JP7097344B2 - 農業用、工業用およびその他の使用のための消毒薬としてのビスマス-チオール - Google Patents
農業用、工業用およびその他の使用のための消毒薬としてのビスマス-チオール Download PDFInfo
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- JP7097344B2 JP7097344B2 JP2019219070A JP2019219070A JP7097344B2 JP 7097344 B2 JP7097344 B2 JP 7097344B2 JP 2019219070 A JP2019219070 A JP 2019219070A JP 2019219070 A JP2019219070 A JP 2019219070A JP 7097344 B2 JP7097344 B2 JP 7097344B2
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Description
本出願は、2010年2月3日出願のPCT出願第PCT/US2011/023549号、および2010年8月12日出願の米国特許仮出願第61/373,188号の利益を主張するものであり、それらは、それぞれ参照により全体が本明細書に組み込まれる。
微生物感染に対する応答および抵抗に、および/または植物および動物(ヒトを含む)身体組織の治癒または保持に寄与する複雑な一連の協調的細胞および分子相互作用は一般的に、種々の外的要因、例えば日和見感染および院内感染(例えば、感染のリスクを高めうる臨床レジメン)、抗生物質の局所もしくは全身投与(細胞の発育、遊走または他の機能に影響を及ぼす場合があり、抗生物質耐性微生物に向けて選択することもできる)、および/またはその他の要因により有害な影響を受ける場合がある。
抗微生物性、特に抗細菌特性を有する複数の天然産物(例えば、抗生物質)および合成化学薬品は、当該技術分野で公知であり、化学構造と、抗微生物効果、例えば微生物を殺傷する能力(殺菌性などの「殺傷」効果)、微生物の増殖を停止もしくは損傷する能力(静菌性などの「静止」効果)、あるいは微生物機能、例えば部位でのコロニー形成もしくは感染、細菌によるエキソポリサッカライド分泌、ならびに/またはプランクトン性集団からバイオフィルム集団への変換もしくはバイオフィルム形成の拡大などを妨害する能力と、により少なくとも一部が特徴づけられている。例えば殺菌または静菌能力、効果的濃度、および宿主組織への毒性のリスクなど、そのような組成物の選択および使用に影響を及ぼす因子を含む抗生物質、殺菌剤、消毒薬など(ビスマス-チオールまたはBT化合物を含む)は、例えば、U.S.6,582,719号で議論されている。
植物および農業産物の防御:関連技術分野の説明
種子および新芽上のバイオフィルム
切花および切断樹木
ec.europa.eu/health/ph_risk/committees/04_scenihr/docs/scenihr_o_016.pdf.参照)。
別の実施形態において、微粒子BT化合物を含む組成物が、経口使用のために配合され、口内の微生物発育を予防または低減するため、そして口腔の微生物感染および炎症を予防および/または処置するための方法において用いてもよい。それゆえこれらの組成物は、歯垢、口臭、歯周病、歯肉炎、および口の他の感染を予防または処置するのに(即ち、それらの発症を低下もしくは阻害する、また発生もしくは再発の尤度を低下させるのに)有用である。微粒子BT化合物を含む経口組成物は、バイオフィルムの発生を予防および/もしくは制御する(即ち、緩徐にする、遅延する、阻害する)、バイオフィルムを崩壊させる、または口内表面、詳細には歯もしくは歯茎上に存在するバイオフィルムの量を減少させるのにも有用となりうる。
抗微生物剤:例えば、クロルヘキシジン:サンギナリンエキス、メトロニダゾール、第四級アンモニウム化合物(例えば、セチルピリジニウムクロリド);ビスグアニド(例えば、クロルヘキシジンジグルコナート、ヘキセチジン、オクテニジン、アレキシジン);ハロゲン化ビスフェノール系化合物(例えば、2,2′-メチレンビス-(4-クロロ-6-ブロモフェノール)または他のフェノール系抗菌化合物;アルキルヒドロキシベンゾアート;陽イオン性抗微生物ペプチド;アミノグリコシド;キノロン;リンコサミド;ペニシリン:セファロスポリン;マクロリド;テトラサイクリン;当該技術分野で公知の他の抗生物質;コレウス・フォルスコリの精油;銀または銀コロイド抗微生物剤;スズまたは銅を基剤とする抗微生物剤;マヌカオイル;オレガノ;タイム;ローズマリー;または他のハーブエキス;およびグレープフルーツシードエキス。
