JP6041811B2 - 細菌由来の感染症を治療する抗細菌剤 - Google Patents
細菌由来の感染症を治療する抗細菌剤 Download PDFInfo
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- JP6041811B2 JP6041811B2 JP2013547373A JP2013547373A JP6041811B2 JP 6041811 B2 JP6041811 B2 JP 6041811B2 JP 2013547373 A JP2013547373 A JP 2013547373A JP 2013547373 A JP2013547373 A JP 2013547373A JP 6041811 B2 JP6041811 B2 JP 6041811B2
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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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
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- 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
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Description
ヨウ素 6〜10
ヨウ化カリウム 9〜15
合成水溶性ポリマー 2〜4
天然ポリマー(多糖)、単糖及びオリゴ糖 8〜120
水 残部
で含有する、殺菌及び殺ウイルス活性を有する既知の薬剤ヨドミドール(Yodomidol)が存在する(KZ6730B、1998年11月16日)。この薬剤の欠点は、その相対的に高い毒性である。
ヨウ素 0.8〜25
ヨウ化カリウム 1.2〜38
塩化リチウム 0.1〜20
合成水溶性ポリマー 0.01〜6
単糖、オリゴ糖及び多糖 8〜400
水 残部
で含有する、抗ウイルス活性を有する既知の殺ウイルス性医薬品が存在する(EP0978289A1、2000年9月2日)。
タンパク質及び/又はハロゲン化タンパク質のプール 0.01〜200
炭水化物及び/又は炭水化物のハロゲン誘導体 0.01〜450
合成水溶性ポリマー 0.01〜100
塩化リチウム 0.01〜200
ヨウ化カリウム又はナトリウム 0.01〜300
ヨウ素 0.01〜200
水又は生理食塩水 1Lになる量
で含有する、結核、ブルセラ病、ペスト、肝炎、HIVを含む単一菌及び混合感染の予防及び治療のための既知の殺菌及び殺ウイルス性医薬品が存在する(KZ15116A、2004年12月15日)。
a)潜在的な製剤では、充填剤、特に発熱物質不含の水、緩衝剤又は通常生理食塩水;
b)軟膏剤、クリーム剤、エアゾール剤では、媒質、特に植物又は合成油、ラノリン、ペトロラタム又は高分子アルコール;
c)錠剤又はカプセル剤では、希釈剤、特にラクトース、結合剤、潤滑物質(例えば、ステアリン酸)並びに分解生成物(例えば、トウモロコシデンプン)
を含むことができる。
本願発明は以下のとおりである。
[発明1]
院内感染及び薬剤耐性TBを含む細菌感染疾患を治療するための、タンパク質及び/又はポリペプチド、炭水化物、アルカリ及びアルカリ土類金属塩と、それらに挿入されたヨウ素から形成されるイオンナノ構造複合体を表し、イオンナノ構造複合体のタンパク質及び/又はポリペプチドが、電子供与体官能基を有する少なくとも1つの鎖末端アミノ酸を含有することを特徴とする、抗細菌剤。
[発明2]
インターロイキンがタンパク質として使用され、鎖末端アミノ酸が、Phe、Ala、Val、Ala、Leu、Ileなどであることを特徴とする、発明1に記載の抗細菌剤。
[発明3]
抗微生物剤が、抗生物質耐性細菌を含めた、細菌の抗生物質に対する感受性を増加することを特徴とする、発明1又は2に記載の抗細菌剤。
[発明4]
院内感染及び薬剤耐性TBを含む細菌感染疾患の抗生物質治療の効率を増加することを特徴とする、発明1、4に記載の抗細菌剤。
[発明5]
抗ウイルス作用を有することを特徴とする、発明1から5までのいずれか一に記載の抗細菌剤。
[発明6]
免疫原活性を有し、単球−マクロファージ及び細胞毒性Tリンパ球の活性を増加することを特徴とする、発明1から6までのいずれか一に記載の抗細菌剤。
[発明7]
骨髄の造血機能を刺激することを特徴とする、発明1から5までのいずれか一に記載の抗細菌剤。
[発明8]
抗新生物質作用を有することを特徴とする、発明1から5までのいずれか一に記載の抗細菌剤。
[発明9]
放射線防護特性を有することを特徴とする、発明1から5までのいずれか一に記載の抗細菌剤。
[発明10]
INSCが以下の式:[{(Ln(MeI3)+)y[Me(Lm)I]+x}(Cl−)y+x+k]を有し、M=30〜300kDaであることを特徴とする、発明1から6までのいずれか一に記載の抗細菌剤。
