JP4708795B2 - 物理的および化学的に安定なニコチン−含有粒状物質 - Google Patents
物理的および化学的に安定なニコチン−含有粒状物質 Download PDFInfo
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- JP4708795B2 JP4708795B2 JP2004561429A JP2004561429A JP4708795B2 JP 4708795 B2 JP4708795 B2 JP 4708795B2 JP 2004561429 A JP2004561429 A JP 2004561429A JP 2004561429 A JP2004561429 A JP 2004561429A JP 4708795 B2 JP4708795 B2 JP 4708795B2
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- Prior art keywords
- nicotine
- particulate material
- pharmaceutical composition
- pharmaceutically acceptable
- solvate
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Description
上記の文献は、物理的および化学的に高い安定性と組み合わされた、口腔粘膜を通してのニコチンの真に速い放出と吸収の必要性について対処されていない。固体担体の必要性は明らかであるが、固体マトリックス中へのニコチン吸着との組合せは、単に安定性に関係するだけでなく、より重要でないにしても、同様に担体からの放出性に関係している。
社会は、より深刻な精神障害を及ぼす違法な薬物から自分自身を守ることにおいてさえも成功していない。それゆえ、喫煙が、多かれ少なかれ、社会的および法律的に禁止されようとしているとき、ニコチン摂取のための他の形態の発見が必要となるだろうことは、非常にありえそうなことである。
ニコチンパッチは、1時間当り1 mgに近い量を与える。しかしながら、ある喫煙者ははるかに多くのニコチンを摂取すること、そしてパッチからのニコチンの薬物動態プロファイルは比較的安定しており、不連続変異を許さないということを留意しなければならない。
本発明による粒状物質は、物理的に安定でもある。したがって、22週以上の期間内で、外見上の変化は観察されなかったし、溶出プロファイルは変化しなかった。
しかしながら、もちろん、ニコチンに対して同じ挙動を有する医薬的に許容される他の賦形剤も、本発明では重要でありうる。適切な微晶質セルロースは、加水分解、典型的には塩化水素のような強い鉱酸との加水分解によって精製されたセルロース原料物質から、アモルファス(繊維質セルロース)部分を除いて得られる微結晶の集合を含む結晶性の高い粒状セルロースである。酸加水分解工程は、典型的に平均サイズ範囲約15〜250 μmを有する主としてきめの粗い粒状集合体の微晶質セルロースを生じる。
少なくとも一人の健康な被験者に、ニコチン4 mgまたはその医薬的に許容される塩、複合体もしくは溶媒和物の等量を含む粒状物質を含むチューインガムの形態で投与したときに、粒状物質が、
i) 投与後、長くても約10分以内に、例えば長くても約9分以内に、長くても約8分で、長くても約7分で、長くても約6分で、長くても約5分で、長くても約4分でまたは長くても約3分で、血漿中のニコチン濃度が少なくとも約6 ng/mlをもたらす(例えば、比較的速い流出の組成物に応用可能)、
iii) 投与後、長くても約30分以内に、例えば長くても約25分以内に、長くても約20分以内に、長くても約15分以内にまたは長くても約10分以内に、血漿中のニコチン濃度が少なくとも約10 ng/mlをもたらす(例えば、より延長された放出の組成物に応用可能)、
