JP6946353B2 - 5′−アデノシン二リン酸リボース(adpr)の使用方法 - Google Patents
5′−アデノシン二リン酸リボース(adpr)の使用方法 Download PDFInfo
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- JP6946353B2 JP6946353B2 JP2018563379A JP2018563379A JP6946353B2 JP 6946353 B2 JP6946353 B2 JP 6946353B2 JP 2018563379 A JP2018563379 A JP 2018563379A JP 2018563379 A JP2018563379 A JP 2018563379A JP 6946353 B2 JP6946353 B2 JP 6946353B2
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Description
本出願は、2016年2月18日に出願された米国仮特許出願第62/296,665号及び2016年12月1日に出願された米国仮特許出願62/428,721の利益を請求しており、これらの各々は、その全体が参照によって本明細書に組み込まれている。
本発明は、アデノウイルスに関連した疾病又は状態、眼疾患、癌、又は感染、炎症、若しくは物理的、化学的、熱による、若しくは放射線による傷害によって引き起こされる疾病又は状態を治療し、管理し、又は予防するための、5′−アデノシン二リン酸リボース(ADPR)の使用方法及びその組成物に向けられている。
ヒトアデノウイルスは、免疫応答性個体と免疫不全性個体の両者において、感染性病原体として十分に証明されている。ヒトのアデノウイルス感染は、免疫不全性個体における高い死亡率(morbidity)及び死亡率(mortality)の原因であることが示されている。生死にかかわるというそれらの特質にもかかわらず、現在のところ、ヒトのアデノウイルス感染のための承認された抗ウイルス治療はない(Lion、2014、「免疫応答性及び免疫不全性患者におけるアデノウイルス感染」、Clin. Microbiol. Rev., 27(3):441-462;Martinez-Aguadoら、2015、「抗アデノウイルス薬の発見:潜在的標的及び評価方法」、Drug Discov. Today, 20(10):1235-1242を参照されたい)。シドフォビル、リバビリン、及びガンシクロビルのような広く作用する抗ウイルス薬は、アデノウイルス感染の治療のための次善の治療法の選択肢の一部である。しかしながら、結果は多様である。シドフォビル は、全てのヒトアデノウイルス種に対して抗ウイルス活性を示すことが明らかとされている。しかしながら、シドフォビル は、低い生物学的利用能、薬理的効果と処方量との低い関連性、及び用量を制限する腎臓毒性と関連づけられている。リバビリンは、異なるヒトアデノウイルス型に対して多様な活性を有しており、サブタイプCに対して最大の活性を示す。しかしながら、イン・ビボにおけるリバビリンの治療有効性の証拠は、この化合物を用いて達成された低血漿濃度に照らして、議論の的となっているままである。ヒトアデノウイルス感染を治療するために、ガンシクロビルの使用も示唆されている。しかし、このウイルスに対するその活性は、相対的に低い。
本明細書において提供されるものは、本明細書において提供される疾病又は状態のような、アデノウイルスに関連した疾病又は状態、眼疾患、癌、又は感染、炎症、若しくは物理的、化学的、熱による、若しくは放射線による傷害によって引き起こされる疾病又は状態を、治療し、管理し、又は予防するための方法であって、アデノウイルスに関連した疾病又は状態、眼疾患、癌、又は感染、炎症、若しくは物理的、化学的、熱による、若しくは放射線による傷害によって引き起こされる疾病又は状態を有しているか又はそれを発症する危険性がある患者に、5′−アデノシン二リン酸リボース (ADPR)又はその薬学的に許容され得る塩、溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、プロドラッグ、若しくは多形体、又はその医薬組成物を投与することを含む方法である。
