JP7267922B2 - 新規製剤 - Google Patents
新規製剤 Download PDFInfo
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- JP7267922B2 JP7267922B2 JP2019537123A JP2019537123A JP7267922B2 JP 7267922 B2 JP7267922 B2 JP 7267922B2 JP 2019537123 A JP2019537123 A JP 2019537123A JP 2019537123 A JP2019537123 A JP 2019537123A JP 7267922 B2 JP7267922 B2 JP 7267922B2
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Description
したがって、粘膜表面は、外来病原体または抗原への曝露から宿主を保護する様々な細胞構造および無細胞構造に富んでいる。これらの重要な表面は、口腔および鼻腔(副鼻腔)の粘膜表面、肺および消化器系ならびに眼の周囲の粘膜組織によって表される。
配列番号1 4mg
ヒドロキシメチルセルロース 7-8mg、任意に7.5mg、
メチルパラベンナトリウム 16.6mM 2.8-3.0mg
プロピルパラベンナトリウム 1.4mM 0.28-3mg
一塩基性リン酸ナトリウム一水和物 37.5 mM 4.4-4.6mg
本発明の第1の態様の全ての特徴は第3の態様にも当てはまる。
本発明の第1の態様の全ての特徴は第4の態様にも当てはまる。患者はヒト(成人または若年)または動物であり得る。
アンチセンスオリゴヌクレオチド配列番号1は、アリカフォルセン(alicaforsen)としても知られている。
組成物は、2、3、4、5、6、7、8またはそれ以上の週にわたって投与することができる。
組成物は、1、2、3、4、5、6、7、8またはそれ以上の週にわたって投与することができる。
組成物は1、2、3、4、5または6日間投与することができる。
・炎症性/免疫細胞(ICAM-1)の流入を遮断し、自然系免疫反応(TLR-9)の活性化を遮断すると、急性反応と持続性反応の両方が可能になる。
・ICAM-1を遮断することが知られている配列番号1の20塩基オリゴヌクレオチドは、それがTLR-9の活性化も阻害するので、急性応答と耐久性応答の両方を発揮する。
・配列番号1の一次配列はそのTLR-9アンタゴニストとしての作用を予測しない。
・配列番号1の特定の一次配列は、TLR-9活性に影響を与える可能性があるが最も安定したまたは最適な構造を予測しない構造の二次配列を示唆する。
・配列番号1の二次構造に影響を与える条件もまた、TLR-9アンタゴニストとしてのその活性に影響を与える。
・配列番号1の一次配列を有するオリゴヌクレオチドは、その二次構造を最適化する条件に供されると、一次配列単独で予測されるよりも強力な粘膜炎症治療剤であることが発見された。
実施例1:TLR-9阻害活性
配列番号1を用量反応活性についてスクリーニングして、7つの異なる用量(0.01、0.05、0.1、0.5、1、5および10μM)で3回の実験でTLR9活性化について可能性のあるEC50を決定した。簡単に説明すると、TLR9/NF-κBルシフェラーゼレポーターHEK 293細胞株(Abeomics、San Diego、CA)を96ウエル白色固体プレートに1ウエルあたり5×104細胞で16時間培養された。細胞を、3回の実験で、異なる用量の配列番号1、ならびにTLR-9の公知のアゴニストであるCpG ODN-2006の20μg/mlで、16時間処理した。次にルシフェラーゼ活性を測定し分析した。
図4に示すホモ二量体は、配列番号1について最もエネルギー的に好ましい二本鎖構造である。興味深いのは、この二次構造がTLR-9阻害活性に影響を及ぼし得るかどうか、そしてどの条件下で二本鎖が最も安定であるかであった。
配列番号1の二次構造を安定化および/または不安定化することが知られている処理の効果を試験するために、一連の実験で、配列番号1のTLR-9アンタゴニスト活性に対する熱、Na+、Mg+およびスペルミンの効果を調べた。これらのテストのサンプルと条件は、図9に示される。
眼の炎症状態に対する配列番号1の効果を試験するために、スコポラミン投与によるドライアイのマウスモデルにおける2つの異なる濃度のアリカフォルセンの効果を調べた。
マウスのモデルでは、尾の中部への経皮スコポラミンパッチの貼付が、涙液生成を減少させる、したがって涙腺機能不全を模倣するために使用された。スコポラミンの機能は、涙腺におけるコリン作動性受容体の薬理学的遮断を誘発し、それゆえ房水生成(aqueous production)を減少させることである。乾燥は環境ストレスを加えることによって増幅され、動物は低湿度環境と一定の気流にさらされる。
研究に使用された動物:
種:マウス。
種類:C57BL/6N(色素沈着)。
年齢:約6-7週間(導入の初日に)。
数/性別:55匹のメス(研究用40、予備15)。
マウスを経皮スコポラミン投与(0.5mg/72時間;Scopoderm TTS(登録商標))で処置した。経皮スコポラミンパッチをマウスの尾の根の近くに巻き付け、セロハンテープで固定した。パッチは48時間ごとに再適用された。
マウスを10匹の動物からなる4群に無作為に分けた。研究は、各群5匹の動物が代表される2つの実験セットに分けられた。全てのマウスを1日目に処置し、次いで以下の計画に従って合計10日間処置した。
- アリカフォルセン(10mMおよび1mM)群:1日1回投与。
