JP4511792B2 - Cox−2阻害剤を含む再構成可能な非経口組成物 - Google Patents
Cox−2阻害剤を含む再構成可能な非経口組成物 Download PDFInfo
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- JP4511792B2 JP4511792B2 JP2002578951A JP2002578951A JP4511792B2 JP 4511792 B2 JP4511792 B2 JP 4511792B2 JP 2002578951 A JP2002578951 A JP 2002578951A JP 2002578951 A JP2002578951 A JP 2002578951A JP 4511792 B2 JP4511792 B2 JP 4511792B2
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- composition
- parecoxib
- sodium
- solution
- therapeutic agent
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Description
本発明は、水溶性の選択的シクロオキシゲナーゼ−2(COX−2)阻害薬剤ならびにその塩およびプロドラッグ、および特に、パレコキシブ(parecoxib)、例えばそのナトリウム塩の形態(パレコキシブナトリウム)に関する。パレコキシブは、選択的COX−2阻害薬剤のバルデコキシブ(valdecoxib)の水溶性プロドラッグである。より具体的には、本発明は、水溶性の選択的COX−2阻害薬剤ならびにその塩およびプロドラッグの、非経口による送達が可能な、例えば注射可能な製剤に関する。さらにより具体的には、本発明は、非経口的投与の前に水性の担体に再構成するための粉末として調製される、当該製剤に関する。本発明はまた、当該再構成可能な製剤の調製方法、当該製剤の使用の治療方法および医薬の製造における当該製剤の使用にも関する。
シクロオキシゲナーゼ(COX)酵素の阻害は、プロスタグランジン合成の阻害を通して、非ステロイド系抗炎症薬(NSAIDs)が特徴的な抗炎症効果、解熱効果および鎮痛効果を発揮するための、少なくとも主要なメカニズムであると考えられている。ケトロラック、ジクロフェナック、ナプロキセンおよびそれらの塩などの従来のNSAIDsは、治療上の薬量において、シクロオキシゲナーゼの構成的に発現されるCOX−1、および炎症関連の、または誘導性のCOX−2イソフォームの双方を阻害する。通常の細胞の機能のために必要なプロスタグランジンを生成するCOX−1の阻害は、従来のNSAIDsの使用に関連するある種の不都合な副作用の原因であると思われる。対照的に、実質的なCOX−1の阻害を伴わないCOX−2の選択的阻害により、そのような不都合な副作用を最小限にするまたは取り除く一方で、抗炎症作用、解熱作用、鎮痛作用およびその他の有用な治療効果が導かれる。従って、1999年に最初に市販された、セレコキシブまたはロフェコキシブなどの選択的COX−2阻害薬剤は、当該技術分野における大きな進歩を意味する。これらの薬剤は、経口による送達が可能な種々の剤形に製剤化されている。
治療剤の水溶液の凍結乾燥(freeze−drying)法による非経口製剤を調製することが知られている。例えば、Remington:The Science and Practice of Pharmacy、第19版(1995)、Mark Publishing、第1544−1546頁を参照のこと。Remingtonによれば、固形物の量を増加させるため多くの場合に治療剤に賦形剤が加えられ、そのために治療剤が非常に少量の場合は、得られた粉体がより容易に目視可能となる。「乾燥生成物の固まりが元の溶液と実質的に同じ容積をしめるのが理想であると一部において考えられている。これを達成するために、元の生成物の固体含有量は約5%と25%の間になければならない。物質の中で、リン酸ナトリウムまたはカリウム、クエン酸、酒石酸、ゼラチンおよびデキストロース、マンニトールおよびデキストリンなどの炭水化物が、通常は組み合わせとして、この目的のために最も有用であることが見いだされている。」(Remington、引用は前掲の通り)。
一つの実施態様として、粉体として、(a)重量で組成物の約30%〜約90%を構成する治療上有効な総量の、選択的COX−2阻害薬剤およびプロドラッグおよびその塩から選択される少なくとも一つの水溶性治療剤、(b)重量で組成物の約5%から約60%の量の非経口的に許容な緩衝剤、および場合によっては(c)重量で組成物の約10%以下の総量の、その他の非経口で許容な賦形剤成分を含む医薬組成物が提供される。当該組成物は、注射用溶液(injectable solution)を形成するために、非経口的に許容な溶媒液、好ましくは水性の液体に再構成可能である。