5.1 定義
本明細書において使用するとき、用語「ADPR」は、ADPRも、その薬学的に許容され得る塩、溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、プロドラッグ、若しくは多形体をも包含すると理解される。
5.2 5′−アデノシン二リン酸リボース (ADPR)
本明細書において提供されるのは、アデノウイルスに関連した疾病又は状態、眼疾患、癌、又は感染、炎症、若しくは物理的、化学的、熱による、若しくは放射線による傷害によって引き起こされる疾病又は状態を治療し及び/又は予防するための方法であって、アデノウイルスに関連した疾病又は状態、眼疾患、癌、又は感染、炎症、若しくは物理的、化学的、熱による、若しくは放射線による傷害によって引き起こされる疾病又は状態を有しているか又はそれを発症する危険性がある患者に、ADPR又はその薬学的に許容され得る塩、溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、プロドラッグ、若しくは多形体、又はその医薬組成物を投与することを含む方法である。
ある種の実施態様において、ADPR又はその薬学的に許容され得る塩、 溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、プロドラッグ、若しくは多形体、又はその医薬組成物は、他の医薬との組合わせで投与され得る。そのような組み合わせ療法は、個々の治療成分の、同時の、順次の又は別々の投与という手段によって達成され得る。加えて、そのような組合せ療法の一成分として投与されるとき、本明細書に開示されているADPR、及び他の医薬は相乗的であり得、その結果、それらの成分のいずれか又は両者の一日用量は、単独療法として通常与えられるいずれかの成分の用量と比べて低減され得る。代わりに、そのような組合せ療法の一成分として投与されるとき、本明細書に開示されているADPR、及び他の医薬は相加的であり得、その結果、それらの成分の各々の一日用量は、単独療法として通常与えられるいずれかの成分の用量と類似であるか又は同じである。
ある種の実施態様において、本明細書に記載されているアデノウイルスに関連した疾病又は状態、眼疾患、癌、又は感染、炎症、若しくは物理的、化学的、熱による、若しくは放射線による傷害によって引き起こされる疾病又は状態は、約0.005 mg/kg乃至約1000 mg/kgの、約0.01 mg/kg乃至約100 mg/kgの、約0.1 mg/kg乃至約10 mg/kgの、又は約0.1 mg/kg乃至約5.0 mg/kgのADPRを、又はその薬学的に許容され得る塩、 溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、プロドラッグ、若しくは多形体を、本明細書に記載されている疾病又は状態を有している患者に投与することによって治療され得る。
医薬組成物は、個々の単一ユニット投薬形態の調製に使用され得る。本発明の医薬組成物及び投薬形態は、ADPR、又はその薬学的に許容され得る塩、溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、プロドラッグ、若しくは多形体を含む。本発明の医薬組成物及び投薬形態は、選択された製品形態を形成し又は製造するための、任意の公知の又はさもなければ有効な方法によって調製され得る。例えば、ADPR、又はその薬学的に許容され得る塩、溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、プロドラッグ、若しくは多形体は、一般的な賦形剤、希釈剤、又は担体と共に製剤化され得、そして錠剤、カプセル、溶液、懸濁物、乳化物、マイクロエマルション、ナノエマルション、シロップ、エリキシル、噴霧剤、粉体、エアロゾル(例えば、乾燥粉末エアロゾル、液体エアロゾル)、溶解媒体(例えば、急速溶解錠、フィルム、又はストリップ)、座薬、軟膏、又は任意の他の適切な投薬形態に形成され得る。具体的な実施態様において、医薬組成物は、溶液の形態である。