[発明11]
非経口、経口、外用又は他の適用に適した医薬形態で提示されることを特徴とする、発明1から5までのいずれか一に記載の抗細菌剤。
[発明12]
特定の許容される濃度の成分において非薬剤であることを特徴とする、発明1から5までのいずれか一に記載の抗細菌剤。
[発明13]
炭水化物及びタンパク質と金属塩の複合体形成反応、並びにイオン強度5・10−4〜15での複合体へのヨウ素の挿入を含み、イムノトロピックタンパク質の導入が5〜95%のヨウ素挿入後の個別の段階で実施されることを特徴とする、発明1に記載の抗細菌剤の生成方法。
また、以下を特許請求する。
[発明1a]
院内感染及び薬剤耐性TBを含む細菌感染疾患を治療するための、タンパク質及び/又はポリペプチド、炭水化物、アルカリ及びアルカリ土類金属塩と、それらに挿入されたヨウ素から形成されるイオンナノ構造複合体を表し、イオンナノ構造複合体のタンパク質及び/又はポリペプチドが、電子供与体官能基を有する少なくとも1つの鎖末端アミノ酸を含有することを特徴とする、抗細菌剤。
[発明2a]
インターロイキンがタンパク質として使用され、鎖末端アミノ酸が、Phe、Ala、Val、Ala、Leu、Ileなどであることを特徴とする、発明1aに記載の抗細菌剤。
[発明3a]
抗微生物剤が、抗生物質耐性細菌を含めた、細菌の抗生物質に対する感受性を増加することを特徴とする、発明1a又は2aに記載の抗細菌剤。
[発明4a]
院内感染及び薬剤耐性TBを含む細菌感染疾患の抗生物質治療の効率を増加することを特徴とする、発明1aから3aまでのいずれか一に記載の抗細菌剤。
[発明5a]
抗ウイルス作用を有することを特徴とする、発明1aから4aまでのいずれか一に記載の抗細菌剤。
[発明6a]
免疫原活性を有し、単球−マクロファージ及び細胞毒性Tリンパ球の活性を増加することを特徴とする、発明1aから5aまでのいずれか一に記載の抗細菌剤。
[発明7a]
骨髄の造血機能を刺激することを特徴とする、発明1aから5aまでのいずれか一に記載の抗細菌剤。
[発明8a]
抗新生物質作用を有することを特徴とする、発明1aから5aまでのいずれか一に記載の抗細菌剤。
[発明9a]
放射線防護特性を有することを特徴とする、発明1aから5aまでのいずれか一に記載の抗細菌剤。
[発明10a]
INSCが以下の式:[{(Ln(MeI3)+)y[Me(Lm)I]+x}(Cl−)y+x+k]を有し、M=30〜300kDaであることを特徴とする、発明1aから6aまでのいずれか一に記載の抗細菌剤。
[発明11a]
非経口、経口、外用又は他の適用に適した医薬形態で提示されることを特徴とする、発明1aから5aまでのいずれか一に記載の抗細菌剤。
[発明12a]
特定の許容される濃度の成分において非薬剤であることを特徴とする、発明1aから5aまでのいずれか一に記載の抗細菌剤。
[発明13a]
炭水化物及びタンパク質と金属塩の複合体形成反応、並びにイオン強度5・10−4〜15での複合体へのヨウ素の挿入を含み、イムノトロピックタンパク質の導入が5〜95%のヨウ素挿入後の個別の段階で実施されることを特徴とする、発明1aに記載の抗細菌剤の生成方法。
また、以下も本願発明である。
[発明1b]
院内感染及び薬剤耐性結核を含む細菌感染疾患を治療するための、タンパク質及び/又はポリペプチド、炭水化物、アルカリ金属、マグネシウム及びアルカリ土類金属の塩と、それらに挿入されたヨウ素から形成されるイオンナノ構造複合体を表し、イオンナノ構造複合体のタンパク質及び/又はポリペプチドが、Phe、Ala、Val、Leu、Ileからなる群から選択される少なくとも1つの鎖末端アミノ酸を含有することを特徴とする、抗細菌剤。
[発明2b]
タンパク質がインターロイキンである、発明1bに記載の抗細菌剤。
[発明3b]
抗細菌剤が、抗生物質耐性細菌を含めた、細菌の抗生物質に対する感受性を増加することを特徴とする、発明1b又は2bに記載の抗細菌剤。
[発明4b]
院内感染及び薬剤耐性結核を含む細菌感染疾患の抗生物質治療の効率を増加することを特徴とする、発明1bから3bまでのいずれか一項に記載の抗細菌剤。
[発明5b]
抗ウイルス作用を有することを特徴とする、発明1bから4bまでのいずれか一項に記載の抗細菌剤。
[発明6b]
免疫原活性を有し、単球−マクロファージ及び細胞毒性Tリンパ球の活性を増加することを特徴とする、発明1bから5bまでのいずれか一項に記載の抗細菌剤。
[発明7b]
骨髄の造血機能を刺激することを特徴とする、発明1bから5bまでのいずれか一項に記載の抗細菌剤。
[発明8b]
抗新生物質作用を有することを特徴とする、発明1bから5bまでのいずれか一項に記載の抗細菌剤。
[発明9b]
放射線防護特性を有することを特徴とする、発明1bから5bまでのいずれか一項に記載の抗細菌剤。
[発明10b]
非経口、経口、外用又は他の適用に適した医薬形態で提示されることを特徴とする、発明1bから5bまでのいずれか一項に記載の抗細菌剤。
[発明11b]
