JP7359519B2 - ライノウイルス感染症の予防又は治療のための薬物 - Google Patents
ライノウイルス感染症の予防又は治療のための薬物 Download PDFInfo
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- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
Description
アルドヘキソースを含む薬学的に許容される製剤を得ること、ここで前記アルドヘキソースの2位炭素のヒドロキシル基がH、F、Cl、Br、I、SH、Me、OMe、及びSMeのうちのいずれか1つで置換されている、及び
有効量の前記製剤を、前記HRV感染症を有する個体、又は前記HRV感染症を発症するリスクのある個体に投与すること、を含む、前記方法が提供される。
ウィーン医科大学(Medical University of Vienna)の倫理委員会による承認、及び参加者からの書面によるインフォームドコンセントを得た後、ヘルシンキ宣言の原則に従って、ヒト材料を含む実験を実施した(議決番号1149/2011:正常なヒト皮膚生検からの細胞の分離及び培養並びに分析)。
2-デオキシグルコースは、HeLa細胞及び初代ヒト線維芽細胞の両方でHRVの複製を強く阻害した(図1Aを参照)。この複製への影響を検証するために、HeLa細胞におけるウイルスタンパク質(VP)1-3の発現によって反映されるタンパク質レベルでのウイルス複製も分析し、RNAレベルと同様の結果が示された(図1A)。前記2-デオキシグルコース剤は、使用した用量で細胞生存率に測定可能な影響を与えなかった(図2)。
全ての動物実験プロトコルは、ウィーン医科大学の動物倫理委員会によって評価され、経済科学省(Ministry of Economy and Science)によって承認された(BMWFW-66.009/0356_WF/V/3b/2015)。畜産及び実験は、実験動物学会連合(Federation of Laboratory Animal Science Association)のガイドラインに従って実施した。全ての実験に、施設内飼育された6~8週齢の雌C57BL/6Jマウス(最初は米国メイン州バーハーバーのジャクソン研究所から入手)を使用した。研究に関係のない動物飼育専門家がランダムに各群にマウスの割り当てを行った。
ライノウイルス気道感染の十分に確立されたマウスモデル(Bartlett et al.,2008)では、インビトロの所見に一致して、2-DGにより、感染した肺組織のHRV量が減少し、ウイルス誘発肺炎が減少した(図3及び図4を参照)。処置されたマウスに観察可能な副作用は全く認められなかった。
医薬組成物(滅菌脱イオン水に溶解した、10mM 2-デオキシ-D-グルコース、0.9重量体積%(%(w/v))NaCl)を10ml含む、例えば、米国特許第6,000,580号に開示されるような、鼻スプレーが提供される。
医薬組成物(滅菌脱イオン水中、0.5mM 2-デオキシ-2-フルオロ-D-マンノース、0.05%(w/v)オキシメタゾリン塩酸塩、0.05重量%(%(w/w))塩化ベンザルコニウム、85体積%(%(v/v))グリセロール)を5ml含む、例えば、欧州特許公開第0170198号に開示されるような、点鼻薬アプリケーターが提供される。
流体リザーバ中に医薬組成物(滅菌脱イオン水に溶解した、35mM 2-デオキシ-D-グルコース、0.9%(w/v)のNaCl)を含む、例えば、米国特許第9,364,618号に開示されているようなネブライザーが提供される。ネブライザーは、肺におけるライノウイルス感染症を患う、免疫抑制されている患者の下気道にエアロゾルとして吸入により組成物を送達するために使用される。
Bartlett,N.W.,Walton,R.P.,Edwards,M.R., Aniscenko,J.,Caramori,G.,Zhu,J.,Glanville,N.,Choy,K.J.,Jourdan,P.,Burnet,J., et al.(2008).Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation.Nat.Med.14,199-204.
Bertino,J.S.(2002).Cost burden of viral respiratory infections:issues for formulary decision makers.Am.J.Med.112 Suppl 6A,42S-49S.
Blaas,D.and Fuchs,R.(2016)Mechanism of human rhinovirus infections.Mol.Cell.Pediatr.3,21
Courtney,Richard J.,Sheldon M.Steiner,and Matilda Benyesh-Melnick.“Effects of 2-deoxy-D-glucose on herpes simplex virus replication.”Virology 52.2(1973):447-455.
Fleischer and Laessig.“Safety and efficacy evaluation of pleconaril for treatment of the common cold.”Clinical infectious diseases 37.12(2003):1722-1722.
Gschwandtner,M.,Paulitschke,V.,Mildner,M.,Brunner,P.M.,Hacker,S.,Eisenwort,G.,Sperr,W.R.,Valent,P.,Gerner,C.,and Tschachler,E.(2017).Proteome analysis identifies L1CAM/CD171 and DPP4/CD26 as novel markers of human skin mast cells.Allergy 72,85-97.