ある種の実施態様において、上記の医薬製剤は、具体的には目への局所適用に適用され得る。ある種の具体的な実施態様において、本明細書に開示されているのは、局所の眼科用溶液又は懸濁物(点眼薬)として本明細書に記載されているADPRを含む医薬製剤であり、それは、任意にさらに防腐剤及び/又は増粘剤を含む無菌等張(即ち、約3乃至約8の、約4乃至約8の、約7乃至約8の、又は約7.4のpHの)溶液として、一般的に入手可能である。
ある種の実施態様において、本明細書において提供される医薬組成物は、経鼻的に又は気道への吸入によって投与される。医薬組成物は、加圧容器、ポンプ、スプレー、噴霧器(霧状ミストを生じさせるための電気流体力学を使用する噴霧器のようなもの)、又は吸入器を使用する送達のために、単独で又は1,1,1,2−テトラフルオロエタン若しくは1,1,1,2,3,3,3−ヘプタフルオロプロパンのような適切な噴射剤との組み合わせで、エアロゾル又は溶液の形態で提供され得る。医薬組成物は、単独で又は乳糖若しくはリン脂質のような不活性担体との組み合わせで、吹送のために乾燥粉末及び点鼻薬として提供され得もする。経鼻用途のために、粉末は、キトサン又はシクロデキストリンを包含する生体接着剤を含み得る。
経口投与に適する医薬組成物は、これらに限定されないが、錠剤(例えば、チュアブル錠剤)、カプレット、カプセル、及び液体(例えば、香味つけされたシロップ)のような個別の投薬形態として提供され得る。そのような投薬形態は、前もって決められた量の活性成分を含み、且つ当業者に周知の調剤学の方法によって調製され得る。
6.1 実施例1. アデノウイルス血清型3に対する二つ(2つ)の化合物のプラーク阻害試験
アデノシン 5´−ジホスホリボース・ナトリウム塩(「化合物A」又はADPR、一つの500 mgバイアル中、Sigma A0752-500 mg、ロットSLBJ4805V)、及びニコチンアミド(「化合物N」、一つの100 gmバイアル中、Sigma N0636-100 G、ロットSLB0315V)(「化合物N」)が、Sigmaから入手された。化合物Aは、潅注用に水中に120 mg/mlとなるように、その後、さらに、DMEM(ダルベッコ変法イーグル培地)、2%FBS(牛胎仔血清;ウイルス培養基)中6 mg/ml及び2 mg/mlの濃度を目標として、可溶化された。化合物Nの240 mg/ml溶液、容量10 mlが、潅注用に水中で作られた。さらに、DMEM、2%FBS中で、化合物Nの希釈物が作られた。同日、アデノウイルス・プラーク阻害アッセイが準備された。可溶化された化合物Aの残りは、暗所で4℃に置かれた。
0 - 毒性なし
1 - 細胞対照ウェルと比べて、細胞が少しばかりまばらである
2 - 細胞対照ウェルと比べて、細胞が適度に(moderate)まばらであり、細胞対照ウェルと比べて、適度に、細胞の染色強度が弱く、ウイルス・プラークが見える
3 - 細胞対照ウェルと比べて、細胞が著しくまばらであり、細胞がなくなっており、細胞対照ウェルと比べて、細胞の染色強度が著しく弱く、細胞がないために染色がなく、ウイルス・プラークが見えない
背景
0 - 毒性なし
1 - 細胞対照ウェルと比べて、細胞が少しばかりまばらである
2 - 細胞対照ウェルと比べて、細胞が適度に(moderate)まばらであり、細胞対照ウェルと比べて、普通に、細胞の染色強度が弱く、ウイルス・プラークが見える
3 - 細胞対照ウェルと比べて、細胞が著しくまばらであり、細胞がなくなっており、細胞対照ウェルと比べて、細胞の染色強度が著しく弱く、細胞がないために染色がなく、ウイルス・プラークが見えない。