v) 投与後、血漿中のニコチン濃度が少なくとも約4 ng/ml、例えば少なくとも約5 ng/mlまたは少なくとも約6 ng/mlをもたらす、そして/または
vi) 投与後、血漿中の濃度が少なくとも約7.5 ng/mlまたは少なくとも約10 ng/mlをもたらす。
したがって、本発明による粒状物質または組成物は、ニコチンおよび一つ以上の医薬的に許容されるその塩、複合体もしくは溶媒和物を含む。特定の具体例として、本発明による粒状物質または組成物は、ニコチンおよびニコチン酒石酸塩またはニコチン二酒石酸塩の少なくとも一つを含む。
医薬組成物において、粒状物質は、通常、医薬賦形剤、すなわち治療上不活性な物質または担体と組み合わされる。
担体は、所望の剤形および投与経路により、広く多様な形態のものが採用される。
もう一つの具体例として、本発明による医薬組成物は、治療的および/または予防的に、さらなる活性物質を含み得る。
本発明による医薬組成物は、ニコチンの放出を調整または制御するために、コーティングもされ得る。前記のコーティング物質が、本組成物に対しても適用される。さらに、味覚マスキングのコーティングが使用され得る。
i) 経口投与後、長くても約45分以内に、例えば長くても約30分で、少なくとも約50% w/w、例えば少なくとも約55% w/w、少なくとも約60% w/w、少なくとも約65% w/w、少なくとも約70% w/wまたは少なくとも約75% w/wのニコチンが放出される(例えば、速い、中程度に速い放出)、
医薬組成物に関する。
i) 投与後、長くても約30分以内に、例えば長くても約25分以内に、長くても約20分以内に、長くても約15分以内にまたは長くても約10分以内に、血漿中のニコチン濃度が少なくとも約5 ng/ml、例えば約6 ng/ml以上、約7 ng/ml以上、約8 ng/ml以上、約9 ng/ml以上または約10 ng/ml以上になる(例えば、比較的に速いから中程度に速い放出および速いから中程度に速い作用開始)、
vi) 投与後、血漿中のニコチン濃度が少なくとも約7.5 ng/mlまたは少なくとも約10 ng/mlになる、
医薬組成物に関する。
さらに、組合せにより、作用開始を早めるために、組成物中に含まれるニコチンの少なくとも一部分が速く放出されるようにし、かつ持続的な効果を得るために、ニコチンの残りの部分が長く放出されるように計画され得る。後者のような場合、経口投与後の血漿中のニコチン濃度は単相、二相または多相の曲線を示す。
チューインガムに用いられる適切な賦形剤および添加剤と同様に、チューインガムの製造は、当業者に周知である(例えば、その中で引用される参考文献を含めたWO 03/084338を参照;これらの参照文献は、言及することにより、ここに含まれる)。
したがって、ガム基剤は、当分野で公知の通常の性質のものであり、例えば、市場で入手可能な天然または合成由来のガム基剤である。天然のガム基剤は、チクル、ジェルトンガム、レチデカスピガム(lechi de caspi gum)、ソーガム(soh gum)、シアクガム(siak gum)、カチアウガム(katiau gum)、ソーワガム(sorwa gum)、バラタガム、ペンダレガム(pendare gum)、マレーガム(malaya gum) とピーチガム(peach gum)、天然ガム(natural cauchouc)ならびにダンマー(dammar) およびマスチック(mastix)のような天然樹脂を含む。合成ガム基剤はエラストマー(ポリマー、咀嚼物質)を含む。通常、可塑剤、充填剤(例えば、結着剤)、軟化剤(例えば、油脂またはワックス)、甘味剤、口あたり改善剤および/または乳化剤のような添加剤が加えられる。