抗炎症剤または抗酸化剤:例えば、イブプロフェン、フルルビプロフェン、アスピリン、インドメタシン、アロエベラ、ターメリック、オリーブリーフエキス、クローブ、パンテノール、レチノール、ω-3脂肪酸、γ-リノレン酸(GLA)、緑茶、生姜、グレープシードなど。虫歯予防剤:例えば、フッ化ナトリウムおよびフッ化第一スズ、フッ化アミン、モノフルオロリン酸ナトリウム、トリメタリン酸ナトリウム、クエン酸亜鉛または他の亜鉛剤、およびカゼイン。プラーク緩衝液:例えば、尿素、乳酸カルシウム、グリセロリン酸カルシウム、およびポリアクリル酸ストロンチウム。ビタミン:例えば、ビタミンA、CおよびE。植物エキス。脱感作剤:例えば、クエン酸カリウム、塩化カリウム、酒石酸カリウム、重炭酸カリウム、シュウ酸カリウム、硝酸カリウム、およびストロンチウム塩。歯石防止剤:例えば、アルカリ金属ピロリン酸塩、次亜リン酸塩含有ポリマー、有機ホスホン酸塩およびホスホクエン酸塩など。生体分子:例えば、バクテリオシン、バクテリオファージ、抗体、酵素など。着香剤:例えば、ペパーミントおよびスペアミントオイル、ウイキョウ、シナモンなど。タンパク質性材料:例えば、コラーゲン。防腐剤。不透明化剤。着色剤。pH調整剤。甘味剤。薬学的に許容しうる担体:例えば、デンプン、スクロース、水または水/アルコール系など。界面活性剤:例えば、陰イオン性、非イオン性、陽イオン性および双性イオン性または両性界面活性剤、植物材料由来のサポニン(例えば、米国特許第6,485,711号参照)。粒子研磨剤:例えば、シリカ、アルミナ、炭酸カルシウム、リン酸二カルシウム、ピロリン酸カルシウム、ヒドロキシアパタイト、トリメタリン酸塩、不溶性ヘキサメタリン酸塩、凝集粒子研磨剤、チョーク、微粉砕性天然チョークなど。保湿剤:例えば、グリセロール、ソルビトール、プロピレングリコール、キシリトール、ラクチトールなど。結合剤および増粘剤:例えば、カルボキシメチルセルロースナトリウム、ヒドロキシエチルセルロース(Natrosol(登録商標))、キサンタンガム、アラビアガム、合成ポリマー(例えば、ポリアクリラートおよびカルボキシビニルポリマー、例えばCarbopol(登録商標))。抗微生物剤などの有効成分の送達を向上させるポリマー化合物。オーラルケア組成物のpHおよびイオン強度を緩衝する緩衝剤および塩。漂白剤:例えば、ペルオキシ化合物(例えば、ペルオキシ二リン酸カリウム)。発泡系:例えば、重炭酸ナトリウム/クエン酸系。変色系。特定の実施形態において、研磨剤は、シリカまたは微粉砕天然チョークである。
参照)。
植物および農業製品の保護のためのビスマス-チオール
(この場合、前記BT組成物は、BT化合物を含む微粒子の実質的に単分散性の懸濁液を含み、前記微粒子は、約0.5μm~約10μmの体積平均直径を有する)、ならびに(b)植物とBT組成物とを接触するステップに関連して、同時的にまたは逐次的に、そして任意の順序で、植物を相乗性または増強性抗生物質と接触すること、を包含する方法が提供される。
ビスマス-チオール(BT)を基剤とする消毒薬
Biomacromolecules 2004;5:1219-30. Ouazzani K, Bentama J. Bio-fouling in membrane processes: micro-organism/surface interactions, hydrodynamic detachment method. Congres 2008;220:290-4. Ozdamar et al., Retina 1999;19:122-6. Piccirillo et al., J Mater Chem 2009;19:6167. Reunala et al., Curr Opin Allergy Clin Immunol 2004;4:397-401. Romo et al., Environ Progress 1999;18:107-12. Saha DC, Shahin S, Rackow EC, Astiz ME, Domenico P. 2000. Cytokine modulation by bismuth-ethanedithiol in experimental sepsis.10th Intl. Conf. Inflamm. Res. Assoc., Hot Springs, VA. Sawada et al., JPRAS 1990;43:78-82. Schultz, J Fluids Eng 2004;126:1039-47. Tiller JC, Hartmann L, Scherble J. Reloadable antimicrobial coatings based on amphiphilic silicone networks. Surface Coatings International Part B: Coatings Transactions 2005;88:1-82. Tsuneda et al., FEMS Microbiol Lett 2003;223:287-92. Vu et al., Molecules 2009;14:2535-54. Yan et al., Ophthalmologica 2008;222:245-8.