目的/目標:この研究の目的は、ニュージーランド白ウサギにおいて、ウイルス性結膜炎モデルを発症させることとした。
ADPR・二リチウム(Li2ADPR)は、水酸化リチウム加水分解条件下で、ニコチンアミド・アデニン・ジヌクレオチド(NAD+)の遊離酸から合成された。合成スキームは、以下に概要が示されている:
背景
Ad3: 4 mg/mL ‐ 29; 2 mg/mL ‐ 10; 1 mg/mL ‐ 44; 0.5 mg/mL ‐ 54; 0 mg/mL ‐ 55
Ad5: 4 mg/mL ‐ 7; 2 mg/mL ‐ 7; 1 mg/mL ‐ 25; 0.5 mg/mL ‐ 53; 0 mg/mL ‐ 65
この研究は、ウサギにおいて、ウイルス性結膜炎モデルに対するADPR・二リチウムの有効性を評価するために計画された。
6.6.1.1 試験系
種:アナウサギ
動物は、Ad5の接種の後、動物バイオセーフティー・レベル2(ABSL-2)条件下で飼育された。動物は、同じケージ内の他の動物からの目の外傷の可能性を低下させるために、研究の前及びその間、単独で飼育された。
1. 接種 ‐ アデノウイルス血清型5(Ad5)
1. 処理前の試験
群割り当て表
* 投薬は、1日に8時間以内で行われた;午前、正午、及び午後の投薬は、すべて、少なくとも約3乃至4時間、間が開けられた。
** 1日目の試験及び写真撮影は、投薬開始前に行われた;全ての他の試験及び写真撮影は、その日の3回目の投薬の後、約30分で行われた。
改変マクドナルド−シャダック採点法は、以下に示されている(T. McDonald及びJ. A. Shadduck、現代毒物学の進歩(Advances in Modern Toxicology)中の「眼刺激(Eye irritation)」:皮膚毒物学(Dermatoxicology)、F. Marzulli及びH. I. Maibach編、579-582頁、Hemisphere 出版社、ワシントン・ディー・シー、アメリカ合衆国、1977を参照されたい):
角膜の傷付け処理及びAd5接種を伴う組合せ損傷及び感染は、一貫性のある角膜及び結膜の炎症を誘導して、全くうまくいった。複合的なスコアは、1日目のベースラインの採点と比べて、3日目及び7日目に、処理群の全てにおいて著しく改善された(p < 0.01)。これらの結果は、図10にグラフを使って示されている。
結果は、溶液中のADPR・二リチウムで処理された目において、アデノウイルス及び物理的損傷の複合的影響の急速な解消を示した。使用したすべての用量(0.5%、1.0%、及び2.0%)が、7日目までの複合スコアにおいて、80%超の低減を伴って、p < 0.01で有効であった。ビヒクル対照群は、7日目まで、意味のある改善を示さなかった。
細胞の生死は、CellTiter-Glo(登録商標)細胞生死判別試験Promega(ウィスコンシン州、マディソン)によって測定された。CellTiter-Glo(登録商標)発光細胞生死判別試験は、代謝的に活性な細胞の存在を知らせる、存在するATPの定量に基づいて、培養物中の生きている細胞の数を測定するための同種の方法である。処理の後、CellTiter-Glo(登録商標)が、処理ウェルに添加され且つ37℃にてインキュベートされた。Molecular Devices Spectramaxマイクロプレートリーダーを使用して、発光値が測定された。
ADPR、ナトリウム塩、(Sigma AO752)、が、複製に対するそれの影響を測定するために、A549(ヒト肺胞腺癌)細胞培養物中で試験された。ADPRは、(前もって単層に増殖された)A549細胞を用いて、37℃で48時間インキュベートすることにより、5種の濃度で評価された。インキュベーションの後、各ウェルにMTT(3−(4,5−ジメチルチアゾール−2−イル)−2,5−ジフェニルテトラゾリウム臭化物)染料が添加され、且つ生きている細胞が、青色染料の取込みで測定された。
