JP6480420B2 - コルヒチンの徐放性製剤およびその使用方法 - Google Patents
コルヒチンの徐放性製剤およびその使用方法 Download PDFInfo
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- JP6480420B2 JP6480420B2 JP2016508251A JP2016508251A JP6480420B2 JP 6480420 B2 JP6480420 B2 JP 6480420B2 JP 2016508251 A JP2016508251 A JP 2016508251A JP 2016508251 A JP2016508251 A JP 2016508251A JP 6480420 B2 JP6480420 B2 JP 6480420B2
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Description
本出願は、2013年4月16日に出願された米国仮出願第61/812,514号および2013年11月26日に出願された欧州特許出願第13194505.7号の利益を主張するものであり、ここに引用することによりそれらの全体を本明細書の一部となすものとする。
本発明の目的上、「コルヒチン」という用語は、コルヒチンまたはその任意の薬学的に許容可能な塩を含む。
以下、本発明に従って使用されるコルヒチンが詳細に説明される。コルヒチン(ChemID2010)の化学構造は、以下の通りである:
本発明は、追加的に、対象における心血管疾患および/または炎症性障害の治療または予防のための徐放性コルヒチン製剤を提供し、ここで、コルヒチンが、所定のもしくは所望の放出プロファイルに沿って持続的な速度で製剤から放出される。そのような放出は、持続放出成分(extended release component)および任意選択の即時放出成分(immediate release component)を製剤中に組み入れることによって達成される。本発明のコルヒチン製剤は、錠剤、丸剤(pill)、カプセル剤、カプレット(caplet)、トローチ剤、サシェ、カシェ剤(cachet)、ポーチ(pouch)、散剤(sprinkle)、または経口投与に好適な任意の他の形態から選択される剤形で製剤化され得る。
本発明は追加的に、徐放性成分および任意選択の即時放出成分を含むコルヒチンの製剤を調製する方法であって、コルヒチンが、所定のおよび所望の放出プロファイルに沿って持続的な速度で製剤から放出される、方法を包含する。
本発明はさらに、対象における心血管疾患および/または炎症性障害の治療または予防の方法であって、本発明のコルヒチン製剤の治療有効量を対象に投与することを含み、コルヒチンが、所定のもしくは所望の放出プロファイルに沿って持続的な速度で製剤から放出される、方法を提示する。本発明の方法は、持続放出成分および任意選択の即時放出成分を含むコルヒチン製剤の新規のデザインにより、患者の状態の性質および必要に応じて、投与される製剤の薬物動態を選択的に調整する柔軟性を有し、両方の成分が所定の放出プロファイルに適合するように、上述したような調製プロセス中に選択的に変更され得る。
本発明のコルヒチン製剤を調製し、それを必要としている対象に投与する方法は、当業者によく知られており、または当業者により容易に特定される。コルヒチン製剤の投与経路は、例えば、経口的な、非経口的な、吸入によるまたは外用であり得る。本明細書において使用される場合、非経口的という用語は、例えば、静脈内の、動脈内の、腹腔内の、筋肉内、皮下の、直腸の、または膣内投与を含む。
本実施例は、コルヒチン徐放性錠剤を例示する。錠剤は、以下の表1に示す成分および濃度を使用する。
上記の成分を利用して、以下の作業指示に従って錠剤を作製する。
コルヒチンの徐放性製剤の溶解を様々な時点で測定した。その組成物を37℃で500mlの水に溶解し、6時間にわたり連続的に撹拌した。試料をいくつかの時点で抽出し、親水性マトリックス系内の原薬の溶解プロセスの動態を調べた。試料中のコルヒチン含量を、HPLC分析法を使用して分析した。
