; n = 10 / group) that respond to sound stimulation with wild running, clonic and tonic spasms Using. Auditory seizures were induced by sound stimulation (90 dB, 10-20 kHz) applied for 30 seconds. Mice are prepared with either saline, brivaracetam (ip, 30 minutes) or levetiracetam (ip, 60 minutes) and the percentage of mice protected against chronic seizures is anticonvulsant. Used as an endpoint to evaluate the action.
マウスにおける化学的に誘導した発作:ペンチレンテトラゾール、83mg kg-1s.c.を用いて、ブリバラセタムの抗けいれん的特性を評価した。服用量は、動物の97%において4本全ての肢の慢性けいれんを誘導するけいれん服用量として、生理食塩水で処理した動物における服用量−効果曲線に基づいて選択した。化学的けいれん誘発剤の投与直後、マウスは、小さなプラスチック製の籠(25 13 8cm)に分けて入れられ、60分間、4本全ての肢に間代性けいれんの存在を観察した。緊張性けいれん(後肢の伸長)の発生及び死亡率もこの間隔中に記録した。間代性けいれんに対して保護されたマウスの比率を計算し、抗けいれん作用についての端点として用いた。 Chemically induced seizures in mice: pentylenetetrazole, 83 mg kg −1 s. c. Was used to evaluate the anticonvulsant properties of brivaracetam. The dose was selected based on a dose-effect curve in saline treated animals as a seizure dose that induces chronic seizures in all four limbs in 97% of the animals. Immediately after administration of the chemical spasm-inducing agent, mice were placed in small plastic sputum (25 13 8 cm) and observed for the presence of clonic spasm in all four limbs for 60 minutes. The occurrence of tension spasm (hind limb extension) and mortality were also recorded during this interval. The ratio of mice protected against clonic convulsions was calculated and used as an endpoint for anticonvulsant action.
結果
海馬スライスにおけるてんかん応答:ラットの海馬スライスの還流を通常のACSFからHKLCFに変更することにより、定電流線毛刺激に応答して、CA3領域において、てんかんFPを増加的に生じた。HKLCF単独に晒された対照スライスでは、PS1振幅は、次第に増加し、20分以内に水平値(4.250.77mV)に到達し、ACSF還流下で記録されたもののほぼ2倍高かった(2.180.15mV;n=10スライスの平均s.d.)。また、反復的なPS(即ち、PS2、PS3等)の定電流の1回刺激によって誘発したバーストは、統計で顕著に増加し、HKLCF還流の最初の30分で、誘発されたバースト当たり1回のPS1から平均7.62.3PSに増加し、記録の終了まで徐々に増加し続け、HKLCFの80分の還流後には、誘発されたバースト当たり平均8.81.6PSに到達した。ブリバラセタム及びレベチラセタムの両方は、これらのてんかん応答を減少させた。HKLCFの15分の還流により、自然なフィールドバーストが、HKLCF単独に晒された10個の対照スライスのうち4個において発生し、HKLCF中の25分から記録の終結まで、全ての対照スライスは、規則的なフィールドバーストを示した。レベチラセタム(32μM)ではなく、ブリバラセタム(3.2M)は、この自然なバーストの速度を減少させた。
Results Epilepsy response in hippocampal slices: By changing the reflux of rat hippocampal slices from normal ACSF to HKLCF, epilepsy FP was increased in the CA3 region in response to constant-current ciliary stimulation. In control slices exposed to HKLCF alone, the PS1 amplitude gradually increased and reached a horizontal value (4.250.77 mV) within 20 minutes, almost twice as high as that recorded under ACSF reflux (2 180.15 mV; n = average of 10 slices sd). Also, bursts induced by a single stimulation of repetitive PS (ie, PS2, PS3, etc.) constant current increased significantly in the statistics, with one per triggered burst in the first 30 minutes of HKLCF reflux. Increased from an average of PS1 to an average of 7.62.3 PS and continued to increase gradually to the end of the recording, reaching an average of 8.81.6 PS per burst induced after 80 minutes of reflux of HKLCF. Both brivaracetam and levetiracetam reduced these epilepsy responses. With a 15 minute reflux of HKLCF, a natural field burst occurred in 4 out of 10 control slices exposed to HKLCF alone, from 25 minutes in HKLCF to the end of the recording, Showed a typical field burst. Brivaracetam (3.2M) but not levetiracetam (32 μM) reduced the rate of this natural burst.