Yeo et al., Water Sci Technol 2007;55:35-42.
付加的参考文献(植物保護および関連文献を含む):Chandler et al., Antimicrob. Agents Chemother 1978;14:60-8. Choudhary et al., Microbiol Res 2009;164:493-513. Cooksey, Annu Rev Phytopathol 1990;28:201-14. Dill K, McGown EL. The biochemistry of arsenic, bismuth and antimony, h S. Patai (ed.), The chemistry of organic arsenic, antimony and bismuth compounds. John Wiley & Sons, New York, 1994, pp. 695-713. Domenico et al., 1996 J Antimicrob Chemother 38:1031-1040. Domenico et al., 2000 Infect Med 17:123-127. Dow et al., Proc Natl Acad Sci USA 2003;100:10995-1000. Dulla et al., PNAS 2008;105:3-082-7. Espinosa- Urgel et al., Microbiol 2002;148:341 -3. Expert, Annu Rev Phytopathol 1999;37:307-34. Ganguli et al., Smart Mater. Struct. 2009;18:104027. Huang et al., J Antimicrob Chemother 1999;44:601 -5. Hung et al., J Exptl Marine Biol Ecol 2008;361:36-41. Johnson et al., Annu Rev Phytopathol 1998;36:227-48. Kang et al., Mol Microbiol 2002; 46:427-37. Kavouras et al., Inverteb Biol 2005;122:138-51. Koczan et al., Phytopathol 2009;99:1237-44. Kumar et al., Nature Materials 2008;7:236-41. Marques et al., Phytopathol 2003;93:S57. McManus et al., Annu Rev Phytopathol 2002;40:443-65. Monier et al., Proc Natl Acad Sci USA 2003;100:15977-82. Norelli JL, Holleran HT, Johnson WC et al. Resistance of Geneva and other apple root- stocks to Erwinia amylovora. Plant Dis 87:26-32. Oh et al., FEMS Microbiology Lett 2005;253:185-192. Omoike et al., Biomacromolecules 2004;5:1219-30. Ramey et al., Curr Opinion Microbiol 2004;7:602-9. Salo et al., Infection 1995;23:371-7. Schultz et al., Biofouling 2007;23:331-41. Siboni et al., FEMS Microbiol Lett 2007;274:24-9. Sosnowski et al., Plant Pathol 2009;58:621-35. Tsuneda et al., FEMS Microbiol Lett 2003;223:287-92. von Bodman et al., Proc Natl Acad Sci USA 1998, 95:7687-7692. Vu et al., Molecules 2009;14:2535-54. Zaini et al., FEMS Microbiol LETT 2009;295:129-34
実施例1
BT化合物の調製
