JP5758904B2 - ニトライトの医薬製剤及びそれらの使用 - Google Patents
ニトライトの医薬製剤及びそれらの使用 Download PDFInfo
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- JP5758904B2 JP5758904B2 JP2012534359A JP2012534359A JP5758904B2 JP 5758904 B2 JP5758904 B2 JP 5758904B2 JP 2012534359 A JP2012534359 A JP 2012534359A JP 2012534359 A JP2012534359 A JP 2012534359A JP 5758904 B2 JP5758904 B2 JP 5758904B2
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- nitrite
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Description
無機ニトライト
本発明の製薬上許容される組成物は、無機ニトライト〔例えば、亜硝酸(HNO2)の塩若しくはエステル〕又はその製薬上許容される塩を含む。亜硝酸塩としては、限定するものではないが、以下のものを挙げることができる:アルカリ金属(例えば、ナトリウム、カリウム)の塩;アルカリ土類金属(例えば、カルシウム、マグネシウム及びバリウム)の塩;並びに、有機塩基(例えば、アミン塩基)及び無機塩基の塩。本発明の化合物は、中間体又は最終化合物の中に存在している原子の全ての同位体も包含する。同位体は、原子番号は同一であるが質量数が異なっている原子を包含する。例えば、水素の同位体には、三重水素及び重水素が包含される。用語「化合物」は、任意の無機ニトライト又はその製薬上許容される塩、溶媒和物若しくはプロドラッグに関連して本明細書中で使用される場合。全ての化合物及びその製薬上許容される塩は、溶媒和(例えば、水和)形態も包含することが意図されている。ニトライトは、化学式「NO2 -」で表され、水中でイオンとして存在し得る。亜硝酸ナトリウムは、化学式「NaNO2」で表され、典型的には、水中で溶解してナトリウムイオン「Na+」及び亜硝酸イオン「NO2 -」を形成する。さらに、本発明がニトライト化合物のそのような全ての溶媒和形態(例えば、水和物)を包含することも理解される。代表的なニトライト化合物は、WO 2008/105730(これは、参照により本明細書中に組み込まれる)に記載されている。
本発明の製薬上許容される組成物は、無機ニトライト〔例えば、亜硝酸(HNO2)の塩、例えば、NaNO2〕又はその製薬上許容される塩、溶媒和物若しくはプロドラッグを含む。医薬品として使用される場合、本発明の化合物は、いずれも、医薬組成物の形態で投与することができる。これらの組成物は、製薬の技術分野でよく知られている方法で調製することが可能であり、及び、局所療法又は全身療法の何れが望ましいかに応じて、及び、治療対象の領域に応じて、さまざまな経路によって投与することができる。投与は、局所投与、非経口投与、静脈内投与、動脈内投与、皮下投与、筋肉内投与、頭蓋内投与、眼窩内投与、眼内投与、脳室内投与、嚢内投与、髄腔内投与、槽内投与、腹腔内投与、鼻腔内投与、エーロゾル投与、坐剤による投与又は経口投与であり得る。
本発明によって意図されている医薬組成物には、経口投与用に製剤化された医薬組成物(「経口投与剤形」)が包含される。経口投与剤形は、例えば、当該活性成分(1種類又は複数種類)を無毒性の製薬上許容される賦形剤と混合された状態で含む錠剤、カプセル剤、液体の溶液剤若しくは懸濁液剤、粉末剤又は液体若しくは固体の結晶の形態にあり得る。