組成物による、許容される濃度において非薬剤としての、発明1bから5bまでのいずれか一項に記載の抗細菌剤の使用。
[発明12b]
炭水化物及びタンパク質とアルカリ金属、マグネシウム及びアルカリ土類金属の塩との複合体形成反応、並びにイオン強度5・10 −4 〜15での複合体へのヨウ素の挿入を含み、Phe、Ala、Val、Leu、Ileからなる群から選択される少なくとも1つの鎖末端アミノ酸を含有するイムノトロピックタンパク質の導入が5〜95%のヨウ素挿入後の個別の段階で実施されることを特徴とする、院内感染及び薬剤耐性結核を含む細菌感染疾患を治療するための抗細菌剤の生成方法。
上記から続けると、本発明によると、抗細菌剤組成物における免疫原性タンパク質の特性の保存を確実にするため、調製方法には複合体形成の第3及び第4の段階が補足される。
ΔE=E(複合体)−(E(LiCl)+E(エタノール)+E(アミド又はイミダゾール)
ΔE=E1(複合体)−(E2+E3) (9)
ここで、E1は総複合体エネルギーであり、E2は総LiClOHC2H5エネルギーであり、E3は、アミノ酸残基とのI2複合体の総エネルギーである。
炭水化物試料を、水、ジオキサン他などの適切な溶媒に溶解する。この溶液において、複合化合物を得るために、金属塩及び塩化ナトリウムの特定の試料を加えて、適切なイオン強度の溶液を生じる(生成物A)。
ABA合成を、実験室用反応器D−55122 Mainz、RuhrgefaB 2L型、QVF ENGINEERING GMBHにおいて一定の撹拌の後に実施する。温度を、サーモスタット「HUBER」−Ministat 230 CC2の使用により維持する。130gの炭水化物を500mlの水に50℃で溶解する。更に、100mlの水に溶解した3.0gの塩化ナトリウム及び1.98mgの塩化カルシウムを加える。混合物を十分に撹拌し、43℃に冷却する(生成物A)。
分析結果:
[5280L1・1.5L2・33I2]・L3
ABA合成を、実験室用反応器D−55122 Mainz、RuhrgefaB 2L型、QVF ENGINEERING GMBHにおいて一定の撹拌の後に実施する。108.3gのデキストランを500mlの水に45℃で溶解する。温度を、サーモスタット「HUBER」−Ministat 230 CC2の使用により維持する。更に、150mlの水に溶解した2.5gのPVA、100mlの水に溶解した4.0gの塩化ナトリウム及び1.65gの塩化カルシウムを加える。混合物を十分に撹拌し、43℃に冷却する(生成物A)。
分析結果:
[38L1・1.5L2・97I2]・L3
ABA合成を、実験室用反応器D−55122 Mainz、RuhrgefaB 2L型、QVF ENGINEERING GMBHにおいて一定の撹拌の後に実施する。72.0gの炭水化物を600mlの水に60℃で加水分解する。温度を、サーモスタット「HUBER」−Ministat 230 CC2の使用により維持する。更に、100mlの水に溶解した1.7gのPVA、100mlの水に溶解した2.8gの塩化ナトリウム及び1.1gの塩化カルシウムを注ぐ。混合物を十分に撹拌し、43℃に冷却する(生成物A)。
分析結果:
[611L1・24L2・294I2]・L3
ABA合成を、実験室用反応器D−55122 Mainz、RuhrgefaB 2L型、QVF ENGINEERING GMBHにおいて一定の撹拌の後に実施する。72.0gの炭水化物を550mlの水に100℃で加水分解する。温度を、サーモスタット「HUBER」−Ministat 230 CC2の使用により維持する。更に、250mlの水に溶解した1.7gのPVAを注ぐ(生成物A)。混合物を20分間十分に撹拌し、その後、反応領域の温度を25℃に低減する。
分析結果:
[37L1・294I2]・L3
ABA合成を、実験室用反応器D−55122 Mainz、RuhrgefaB 2L型、QVF ENGINEERING GMBHにおいて一定の撹拌の後に実施する。アミラーゼとアミロペクチンの1:4の比の130gの混合物を、500mlの水に43℃で溶解する。温度を、サーモスタット「HUBER」−Ministat 230 CC2の使用により維持する。更に、150mlの水に溶解した3.0gのPVA、100mlの水に溶解した4.5gの塩化ナトリウム及び2.0gの塩化カルシウムを注ぐ(生成物A)。
分析結果:
[38L1・2L2・333I2]・L3
ABA合成を、実験室用反応器D−55122 Mainz、RuhrgefaB 2L型、QVF ENGINEERING GMBHにおいて一定の撹拌の後に実施する。24.1gの炭水化物を、特定のモル重量に達するまで500mlの水に80℃で加水分解する。温度を、サーモスタット「HUBER」−Ministat 230 CC2の使用により維持する。更に、150mlの水に溶解した2.8gのPVAを注ぐ。混合物を十分に撹拌し、43℃に冷却する(生成物A)。
分析結果:
[8L1・1488I2]・L3