以下のBT化合物を、Domenico他(U.S RE37,793号、U.S.6,248,371号、同6,086,921号、同6,380,248号)の方法により、またはBisEDTに関して以下に記載された合成プロトコルによる微粒子として、調製した。示されているのは、硫黄含有化合物と三価錯体を形成するのに用いられた反応体の理論比およびビスマスの公知の性向に基づく、比較としての、単一ビスマス原子に対する原子比である。カッコ内の数値は、1種の(または数種の)チオール剤に対するビスマスの比である(例えば、Bi:チオール1/チオール2;表1も参照)。
1)CPD 1B-1 Bis-EDT(1:1) BiC2H4S2
2)CPD 1B-2 Bis-EDT(1:1.5) BiC3H6S3
3)CPD 1B-3 Bis-EDT(1:1.5) BiC3H6S3
4)CPD 1C Bis-EDT(可溶性Bi調製物)(1:1.5) BiC3H6S3
5)CPD 2A Bis-Bal(1:1) BiC3H6S2O
6)CPD 2B Bis-Bal(1:1.5) BiC4.5H9O1.5S3
7)CPD 3A Bis-Pyr(1:1.5) BiC7.5H6N1.5O1.5S1.5
8)CPD 3B Bis-Pyr(1:3) BiC15H12N3O3S3
9)CPD 4 Bis-Ery(1:1.5) BiC6H12O3S3
10)CPD 5 Bis-Tol(1:1.5) BiC10.5H9S3
11)CPD 6 Bis-BDT(1:1.5) BiC6H12S3
12)CPD 7 Bis-PDT(1:1.5) BiC4.5H9S3
13)CPD 8-1 Bis-Pyr/BDT(1:1/1)
14)CPD 8-2 Bis-Pyr/BDT(1:1/0.5)
15)CPD 9 Bis-2ヒドロキシ,プロパンチオール(1:3)
16)CPD 10 Bis-Pyr/Bal(1:1/0.5)
17)CPD 11 Bis-Pyr/EDT(1:1/0.5)
18)CPD 12 Bis-Pyr/Tol(1:1/0.5)
19)CPD 13 Bis-Pyr/PDT(1:1/0.5)
20)CPD 14 Bis-Pyr/Ery(1:1/0.5)
21)CPD 15 Bis-EDT/2ヒドロキシ,プロパンチオール(1:1/1)
慢性創傷感染のコロニーバイオフィルムモデル:BT化合物による阻害
慢性創傷内に存在する細菌は、バイオフィルムのライフスタイルを採り入れるため、本質的には記載された方法に従って(Anderl et al., 2003 Antimicrob Agents Chemother 47:1251-56; Walters et al., 2003 Antimicrob Agents Chemother 47:317; Wentland et al., 1996 Biotchnol. Prog. 12:316; Zheng et al., 2002 Antimicrob Agents Chemother 46:900)、調製されたバイオフィルムを用いて、細菌細胞生存に対する効果について、BTをバイオフィルムに対して検査した。
慢性創傷感染のドリップフローバイオフィルムモデル
BT化合物による阻害
ドリップフローバイオフィルムは、細菌バイオフィルムを形成させて、それに対して候補となる抗菌化合物の効果を検査するための公認の信頼性のあるモデルである。ドリップフローバイオフィルムは、ドリップフローリアクターの溝に入れたクーポン(基質)上に生成する。すりガラス顕微鏡スライドなど、多くの異なるタイプの材料を、細菌バイオフィルム形成用の基板として用いることができる。栄養性液体培地をドリップフローバイオリアクターの細胞チャンバーに上部付近で滴加することにより、培地をチャンバーに入れ、その後、クーポンの長さに10℃の傾斜で流す。
創傷バイオフィルムによる、角化細胞の掻き傷修復の阻害:BT化合物によるバイオフィルム抑制
この実施例は、創傷治癒の確立されたインビトロ角化細胞掻き傷モデルを改変して、バイオフィルム関連の創傷病理および創傷治癒への関連性、詳細には急性もしくは慢性創傷または本明細書に記載された創傷含有バイオフィルムへの関連性を有するモデルへ到達することを記載している。慢性創傷バイオフィルムの効果についての角化細胞掻き傷モデルにより、ホ乳類(例えばヒト)角化細胞および細菌バイオフィルム集団の培養を、互いに流動接触している別個のチャンバー内で進行させて、バイオフィルムにより同化された可溶性成分の、角化細胞創傷治癒事象に対する効果に影響を及ぼす条件の効果の評価を可能にする。
創傷バイオフィルムによる、角化細胞の掻き傷修復の阻害