本件出願は、以下の構成の発明を提供する。
(構成1)
ヒトの患者において、アデノウイルスに関連した疾病又は状態を、治療し、管理し、又は予防するための方法であって、当該方法は、患者に、有効量の5′−アデノシン二リン酸リボース (ADPR)、又はその薬学的に許容され得る塩、溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、プロドラッグ、若しくは多形体を投与することを含み;ここで、患者は、アデノウイルスに関連した疾病又は状態を有しているか、又はそれを発症する危険性がある、方法。
(構成2)
アデノウイルスに関連した疾病又は状態が、目、耳、口、上気道、又は下気道の任意の部分に影響を与える疾病又は状態である、構成1の方法。
(構成3)
アデノウイルスに関連した疾病又は状態が、眼球上の疾病、結膜炎、角膜炎、角結膜炎、角膜剥離、潰瘍性感染性角膜炎、表層角膜炎、間質性角膜炎、ブドウ膜炎、急性緑内障、眼瞼炎、中耳炎、外耳炎、歯肉炎、粘膜炎、咽頭炎、扁桃炎、鼻炎、副鼻腔炎、喉頭炎、クループ、気管炎、気管支炎、細気管支炎、気管支肺炎、肺炎、喘息憎悪、慢性閉塞性肺疾患の憎悪、又は肺気腫の憎悪である、構成1の方法。
(構成4)
アデノウイルスに関連した疾病又は状態が、結膜炎、角膜炎、角結膜炎、咽頭炎、扁桃炎、喉頭炎、鼻炎、副鼻腔炎、気管支炎、細気管支炎、又は肺炎である、構成3の方法。
(構成5)
アデノウイルスに関連した疾病又は状態が、角膜炎、結膜炎、又は角結膜炎である、構成4の方法。
(構成6)
アデノウイルスに関連した疾病又は状態が、気管支炎又は細気管支炎である、構成4の方法。
(構成7)
アデノウイルスに関連した疾病又は状態が、咽頭炎、扁桃炎、又は喉頭炎である、構成4の方法。
(構成8)
投与が、局所、経口、非経口、経粘膜、又は吸入の投与ルートによって行われる、構成1の方法。
(構成9)
投与が、局所投与によって行われる、構成1の方法。
(構成10)
局所投与が、ヒトの患者の内部の細胞又は組織表面へである、構成9の方法。
(構成11)
局所投与が、エアロゾル化、噴霧、経口デリバリー、気管内注入、気管支内、又は気道表面への注入による、構成10の方法。
(構成12)
局所投与が、経口デリバリー、注入、又は消化管の表面への注腸による、構成10の方法。
(構成13)
局所投与が、内部器官への非経口の注射又は注入による、構成10の方法。
(構成14)
局所投与が、外部の細胞又は組織表面へである、構成9の方法。
(構成15)
外部の細胞又は組織表面が、皮膚、目、爪、髪、又は耳の表面である、構成14の方法。
(構成16)
投与が、静脈、動脈、又は導管内注入によって行われる、構成1の方法。
(構成17)
ADPRを含む医薬組成物が、溶液、懸濁物、乳化物、マイクロエマルション、ナノエマルション、シロップ、エリキシル、乾燥粉末エアロゾル、液体エアロゾル、錠剤、又は溶解媒体の形態である、構成1の方法。
(構成18)
溶解媒体が、急速溶解錠剤、フィルム、又はストリップである、構成17の方法。
(構成19)
ADPRを含む医薬組成物が、溶液の形態である、構成17の方法。
(構成20)
ADPRを含む医薬組成物が、他の医薬との組み合わせで投与される、構成1乃至19のいずれか一項の方法。
(構成21)
他の医薬が、抗ウイルス化合物である、構成20の方法。
(構成22)
他の医薬が、シドフォビル、アシクロビル、又はガンシクロビルである、構成20の方法。
(構成23)
他の医薬がシドフォビルである、構成22の方法。
(構成24)
他の医薬が金属塩である、構成20の方法。
(構成25)
他の医薬が、リチウム、亜鉛、コバルト、又は銅塩である、構成24の方法。
(構成26)
リチウム塩が塩化リチウムである、構成25の方法。
(構成27)