より具体的には、上記ニコチン関連疾病とは、タバコ依存症、パーキンソン病、アルツハイマー病、統合失調症、ADHD(注意欠陥多動性障害)、トゥーレット症候群、潰瘍性大腸炎および禁煙後の体重コントロールである。
本発明は、本発明を限定するものではない以下の実施例および図で、さらに説明される。ここで、図1は市場で入手可能な製品からのニコチンの時間に対する血漿中濃度プロファイルを示し、図2は市場で入手可能な製品と比較した、本発明による組成物からのニコチンの血漿中濃度プロファイルを示す。
MCCへのニコチンの取込み
ニコチン塩基を、乾燥された付加物で計算して、0.1〜8%(w/w)の濃度になるようにエタノールに溶解し、真空乾燥または同等な装置を備えた高剪断混合機中で、MCCに加える。混合/分配工程後、粉末を乾燥し、ニコチン濃度をHPLCで測定する。in vitroでの放出は、USP(パドル法)に記載された標準溶出装置およびHPLCを用いて測定する。例えば、ニコチン酒石酸塩のようなニコチン塩は、水/エタノール混液に溶解し、上記のように処理する。
安定性
安定性は、1%(w/w)ニコチン濃度を有するニコチン/MCC粒状物質について測定した。その乾燥粉末は、20℃/55%RHおよび40℃/50%RHで、薄層状に開放状態で保存した。
取込み比
出発ニコチン濃度約12%(w/w)を有するニコチン/MCC粒状物質に対して、取込み比を測定した。乾燥粉末は、20℃/55%RHおよび40℃/50%RHで、薄層状に開放状態で保存した。
ニコチンの起源、すなわち塩基および塩の形態によって、in vitroでの放出を変化させることができる。放出は、試験された全ての組合せに対して急速であり、一般にニコチン塩基が使用されるときにより顕著である。
乾燥されたニコチン/MCC粒状物質をコーティングすることにより、より長い放出プロファイルを達成できた。放出プロファイルの少しの遅延は、約50%(w/w)のポリエチレングリコール(PEG)8000の使用により達成された。より遅延された放出プロファイルは、約50%の水素化綿実油(Akofine E:アコファインE)の使用により達成された。
2乾燥付加物を50%(w/w)水素化綿実油(アコファインE)でコーティングした。
3乾燥付加物を60%(w/w)硬化油脂(ウィテップゾールE-76およびE-85の1:1混合物)でコーティングした。
4〜5%(w/w)のニコチン/MCC粒状物質を、ニコチン/ガムの最終濃度が2および4mgになるように、チューインガム組成物中に混合した。ガムは直接圧縮を使用して作り、初期のニコチン容量を分析した。ガムは、同一の被験者によりかまれ、ガムをかむ前、5、10、15および20分後に血液サンプルを採取した。血液サンプルを、ニコチンおよびコチニンについて分析した。in vivoのヒト血漿中プロファイルは、所望のプロファイルが、ある剤形、すなわちチューインガムにニコチン/MCC粒状物質を使用することによって、十分に余裕をもって達成されたことを示す。錠剤、トローチ剤、ゲル剤、懸濁剤、噴霧剤、パッチ剤等の他の製品も、適当な製剤計画に対して使用され得る。図2に、in vivo研究での結果を示す。
ニコチンをMCC中に取り込む。ニコチン塩基を顆粒化液体、99.5%エタノールに前もって加え、真空高剪断混合器、すなわちザンチェッタ ロトラブ(Zanchetta Rotolab)またはそれと均等物中のMCCに加える。湿潤混練物を混合器中で真空下に乾燥する。トレー上での乾燥もその代わりに使用できた。
成分 分量 機能
(mg/単位)
ニコチン塩基* 2.00 活性成分
ガム粉末 1000 ガム基剤
イソマルト、DC 100 134 充填剤、甘味剤
微晶質セルロース、
型PH-102 61.0 ニコチン担体
タルク 37.5 固結防止剤
ステアリン酸マグネシウム 12.5 滑沢剤
コロイド状、無水シリカ