アルコール中での組成物の過量放出または溶解の可能性を評価するために、エタノール中のコルヒチン徐放性製剤の溶解を様々な時点で測定した。組成物を500mlの3種類の溶液、すなわち5%、20%および40%のエタノール中に37℃で溶解させ、6時間にわたり継続的に撹拌した。試料をいくつかの時点で抽出し、親水性マトリックス系内の原薬の溶解プロセスの動態を調べた。試料中のコルヒチン含量を、HPLC分析法を使用して分析した。
コルヒチンを含有する徐放性製剤の治療効果を、健常被験者に投与される0.5mg即時放出製剤(対照製品)に対する、コルヒチンの約3種類の異なる0.5mg徐放性製剤(例えば、被験製品1、2、3)の生物学的利用率を評価する、複数回投与の無作為化クロスオーバー研究である臨床試験において評価した。研究の主なねらいは、血中ならびに好中球もしくは白血球中の被験および対照薬物の薬物動態(PK)を評価することである。
心血管疾患の患者における即時放出製剤の治療効果を評価するために、アスピリンおよび高用量のスタチンを含む標準的な二次予防療法に対して0.5mg/日のコルヒチンを併用することで、客観的に診断され、および臨床的に安定した冠動脈疾患を有する患者における心血管事象リスクを減少させられるかどうかを明らかにするために、前向き無作為化観察者盲検評価項目試験を行った。本研究はPCT/AU2013/001261に記載されており、参照によりその内容全体が本明細書に組み込まれる。
適切な用量を決定するために、徐放性製剤を、異なる体重の患者母集団に投与し得る。0.5mg錠剤が平均体重の患者におけるある一定のコルヒチンの血漿中レベルをもたらし、この特定のレベルが、有効性を達成するうえですべての患者において到達されることを要すると仮定し、異なる体重群において0.5mg錠剤のPK分析を行うことができる。体重の重い患者において血中のレベル(CmaxおよびAUC)がより低く、高用量への用量調整が必要であることを示唆することが予想される。
本実験において、十分に多くの数の適切な実験動物(例えば、マウスもしくはラットなどのげっ歯類、各群につき少なくとも5匹)を使用する。対照薬物はコルヒチンのIR錠剤である。被験薬物はコルヒチンのSR錠剤である。
本実験において、十分に多くの数の適切な実験動物(例えば、マウスもしくはラットなどのげっ歯類、各群につき少なくとも5匹)を使用する。対照薬物はコルヒチンのIR錠剤である。被験薬物はコルヒチンのSR錠剤である。
実験動物がコルヒチン投与に関係する有害事象の調査に適していないことが判明した場合、同等の実験をヒトで行う。実験は、成人健常被験者または追加としてコルヒチンを必要とする患者で実施する。統計学有意性に達するように、十分に多くの人数を対象とする。被験および対照の薬物治療は、0.25〜1mgの強度のコルヒチンのSRまたはIR経口固形剤形からなる。コルヒチンの治療レベルに達するように、十分に高用量を投与する。1日1回投与に対する代替として、被験薬物を上記実施例3に示すように1日2回与える。対照プラセボ効果に対する代替として、プラセボ群を両方の実験設定に含める。実験の期間は、2週間から1カ月の間とする。
Claims (43)
- コルヒチン徐放性製剤であって、
(a)0.6mg以下のコルヒチンまたはその薬学的に許容可能な塩と、前記製剤の1重量%から30重量%の量のヒドロキシプロピルメチルセルロース(HPMC)6mPa*sを含む結合剤とを含む顆粒と
(b)前記顆粒に混合されている放出遅延剤であって、前記放出遅延剤が、前記製剤の5重量%から40重量%の量であり、且つ前記放出遅延剤が、4000mPa*sの粘度グレードを有するHPMCとラクトース一水和物とを同重量部で含む、放出遅延剤と
(c)前記顆粒に混合されている少なくとも1つの薬学的に許容可能な賦形剤と
を含む、コルヒチン徐放性製剤。 - 前記コルヒチンまたはその薬学的に許容可能な塩の少なくとも約70%以下をインビトロにおいて、37℃で、2時間以内で放出する、請求項1に記載の製剤。