これらの賦形剤は、以下のものであり得る:例えば、不活性な希釈剤又は増量剤(例えば、スクロース、ソルビトール、糖、マンニトール、微結晶性セルロース、デンプン類、例えば、ジャガイモデンプン、炭酸カルシウム、塩化ナトリウム、ラクトース、リン酸カルシウム、硫酸カルシウム、又は、リン酸ナトリウム);造粒剤及び崩壊剤(例えば、セルロース誘導体、例えば、微結晶性セルロース、デンプン類、例えば、ジャガイモデンプン、クロスカルメロースナトリウム、アルギン酸塩類、又は、アルギン酸);結合剤(例えば、スクロース、グルコース、ソルビトール、アラビアゴム、アルギン酸、アルギン酸ナトリウム、ゼラチン、デンプン、アルファデンプン、微結晶性セルロース、ケイ酸アルミニウムマグネシウム、カルボキシメチルセルロースナトリウム、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、エチルセルロース、ポリビニルピロリドン、又は、ポリエチレングリコール);並びに、平滑剤、流動促進剤及び接着防止剤(例えば、ステアリン酸マグネシウム、ステアリン酸亜鉛、ステアリン酸、シリカ、硬化植物油、又は、タルク)。別の製薬上許容される賦形剤は、着色剤、矯味矯臭薬、可塑剤、保湿剤、緩衝剤などであり得る。
本発明の経口送達用に製剤化された医薬組成物(例えば、錠剤又はカプセル剤)は、コーティングを施すか又は調合して、遅延放出又は長期にわたる放出の有利点をもたらす投与剤形とすることができる。該コーティングは、該活性薬物物質を予め定められたパターンで放出するように(例えば、制御放出製剤を達成するために)適合させることができるか、又は、例えば腸溶コーティング(例えば、pH感受性ポリマー(「pH制御放出(pH controlled release)」)、膨潤、溶解若しくは侵食の速度が遅いか又は膨潤、溶解若しくは侵食の速度がpH依存性であるポリマー(「時間制御放出(time-controlled release)」)、酵素によって分解されるポリマー(「酵素制御放出(enzyme-controlled release)」又は「生物分解性放出(biodegradable release)」)、及び、圧力が増大することにより破壊されるフィルム層を形成するポリマー(「圧力制御放出(pressure-controlled release)))を使用して、胃を通過し終えるまで活性薬物物質を放出しないように適合させることができる。本明細書中に記載されてる医薬組成物の中で使用することが可能な代表的な腸溶コーティングとしては、糖衣、フィルムコーティング(例えば、ヒドロキシプロピルメチルセルロース、メチルセルロース、メチル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、カルボキシメチルセルロース、アクリレートコポリマー、ポリエチレングリコール及び/又はポリビニルピロリドンに基づくフィルムコーティング)、又は、メタクリル酸コポリマー、フタル酸酢酸セルロース、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートスクシネート、ポリビニルアセテートフタレート、セラック及び/若しくはエチルセルロースに基づくコーティングなどがある。さらに、例えばモノステアリン酸グリセリル又はジステアリン酸グリセリルなどの、時間遅延物質(time delay material)を使用することもできる。
一部の実施形態では、結腸を目標とする薬物送達システムを使用することが可能である。代表的なアプローチとしては、限定するものではないが、以下のものを挙げることができる:
(a) 薬物を担体と共有結合させて、胃及び小腸の中では安定であり且つ大腸の中で腸内微生物叢(intestinal microflora)による酵素的変換を受けて薬物を放出するプロドラッグを形成させること;そのようなプロドラッグの例としては、アゾ-コンジュゲート、シクロデキストリン-コンジュゲート、グリコシド-コンジュゲート、グルクロネートコンジュゲート、デキストラン-コンジュゲート、ポリペプチド及びポリマーコンジュゲートなどを挙げることができる;
(b) そのままの分子を結腸まで送達するアプローチ、例えば、中性pH若しくはアルカリ性pHで薬物を放出するpH感受性ポリマーによるコーティング、又は、結腸内で細菌による分解を受けて薬物を放出する生物分解性ポリマーによるコーティング;
(c) pH又は生物分解に応答して薬物を放出する生物分解性マトリックス及びヒドロゲルの中に薬物を埋め込むこと;
(d) 時間放出システム(time released systems)〔該時間放出システムにおいては、多層コーティングされた製剤が胃を通過したあとで、3〜5時間(これは、小腸を通過する時間に相当する)の遅延時間(lag time)が経過した後、薬物が放出される〕;
(e) アゾポリマーとジスルフィドポリマーの組合せが結腸の酸化還元電位に応答して薬物を放出させる酸化還元感受性ポリマー(redox-sensitive polymers)の使用;