単離されたヒト角化細胞を、ガラスカバースリップ上で培養して、先の実施例4に記載された方法論に従って掻き傷を作製した。創傷された培養物を、角化細胞培養物と流体連通している膜支持体上で、培養条件下、単独で、または共培養されたバイオフィルムの存在下で保持した。その後、角化細胞の細胞発育および/または遊走が掻き傷のゾーン全体で角化細胞単層を再度定着させる間の掻き傷閉鎖の時間間隔を、測定した。図3は、バイオフィルムの流体連通による(しかし直接接触していない)存在が引っ掻かれた角化細胞単層の治癒時間に与えた効果を示している。
相乗的なビスマス-チオール(BT)抗生物質の組み合わせ
この実施例は、1種以上のビスマス-チオール化合物と、複数の抗生物質耐性菌など様々な菌種および菌株に対する1種以上の抗生物質との組み合わせによる、実証された相乗的効果の例を示す。
抗生物質耐性菌株を含むグラム陽性およびグラム陰性菌に対するビスマス-チオール(BT)および抗生物質の効果の比較
この実施例において、BisEDTおよび比較剤のインビトロ活性を、皮膚および軟部組織感染を担うグラム陽性および陰性菌の複数の臨床単離物に対して評価した。
微粒子BT-抗生物質の増強および相乗活性
この実施例は、微粒子ビスマス-チオール(BT)が、増強的および/または相乗的相互作用を通して抗生物質活性を促進することを示している。
Domenico P, R O′Leary, BA Cunha. 1992. Differential effect of bismuth and salicylate compounds on antibiotic sensitivity of Pseudomanas aeruginosa. Eur J Clin Microbiol Infec Dis 11:170-175; Domenico P, D Parikh, BA Cunha. 1994. Bismuth modulation of antibiotic activity against gastrointestinal bacterial pathogens. Med Microbiol Lett 3:114-119; Domenico P, Kazzaz JA, Davis JM, Niederman MS.2002. Subinhibitory bismuth ethanedithiol(BisEDT)sensitizes resistant Staphylococcus aureus to nafcillin or gentamicin. Annual Meeting, ASM, Salt Lake City, UT; Domenico P, Kazzaz JA, Davis JM. 2003. Combating antibiotic resistance with bismuth-thiol. Research Advances in Antimicrob Agents Chemother 3:79-85; Domenico P, E Gurzenda, A Giacometti, O Cirioni, R Ghiselli, F Orland, M Korem, V Saba, G Scalise, N Balaban. 2004. BisEDT and RIP act in synergy to prevent graft infections by resistant staphylococci. Peptides 25:2047-2053; Halwani M, Blomme S, Suntres ZE, Alipour M, Azghani AO, Kumar A, Omri A. 2008. Liposomal bismuth-ethanedithiol formulation enhances antimicrobial activity of tobramycin. Intl J Pharmaceut 358:278-84;Halwani M, Hebert S, Suntres ZE, Lafrenie RM, Azghani AO, Omri A. 2009. Bismuth-thiol incorporation enhances biological activities of liposomal tobramycin against bacterial biofilm and quorum sensing molecules production by Pseudomonas aeruginosa. Int J Pharmaceut 373:141-6; Veloira WG, Gurzenda EM, Domenico P, Davis JM, Kazzaz JA. 2003. Synergy of tobramycin and bismuth thiols against Burkholderia cepacia. J Antimicrob Chemother 52:915-919.