- ビヒクルグループ:1日1回投与。
マイクロピペットを使用して、全ての試験用物質、対照用物質および比較用物質を両眼に注入した(投与当たり5μL)。
体重:全ての動物の体重を記録した。
全体的な見かけ:毎日、一般的な臨床徴候および全ての動物の外観が観察された。
眼科検査:2種類の眼科検査が実施された。
試験の3日目の投与前および、試験の他の日での2回目の処置の少なくとも1時間後に、涙の産生を両眼のPRT試験(Zone-Quick、FCI-Ophthalmics)で測定した。糸を外側結膜円蓋の外側角に30秒間置いた。涙で濡れた糸は赤くなり、水性涙液の生成を示した。このデータはミリメートル単位で表した。
異なる時点で、試験の3日目の投与前および、試験の他の日での2回目の処置の少なくとも1時間後に測定を実施した。0.5%フルオレセイン点眼(0.5μL)点眼後、青色光を用いた細隙灯観察によって全群の動物の眼を調べた。点状染色は、角膜が分割された5つの領域の各々に0から3のスコアを与える標準化された国立眼科研究所(NEI)等級付けシステムを用いて記録された。
動物の行動と体重
ドライアイの状態のため、0日目から10日目までの間に全群の大部分の動物でわずかな体重減少が観察された。
アリカフォルセン(10mMおよび1mM)、ビヒクル、およびOptimmune(登録商標)は動物の行動に影響を及ぼさなかった。
3日目に、全ての群について涙液産生量が減少した。未処置群の値は10日目まで安定していた。これらのデータはこのマウスモデルにおいてドライアイの良好な誘発を示した。
CFSからの結果は、以下の表1および図11に要約されている。
Optimmune(登録商標)で処置した群は、6日目(p=0.0021)および10日目(p=0.0020)において、ビヒクル群よりも低い角膜蛍光染色スコアを示した。
これらの実験条件下で、アリカフォルセンの複数回局所投与(1mMおよび10mM)は臨床的に十分に許容された。
ビヒクル群は3日目から10日目までドライアイ症状を示し、この試験が有効であることを示した。
0.2%Optimmune(登録商標)とアリカフォルセン(1mM)の群は、角膜蛍光染色により測定された時にドライアイ症状の統計的に有意な減少を示した
喘息、オボアルブミンなどの症状に対するアリカフォルセンの効果をテストするために、(OVA)誘発アレルギー性喘息マウスモデルを、アリカフォルセンで治療した。
アレルギー性喘息は、OVAに対する最初の感作とそれに続く精製OVAのその後の鼻腔内攻撃によって、雌性BALB/cマウスにおいてモデル化された。
試験アイテム
以下の表2および3は、試験中に使用された試験アイテムおよび試験材料を詳述する。
鶏卵OVAアルブミン(OVA)をPBSに溶解して1mg/mLの濃度にした。1mg/mLのOVA溶液を水酸化アルミニウムアジュバントで1:1に希釈し、使用するまで2-8℃で一晩保存した。最終投与濃度は、200μLのOVA/水酸化アルミニウム混合物あたり100μgのOVAであった。
1mgの滅菌PBSを10mgのOVAに添加して10mg/mLの溶液濃度とした。0.35mLのOVA原液を1.75mLのPBSに添加して1.67mg/mLの溶液濃度とした。最終投与濃度=30μL中50gのOVA。
テストグループ
OVA感作:
0日目および14日目に、各動物に、100μgのOVAを含有する200μLのOVA/Alm(水酸化アルミニウム)乳剤のIP注射を投与した。
14日目および25から27日目に、各動物に、50μgのOVAを含有する30μLのPBSの鼻腔内攻撃を投与した。
アリカフォルセンを1mMの濃度で鼻腔内(IN)に30μL投与した。処置は、試験日14日目および25から27日目のOVA攻撃と同じ日に行われた(合計4処置)。処置は、OVA攻撃の1時間後に投与した。
10mg/kgのデキサメタゾンを、試験日4日目および25から27日目に200μL体積/動物(腹腔内)で投与した(合計4回の処置)。
臨床徴候:
注意深い検査は毎日行われた。皮膚、毛皮、目、粘膜、分泌物および排泄物の発生、ならびに自律神経活動の変化に関する観察が行われた。歩行、姿勢、および取扱いに対する反応、または奇妙な行動、振戦、痙攣、睡眠および昏睡の存在における有意な変化が記録された。
動物の体重を試験開始直前およびその後週2回測定した。
28日目に、すべてのマウスをデタミン+キシラジン過量投与および放血により安楽死させた。
安楽死させた動物に気管支肺胞洗浄を行った。簡単に説明すると、血管カテーテルを気管内に配置した。1mlのPBSを肺に注入し、シリンジに戻した。次いでPBSを滴下し、そして再び回収した。得られた気管支肺胞洗浄液(BALF)を500×gで5分間遠心分離した。
BALFの細胞部分を用いて細胞流入を分析した。BALF内の白血球の総数および存在する異なる細胞型をフローサイトメトリーによって調べた。
顆粒球:CD45+;非自家蛍光:Gr-1+
好酸球:CD45+:非自家蛍光;Gr-1+;シグレックF+
未感作マウス(naive mice)と比較した場合、感作され、OVAタンパク質で攻撃された動物は、実験の終了時に、有意に増加した総白血球、顆粒球および好酸球の肺胞流入を含む疾患の徴候を示した。さらに、罹患動物は、BALF中の有意に増加したIL-13レベルを示した。
Claims (10)
- 配列番号1のオリゴヌクレオチドとNa+、およびMg++を含み、該オリゴヌクレオチドの骨格が20のホスホロチオエート修飾を含む、医薬品組成物。
- Na+が40-200mMであり、Mg++が2-20mMである、請求項1記載の医薬品組成物。