(f) 結腸粘膜に選択的に付着して薬物を徐々に放出する生体付着性ポリマー(bioadhesive polymers)の使用;及び、
(g) 浸透圧に起因して半透膜を通して薬物が放出される浸透性制御薬物送達(osmotic controlled drug delivery)。
本発明の範囲内には、生物分解性ポリマーによる非経口デポーシステム(parenteral depot systems)もある。これらのシステムは、筋肉又は皮下組織の中に注入されるか又は埋め込まれてそのシステムの中に組み入れられている薬物を数日間から数ヶ月間に及ぶ長期間にわたって放出する。ポリマーの特徴と装置の構造は、両方とも、連続的又は拍動的であり得る放出動力学を制御することができる。ポリマーに基づく非経口デポーシステムは、インプラント又は微粒子として分類され得る。前者は、皮下組織の中に注入される円筒形の装置であり、後者は、10〜100μmの範囲内にある球形粒子として定義される。押出成形、圧縮成型又は射出成形を用いてインプラントを製造するのに対して、微粒子に関しては、多くの場合、相分離法、噴霧乾燥法及び水中油中水エマルション法が使用される。微粒子を形成させるために最も一般的に使用される生物分解性ポリマーは、乳酸及び/又はグリコール酸から得られるポリエステル類、即ち、ポリ(グリコール酸)及びポリ(L-乳酸)(PLG/PLAミクロスフィア)である。特に興味深いのは、その場で形成させるデポーシステム、例えば、固化させることにより若しくは冷却することにより若しくはゾルゲル転換により形成される熱可塑性ペースト及びゲル化システム、架橋システム並びに両親媒性脂質によって形成される有機ゲルである。上記システムの中で使用される熱感受性ポリマーの例としては、N-イソプロピルアクリルアミド、ポロキサマー類(エチレンオキシドとプロピレンオキシドのブロックコポリマー、例えば、ポロキサマー188及びポロキサマー407)、ポリ(N-ビニルカプロラクタム)、ポリ(シロエチレングリコール)(poly(siloethylene glycol))、ポリホスファゼン誘導体及びPLGA-PEG-PLGAなどがある。
慢性組織虚血を治療するための本発明の方法は、虚血性組織の中で新生血管の成長をもたらすのに充分な期間にわたり充分な量の無機ニトライトを投与することによって、実施する。
本明細書中に記載されている本発明の医薬組成物は、いずれも、一式の使用説明書と一緒に使用され得る、即ち、キットを形成し得る。該キットは、本明細書中に記載されている治療として該医薬組成物を使用するための使用説明書を含有し得る。例えば、該使用説明書は、慢性組織虚血を軽減させるために本発明の化合物を使用するための投与計画及び治療計画を提供し得る。
栄養補給としてのニトライト
血漿ニトライト濃度は、最大数の危険因子を有し、血漿ニトライトの濃度が最も低い対象において、心臓血管の危険因子と逆相関性を有することが示されている(Kleinbongard et al., Free Radical Biology & Medicine 40: 295-302,2006)。正常の対象においては、運動することによって貯蔵されているニトライトが血漿中に放出され、血漿ニトライトの濃度が上昇する;しかしながら、糖尿病患者及びPAD患者おいては、運動は血漿ニトライトの濃度を上昇させず、実際には、循環ニトライト濃度がさらに低下する(Allen et al., Nitric Oxide 20: 231-237, 2009)。かくして、ニトライトの栄養補給は、心臓血管障害及び血管障害における血漿ニトライト濃度の不足、及び、ニトライトと一酸化窒素の関係を仮定すれば、上記疾患で認められる一酸化窒素の不足、又は、ニトライトの食餌性欠乏に起因する血漿ニトライト濃度の不足を克服する上で有効であると考えられる。