ABA合成を、実験室用反応器D−55122 Mainz、RuhrgefaB 2L型、QVF ENGINEERING GMBHにおいて一定の撹拌の後に実施する。24.1gの炭水化物を、特定のモル重量に達するまで500mlの水に100℃で加水分解する。温度を、サーモスタット「HUBER」−Ministat 230 CC2の使用により維持する。更に、150mlの水に溶解した2.8gのPVA、100mlの水に溶解した0.8gの塩化ナトリウム及び0.37gの塩化カルシウムを注ぐ。混合物を十分に撹拌し、43℃に冷却する(生成物A)。
分析結果:
[26L1・L2・4970I2]・3L3
ABA合成を、実験室用反応器D−55122 Mainz、RuhrgefaB 2L型、QVF ENGINEERING GMBHにおいて一定の撹拌の後に実施する。130.0gのデキストリン及び3.0gのPVAを500mlの水に50℃で溶解する。温度を、サーモスタット「HUBER」−Ministat 230 CC2の使用により維持する。更に、100mlの水に溶解した4.0gの塩化ナトリウム及び2.0gの塩化カルシウムを注ぐ。混合物を十分に撹拌し、43℃に冷却する(生成物A)。
分析結果:
[79L1・3L2・Il−2・684I2]・2L3
ABA合成を、実験室用反応器D−55122 Mainz、RuhrgefaB 2L型、QVF ENGINEERING GMBHにおいて一定の撹拌の後に実施する。13.1gの炭水化物を100mlの水に130℃で加水分解する。温度を、サーモスタット「HUBER」−Ministat 230 CC2の使用により維持する。更に、150mlの水に溶解した3.0gのPVA、100mlの水に溶解した0.3gの塩化ナトリウム及び0.2gの塩化カルシウムを注ぐ(生成物A)。混合物を十分に撹拌し、43℃に冷却する。
分析結果:
[25L1・L2・19575I2]・7L3
Claims (12)
- 院内感染及び薬剤耐性結核を含む細菌感染疾患を治療するための、タンパク質及び/又はポリペプチド、炭水化物、アルカリ金属、マグネシウム及びアルカリ土類金属の塩と、それらに挿入されたヨウ素から形成されるイオンナノ構造複合体を表し、イオンナノ構造複合体のタンパク質及び/又はポリペプチドが、Phe、Ala、Val、Leu、Ileからなる群から選択される少なくとも1つの鎖末端アミノ酸を含有することを特徴とする、抗細菌剤。
- タンパク質がインターロイキンである、請求項1に記載の抗細菌剤。
- 抗細菌剤が、抗生物質耐性細菌を含めた、細菌の抗生物質に対する感受性を増加することを特徴とする、請求項1又は2に記載の抗細菌剤。
- 院内感染及び薬剤耐性結核を含む細菌感染疾患の抗生物質治療の効率を増加することを特徴とする、請求項1から3までのいずれか一項に記載の抗細菌剤。
- 抗ウイルス作用を有することを特徴とする、請求項1から4までのいずれか一項に記載の抗細菌剤。
- 免疫原活性を有し、単球−マクロファージ及び細胞毒性Tリンパ球の活性を増加することを特徴とする、請求項1から5までのいずれか一項に記載の抗細菌剤。
- 骨髄の造血機能を刺激することを特徴とする、請求項1から5までのいずれか一項に記載の抗細菌剤。
- 抗新生物質作用を有することを特徴とする、請求項1から5までのいずれか一項に記載の抗細菌剤。
- 放射線防護特性を有することを特徴とする、請求項1から5までのいずれか一項に記載の抗細菌剤。
- 非経口、経口、外用又は他の適用に適した医薬形態で提示されることを特徴とする、請求項1から5までのいずれか一項に記載の抗細菌剤。
- 許容される濃度の、請求項1から5までのいずれか一項に記載の抗細菌剤を含む非医薬組成物の製造のための、前記抗細菌剤の使用。
- 炭水化物及びタンパク質とアルカリ金属、マグネシウム及びアルカリ土類金属の塩との複合体形成反応、並びにイオン強度5・10−4〜15での複合体へのヨウ素の挿入を含み、当該タンパク質は、Phe、Ala、Val、Leu、Ileからなる群から選択される少なくとも1つの鎖末端アミノ酸を含有するイムノトロピックタンパク質を含み、当該タンパク質の導入が5〜95%のヨウ素挿入後の個別の段階で実施されることを特徴とする、院内感染及び薬剤耐性結核を含む細菌感染疾患を治療するための抗細菌剤の生成方法。
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KZ2010/1816.1 | 2010-12-30 | ||
KZ20101816 | 2010-12-30 | ||
PCT/KZ2011/000019 WO2012091534A1 (ru) | 2010-12-30 | 2011-12-09 | Антибактериальный агент для лечения инфекционных заболеваний бактериальной природы |
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CN114634762A (zh) * | 2022-03-17 | 2022-06-17 | 东莞市人民医院 | 金属离子介导的蛋白质涂层、其制备方法及其应用 |