- Na+が100-190mMである、請求項1に記載の組成物。
- メチルパラベンナトリウム、プロピルパラベンナトリウム、一塩基性リン酸ナトリウム一水和物、水酸化ナトリウム、塩酸および/または水の1つ以上をさらに含む、請求項1から3のいずれか1項記載の組成物。
- 前記組成物が、液体シロップ、ゲル、フィルム、クリーム、粉末、錠剤および/または浣腸剤の形態である、請求項1から3のいずれか1項に記載の組成物。
- 医薬に使用するための、請求項1から5のいずれか1項に記載の組成物。
- 前記使用が、炎症性腸疾患、直腸断端病、放射線誘発性直腸炎、嚢炎、喘息、眼の炎症、ドライアイ、鼻炎または副鼻腔炎または移植片対宿主病の予防または治療のための医薬での使用である、請求項6記載の組成物。
- 請求項1から5のいずれか1項に記載の組成物を製造する方法であって、配列番号1のオリゴヌクレオチドであって、骨格が20のホスホロチオエート修飾を含むオリゴヌクレオチド、Na+、およびMg++を混合することを含む、方法。
- 前記組成物が浣腸剤の形態であり、前記組成物中の前記配列番号1のオリゴヌクレオチドであって、骨格が20のホスホロチオエート修飾を含むオリゴヌクレオチドの濃度が2mg/mlである、請求項1から5のいずれか1項に記載の組成物。
- 前記組成物が浣腸剤の形態であり、前記組成物中の前記配列番号1のオリゴヌクレオチドであって、骨格が20のホスホロチオエート修飾を含むオリゴヌクレオチドの濃度が1-4mg/mlである、請求項1から5のいずれか1項に記載の組成物。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003524586A (ja) | 1998-05-21 | 2003-08-19 | アイシス・ファーマシューティカルス・インコーポレーテッド | オリゴヌクレオチドの非−非経口投与のための組成物と方法 |
JP2013527134A (ja) | 2010-02-10 | 2013-06-27 | ステルナ ビオロジカルス ゲーエムベーハー ウント コー. カーゲー | オリゴヌクレオチドに適した皮膚科的、薬学的組成 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040033977A1 (en) | 1990-08-14 | 2004-02-19 | Bennett C. Frank | Oligonucleotide modulation of cell adhesion |
US6096722A (en) * | 1990-08-14 | 2000-08-01 | Isis Pharmaceuticals Inc. | Antisense modulation of cell adhesion molecule expression and treatment of cell adhesion molecule-associated diseases |
US5576302A (en) | 1991-10-15 | 1996-11-19 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating hepatitis C virus having phosphorothioate linkages of high chiral purity |
AU7559894A (en) | 1993-08-05 | 1995-02-28 | Isis Pharmaceuticals, Inc. | Oligomers for modulating metabolic function |
US7235653B2 (en) | 1996-12-31 | 2007-06-26 | Isis Pharmaceuticals, Inc. | Oligonucleotide compositions and methods for the modulation of the expression of B7 protein |
ATE321882T1 (de) * | 1997-07-01 | 2006-04-15 | Isis Pharmaceuticals Inc | Zusammensetzungen und verfahren zur verabreichung von oligonukleotiden über die speiseröhre |
ES2196864T3 (es) | 1998-09-25 | 2003-12-16 | Deutsches Krebsforsch | Secuencia antisentido para la inhibicion de la expresion de la molecula de adhesion icam-1. |
US7960355B2 (en) * | 2003-05-23 | 2011-06-14 | Isis Pharmaceuticals, Inc. | Compositions and methods for the modulation of the expression of B7 protein |
SG146624A1 (en) | 2003-09-11 | 2008-10-30 | Kemia Inc | Cytokine inhibitors |
JP2007519724A (ja) | 2004-01-26 | 2007-07-19 | シヴィダ・インコーポレイテッド | 核酸を基剤とする治療剤の制御送達および持続的送達 |