- 前記コルヒチンまたはその薬学的に許容可能な塩の少なくとも約20%をインビトロにおいて、30分以内で放出する、請求項1または2に記載の製剤。
- 前記薬学的に許容可能な賦形剤が、結合剤、充填剤、滑剤および滑沢剤のうちの1つ又は複数である、請求項1〜3のいずれか1項に記載の製剤。
- 前記薬学的に許容可能な賦形剤が、結合剤を含み、この結合剤が、デンプン、ゼラチン、ポリビニルピロリドン、ヒドロキシプロピルセルロース(HPC)、およびポリビニルアルコールのうちの1つ又は複数である、請求項1〜4のいずれか1項に記載の製剤。
- 前記ヒドロキシプロピルセルロース(HPC)が親水性マトリックスを形成する、請求項5に記載の製剤。
- 前記薬学的に許容可能な賦形剤が、充填剤を含み、この充填剤が、スクロース、ラクトース、特にラクトース一水和物、トレハロース、マルトース、マンニトールおよびソルビトール、クロスカルメロースナトリウム、クロスポビドン、アルギン酸、アルギン酸ナトリウム、メタクリル酸ジビニルベンゼン(DVB)、架橋ポリビニルピロリドン(PVP)、微結晶セルロース、ポラクリリンカリウム、デンプングリコール酸ナトリウム、デンプン、およびアルファ化デンプンのうちの1つ又は複数である、請求項1〜6のいずれか1項に記載の製剤。
- 前記製剤中の充填剤の総量が、前記製剤の5.0重量%から90.0重量%の間である、請求項7に記載の製剤。
- 前記薬学的に許容可能な賦形剤が、滑剤を含み、この滑剤が、コロイド二酸化ケイ素、三ケイ酸マグネシウム、粉末セルロース、タルク、およびリン酸三カルシウムのうちの1つ又は複数である、請求項1〜8のいずれか1項に記載の製剤。
- 前記製剤中の滑剤の総量が、前記製剤の0.5重量%から5重量%の間である、請求項9に記載の製剤。
- 前記薬学的に許容可能な賦形剤が、滑沢剤を含み、この滑沢剤が、ベヘン酸グリセリル、ステアリン酸、水素化植物油、ステアリルアルコール、ロイシン、ポリエチレングリコール、ステアリン酸マグネシウム、モノステアリン酸グリセリン、ポリエチレングリコール、エチレンオキシドポリマー、ラウリル硫酸ナトリウム、ラウリル硫酸マグネシウム、オレイン酸ナトリウム、フマル酸ステアリルナトリウム、DL−ロイシン、およびコロイド状シリカのうちの1つ又は複数である、請求項1〜10のいずれか1項に記載の製剤。
- 前記製剤中の滑沢剤の総量が、前記製剤の0.5重量%から5重量%の間である、請求項11に記載の製剤。
- 前記製剤が、錠剤、丸剤、カプセル剤、カプレット、坐剤、経皮パッチ、クリーム剤、舌下製剤、点眼剤、ゲル剤、軟膏剤、トローチ剤、ポーチ、散剤からなる群から選択される剤形、または外科的に挿入可能な医療機器への組合せである、請求項1〜12のいずれか1項に記載の製剤。
- 前記製剤の剤形が錠剤である、請求項1〜13のいずれか1項に記載の製剤。
- 前記錠剤の圧縮強度が、30Nから130Nの間である、請求項14に記載の製剤。
- 前記製剤中のコルヒチンまたはその薬学的に許容可能な塩の総量が、投与量当たり0.5から0.6mgである、請求項1〜15のいずれか1項に記載の製剤。
- 心血管疾患の予防および/または治療における使用のための請求項1〜16のいずれか1項に記載の製剤。
- 前記心血管疾患が、急性心膜炎、再発性心膜炎、心膜切開後症候群(PPS)、または安定冠動脈疾患の対象における心血管事象である、請求項17に記載の製剤。
- 確定診断された安定冠動脈疾患の患者における急性心血管事象を予防するための第2薬剤との併用での使用のための請求項1〜18のいずれか1項に記載の製剤。
- 前記急性心血管事象が、急性冠症候群、院外心停止または非心原性虚血性脳卒中である、請求項19に記載の製剤。
- スタチンを更に含む、請求項1〜20のいずれか1項に記載の製剤。
- 前記スタチンが、前記製剤に混合されている、請求項21に記載の製剤。
- 前記スタチンが、アトルバスタチン、ロスバスタチン、シンバスタチン、プラバスタチン、及びそれらの塩のうちの1つ又は複数である、請求項21または22に記載の製剤。