本明細書中に記載されている医薬組成物及び方法を使用して、先天性及び後天性の炎症性疾患を治療することができる。本発明の方法に包含される炎症性疾患は、炎症を引き起こす広範な医学的状態から生じ得る。本発明において記載されている組成物及び方法によって治療することが可能な炎症性疾患の1つのタイプは、免疫-炎症性疾患である。免疫-炎症性疾患の例としては、関節リウマチ、若年性関節リウマチ、変形性関節症、移植拒絶反応、敗血症、急性呼吸窮迫症候群、喘息及び癌などを挙げることができる。本発明において記載されている組成物及び方法によって治療することが可能な炎症性疾患の別のタイプは、自己免疫疾患である。自己免疫疾患の例としては、多発性硬化症、乾癬、炎症性腸疾患、糸球体腎炎、狼瘡、ブドウ膜炎及び慢性肝炎などのような状態を挙げることができる。別の炎症性疾患も本発明において記載されている組成物及び方法によって治療することが可能であり、ここで、そのような別の炎症性疾患としては、外傷、酸化的ストレス、細胞死、放射線による損傷、虚血、再潅流、癌、移植拒絶反応及びウイルス感染症に起因する状態などを挙げることができる。
例えば、外傷、瘢痕化、異常タンパク質沈着、アミロイド症、虚血若しくは糖尿病、感染症又は外科的処置のような状態又は組織に損傷を生じるヘルニア、心臓障害及び胃腸障害のような先天性奇型に起因して組織又は器官が損傷を受けた後で、本明細書中に記載されている医薬組成物及び方法を用いて組織の再生を刺激することができる。
慢性組織虚血は、体の一部分又は体の一部分を含む組織に対する血流の部分的な、実質的に全体的な又は全体的な低減をもたらす広範な医学的状態と関連していて、疾患、傷害又は未知の原因の結果であり得る。また、慢性組織虚血は、個人の遺伝子構成に影響され得る。慢性組織虚血へと至る医学的状態に関係なく、慢性組織虚血を患っている患者は、本明細書中に記載されている無機ニトライトを含む製薬上許容される組成物を用いた治療の対象である。治療は、慢性組織虚血の徴候及び症状の一部又は全てを完全に又は部分的に取り除くことが可能であり、その症状の重症度を低減させることが可能であり、それらの発症を遅延させることが可能であり、又は、その後で現れる症状の進行を遅くすること若しくは重症度を軽減させることが可能である。
以下においてさらに記載されているように、本発明の組成物は、虚血性組織の中で新生血管の成長をもたらすのに充分な期間にわたり充分な量で投与される。用語「新生血管の成長(new blood vessel growth)」、「新生血管の形成(new blood vessel formation)」及び「新生血管の発生(new blood vessel development)」は、互いに交換可能に使用することができる。新生血管の成長は、最初のシグナル伝達イベント、内皮細胞の細胞動員(cellular recruitment)、新生血管の形成及び拡大及び新生血管と既存の血管の結合を包含する、血管形成のプロセスの全ての相を意味する。新生血管の成長は、虚血性組織の血管再建又は新血管形成をもたらす任意のプロセス(例えば、血管形成、又は、動脈形成、又は、血管形成と動脈形成との組み合わせなど)から生じ得る。用語「血管形成」は、典型的には、血管芽細胞からの血管の胚発生を表現するために用いられる。血管形成は、一般的に、創傷治癒に必要な生後の生理学的プロセスであると理解される。血管形成には、一般的に、既存の毛細血管からの発芽、出芽及び挿入成長による新たな毛細血管又は毛細血管枝(capillary branch)の形成が包含される。動脈形成、即ち、既存の細動脈連結部の本来の側副動脈への成長は、一般的に、動脈閉塞後に、既存の相互連結させる細動脈から成熟動脈が形成されることを包含するものと理解される。それは血管形成といくつかの特徴を共有するが、それに至るまでの経路や、最終的な結果が異なり得る:動脈形成は、潜在的に、閉塞した動脈に完全に取って代わることができるのに対し、血管形成は一般的にそのように取って代わることはできない。虚血性領域内の毛細血管の数が増加しても、律速的構造(limiting structure)が新しい毛細血管の上流に存在している場合には、血流量は増大され得ない;閉塞部位の周辺の血流を迂回させる新しい側副血管の形成。加えて、血管形成によって形成される構造と動脈形成によって形成される構造は、それらの細胞組成の点で異なっている。毛細血管は、血管周皮細胞によって支持されている内皮細胞によって形成された管である。動脈及び静脈は、多層(即ち、内皮細胞、周皮細胞及び基底膜で構成される、内膜;主に平滑筋細胞及びその細胞外マトリックスで構成される、中膜;及び、最も大きな血管内において、主に線維芽細胞とその細胞外マトリックスで構成される、外膜)からなる管である。