インビボ試験:完全に扁桃体燃え上がりラットでは、ブリバラセタムは、21.2mg kg-1の服用量から運動発作強度において有意な抑制を誘導し、レベチラセタムは、170mg kg-1の服用量から同様の効果を誘導した。ブリバラセタムはまた、試験した最も高い服用量(212.3mg kg-1)で放出後の持続期間を有意に減少させ、レベチラセタムは、最大1700mg kg-1までこのパラメータに不活性であった。 In vivo test: In a fully amygdala kindled rats, brivaracetam induced a significant suppression in motor seizures intensity from dose of 21.2 mg kg -1, levetiracetam, induce a similar effect from a dose of 170 mg kg -1 did. Brivaracetam also significantly reduced the duration after release at the highest dose tested (212.3 mg kg −1 ), and levetiracetam was inactive on this parameter up to 1700 mg kg −1 .
聴原発作感受性マウスは、ブリバラセタム及びレベチラセタムによる間代性けいれんの発祥に対して保護した;ED50値は、表2に示されている。マウスにおいて発作誘導の30分前にi.p.投与したブリバラセタムはまた、より高いED50値ではあるが、ペンチレンテトラゾールによって誘導された間代性けいれんに対して、並びにマウスにおける最大の電気ショックによって誘導された緊張性の後肢の伸長に対して保護した。 Audiogenic seizure susceptible mice were protected against the occurrence of clonic seizures due to brivaracetam and levetiracetam; ED 50 values are shown in Table 2. 30 minutes prior to seizure induction in mice i. p. Administered brivaracetam also has higher ED 50 values, but against clonic convulsions induced by pentylenetetrazole, as well as tension hindlimb elongation induced by maximal electric shock in mice. Protected.
ブリバラセタムは、試験した最大の服用量(67.9mg kg-1)で出現する完全な阻害を伴って、2.1mg kg-1の服用量からGAERSラットにおいて自然なSWDを有意に抑制した。一方、レベチラセタムは、5.4mg kg-1の服用量からのSWDの有意な抑制を誘導した。 Brivaracetam significantly suppressed natural SWD in GAERS rats from a 2.1 mg kg -1 dose with complete inhibition appearing at the highest dose tested (67.9 mg kg -1 ). On the other hand, levetiracetam induced significant suppression of SWD from a dose of 5.4 mg kg −1 .
マウスの角膜燃え上がり中のブリバラセタムによる前処理は、全身性運動発作の発生における有意な減少をもたらし、類似の発生減少は、より高い服用量でのレベチラセタムを用いて観察された。連続的な角膜刺激と続く処置の終了は、最大の服用量のブリバラセタムを用いて予め処理した群における全身性運動発作の発生における持続的低下を示した。 Pretreatment with brivaracetam during corneal burning in mice resulted in a significant reduction in the occurrence of generalized motor seizures, and a similar reduction in incidence was observed with levetiracetam at higher doses. Continuous corneal stimulation and subsequent termination of treatment showed a sustained decrease in the occurrence of generalized motor seizures in the group pre-treated with the highest dose of brivaracetam.
実施例8:レベチラセタムドライシロップ50%(500mgサシェ、1000mgサシェ及び500mg/gボトル)
顆粒の組成を以下の通りである(表6)。
Example 8: Levetiracetam dry syrup 50% (500 mg sachet, 1000 mg sachet and 500 mg / g bottle)
The composition of the granules is as follows (Table 6).
粒子分布は以下の通りである:10%以内<75μm;5%>500μm;0%>850μm。 The particle distribution is as follows: within 10% <75 μm; 5%> 500 μm; 0%> 850 μm.
この組成物は、満足のいく味を示す。 This composition exhibits a satisfactory taste.
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RU2480214C1 (en) * | 2011-09-22 | 2013-04-27 | Валентина Ивановна Ахапкина | Formulation possessing modulatory activity with adequate effect, pharmaceutical substance (versions), use of pharmaceutical substance, pharmaceutical and parapharmaceutical composition (versions), method for preparing pharmaceutical formulations |
DK2790695T3 (en) | 2011-12-16 | 2016-04-18 | Uni Pharma Kleon Tsetis Pharmaceutical Lab S A | A pharmaceutical composition comprising (S) -2- (2-oxopyrrolidin-1-yl) butanamide |
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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 |
JP7023054B2 (en) | 2017-04-05 | 2022-02-21 | 東和薬品株式会社 | Levetiracetam-containing pharmaceutical composition and method for producing the same |
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JP2011513372A (en) | 2011-04-28 |
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