Gualdoni,G.A.,Lingscheid,T.,Schmetterer,K.G.,Hennig,A.,Steinberger,P.,and Zlabinger,G.J.(2015).Azithromycin inhibits IL-1 secretion and non-canonical inflammasome activation.Sci.Rep.5,12016.
Kaiser,L.,Aubert,J.-D.,Pache,J.-C.,Deffernez,C.,Rochat,T.,Garbino,J.,Wunderli,W.,Meylan,P.,Yerly,S.,Perrin,L.,et al.(2006).Chronic rhinoviral infection in lung transplant recipients.Am.J.Respir.Crit.Care Med.174,1392-1399.
Kang,Hyun Tae,and Eun Seong Hwang.“2-Deoxyglucose:an anticancer and antiviral therapeutic,but not any more a low glucose mimetic.”Life sciences 78.12(2006):1392-1399.
Kilbourne,Edwin D.“Inhibition of influenza virus multiplication with a glucose antimetabolite(2-deoxy-D-glucose).”Nature 183.4656(1959):271-272.
Liu,M.,Mallory,G.B.,Schecter,M.G.,Worley,S.,Arrigain,S.,Robertson,J.,Elidemir,O.,and Danziger-Isakov,L.A.(2010).Long-term impact of respiratory viral infection after pediatric lung transplantation.Pediatr.Transplant.14,431-436.
Palmenberg,Ann C.,et al.“Sequencing and analyses of all known human rhinovirus genomes reveal structure and evolution.”Science 324.5923(2009):55-59.
Papi,A.,Bellettato,C.M.,Braccioni,F.,Romagnoli,M.,Casolari,P.,Caramori,G.,Fabbri,L.M.,and Johnston,S.L.(2006).Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations.Am.J.Respir.Crit.Care Med.173,1114-1121.
Steinke,J.W.,and Borish,L.(2016).Immune Responses in Rhinovirus-Induced Asthma Exacerbations.Curr.Allergy Asthma Rep.16.
Sun,X.and Whittaker,G.R.(2013)Entry of influenza virus.Adv.Exp.Med.Biol.790,72-82
Watanabe,T.and Kawaoka,Y.(2015)Influenza virus-host interactomes as a basis for antiviral drug development.Curr.Opin.Virol.14,71-78.
本開示に係る態様は以下の態様も含む。
<1>
アルドヘキソースを含むヒトライノウイルス(HRV)感染症の予防又は治療に使用するための医薬組成物であって、
前記アルドヘキソースの2位炭素のヒドロキシル基は、H、F、Cl、Br、I、SH、Me、OMe、及びSMeのうちのいずれか1つで置換されており、好ましくは前記アルドヘキソースはD-アルドヘキソースである、
前記組成物。
<2>
前記アルドヘキソースは、グルコース、好ましくはD-グルコースであり、前記アルドヘキソースの2位炭素のヒドロキシル基は、H、F、Cl、Br、I、SH、Me、OMe、及びSMeのうちのいずれか1つで置換されている、<1>に記載の組成物。
<3>
2-デオキシ-D-グルコースを含む、HRV感染症の予防又は治療に使用するための医薬組成物。
<4>
前記組成物が液体であり、好ましくは前記組成物が水溶液である、<1>~<3>のいずれか一項に記載の組成物。
<5>
前記アルドヘキソース、特に2-デオキシ-D-グルコースの濃度が、0.01mM~1000mM、好ましくは0.1mM~500mM、より好ましくは0.25mM~250mM、さらにより好ましくは0.5mM~100mM、特に1mM~50mM又はさらには2.5mM~25mMである、<1>~<4>のいずれか一項に記載の組成物。
<6>
前記組成物が、少なくとも1種類の非薬効成分(excipient)及び/又は少なくとも1種類の追加の活性剤をさらに含み、好ましくは、前記追加の活性剤は、充血除去剤(特にノルエピネフリン放出剤、α-アドレナリン受容体作動薬、及びコルチコステロイド)、及び非ステロイド性抗炎症薬からなる群から選択される、<1>~<5>のいずれか一項に記載の組成物。
<7>
前記組成物の用量がヒト個体に投与され、好ましくは、前記用量中の前記アルドヘキソース、特に2-デオキシ-D-グルコースの全量は、0.001μmol~100μmol、好ましくは0.01μmol~50μmol、より好ましくは0.025μmol~25μmol、さらにより好ましくは0.05μmol~5μmol、特に0.1μmol~2.5μmol又はさらには0.2μmol~1.25μmolである、<1>~<6>のいずれか一項に記載の組成物。