本発明の方法は、基底にある特徴として、組織若しくは器官への血流が持続的に低減されているか、又は、組織若しくは器官への血流が部分的に若しくは完全に遮断されている、広範な医学的状態のいずれにも適用することが可能である。かくして、該方法は、疾患、外傷又は環境ストレスに関連する慢性組織虚血の治療に適用することができる。組織への血流の減少は、例えば、凝血塊の存在又はアテロームプラーク(atheromatous plaque)に起因する硬化及び/又は弾性損失による動脈の進行性閉塞の結果であり得る。組織への血流の減少は、さらにまた、環境による傷害(environmental insult)、例えば、組織又は器官への血流量を遮断する外傷性損傷又は外科手術などの結果でもあり得る。典型的には、創傷の酸素圧は急速に且つ進行的に低下し、創傷領域全体にわたってさまざまな程度の低酸素状態を発症する。低酸素症を引き起こす環境条件も本発明の範囲内にある。
経口投与用の代表的な製剤としては、錠剤製剤及びカプセル剤製剤などがある。例えば、錠剤製剤に関して記載されている粉末状成分を使用して、カプセル剤製剤を調製することが可能であり、カプセルの適切な寸法は、活性成分の用量及び充填密度に依存して、例えば、サイズ1カプセル、サイズ0カプセル又はサイズ00カプセルなどである。一部の実施形態では、錠剤又はカプセル剤には、腸溶コーティングを施さなくてもよい。別の実施形態では、本発明の医薬組成物は、亜硝酸イオンを制御放出するように製剤化することができる。カプセル剤がコーティングされていると記載されている場合、そのコーティングは、充填後にカプセル剤に施すことができる。カプセル剤製剤は、コーティングプロセスに際して取扱いを容易にするために、場合により、セルフロッキングカプセル殻(self-locking capsule shell)(例えば、「Coni-Snap(登録商標)」、「Posilok(登録商標)」又は「Snap-Fit(登録商標)」など)を使用することができる。
亜硝酸ナトリウムを包含する全ての固体成分を秤量して、成分の望ましい重量比の錠剤を製造した。4〜5の錠剤を調製するために、充分な量のパウダーブレンドを調製した。その粉末状成分を充分に混合させた後、圧縮して錠剤とした。蝋状成分(即ち Castorwax(登録商標))を含む錠剤のために、亜硝酸ナトリウムと他の成分を溶融蝋の中に分散させ、均質なブレンド状態を維持するために混合させながら、その混合物を固化させた。固化後、必要に応じて、さらに混合させるために、その混合物を粉砕して粉末とした。全ての粉末状成分の混合は、乳鉢と乳棒を用いて行った。
580mg錠剤: 1.27cm(直径)×0.38cm(厚さ)(1/2"×1/7");又は、
480mg錠剤: 1.27cm(直径)×0.32cm(厚さ)(1/2"×1/8")。
動物試験(ウサギへの経口投与)用に、5mgの亜硝酸ナトリウムを含む小ペレット剤を以下の方法に準じて調製した。亜硝酸ナトリウムを包含する全ての固体成分を秤量して、成分の望ましい重量比のペレット剤を製造した。40〜50のペレット剤を調製するために、充分な量のパウダーブレンドを調製した。その粉末状成分を篩(150〜250ミクロン)にかけ、幾何学的希釈によって充分に混合させた後、圧縮してペレット剤とした。そのペレット剤は、3mm穿孔及びダイを有する「Parr Model 2811 pellet press」を用いて圧縮した。ペレット剤の圧縮は、手動式圧縮で行い、加えられる力を制御することはできなかったが、全ての製剤に関して粘性を有するペレットを製造した。ペレット剤の重さは、使用する製剤に応じて、23〜35mgであった。1つのペレットバッチは、当該ペレットの重量の11〜15%であるエチルセルロース/トリアセチンコーティング(4/1)を用いて手動でコーティングした。
測定された体積のコーティング溶液を錠剤の表面上に注意深く滴下し、その滴下されたコーティング溶液を錠剤の表面及び縁に注意深く拡げることによって、亜硝酸ナトリウム錠剤に手動でコーティングした。溶媒を蒸発させた後、充分な量のコーティングが塗布されるまで、上記方法を何度も繰り返した。ペレット剤及び一部の錠剤バッチについて、ペレット剤/錠剤をコーティング溶液に注意深く浸漬し、ピンセットで保持しながら風乾させることを含む浸漬コーティング法を用いた。充分な量のコーティングが塗布されるまで、上記浸漬法を繰り返した。
・ 亜硝酸ナトリウム, Certified ACS Reagent, 結晶質, Fisher Scientific, Lot # 080939A;