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CN1066979A (zh) * | 1991-05-20 | 1992-12-16 | 中国人民解放军军事医学科学院微生物流行病研究所 | 烧伤创面抗菌制剂的制备方法 |
US6777003B1 (en) | 1995-06-07 | 2004-08-17 | Cognis Corporation | Iodine complex of alkyl polyglycosides |
KZ6730B (ja) | 1996-01-26 | 1998-11-16 | ||
HUP0102892A3 (en) | 1998-05-27 | 2002-12-28 | Euro Celtique Sa | Drug delivery system comprising a tightly compacted solid medicament stock, process for its preparation and for its use |
CZ295765B6 (cs) | 1998-07-29 | 2005-10-12 | Apa - Praha, S.R.O. | Léčebný přípravek s virucidním účinkem |
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WO2001078751A1 (en) * | 2000-04-17 | 2001-10-25 | 'armenicum+' Jsc | Antiviral and antibacterial pharmaceutical preparation 'armenicum' and its use for treatment of infectious diseases |
CN1162399C (zh) * | 2001-04-28 | 2004-08-18 | 曾雄飞 | 氨基酸碘络合物 |
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AU2004234003A1 (en) * | 2003-04-29 | 2004-11-11 | Baxter International Inc. | Formulation to render an antimicrobial drug potent against organisms normally considered to be resistant to the drug |
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US10149890B2 (en) | 2018-12-11 |
US10251939B2 (en) | 2019-04-09 |
SI2722053T1 (en) | 2018-02-28 |
DK2722053T3 (da) | 2017-11-20 |
HRP20180075T1 (hr) | 2018-02-23 |
US20140010782A1 (en) | 2014-01-09 |
PL2722053T3 (pl) | 2018-04-30 |
US20190134157A1 (en) | 2019-05-09 |
JP2014502616A (ja) | 2014-02-03 |
ES2476240T1 (es) | 2014-07-14 |
CN103442728B (zh) | 2017-04-12 |
US20150374837A1 (en) | 2015-12-31 |
SG192563A1 (en) | 2013-09-30 |
EP2722053A1 (en) | 2014-04-23 |
CN103442728A (zh) | 2013-12-11 |
LT2722053T (lt) | 2017-12-11 |
CY20142200001T2 (el) | 2016-06-22 |
EA201290002A1 (ru) | 2012-09-28 |
EP2722053B1 (en) | 2017-10-25 |
WO2012091534A1 (ru) | 2012-07-05 |
ES2476240T3 (es) | 2018-03-06 |
EA024595B1 (ru) | 2016-10-31 |
NO2722053T3 (ja) | 2018-03-24 |
DE11853027T1 (de) | 2014-09-11 |
HUE035149T2 (en) | 2018-05-02 |
RS56687B1 (sr) | 2018-03-30 |
EP2722053A4 (en) | 2014-09-03 |
IL227132B (en) | 2019-01-31 |
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