微粒子BT-抗生物質の増強および相乗活性
この実施例は、微粒子ビスマスチオールであるBisEDTが、特異的な微生物標的生物体に対する特異的抗生物質との増強的および/または相乗的相互作用を通して抗生物質活性を促進することを示す。表26に示された各組み合わせの一点データは、本質的には実施例8で用いられた方法に従って作成した。
微粒子BT-抗生物質の増強および相乗活性
先に記載された通り調製された微粒子BisEDTおよび4種のBisEDT類似体と他の薬剤との組み合わせの、複数のグラム陰性病原菌の代表的菌株に対する効果を検査した。一般的検査法の変法を利用して、用いられた部分阻止濃度(FIC)およびFIC指数(FICI)の相乗性(FICI≦0.5)、増強性(0.5<FICI≦1.0)、拮抗性(FICI>4.0)および重要性なし(1.0<FICI≦4.0)を決定した(V Lorian. Williams and Wikins, Baltimore, MDにより編集されたAntibiotics in Laboratory Medicine, Third Edition, pp.432-492内のElipoulos G and R Moellering. 1991. Antimicrobial combinations.; Odds, 2003 J. Antimicrob. Chemother. 52(1):1)。チェッカーボード技術を用いて、FIC指数を決定し、この試験に用いた。
ドブネズミの大腿骨臨界欠損における感染へのビスマス-チオールの効果
開放骨折のための現行のケア標準法は、イリゲーション、壊死組織除去および抗生物質であり、これは、創傷における細菌量を感染が生じない程度に減少させることを意図するものである。これらの処置にもかかわらず、感染は、戦争による重度の脛骨開放骨折の最大75%を複雑化させる。興味深いことに、初期感染が、多くの場合グラム陰性菌により起こるとしても、治癒問題および切断に関与する後期感染は、グラム陽性菌感染、多くはスタフィロコッカス種によるものである(Johnson 2007)。
黄色ブドウ球菌の接種後6時間目に、創傷の壊死組織を除去して、生理食塩水でイリゲーションし、BTゲル 1mlを欠損内に挿入した。
黄色ブドウ球菌の接種後6時間目に、創傷の壊死組織除を除去して、生理食塩水でイリゲーションし、添加されたBTゲル 1mlを欠損内に挿入した。用いられた抗生物質は、損傷後合計3日間に1日2回の皮下注射により送達された5mgkg-1と等しい用量のセファゾリンであった。最初の用量は、壊死組織除去の直前に投与した。過去のデータから、この用量が細菌レベルを約106から約104へ低減し、それゆえ異なるBTの相対的効果を測定する可能性が示唆された。
黄色ブドウ球菌の接種後6時間目に、創傷の壊死組織を除去して、生理食塩水でイリゲーションした。対照動物は、先に記載されたレジメンによりセファゾリンでも処置した。
インビボラット損傷モデルの手順を、Chen他により記載された通り実施した(2002 J. Orthop. Res.20:142;2005 J. Orthop. Res. 23:816;2006 J. Bone Joint Surg. Am. 88:1510; 2007 J. Orthop. Trauma 21:693)。ラットに麻酔をかけて、手術の準備をした。大腿骨骨幹部の前外側面を、3cm切開して暴露させた。骨膜および付着した筋肉を、骨から剥離させた。ポリアセチルプレート(27×4×4mm)を大腿骨の前外側表面に配置した。プレートをプレドリルして、0.9mm径のねじれたキルシュナーワイヤを通した。これらのプレートの基板は、大腿骨骨幹部の輪郭に適合するようにかたどった。プレートを鋳型として用いて両方の大腿皮質骨を通して、パイロットホールを削り、プレートおよび大腿骨を通してねじれたキルシュナーワイヤを挿入した。プレート上の6mm間隔に存在するくぼみが、骨の除去のためのガイドになった。熱による損傷を予防する試みとして、組織を継続的なイリゲーションにより冷却しながら、小型の振動鋸を用いて欠損を作製した。
実施例12
海洋生物に対するビスマス含有化合物の活性
フジツボ着生行動に及ぼすビスマス含有化合物の作用
実施例14
藻類の着生に及ぼすビスマス含有化合物の作用
実施例15
藻類の着生に及ぼすビスマス含有化合物の作用
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Claims (17)
- バイオフィルム形成に感受性のある細菌感染を有するリスクのあった、または前記細菌感染を有するリスクのある、開放型創傷、慢性創傷、または急性創傷において、前記細菌感染に基づくバイオフィルム形成を除去、低減、または阻害するための医薬の製造における、ビスマスチオール(BT)組成物の使用であって、