本発明の更なる実施態様は、無菌状態で単位投薬量の組成物をその中に包含する密封されたバイアルである。
本発明の医薬組成物は、治療剤として:
(a)水溶性の選択的COX−2阻害薬剤;
(b)選択的COX−2阻害薬剤の水溶性塩(その薬剤自身が水溶性であるか否かにはよらない);
(c)選択的COX−2阻害薬剤の水溶性プロドラッグ(その薬剤自身が水溶性であるか否かにはよらない);または
(d)選択的COX−2阻害薬剤の水溶性プロドラッグの塩(そのプロドラッグ自身が水溶性であるか否かにはよらない)
を含む。
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国際特許公開第WO00/26216
国際特許公開第WO00/31072
国際特許公開第WO00/40087
国際特許公開第WO00/56348
ヨーロッパ特許公開第0799823
ヨーロッパ特許公開第0846689
ヨーロッパ特許公開第0863134
ヨーロッパ特許公開第0985666。
Aは、部分的に不飽和または不飽和のヘテロ環および部分的に不飽和または不飽和の炭素環式環、好ましくはピラゾリル、フラノニル、イソキサゾリル、ピリジニル、シクロペンテノニルおよびピリダジノニル基から選択されるヘテロ環基であり;
XはO、SまたはCH2であり;
nは、0または1であり;
R1はヘテロ環、シクロアルキル、シクロアルケニルおよびアリールから選択される少なくとも1つの置換基であり、場合によっては置換可能な位置において、アルキル、ハロアルキル、シアノ、カルボキシル、アルコキシカルボニル、ヒドロキシル、ヒドロキシアルキル、ハロアルコキシ、アミノ、アルキルアミノ、アリールアミノ、ニトロ、アルコキシアルキル、アルキルスルフィニル、ハロ、アルコキシおよびアルキルチオから選択される1またはそれ以上の基により置換されていてもよく;
R2はメチル、アミノまたはアミノカルボニルアルキルであり;
R3は、ヒドリド、ハロ、アルキル、アルケニル、アルキニル、オキソ、シアノ、カルボキシル、シアノアルキル、ヘテロ環オキシ、アルキルオキシ、アルキルチオ、アルキルカルボニル、シクロアルキル、アリール、ハロアルキル、ヘテロ環、シクロアルケニル、アラルキル、ヘテロ環アルキル、アシル、アルキルチオアルキル、ヒドロキシアルキル、アルコキシカルボニル、アリールカルボニル、アラルキルカルボニル、アラルケニル、アルコキシアルキル、アリールチオアルキル、アリールオキシアルキル、アラルキルチオアルキル、アラルコキシアルキル、アルコキシアラルコキシアルキル、アルコキシカルボニルアルキル、アミノカルボニル、アミノカルボニルアルキル、アルキルアミノカルボニル、N−アリールアミノカルボニル、N−アルキル−N−アリールアミノカルボニル、アルキルアミノカルボニルアルキル、カルボキシアルキル、アルキルアミノ、N−アリールアミノ、N−アラルキルアミノ、N−アルキル−N−アラルキルアミノ、N−アルキル−N−アリールアミノ、アミノアルキル、アルキルアミノアルキル、N−アリールアミノアルキル、N−アラルキルアミノアルキル、N−アルキル−N−アラルキルアミノアルキル、N−アルキル−N−アリールアミノアルキル、アリールオキシ、アラルコキシ、アリールチオ、アラルキルチオ、アルキルスルフィニル、アルキルスルホニル、アミノスルホニル、アルキルアミノスルホニル、N−アリールアミノスルホニル、アリールスルホニルおよびN−アルキル−N−アリールアミノスルホニルから選択される1またはそれ以上の基であり、R3は、場合によっては置換可能な位置において、アルキル、ハロアルキル、シアノ、カルボキシル、アルコキシカルボニル、ヒドロキシル、ヒドロキシアルキル、ハロアルコキシ、アミノ、アルキルアミノ、アリールアミノ、ニトロ、アルコキシアルキル、アルキルスルフィニル、ハロ、アルコキシおよびアルキルチオから選択される1またはそれ以上の基により置換されていてもよく;および
R4は、ヒドリドおよびハロから選択される。]
の化合物である。
の選択的COX−2阻害薬剤、その異性体またはその互変異性体の水溶性塩、プロドラッグおよびプロドラッグの塩において特に有用である。好ましい前記5〜6員環は、シクロペンテノン、フラノン、メチルピラゾール、イソキサゾールおよびピリジン環である。
本発明の組成物はまた、式(VI):
の化合物、およびその薬学的に許容な塩についても有用である。