・ Polyox(登録商標) Coagulant, Blend # C-289, 分子量 5百万, N.F. Grade, Union Carbide;
・ Polyox(登録商標) WSR 303, 分子量 7百万, N.F. Grade, Colorcon;
・ Avicel(登録商標) PH-302, 微結晶性セルロース, FMC Corporation, Lot # Q939C;
・ Ethocel(登録商標), エチルセルロース, Standard 100 premium, Colorcon;
・ Castorwax(登録商標), NF, 硬化ひまし油, CASCHEM, Lot # 00121431;
・ Methocel(登録商標) K100M, ヒドロキシプロピル メチルセルロース, premium CR grade, Colorcon;
・ Klucel(登録商標) HXAF Pharm., ヒドロキシプロピルセルロース, 分子量 1.15 百万, Aqualon Division, Hercules, Inc.;
・ Klucel(登録商標) MF Pharm., ヒドロキシプロピルセルロース, 分子量 850,000, Aqualon Division, Hercules, Inc.;
・ 塩化ナトリウム, Certified ACS Reagent, Fisher Scientific;
・ 酢酸ナトリウム三水和物, ACS Reagent, Fisher Scientific。
全てのニトライト放出試験について、50RPMの撹拌で、USPパドル法を用いた。Vankel(登録商標) USP 6-ステーション溶解装置を使用した。体積500mLの37℃の蒸留水を各放出容器内の放出媒体として使用した。錠剤の放出試験は、各被験製剤に対して2反復又は3反復で実施した。
Hewlett-Packard(登録商標) 8453 ダイオードアレイ UV-可視分光光度計を用いて、10-cm 石英キュベット内で、各放出サンプルについて355nmでの紫外線吸光度を測定した。
上記製剤のうちの何種類かを、ニトライト血漿濃度の測定に関して、模擬実験に付した。該模擬実験によって、ミッドレンジ薬物動態学的定数(mid-range pharmacokinetic constant)及び80mg用量が推定される。NaNO2に関する推定されたPKパラメータは、以下のとおりである:半減期=45分;クリアランス=60.375L/時間;経口による生物学的利用能=100%(但し、製剤27(生物学的利用能=27%)は除く);投与から放出が起こり得るpHに達するまでの遅延時間=0.5時間。該模擬実験は、最初の2日間は、1日当たり2回投与する。69ng/mLの濃度は、1μMと同等であり、138ng/mLの濃度は、2μMと同等である。結果は、図1〜図10に示されている。
一部の実施形態では、該医薬組成物は、腸溶コーティングされたカプセル剤として製剤化することができる。表8及び表9は、腸溶コーティングされたカプセル剤製剤の処方を提供する。
持続放出亜硝酸ナトリウム製剤を薬物動態学的分析に付すために、体重3.0〜3.2kgのニュージーランドウサギを使用した。6時間にわたって、14時点において、1mLの血液を採取した。
7.85gのKFeCN + 25mLのPBS =1;
66mgのNEM + 3mLのPBS =2;
1.5mLのノニデット P40 =3;
1(21mL) + 2(2.5mL) + 3=ニトライト保存溶液。
「Sievers 280i Nitric oxide analyzer (NOA)」を使用して、ニトライト/NO濃度の標準曲線を構築し、及び、総NOxの試料、ニトロソチオール類(SNO)+ニトロソヘム+ニトレートの試料及び遊離ニトライトの試料を測定した。ニトライトを測定するために、パージ容器に還元剤(7mLの氷酢酸の中の2mLのヨウ化ナトリウム)を含ませて、ニトライト化合物、ニトレート化合物及びニトロソ化合物を遊離一酸化窒素に還元した。次いで、NOガスを、オゾンとの反応(これは、化学発光検出器で検出される光のフォトンを放射する)を通して、NOAで検出する。存在しているNOの量は、長時間にわたって放射シグナルを積分することにより決定し、NOに関するソース標準(source standard)としての亜硝酸ナトリウムの既知量(0μM、0.1μM、0.5μM、1μM、10μM及び100μM)に対して較正した。血漿ニトライトは、血漿のアリコートを1N HClの中の580nMのスルファニルアミドと15分間反応させて遊離ニトライトを捕捉することによって測定した。遊離ニトライトの総量は、総NOx値からスルファニルアミド値を減じることによって決定した。