- 炎症性疾患の予防および/または治療における使用のための請求項1から23のいずれか1項に記載の製剤。
- 前記炎症性疾患が、痛風、家族性地中海熱、ベーチェット病、加齢性黄斑変性症およびアルツハイマー病からなる群から選択される、請求項24に記載の製剤。
- 心血管疾患を治療および/または予防する医薬を製造するための、請求項1〜23のいずれか1項に記載のコルヒチンの徐放性製剤の使用。
- 前記心血管疾患が、急性心膜炎、再発性心膜炎、心膜切開後症候群(PPS)、または安定冠動脈疾患の対象における心血管事象である、請求項26に記載の使用。
- 前記急性心血管事象が、急性冠症候群、院外心停止または非心原性虚血性脳卒中である、請求項26または27に記載の使用。
- 前記医薬が、スタチンを更に含む、請求項26〜28のいずれか1項に記載の使用。
- 前記スタチンが、アトルバスタチン、ロスバスタチン、シンバスタチン、またはプラバスタチンである、請求項29に記載の使用。
- 炎症性疾患を治療および/または予防する医薬を製造するための、請求項1〜23のいずれか1項に記載のコルヒチンの徐放性製剤の使用。
- 前記炎症性疾患が、痛風、家族性地中海熱、ベーチェット病、加齢性黄斑変性症、またはアルツハイマー病である、請求項31に記載の使用。
- コルヒチン徐放性錠剤を調製するプロセスであって、
(A)0.5mgから0.6mgのコルヒチンまたはその薬学的に許容可能な塩を、許容可能な溶媒である水に溶解することによって、顆粒を形成するステップと、
(B)ステップAに、前記錠剤の1重量%から30重量%までの量のヒドロキシプロピルメチルセルロース(HPMC)6mPa*sを含む結合剤および前記錠剤の10重量%から80重量%までの量のラクトース一水和物と、アルファ化デンプンとを含む充填剤を添加して、湿顆粒を形成するステップと、
(C)ステップBの湿顆粒を乾燥するステップと、
(D)ステップCで乾燥させた顆粒を、放出遅延剤とブレンドするステップであって、前記放出遅延剤が、前記錠剤の5重量%から40重量%の量であり、且つ前記放出遅延剤が、4000mPa*sの粘度グレードを有するHPMCとラクトース一水和物とを同重量部で含む、ステップと、
(E)ステップDで最終的に得られた顆粒を錠剤に圧縮するステップと
を含む、コルヒチン徐放性錠剤を調製するプロセス。 - ステップDにおいて、滑剤としてタルクを添加し、滑沢剤としてステアリン酸を添加する、請求項33に記載のプロセス。
- 各成分の量が、
- 成形および圧縮された徐放性治療組成物であって、
0.6mg以下のコルヒチンまたはその薬学的に許容可能な塩と、前記組成物の10重量%から80重量%の量のラクトース一水和物を含む充填剤と、前記組成物の1重量%から30重量%の量のヒドロキシプロピルメチルセルロース(HPMC)6mPa*sを含む結合剤と、
少なくとも1つの薬学的に許容可能な賦形剤と
を含み、
前記コルヒチンまたはその薬学的に許容可能な塩と前記少なくとも1つの薬学的に許容可能な賦形剤が、徐放性固形マトリックス中で結合されており、
前記賦形剤が、4000mPa*sの粘度グレードを有するHPMCとラクトース一水和物とを同重量部で含み、
前記賦形剤の総量が、前記徐放性固形マトリックス中の前記コルヒチンまたはその薬学的に許容可能な塩を結合するのに有効であり、前記成形および圧縮された徐放性治療組成物の重量の少なくとも約99%である、徐放性治療組成物。 - 前記コルヒチンまたはその薬学的に許容可能な塩の少なくとも70%以下をインビトロにおいて、37℃で、2時間以内で放出する、請求項36に記載の徐放性治療組成物。
- 前記コルヒチンまたはその薬学的に許容可能な塩の少なくとも20%をインビトロにおいて、30分以内で放出する、請求項36または37に記載の徐放性治療組成物。
- 前記製剤が、約0.5から5ng/mLの範囲の最大コルヒチン血漿中濃度(Cmax)、および約1.5から8時間の初回投与後Cmax到達時間(Tmax)をもたらす、0.5mg以下のコルヒチンまたはその薬学的に許容可能な塩を含む、請求項1から23のいずれか1項に記載の製剤。