アエロジル 200 2.00 流動促進剤
アセスルファムカリウム 0.625 甘味剤
エタノール99.5%(w/w)* --- 顆粒化液体
目的重量 1 250
成分 量 機能
(%)
イソマルト、GS 65.00 コーティング糖質
精製水 29.80 溶媒
アラビアゴム、50% 4.10 結合剤
チタンジオキサイド 1.00 着色剤
アスパルテーム 0.05 甘味剤
アセスルファムカリウム 0.05 甘味剤
目的重量 100
成分 分量 機能
(mg/単位)
ニコチン塩基* 4.00 活性成分
ガム粉末 1000 ガム基材
イソマルト、DC 100 125 充填剤、甘味剤
微晶質セルロース、
型PH-102 70.0 ニコチン担体
タルク 37.5 固結防止剤
ステアリン酸マグネシウム 12.5 滑沢剤
コロイド状、無水シリカ
アエロジル 200 2.00 流動促進剤
アセスルファムカリウム 0.625 甘味剤
エタノール99.5%(w/w)* --- 顆粒化液体
目的重量 1 250
Claims (58)
- 粒状物質がニコチンまたは医薬的に許容されるその塩もしくは溶媒和物と微晶質セルロースとの組合せを含み、ニコチンまたは医薬的に許容されるその塩もしくは溶媒和物が、水、アルコールまたはそれらの混液を含む親水性溶媒に溶解されて、微晶質セルロースの間隙に導入され、ニコチンまたは医薬的に許容されるその塩もしくは溶媒和物が微晶質セルロースの間隙に残っていて、該粒状物質がインビトロ溶出試験で試験されたとき、ニコチンまたは医薬的に許容されるその塩もしくは溶媒和物を、長くても30分以内に、少なくとも90重量%放出する、ニコチン放出用のニコチン−含有粒状物質。
- 粒状物質がインビトロ溶出試験で試験されたとき、ニコチンまたは医薬的に許容されるその塩もしくは溶媒和物を、長くても20分以内に、少なくとも90重量%放出する、速いニコチン放出用の、請求項1に記載の粒状物質。
- 粒状物質中のニコチンまたは医薬的に許容されるその塩もしくは溶媒和物の濃度が、ニコチン塩基として計算して、多くても20重量%である、請求項1または2に記載の粒状物質。
- 粒状物質中のニコチンまたは医薬的に許容されるその塩もしくは溶媒和物の濃度が、ニコチン塩基として計算して、多くても7.5重量%である、請求項1〜3のいずれか一つに記載の粒状物質。
- 少なくともニコチンまたは医薬的に許容されるその塩もしくは溶媒和物の部分が微晶質セルロースに吸着されている、請求項1〜4のいずれか一つに記載の粒状物質。
- 少なくとも一人の健康な被験者に、ニコチン4 mgまたは医薬的に許容されるその塩もしくは溶媒和物の等量を含む粒状物質を含むチューインガムの形態で投与したときに、投与後、長くても30分以内に、血漿中のニコチン濃度が少なくとも5 ng/mlになるような、請求項1〜5のいずれか一つに記載の粒状物質。
- 少なくとも一人の健康な被験者に、ニコチン4 mgまたは医薬的に許容されるその塩もしくは溶媒和物の等量を含む粒状物質を含むチューインガムの形態で投与したときに、投与後、長くても15分以内に、血漿中のニコチン濃度が少なくとも5 ng/mlになるような、請求項1〜6のいずれか一つに記載の粒状物質。
- 少なくとも一人の健康な被験者に、ニコチン4 mgまたは医薬的に許容されるその塩もしくは溶媒和物の等量を含む粒状物質を含むチューインガムの形態で投与したときに、投与後、長くても10分以内に、血漿中のニコチン濃度が少なくとも6 ng/mlになるような、請求項1〜7のいずれか一つに記載の粒状物質。
- 健康な被験者に、ニコチン4 mgまたは医薬的に許容されるその塩もしくは溶媒和物の等量を含む粒状物質を含むチューインガムの形態で投与したときに、投与後、血漿中のニコチン濃度が少なくとも4 ng/mlになるような、請求項1〜6のいずれか一つに記載の粒状物質。