目、気道、及び/又は消化管の少なくとも一つの組織の微生物感染又は疾患の治療及び/又は予防に有効な、目、気道、及び/又は消化管への局所投与に適する医薬組成物であって、ここで、医薬組成物はADPRを含み、ここで、ADPRの量は、医薬組成物の約0.01%w/w乃至約10%w/wの範囲内である、医薬組成物。
(構成28)
目、気道、及び/又は消化管の少なくとも一つの組織の微生物感染又は疾患の治療及び/又は予防に有効な、目、気道、及び/又は消化管への局所投与に適する医薬組成物であって、ここで、医薬組成物は、a)ADPR、ここにおいて、ADPRの量は、医薬組成物の約0.01%w/w乃至約10%w/wの範囲内である;及びb)一種以上の金属塩、ここにおいて、金属は、リチウム、亜鉛、コバルト、及び銅からなる群から選択される、を含む、医薬組成物。
(構成29)
ADPRがそのナトリウム塩の形態である、構成1の方法。
(構成30)
ADPRがそのリチウム塩の形態である、構成1の方法。
(構成31)
ADPRがその二リチウム塩の形態である、構成1の方法。
(構成32)
式
(化1)
を有する化合物、又はその溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、プロドラッグ、若しくは多形体。
(構成33)
(i)ADPR・二リチウム、又はその溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、プロドラッグ、若しくは多形体、及び(ii) 一つ以上の薬学的に許容され得る賦形剤を含む医薬組成物であって、ここで、医薬組成物中におけるADPR・二リチウムの量は、医薬組成物の約0.001%w/w乃至約10%w/wの範囲内である、医薬組成物。
(構成34)
ヒトの患者において癌を治療し、管理し、又は予防するための方法であって、当該方法は、患者に、有効量の、ADPR・二リチウム、又はその溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、プロドラッグ、若しくは多形体を投与することを含み;ここで、当該患者は、癌を有しているか又はそれを発症する危険性がある、方法。
(構成35)
癌が、肺癌、肺腺癌、非小細胞肺癌、膵臓癌、膵臓腺癌、神経膠腫、多形性膠芽腫、又は急性骨髄性白血病である、構成34の方法。
(構成36)
ヒトの患者において、眼疾患、又は感染、炎症、若しくは物理的、化学的、熱による、若しくは放射線による傷害によって引き起こされる疾病又は状態を、治療し、管理し、又は予防するための方法であって、当該方法は、患者に、有効量のADPR・二リチウム、又はその溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、プロドラッグ、若しくは多形体を投与することを含み;ここで、患者は、眼疾患、又は感染、炎症、若しくは物理的、化学的、熱による、若しくは放射線による傷害によって引き起こされる疾病又は状態を有しているか又はそれを発症する危険性がある、方法。
(構成37)
高い細胞毒性ストレス状態において、ADPR又はATP欠損細胞における遊離ADPR又はATPの量を増加させる方法であって、当該細胞を、正常な生理的細胞ADPR又はATPレベルに回復させるのに充分な量のADPRと接触させることを含む、方法。
Claims (32)
- ヒトの患者において、アデノウイルスに関連した疾病又は状態を、治療し、管理し、又は予防するための医薬組成物であって、5′−アデノシン二リン酸リボース(ADPR)、又はその薬学的に許容され得る塩、溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、若しくは多形体を含む、前記医薬組成物。
- 前記アデノウイルスに関連した疾病又は状態が、目、耳、口、上気道、又は下気道の任意の部分に影響を与える疾病又は状態である、請求項1記載の医薬組成物。