<8>
前記用量は、少なくとも隔日で1回、好ましくは少なくとも1日1回、より好ましくは少なくとも1日2回、特に少なくとも1日3回の頻度で、好ましくは2~14日間、より好ましくは3~10日間、特に4~7日間投与される、<7に記載の組成物。
<9>
前記用量は、前記個体の鼻孔に、好ましくは各鼻孔に別々に投与される、<7>~<8>のいずれか一項に記載の組成物。
<10>
前記組成物は、粘膜、好ましくは気道の粘膜、特に鼻腔又は下気道の粘膜に投与される、<1>~<9>のいずれか一項に記載の組成物。
<11>
感冒、鼻炎、又は下気道感染症の予防又は治療において、特に免疫抑制されている個体又は慢性閉塞性肺疾患(COPD)若しくは喘息を有する個体における感冒、鼻炎、又は下気道感染症の予防又は治療において使用するための、<1>~<10>のいずれか一項に記載の組成物。
<12>
医薬組成物の鼻腔内投与用のディスペンサーであって、
前記ディスペンサーは前記医薬組成物を収容し、
前記組成物はアルドヘキソースを含み、
前記アルドヘキソースは、2位炭素のヒドロキシル基がH、F、Cl、Br、I、SH、Me、OMe、及びSMeのうちのいずれか1つで置換されており、好ましくは2-デオキシ-D-グルコースであり、
好ましくは、前記医薬組成物は、<1>~<11>のいずれか一項で定義される医薬組成物である、
前記ディスペンサー。
<13>
前記ディスペンサーが、鼻スプレー又は点鼻薬アプリケーターである、<12に記載のディスペンサー。
<14>
医薬組成物を投与するための、好ましくは下気道に医薬組成物を投与するための吸入装置であって、
前記装置は前記医薬組成物を収容し、
前記組成物はアルドヘキソースを含み、
前記アルドヘキソースは、2位炭素のヒドロキシル基がH、F、Cl、Br、I、SH、Me、OMe、及びSMeのうちのいずれか1つで置換されており、好ましくは2-デオキシ-D-グルコースであり、
好ましくは、前記吸入装置は、定量吸入器、乾燥粉末吸入器、又はネブライザーであり、及び/又は
好ましくは、前記医薬組成物は、<1>~<11>のいずれか一項で定義される医薬組成物である、
前記吸入装置。
<15>
HRV感染症の発症を遅らせる又はHRV感染症を治療する方法であって、
アルドヘキソースを含む薬学的に許容される製剤を得ること、ここで前記アルドヘキソースの2位炭素のヒドロキシル基がH、F、Cl、Br、I、SH、Me、OMe、及びSMeのうちのいずれか1つで置換されている、及び
有効量の前記製剤を、前記HRV感染症を有する個体、又は前記HRV感染症を発症するリスクのある個体に投与すること、を含み、
好ましくは、前記アルドヘキソースは、<2>~<11>のいずれか一項に記載されるようにさらに定義されるか又は<2>~<11>のいずれか一項に記載される使用のためのものである、
前記方法。
Claims (13)
- 2-デオキシ-D-グルコースを含む、HRV感染症の予防又は治療に使用するための医薬組成物。
- 前記医薬組成物が液体である、請求項1に記載の医薬組成物。
- 2-デオキシ-D-グルコースの濃度が、0.1mM~500mMである、請求項1又は請求項2に記載の医薬組成物。
- 2-デオキシ-D-グルコースの濃度が、0.25mM~250mMである、請求項1~請求項3のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が、少なくとも1種類の非薬効成分(excipient)及び/又は少なくとも1種類の追加の活性剤をさらに含む、請求項1~請求項4のいずれか一項に記載の医薬組成物。
- 前記医薬組成物が、充血除去剤及び非ステロイド性抗炎症薬からなる群から選択される少なくとも1種類の追加の活性剤をさらに含む、請求項1~請求項5のいずれか一項に記載の医薬組成物。
- 前記追加の活性剤は、ノルエピネフリン放出剤、α-アドレナリン受容体作動薬、及びコルチコステロイドからなる群から選択される充血除去剤である、請求項6に記載の医薬組成物。
- 前記医薬組成物の用量がヒト個体に投与され、前記用量中の2-デオキシ-D-グルコースの全量は、0.01μmol~50μmolである、請求項1~請求項7のいずれか一項に記載の医薬組成物。
- 前記用量は、少なくとも1日1回の頻度で、2~14日間投与される、請求項8に記載の医薬組成物。
- 前記用量は、前記ヒト個体の各鼻孔に別々に投与される、請求項8又は請求項9に記載の医薬組成物。
- 前記医薬組成物は、気道の粘膜に投与される、請求項1~請求項10のいずれか一項に記載の医薬組成物。
- 感冒、鼻炎、又は下気道感染症の予防又は治療において使用するための、請求項1~請求項11のいずれか一項に記載の医薬組成物。
- 免疫抑制されている個体又は慢性閉塞性肺疾患(COPD)若しくは喘息を有する個体における下気道感染症の予防又は治療において使用するための、請求項12に記載の医薬組成物。
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WO2021205412A1 (en) * | 2020-04-11 | 2021-10-14 | Exploration Invest Pte Ltd | 2-deoxy-d-glucose for prevention and treatment of a viral disease, in particular of covid-19 |
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