- 健康な被験者に、ニコチン4 mgまたは医薬的に許容されるその塩もしくは溶媒和物の等量を含む粒状物質を含むチューインガムの形態で投与したときに、投与後、血漿中の濃度が少なくとも7.5 ng/mlになるような、請求項1〜6のいずれか一つに記載の粒状物質。
- 健康な被験者に、ニコチン4 mgまたは医薬的に許容されるその塩もしくは溶媒和物の等量を含む粒状物質を含むチューインガムの形態で投与したときに、投与後、長くても10分以内に、血漿中のニコチン濃度が少なくとも8 ng/mlになるような、請求項1〜10のいずれか一つに記載の粒状物質。
- 少なくとも物質部分が、その物質部分からニコチンまたは医薬的に許容されるその塩もしくは溶媒和物の放出を遅らせるようにコーティングされている、請求項1〜11のいずれか一つに記載の粒状物質。
- 物質が、カルボマー、カルボキシメチルセルロース、セルロースアセテート、セルロースアセテートフタレート、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、ヒドロキシプロピルメチルセルロースフタレート、メチルセルロース、ポリメタクリレート、ポリビニルアルコール、ポビドンもしくはセラックを含むフィルム形成性ポリマー、硬化油脂、水素化綿実油、水素化植物油、ポリエチレングリコール、ポリエチレンオキシド、ワックスもしくはゼインを含む脂肪物質、グルコース、マルトデキストリン、ポリデキストロース、蔗糖、乳糖、アルギン酸もしくはカラギナンを含む糖もしくは糖誘導体、またはマンニトール、マルチトール、イソマルト、キシリトールもしくはソルビトールを含む糖アルコールもしくは糖アルコール誘導体でコーティングされている、請求項12に記載の粒状物質。
- 微晶質セルロースが、部分的に加水分解されていてもよい微晶質セルロースである、請求項1〜13のいずれか一つに記載の粒状物質。
- ニコチンまたは医薬的に許容されるその塩もしくは溶媒和物が、ニコチン塩基、ニコチン塩酸塩、ニコチン二塩酸塩、ニコチン酒石酸塩、ニコチン二酒石酸塩、ニコチン硫酸塩、ニコチン塩化亜鉛およびニコチンサルチル酸塩から選択される、請求項1〜14のいずれか一つに記載の粒状物質。
- ニコチンおよび一つ以上の医薬的に許容されるその塩または溶媒和物を含む、請求項1〜16のいずれか一つに記載の粒状物質。
- ニコチンおよびニコチン酒石酸塩またはニコチン二酒石酸塩を少なくとも一つ含む、請求項1〜16のいずれか一つに記載の粒状物質。
- ニコチンが、ラセミとして、またはそのエナンチオマーのいずれかの形態もしくはそれらの混合物の形態で存在する、請求項1〜17のいずれか一つに記載の粒状物質。
- さらに緩衝物質を含む、請求項1〜18のいずれか一つに記載の粒状物質。
- 緩衝物質が少なくとも部分的に微晶質セルロースに吸着されている、請求項19に記載の粒状物質。
- 緩衝物質が、モノ炭酸塩、重炭酸塩およびセスキ炭酸塩を含む炭酸塩、グリシン塩、リン酸一水素塩、リン酸二水素塩およびリン酸三水素塩を含むリン酸塩、グリセロリン酸塩、酢酸塩、グルコン酸塩、クエン酸塩、ホウ酸塩、アンモニウム塩およびそれらの混合物よりなる群から選択される、請求項19または20に記載の粒状物質。
- 請求項1〜21のいずれか一つに記載の粒状物質を含む医薬組成物。
- 経口投与後、長くても45分以内に、ニコチンが少なくとも50重量%放出される、請求項22に記載の医薬組成物。
- ヨーロッパ薬局方に従ったインビトロ溶出試験で、長くても45分以内に、ニコチンが少なくとも50重量%放出される、請求項22または23に記載の医薬組成物。
- 一つ以上の医薬的に許容される賦形剤をさらに含む、請求項22〜24のいずれか一つに記載の医薬組成物。
- 組成物中のニコチンまたは医薬的に許容されるその塩もしくは溶媒和物の有効用量が、ニコチン塩基として計算して0.5〜6 mgである、請求項22〜25のいずれか一つに記載の医薬組成物。