前記BT組成物が、0.4μmないし5μmの体積平均直径を有するビスマス-エタンジチオール(BisEDT)の固体微粒子の単分散懸濁液を含有する、使用。 - 前記開放型創傷、慢性創傷、または急性創傷が、開放型創傷である、請求項1に記載の使用。
- 前記開放型創傷が、開放骨折を含む、請求項2に記載の使用。
- 前記開放型創傷、慢性創傷、または急性創傷が、慢性創傷である、請求項1に記載の使用。
- 前記開放型創傷、慢性創傷、または急性創傷が、急性創傷である、請求項1に記載の使用。
- 前記開放型創傷、慢性創傷、または急性創傷が、(i)天然表面、または(ii)天然表面および人工表面を含む、請求項1ないし5のいずれか1項に記載の使用。
- 前記医薬が骨セメントである、請求項1または3のいずれか1項に記載の使用。
- 前記組成物がヒドロゲルを含有する、請求項7に記載の使用。
- 前記ヒドロゲルがポリメチルメタクリレート(PMMA)を含有する、請求項8に記載の使用。
- 前記細菌感染が、以下項目(i)ないし(v)のうち少なくとも1つを含む、請求項1に記載の使用:
(i)1種以上のグラム陰性菌;
(ii)1種以上のグラム陽性菌;
(iii)1種以上の抗生物質感受性細菌;
(iv)1種以上の抗生物質耐性細菌;および
(v)スタフィロコッカス・アウレウス(黄色ブドウ球菌)、MRSA(メチシリン耐性黄色ブドウ球菌)、スタフィロコッカス・エピデルミディス、MRSE(メチシリン耐性S.エピデルミディス)、マイコバクテリウム・ツベルクローシス、マイコバクテリウム・アビウム、シュードモナス・エルギノーサ、薬物耐性緑膿菌、大腸菌、腸管毒素原性大腸菌、腸管出血性大腸菌、クレブシエラ・ニューモニエ、クロストリジウム・ディフィシル、ヘリコバクター・ピロリ、レジオネラ・ニューモフィラ、エンテロコッカス・フェカーリス、メチシリン感受性エンテロコッカス・フェカーリス、エンテロバクター・クロアカエ、サルモネラ・ティフィムリウム、プロテウス・ブルガリス、エルシニア・エンテロコリチカ、ビブリオ・コレレ、シゲラ・フレクスネリ、バンコマイシン耐性エンテロコッカス(VRE)、フランシセラ・ツラレンシス、バチルス・アントラシス、エルシニア・ペスチス、シュードモナス・エルギノーサ、ストレプトコッカス・ニューモニエ、ペニシリン耐性ストレプトコッカス・ニューモニエ、バークホルデリア・セパシア、バークホルデリア・マルチボランス、マイコバクテリウム・スメグマチスおよびアシネトバクター・バウマニーから選択される細菌病原体。 - 細菌性病原体から製品を保護するための医薬の製造におけるビスマスチオール(BT)組成物の使用であって、
前記医薬は、以下(i)ないし(iv)のうち1つ以上のための十分な条件または時間で、前記製品の表面と有効量の前記BT組成物が接触する際、または前記製品に組込む際に使用され、
(i)細菌性病原体による製品の感染の予防、
(ii)細性病原体の実質的に全てのプランクトン性細胞の細胞生存性または細胞増殖の阻害、
(iii)細菌性病原体によるバイオフィルム形成の阻害、および
(iv)細菌性病原体の実質的に全てのバイオフィルム型細胞のバイオフィルム生存性またはバイオフィルム成長の阻害、
ここで、前記BT組成物が、0.4μmないし5μmの体積平均直径を有するビスマス-エタンジチオール(BisEDT)の固体微粒子の単分散懸濁液を備え、かつ前記医薬と前記製品の表面を接触させること、または前記製品に前記医薬を組込むことが、生体外で実行されることを特徴とし、
前記製品の表面が、(i)医療用装置または医療用インプラント上に存在するか、または(ii)歯科用装置または歯科用インプラント上に存在することを特徴とする、使用。 - 前記医療用装置または前記医療用インプラントが人工骨、人工関節、カテーテル、ステント、栄養チューブ、または胃瘻用チューブである、請求項11に記載の使用。
- 前記製品が、セメント表面、コンクリート表面、ゴム表面、シリコン表面、プラスチック表面、塗料表面、または被覆表面を備える、請求項11に記載の使用。
- 前記製品が、細菌性病原体から保護され、
前記製品が、人工骨または人工関節を備え、かつ
前記BT組成物が、骨セメントをさらに含有する、
請求項11に記載の使用。 - 前記組成物がヒドロゲルを含有する、請求項14に記載の使用。
- 前記ヒドロゲルがポリメチルメタクリレートを含有する、請求項15に記載の使用。
- 前記微粒子が、摩砕されず、または超臨界流体プロセシングを受けないことを特徴とする、請求項1ないし16のいずれか1項に記載の使用。
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