凍結乾燥サイクルの最初の段階において、各バイアルの溶液を、溶液のガラス転移温度未満の温度で凍結させる。パレコキシブナトリウムおよび第二リン酸ナトリウムを含む本発明の組成物において、ガラス転移温度は約−20℃である。ガラス転移温度は、例えば凍結乾燥顕微鏡の使用または電気抵抗測定などの、当該技術分野で既知のいかなる技術によっても測定されうる。この凍結段階に適した温度は、一般的には約−30℃〜約−60℃、例えば約−40℃〜−50℃である。温度は、一般的には約1〜約5時間かけて、より一般的には約2〜約4時間かけて、室温から望ましい凍結温度まで徐々に下げられる。その後温度は、一般的には約0.5〜約24時間、より一般的には約0.75〜約3時間保持される。
当該組成物は、例えば片頭痛、結節性動脈周囲炎、甲状腺炎、再生不良性貧血、ホジキン病、セレロドーマ(sclerodoma)、リウマチ熱、I型糖尿病、重症筋無力症を含む神経筋接合部疾患、多発性硬化症を含む白質疾患、サルコイドーシス、ネフローゼ症候群、ベーチェット症候群、多発性筋炎、歯肉炎、腎炎、過敏症、脳浮腫を含む損傷の後に生じる腫脹、心筋虚血症などの疾患における炎症を治療することにおいて有用である。
当該組成物は、アルツハイマー病を含む皮質痴呆、神経変性疾患(neurodegeneration)、および卒中、虚血および外傷に起因する中枢神経系損傷などの特定の中枢神経系の障害の治療のために有用である。本文脈における用語「治療」は、アルツハイマー病、血管性痴呆、多発梗塞性痴呆、初老性痴呆、アルコール性痴呆および老人性痴呆を含む、痴呆の部分的または全体的な抑制を含む。
当該組成物は、限定はされないが、術後疼痛、歯痛、筋肉痛、および癌に起因する疼痛を含む疼痛の治療に有用である。例えば、当該組成物は、リウマチ熱、インフルエンザおよび風邪を含む他のウイルス感染症、腰痛および頚部痛、月経困難症、頭痛、歯痛、捻挫および挫傷、筋炎、神経痛、滑膜炎、リウマチ様関節炎、変形性関節疾患(変形性関節炎)、痛風および強直性脊髄炎、滑液包炎、熱傷、および外科的および歯科的処置後の外傷を含む種々の状態における、疼痛、熱および炎症の軽減に有用である。
実施例
以下の実施例により本発明の側面が説明されるが、限定として解釈されるべきではない。
パレコキシブナトリウムの形態でそれぞれ5、10、20および40mgの薬量のパレコキシブを含む、ここで製剤A−Dとして特定する再構成可能な粉体組成物を、以下に示すように調製した。
表1.凍結乾燥用の溶液A−Dの組成
実施例2
パレコキシブナトリウムの形で各々20mgのパレコキシブを含む、ここで製剤E−Jとして特定される再構成可能な粉体組成物を以下に記載するとおりに調製した。まず、表5に示す組成を有する凍結乾燥用の溶液を調製した。凍結乾燥用溶液E−Jは、それぞれ製剤E−Jに対応する。溶液および凍結乾燥した粉体組成物の調製は、実施例1の製剤A−Dのための手法と同様の手法により行った。
ヒトである対象におけるバルデコキシブの血漿濃度を、薬理動態研究において決定した。11人の健康な成人の対象において、単回で静脈内へ20mgのパレコキシブの薬量をパレコキシブナトリウムとして1mLボーラス(bolus)において投与するか、または単回で20mgのバルデコキシブの薬量を即時放出型錠剤の形態で、240mLの水と共に経口投与した。対象は投薬後、1、2および3時間後に180mLの水を飲んだ。
実施例4
単一施設、単回投与、無作為化、プラセボ比較、並行群間比較24時間試験において、骨切除を含めた同じ側の2つの埋伏智歯(impacted third molars)の抜歯を必要とする、男女、18〜45歳の年齢を含む、224の患者(56の各処理群)のグループは、ランダムに、0.9%塩化ナトリウム水溶液4mL中の20mg、40mgまたは80mgのパレコキシブ、またはプラセボの予防的な静脈内への単回投薬を受けた。
Claims (33)
- 医薬組成物であって、粉末形状で:
(a)当該組成物の30重量%〜90重量%を構成する治療上有効な総量の、治療剤としての、パレコキシブまたはその塩、
(b)当該組成物の5重量%〜60重量%の量の非経口的に許容な緩衝剤、および
(c)当該組成物の0〜10重量%の総量の非経口的に許容な他の賦形成分
を含み;注射可能な溶液を形成するために非経口的に許容な溶媒液中において再構成可能である前記組成物。 - 治療剤がパレコキシブナトリウムを含む、請求項1に記載の組成物。
- 治療剤が組成物の40重量%〜85重量%の量で存在する、請求項1または2に記載の組成物。
- 治療剤が組成物の50重量%〜80重量%の量で存在する、請求項3に記載の組成物。
- 緩衝剤が組成物の10重量%〜60重量%の量で存在する、請求項1〜4のいずれか1項に記載の組成物。