- 固体、半固体または流動体の形態にある、請求項22〜26のいずれか一つに記載の医薬組成物。
- 経口懸濁液剤、溶解錠剤、経口ゲル剤、経口散剤、顆粒剤、サッシェ剤、カプセル剤、錠剤、放出制御錠剤、経口用凍結乾燥剤、経口用分散錠剤、咀しゃく錠剤、経口ガム剤、経口粘膜懸濁液剤、経口粘膜噴霧剤、舌下噴霧剤、経口粘膜ゲル剤、経口粘膜ペースト剤、薬用チューインガム剤、歯肉ゲル剤、歯肉ペースト剤、歯肉パッチ剤、経口粘膜カプセル剤、舌下錠剤、粘膜−付着口腔錠剤、口腔錠剤、口腔パッチ剤、口腔カシェ剤、トローチ剤、ゲル剤、皮膚ペースト剤、軟膏剤、皮膚噴霧剤、経皮パッチ剤、皮膚粘着剤または浸透性包帯の形態にある、請求項22〜27のいずれか一つに記載の医薬組成物。
- pH−調整剤、安定化剤、保存剤、芳香−調整剤、香味−調整剤、着色剤、放出−調整剤、EDTAを含む錯化剤よりなる群から選択される添加物をさらに含む、請求項23〜29のいずれか一つに記載の医薬組成物。
- 緩衝物質を含む、請求項22〜29のいずれか一つに記載の医薬組成物。
- 緩衝物質が、モノ炭酸塩、重炭酸塩およびセスキ炭酸塩を含む炭酸塩、グリシン塩、リン酸一水素塩、リン酸二水素塩およびリン酸三水素塩を含むリン酸塩、グリセロリン酸塩、酢酸塩、グルコン酸塩、クエン酸塩、ホウ酸塩、アンモニウム塩およびそれらの混合物よりなる群から選択される、請求項30に記載の医薬組成物。
- モノ−、ジ−、トリ−およびポリサッカライドならびに天然および合成の非サッカライドをベースとした甘味剤からなる群から選択される一つ以上のバルク甘味剤を含む、請求項22〜31のいずれか一つに記載の医薬組成物。
- バルク甘味剤がイソマルト、キシリトールもしくはソルビトールまたはそれらの組合せである、請求項32に記載の医薬組成物。
- 経口投与を目的とした固体または半固体の形態にある、請求項22〜33のいずれか一つに記載の医薬組成物。
- 医薬組成物が、チューインガムまたはトローチの形態にある、請求項34に記載の医薬組成物。
- さらなる活性物質を含む、請求項22〜35のいずれか一つに記載の医薬組成物。
- ニコチンのさらなる量が組成物中に取り込まれている、請求項22〜36のいずれか一つに記載の医薬組成物。
- ニコチンが、医薬的に許容される塩、溶媒和物およびニコチン複合体からなる群から選択され、該ニコチン複合体は、カチオン交換体がカルボン酸官能基を有するメタクリル酸タイプまたはスルホン酸官能基もしくはホスホン酸官能基のいずれかを有するポリスチレンタイプからなる群から選択されるニコチンカチオン交換樹脂複合体を含む、請求項37に記載の医薬組成物。
- 組成物中に含まれる粒状物質が、ニコチン塩基および組成物中に取り込まれるさらなる量の、ニコチン酒石酸塩およびニコチン二酒石酸塩からなる群から選択されるニコチンを含む、請求項37に記載の医薬組成物。
- 組成物が、カルボマー、カルボキシメチルセルロース、セルロースアセテート、セルロースアセテートフタレート、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、ヒドロキシプロピルメチルセルロースフタレート、メチルセルロース、ポリメタクリレート、ポリビニルアルコール、ポビドンもしくはセラックを含むフィルム形成性ポリマー、硬化油脂、水素化綿実油、水素化植物油、ポリエチレングリコール、ポリエチレンオキシド、ワックスもしくはゼインを含む脂肪物質、グルコース、マルトデキストリン、ポリデキストロース、蔗糖、乳糖、アルギン酸もしくはカラギナンを含む糖もしくは糖誘導体、またはマンニトール、マルチトール、イソマルト、キシリトールもしくはソルビトールを含む糖アルコールもしくは糖アルコール誘導体でコーティングされている、請求項22〜39のいずれか一つに記載の医薬組成物。