本発明の特定の実施形態に関連して本発明について記述してきたが、さらなる変更が可能であるということ、及び、本出願が本発明の原理に概して従う本発明の全ての変形、使用又は適応(ここで、そのような変形、使用又は適応には、本発明が関連する技術の範囲内で知られているか又は慣習的に実施されていて上記で説明した本質的特徴に応用され得るような、本開示に含まれていないことも包含される)を包含することが意図されているということは理解されるであろう。
Claims (10)
- 40mg〜100mgの無機ニトライト又はその製薬上許容される塩、及び製薬上許容される賦形剤を含む持続放出性医薬組成物であって、該医薬組成物のヒトへの投与により前記無機ニトライト又はその製薬上許容される塩が6〜12時間にわたって徐々に放出され、該医薬組成物は経口投与用の固体投与剤形として製剤化され、該医薬組成物の前記ヒトへの投与により、4〜14時間、亜硝酸イオンの血漿濃度が0.1μM〜5.0μMに維持される、前記組成物。
- 血漿濃度が維持される期間が血漿濃度がピークにある時間の後に起こる、請求項1に記載の医薬組成物。
- 前記亜硝酸イオンの30〜50%が最初の1時間に放出され、前記亜硝酸イオンの残部はその後の2〜14時間で放出される、請求項1に記載の医薬組成物。
- 前記無機ニトライトがヒトの体重1kg当たり0.05mg〜10mgの用量で投与される、請求項1に記載の医薬組成物。
- 該無機ニトライトを遅延放出させるための製薬上許容される賦形剤をさらに含み、それによって、前記ヒトに経口投与されたときに、該無機ニトライトは当該ヒトの胃内では実質的に放出されない、請求項1に記載の医薬組成物。
- 請求項1に記載の医薬組成物であって、
腸溶性又は遅延放出性コーティング層をさらに含んでおり、
ここで、前記医薬組成物は、前記ヒトに投与されたときに、該無機ニトライトが前記ヒトの胃内では実質的に放出されないように、製剤化されている、前記医薬組成物。 - ヒトにおける慢性組織虚血を治療又は予防するための、請求項1に記載の医薬組成物。
- ヒトの体内において見いだされる循環ニトライトの不足を補うための、請求項1に記載の医薬組成物。
- 前記亜硝酸イオンがNaNO 2 として提供される、請求項1に記載の医薬組成物。
- 前記製薬上許容される賦形剤が、メタクリル酸コポリマー、ポリオックス水溶性樹脂、酢酸フタル酸セルロース、酢酸トリメリト酸セルロース、ポリビニルアセテートフタレート、フタル酸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、エチルセルロース/トリアセチン、酢酸ナトリウム、硬化ひまし油、及びフタル酸ヒドロキシプロピルメチルセルロース、セラック、又はそれらの水性分散液からなる群から選ばれる、請求項1に記載の医薬組成物。
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AU2010306755A1 (en) | 2012-05-03 |
CN107260756A (zh) | 2017-10-20 |
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AU2010306755B2 (en) | 2015-12-24 |
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WO2011047161A1 (en) | 2011-04-21 |
JP2013508289A (ja) | 2013-03-07 |
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US10307441B2 (en) | 2019-06-04 |
US20200085861A1 (en) | 2020-03-19 |
IL219155A0 (en) | 2012-06-28 |
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