JP5659388B2 - 医学及び獣医眼科の使用のための医薬組成物 - Google Patents
医学及び獣医眼科の使用のための医薬組成物 Download PDFInfo
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- JP5659388B2 JP5659388B2 JP2012514912A JP2012514912A JP5659388B2 JP 5659388 B2 JP5659388 B2 JP 5659388B2 JP 2012514912 A JP2012514912 A JP 2012514912A JP 2012514912 A JP2012514912 A JP 2012514912A JP 5659388 B2 JP5659388 B2 JP 5659388B2
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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Landscapes
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本発明は、薬剤学、医薬、特に、ヒト及び動物の眼疾患のための効率的な治療を提供する、ミトコンドリアに対処する(mitochondria-addressed)抗酸化剤及び一連の補助物質を含む薬剤の医薬組成物(眼科調製物)の製造及び使用に関する。
酸化的ストレスは、様々な眼病理学の発展のための重要な理由の一つであるので、天然の及び合成の抗酸化剤は、眼疾患の治療及び予防のための医療行為に、広く用いられる。
本発明は、ヒト及び動物において、眼疾患の治療のためのミトコンドリアの抗酸化剤の効率的な使用を提供することを可能にする医薬組成物(点眼剤を)を扱う。
成分A1−ミトコンドリアに対処する抗酸化剤
成分A2−pHバッファ
成分A3−ミトコンドリアの抗酸化剤の濃度安定化剤
成分A4−延長剤(増粘剤)
成分A5−等張成分
成分A6−保存剤
を含む、溶液(処方1)である。
成分A1:標的化部分、リンカー基、及び抗酸化剤を含む化合物。この化合物の一般的な化学構造は、下記の構造(I):
mは1〜3の整数であり;
それぞれのYは独立して、低級アルキル、低級アルコキシからなる群から選択され;又は二つの隣接したY基は、それらが結合する炭素原子と一緒になって下記の構造:
R1及びR2は、同一又は異なっており、それぞれ独立して低級アルキル又は低級アルコキシである)
及び/又はその還元された形態を形成する]
を随意的に有する抗酸化剤、及び/又はその還元された形態であり、
L−リンカー基は、以下:
a) 一つ若しくはそれ以上の置換基により随意的に置換され、一つ若しくはそれ以上の二重又は三重結合を随意的に含む、直線又は分枝の炭化水素鎖;
b) 天然のイソプレン鎖;
を含み、
nは1〜40、好ましくは2〜15の、特に好ましくは5〜11の整数であり;
B−標的化基は、以下:
a) スクラチェフ(Skulachev)‐イオン Sk:
b) 2〜20のアミノ酸残基を含む荷電した疎水性ペプチド、
を含む}
により表され、あるいはその溶媒和物、塩、異性体、又はプロドラッグであり、
成分A1としての使用のための好適な化合物の一つは、SkQ1-臭化物:
N-アセチルシステイン、水溶性ビタミンE誘導体、アスコルビン酸、マンニトール、トロロクス、メチルエチルピリジノール、タウホン(taufon)などを含む。
フラシリヌム(furacilinum)
過マンガン酸カリウム(Kaliihypermanganicum)
ブリリアントグリーン(Viride Nitens)
ヨード溶液アルコール、ヨードチンキ(Sol. jodi spirituosae, Tinctura iodi 5%)
過酸化水素(Sol. Hydrogeniiperoxididiluta)
ノボイマニヌム(Novoimaninum)
コラルゴルム(collargolum)
レゾルシノール(Resorcinum)
硫酸亜鉛(Zinci sulfas)
タンニン(Tanninum、Acidum tannicum)
ゼロフォルム(Xeroformium)
塩酸エチルモルヒネ、ジオニン(Aethylmorphini hydrochloridum、dioninum)
酸素(Oxygenium)
ヨウ化ナトリウム(Natrium jodidum)
ヨウ化カリウム(Kalium jodidum)
リダスム(Lydasum)
アレルゴフタル(Alergoftal)
アロマイド(Alomide)