- 少なくとも一人の健康な被験者に、ニコチン4 mgまたは医薬的に許容されるその塩もしくは溶媒和物の等量を投与したときに、投与後、長くても30分以内に、血漿中のニコチン濃度が少なくとも5 ng/mlになるような、請求項22〜40のいずれか一つに記載の医薬組成物。
- 少なくとも一人の健康な被験者に、ニコチン4 mgまたは医薬的に許容されるその塩もしくは溶媒和物の等量を投与したときに、投与後、長くても15分以内に、血漿中のニコチン濃度が少なくとも5 ng/mlになるような、請求項22〜41のいずれか一つに記載の医薬組成物。
- 少なくとも一人の健康な被験者に、ニコチン4 mgまたは医薬的に許容されるその塩もしくは溶媒和物の等量を投与したときに、投与後、長くても10分以内に、血漿中のニコチン濃度が少なくとも6 ng/mlになるような、請求項22〜42のいずれか一つに記載の医薬組成物。
- 健康な被験者に、ニコチン4 mgまたは医薬的に許容されるその塩もしくは溶媒和物の等量を投与したときに、投与後、血漿中のニコチン濃度が少なくとも4 ng/mlになるような、請求項22〜40のいずれか一つに記載の医薬組成物。
- 健康な被験者に、ニコチン4 mgまたは医薬的に許容されるその塩もしくは溶媒和物の等量を投与したときに、投与後、血漿中のニコチン濃度が少なくとも7.5 ng/mlになるような、請求項22〜40のいずれか一つに記載の医薬組成物。
- 健康な被験者に、ニコチン4 mgまたは医薬的に許容されるその塩もしくは溶媒和物の等量を投与したときに、投与後、長くても10分以内に、血漿中のニコチン濃度が少なくとも8 ng/mlになるような、請求項22〜45のいずれか一つに記載の医薬組成物。
- チューインガムの形態にある、請求項22〜46のいずれか一つに記載の医薬組成物。
- 請求項1〜21のいずれか一つに記載の粒状物質であって、コーティングされている粒状物質とコーティングされていな粒状物質との混合物を含む、請求項22〜47のいずれか一つに記載の医薬組成物。
- 作用開始を早めるために、ニコチンを速く放出することを目的とした、請求項22〜48のいずれか一つに記載の医薬組成物。
- ニコチンの放出延長を目的とした、請求項22〜48のいずれか一つに記載の医薬組成物。
- 組成物中に含まれるニコチンの少なくとも一部分が作用開始を早めるために速く、そしてニコチンの残りの部分が長時間の作用を得るために長く放出されることを目的とした、請求項22〜50のいずれか一つに記載の医薬組成物。
- 経口投与後、ニコチンの血漿中濃度が一相、二相または多相曲線を示す、請求項51に記載の医薬組成物。
- 溶出試験がヨーロッパ薬局方に従って行われ、ニコチンのインビトロの溶出プロファイルが一相、二相または多相曲線を示す、請求項51に記載の医薬組成物。
- 多くても60重量%のニコチンが、経口投与後、長くても45分以内に放出される、請求項22、25〜53のいずれか一つに記載の医薬組成物。
- ヨーロッパ薬局方に従ったインビトロの溶出試験で測定され、多くても60重量%のニコチンが、長くても45分以内に放出される、請求項22、25〜53のいずれか一つに記載の医薬組成物。
- 投与後、ニコチンの早い作用開始を有する医薬組成物を製造するための、請求項1〜21のいずれか一つに記載の粒状物質の使用。
- 投与後、ニコチンの長い放出を有する医薬組成物を製造するための、請求項1〜21のいずれか一つに記載の粒状物質の使用。
- タバコ依存症、パーキンソン病、潰瘍性大腸炎、アルツハイマー病、統合失調症、ADHD、トゥーレット症候群、潰瘍性大腸炎または禁煙後の体重コントロールの治療のための、請求項22〜55のいずれか一つに記載の医薬組成物。
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