- 緩衝剤が組成物の20重量%〜50重量%の量で存在する、請求項5に記載の組成物。
- 実質的に治療剤および緩衝剤からなる、請求項1または2に記載の組成物。
- 緩衝剤が、リン酸ナトリウムおよびカリウム、クエン酸ナトリウムおよびカリウム、モノ−、ジ−およびトリエタノールアミン、トロメタミンおよびその混合物から選択される、請求項1〜7のいずれか1項に記載の組成物。
- 緩衝剤が第二リン酸ナトリウム、第二リン酸カリウムおよびトロメタミンから選択される、請求項8に記載の組成物。
- 緩衝剤が第二リン酸ナトリウムである、請求項9に記載の組成物。
- 再構成の際に7〜9のpHを有する、請求項1〜10のいずれか1項に記載の組成物。
- 再構成の際に治療剤のすばやい溶解を可能とするために十分な多孔度を有する、請求項1〜11のいずれか1項に記載の組成物。
- 非経口的に許容な溶媒中に請求項1〜12のいずれか1項に記載の組成物を再構成することにより調製される注射可能な溶液。
- 溶媒が水性溶媒である、請求項13に記載の溶液。
- 7.5〜8.5のpHを有する、請求項14に記載の溶液。
- 水性溶液がデキストロースおよび/または塩化ナトリウムを含む、請求項14に記載の溶液。
- 無菌状態で請求項1〜12のいずれか1項に記載の組成物の単位投薬量を含有する密封されたバイアルを含む製品。
- 1mg〜200mgのパレコキシブの薬量で、パレコキシブナトリウムを治療剤として含む、請求項17に記載の製品。
- 5mg〜120mgのパレコキシブの薬量で、パレコキシブナトリウムを治療剤として含む、請求項18に記載の製品。
- 10mg〜100mgのパレコキシブの薬量で、パレコキシブナトリウムを治療剤として含む、請求項19に記載の製品。
- バイアルがマルチコンパートメントバイアルである、請求項17〜20のいずれかに1項に記載の製品。
- パレコキシブまたはその塩を含む再構成可能な組成物の調製方法であって、:
(a)水を除く当該組成物の30重量%〜90重量%を構成する治療上有効な総量の、治療剤としてのパレコキシブおよびその塩、
(b)水を除く当該組成物の5重量%〜60重量%の量の非経口的に許容な緩衝剤、
(c)水を除く当該組成物の0〜10重量%の総量の非経口的に許容な他の賦形成分、
を含む水性溶液を凍結乾燥する工程を含み、当該凍結乾燥工程により容易に再構成可能な粉末が形成される、前記方法。 - 治療剤がパレコキシブナトリウムである、請求項22に記載の方法。
- 緩衝剤が第二リン酸ナトリウムである、請求項22に記載の方法。
- 凍結乾燥工程の前に、パレコキシブナトリウムおよび第二リン酸ナトリウムを注射用水に溶解することにより溶液を調製し、滅菌し、その後バイアルの中へ計量し、各バイアルがパレコキシブナトリウムの単位投薬量を含む量の溶液を含み、当該バイアルを凍結乾燥チャンバーの中に設置する、請求項24に記載の方法。
- 溶液調製の工程においてパレコキシブナトリウムを最後に加える、請求項25に記載の方法。
- 凍結乾燥の工程が、凍結段階、第1の乾燥段階および第2の乾燥段階を含む、請求項24〜26のいずれか1項に記載の方法。
- (a)凍結段階において、1時間〜5時間の時間をかけて、−30℃〜−60℃の凍結温度まで温度を低下させ、当該凍結温度を0.5〜24時間保持し;
(b)第1の乾燥段階において、25〜500μmHgの真空度まで減圧し、1〜5時間の時間をかけて凍結温度から約0℃まで温度を上昇させ;および
(c)第2の乾燥段階において、25〜500μmHgの真空状態で1〜4時間の時間をかけて0℃から室温を上回るレベルまで温度を上昇させ、3〜12時間上昇させた温度レベルを保持し;2重量%未満の含水量の粉末を得る、請求項27に記載の方法。 - 全体の凍結乾燥サイクルの時間が18〜24時間である、請求項27に記載の方法。
- 対象におけるCOX−2媒介疾患の予防または治療のための医薬の製造のための請求項1〜12にいずれか1項に記載の組成物の使用であって、前記医薬が注射可能な溶液を形成するために生理的に許容な量の非経口的に許容な溶媒液に、請求項1〜12のいずれか1項に記載の組成物の単位投薬量を再構成すること、および当該溶液を当該対象に非経口的に投与することに適合する、前記使用。
- 非経口的投与が、皮内、皮下、筋肉内、静脈内、骨髄内、関節内、滑液包内、髄腔内、鞘内または心臓内の注射または注入によるものである、請求項30に記載の使用。
- 非経口的投与が静脈内注射または注入によるものである、請求項30に記載の使用。
- 組成物がボーラスとして静脈内注射される、請求項32に記載の使用。
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