- 前記アデノウイルスに関連した疾病又は状態が、眼球上の疾病、結膜炎、角膜炎、角結膜炎、角膜剥離、潰瘍性感染性角膜炎、表層角膜炎、間質性角膜炎、ブドウ膜炎、急性緑内障、眼瞼炎、中耳炎、外耳炎、歯肉炎、粘膜炎、咽頭炎、扁桃炎、鼻炎、副鼻腔炎、喉頭炎、クループ、気管炎、気管支炎、細気管支炎、気管支肺炎、肺炎、喘息憎悪、慢性閉塞性肺疾患の憎悪、又は肺気腫の憎悪である、請求項1記載の医薬組成物。
- 前記アデノウイルスに関連した疾病又は状態が、結膜炎、角膜炎、角結膜炎、咽頭炎、扁桃炎、喉頭炎、鼻炎、副鼻腔炎、気管支炎、細気管支炎、又は肺炎である、請求項3記載の医薬組成物。
- 前記アデノウイルスに関連した疾病又は状態が、角膜炎、結膜炎、又は角結膜炎である、請求項4記載の医薬組成物。
- 前記アデノウイルスに関連した疾病又は状態が、気管支炎又は細気管支炎である、請求項4記載の医薬組成物。
- 前記アデノウイルスに関連した疾病又は状態が、咽頭炎、扁桃炎、又は喉頭炎である、請求項4記載の医薬組成物。
- 前記医薬組成物が、前記ADPRを局所、経口、非経口、経粘膜、又は吸入の投与ルートによって投与するように使用される、請求項1記載の医薬組成物。
- 前記医薬組成物が、前記ADPRを局所投与によって投与するように使用される、請求項1記載の医薬組成物。
- 前記局所投与が、前記ヒトの患者の内部の細胞又は組織表面へのものである、請求項9記載の医薬組成物。
- 前記局所投与が、気道表面へのエアロゾル化、噴霧、経口デリバリー、気管内注入、気管支内、又は注入によるものである、請求項10記載の医薬組成物。
- 前記局所投与が、消化管の表面への経口デリバリー、注入、又は注腸によるものである、請求項10記載の医薬組成物。
- 前記局所投与が、内部器官への非経口の注射又は注入によるものである、請求項10記載の医薬組成物。
- 前記局所投与が、外部の細胞又は組織表面へのものである、請求項9記載の医薬組成物。
- 前記外部の細胞又は組織表面が、皮膚、目、爪、髪、又は耳の表面である、請求項14記載の医薬組成物。
- 前記医薬組成物が、前記ADPRを非経口投与によって投与するように使用され、該非経口投与が、静脈、動脈、又は導管内注入によるものである、請求項8記載の医薬組成物。
- 前記医薬組成物が、溶液、懸濁物、乳化物、マイクロエマルション、ナノエマルション、シロップ、エリキシル、乾燥粉末エアロゾル、液体エアロゾル、錠剤、又は溶解媒体の形態である、請求項1記載の医薬組成物。
- 前記溶解媒体が、急速溶解錠剤、フィルム、又はストリップである、請求項17記載の医薬組成物。
- 前記医薬組成物が、溶液の形態である、請求項17記載の医薬組成物。
- 前記医薬組成物が、他の医薬との組み合わせて使用される、請求項1乃至19のいずれか一項記載の医薬組成物。
- 前記他の医薬が、抗ウイルス化合物である、請求項20記載の医薬組成物。
- 前記他の医薬が、シドフォビル、アシクロビル、又はガンシクロビルである、請求項20記載の医薬組成物。
- 前記他の医薬が、シドフォビルである、請求項22記載の医薬組成物。
- 前記他の医薬が、金属塩である、請求項20記載の医薬組成物。
- 前記他の医薬が、リチウム、亜鉛、コバルト、又は銅塩である、請求項24記載の医薬組成物。
- 前記リチウム塩が、塩化リチウムである、請求項25記載の医薬組成物。
- 前記ADPRが、そのナトリウム塩の形態である、請求項1記載の医薬組成物。
- 前記ADPRが、そのリチウム塩の形態である、請求項1記載の医薬組成物。
- 前記ADPRが、その二リチウム塩の形態である、請求項1記載の医薬組成物。
- ADPR・二リチウム、又はその溶媒和物、水和物、互変異性体、立体異性体、同位体分子種、若しくは多形体を含む医薬組成物であって、該医薬組成物中におけるADPR・二リチウムの量が、該医薬組成物の約0.001%w/w乃至約10%w/wの範囲内である、前記医薬組成物。
- 一つ以上の薬学的に許容され得る賦形剤を更に含む、請求項31記載の医薬組成物。
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