- 前記製剤が、約4から20ng・hr/mLの範囲で、時間0から時間tまでのコルヒチン血漿中濃度対時間の曲線下の面積(AUC0−t)(tは測定可能なコルヒチン血漿中濃度に対応する最終時点である)をさらにもたらす、請求項39に記載の製剤。
- 前記製剤が、4から20ng・hr/mLの範囲で、時間0から時間無限までのコルヒチン血漿中濃度対時間曲線下面積(AUC0−∞)をさらにもたらす、請求項39または40に記載の製剤。
- 前記製剤が、約4から20ng・hr/mLの範囲の、時間0から時間tまでのコルヒチン血漿中濃度対時間の曲線下の面積(AUC0−t)(tは測定可能なコルヒチン血漿中濃度に対応する最終時点である)、および、約4から20ng・hr/mLの範囲で、時間0から時間無限までのコルヒチン血漿中濃度対時間の曲線下の面積(AUC0−∞)をさらにもたらす、請求項39〜41のいずれか1項に記載の製剤。
- 前記製剤の剤形が錠剤である、請求項39〜42のいずれか1項に記載の製剤。
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JP (1) | JP6480420B2 (ja) |
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US9907751B2 (en) * | 2016-03-10 | 2018-03-06 | RxOMEG Therapeutics LLC | Composition and method of use of colchicine oral liquid |
EP3641726A1 (en) * | 2017-06-23 | 2020-04-29 | MedCan Pharma A/S | Cannabinoid pouch |
US10226423B1 (en) * | 2017-12-20 | 2019-03-12 | RxOMEG Therapeutics LLC | Colchicine drug-to-drug interactions |
CN111954524A (zh) * | 2018-02-02 | 2020-11-17 | 默里和普尔企业有限公司 | 秋水仙碱抑制肿瘤生长和转移的用途 |
CN110448527B (zh) * | 2019-09-23 | 2021-11-26 | 杭州百诚医药科技股份有限公司 | 一种秋水仙碱口服溶液及其处方组成 |
KR102112456B1 (ko) | 2019-11-13 | 2020-05-19 | 주식회사 에이스바이오메드 | 간 질환 치료용 또는 치료 효과 증진을 위한 콜히친 복합제제 |
CN111150702B (zh) * | 2019-12-04 | 2021-06-22 | 复旦大学 | 一种凝胶药物缓释制剂及其制备方法与应用 |
KR102584738B1 (ko) | 2020-01-17 | 2023-10-06 | 한국생명공학연구원 | 콜히친을 포함하는 피부 질환 치료용 조성물 |
KR20210095249A (ko) | 2020-01-22 | 2021-08-02 | 주식회사 에이스바이오메드 | 간 질환 치료용 또는 치료 효과 증진을 위한 콜히친 복합제제 |
KR102150821B1 (ko) | 2020-01-22 | 2020-09-03 | 주식회사 에이스바이오메드 | 간 질환 치료용 또는 치료 효과 증진을 위한 콜히친 복합제제 |
KR102177781B1 (ko) | 2020-04-27 | 2020-11-12 | 주식회사 에이스바이오메드 | 간 질환 치료용 또는 치료 효과 증진을 위한 콜히친, 우르소데옥시콜산 및 비페닐디메틸디카르복실레이트의 복합제제 |
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