US8168600B2 (en) * | 2004-04-23 | 2012-05-01 | Isis Pharmaceuticals, Inc. | Compositions and methods for topical delivery of oligonucleotides |
KR20070089980A (ko) | 2004-12-02 | 2007-09-04 | 아이시스 파마수티컬즈 인코포레이티드 | 염증성 장 질환의 치료를 위한 치료용 안티센스올리고뉴클레오티드 조성물 |
US20080152654A1 (en) * | 2006-06-12 | 2008-06-26 | Exegenics, Inc., D/B/A Opko Health, Inc. | COMPOSITIONS AND METHODS FOR siRNA INHIBITION OF ANGIOGENESIS |
EP2411517A2 (en) | 2009-03-27 | 2012-02-01 | Merck Sharp&Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF THE INTERCELLULAR ADHESION MOLECULE 1 (ICAM-1)GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
WO2013123996A1 (en) | 2012-02-24 | 2013-08-29 | Astrazeneca Uk Limited | Novel sirna inhibitors of human icam-1 |
US20170051290A1 (en) | 2014-05-01 | 2017-02-23 | Rxi Pharmaceuticals Corporation | Methods for treatment of disorders in the front of the eye utilizing nucleic acid molecules |
GB201407822D0 (en) * | 2014-05-02 | 2014-06-18 | Atlantic Pharmaceuticals Holdings Ltd | Use of a composition |
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2017
- 2017-01-06 GB GBGB1700257.7A patent/GB201700257D0/en not_active Ceased
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2018
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- 2018-01-08 JP JP2019537123A patent/JP7267922B2/ja active Active
- 2018-01-08 EP EP18702408.8A patent/EP3565571B1/en active Active
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2022
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2023
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003524586A (ja) | 1998-05-21 | 2003-08-19 | アイシス・ファーマシューティカルス・インコーポレーテッド | オリゴヌクレオチドの非−非経口投与のための組成物と方法 |
JP2013527134A (ja) | 2010-02-10 | 2013-06-27 | ステルナ ビオロジカルス ゲーエムベーハー ウント コー. カーゲー | オリゴヌクレオチドに適した皮膚科的、薬学的組成 |
Non-Patent Citations (2)
Title |
---|
Alimentary Pharmacology and Therapeutics,2006年,Vol.23,pp.1403-1413 |
Nucleic Acids Research,2000年,Vol.28,pp.1935-1940 |
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EP4052720A2 (en) | 2022-09-07 |
JP2020504145A (ja) | 2020-02-06 |
EP4052720A3 (en) | 2022-11-09 |
US11220690B2 (en) | 2022-01-11 |
ES2920052T3 (es) | 2022-08-01 |
GB201700257D0 (en) | 2017-02-22 |
EP3565571A2 (en) | 2019-11-13 |
US20190367927A1 (en) | 2019-12-05 |
EP3565571B1 (en) | 2022-03-23 |
US20220119819A1 (en) | 2022-04-21 |
WO2018127582A2 (en) | 2018-07-12 |
JP2023093639A (ja) | 2023-07-04 |
WO2018127582A3 (en) | 2018-08-09 |
CA3049479A1 (en) | 2018-07-12 |
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