スパサラー(Spersallerg)
塩化カルシウム(Calcii chloridum)
グルコン酸カルシウム(Calcii gluconas)
ジフェンヒドラミン(Dimedrolum)
ジパラジヌム(Diprazinum)、ピポルフェン(Pipolphen)
スプラスチン(Suprastin)
クシクロム(Cusicrom)
マキシデックス(Maxidex)
プレナシド(Prenacid)
レクロリン(Lecrolyn)、シノニム(Synonym)、オプティクロム(Opticrom)、ハイ-クロム(Hay-Crom)
ベンジルペニシリンナトリウム(カリウム)塩(Benzyl-penicillinum-natrium,-kalium)
アンピシリン三水和物(Ampicillini trihydras)
アンピシリンナトリウム塩(Ampicillinum-natrium)
メチシリンナトリウム塩(Methicillinum-natrium)
テトラサイクリン(Tetracyclinum)
メタサイクリン塩酸塩、ロンドマイシン(Methacyclinum hydrochloridum, Rondomycinum)
クロラムフェニコール(Laevomycetinum)
オレテトリヌム(Oletetrinum)
テトラオリーン(Tetraolean)、シグママイシン(Sigmamycin)
シントマイシン(Synthomycin)(Synthomycinum)
ストレプトマイシン硫酸塩(Streptomycini sulfas)
エリスロマイシン(Erythromycinum)
ゲンタマイシン、ガラマイシン(Gentamycini sulfas, Garamycin)
モノマイシン(Monomycinum)
ネオマイシン(Neomycinum)
セファロリジヌム(Cefaloridinum)、セポリン(Ceporin)
リンコマイシン塩酸塩(Lincomycinum hydrochloridum)
ニスタチン(Nystatinum)
ガラソン(Garasone)
デキサゲンタマイシン(Dexagentamycin)
マキシトロール(Maxitrol)
トブラデックス(Tobradex)
ビタバクト(Vitabact)、ピクロキシジン(Picloxidine)
フシタルミック(Fucithalmic)
コルビオシン(Colbiocin)、エウベタル(Eubetal)
オカシン(Okacin)、ロメフロキサシン(Lomefloxacin)
シプロメド(Cipromed)、シプロフロキサシン(Ciprofloxacin)
スルファシルナトリウム(Sulfacyl-sodium)、スルファセタミド(Sulfacylum-natrium)
スルファジメジン(Sulfadimezinum)
アエサゾール(Aethazol)(Aethazolum)
スルファレン(Sulfalen)、スルファメトピラジン(Sulfametopyrazine)(Sulfalenum、Kelfizina)
スルファピリダジヌム(Sulfapyridazinum)
スルファジメトキシン(Sulfadimethoxin)、マドリボン(madribon)(Sulfadimethoxinum)
イドクスウリジン(Idoxuridin)、ケレシド(Kerecid)、オフタン-IDU(Oftan-IDU)
ポルダヌム(Poludanum)
テブロフェン(Tebrophen)(Tebrophenum)
フロレナル(Florenal)(Florenalum)
オキソリン(Oxolin)(Oxolinum)
デオキシリボヌクレアーゼ(Desoxyribonucleasa)
ゾビラックス(Zovirax)、アシクロビル(Aciclovir)
バルトレックス(Valtrex)、バラシクロビル(Valaciclovir)
リコピド(Licopid)
アミドピリン、ピラミドン(Amidopyrinum)
アセチルサリチル酸、アスピリン(Acidumacetylsalicylicum)
フェニルブタゾン(Butadionum)
レオピリニ(Reopyrini)
インドメタシン(Indometacinum)
ピロゲナルム(Pyrogenalum)
ナクロフ(Naclof)、ジクロ-F(Diclo-F)、ジクロフェナク(Diclofenac)
塩酸コカイン(Cocaini hydrocloridum)
ノボカイン(Novocainum)
ジカイン(Dicain)(Daicainum)
トリメカイヌム(Trimecainum)
イノカイヌム(Inocainum)
グルタミン酸(Acidumglutaminicum)
ハリドール(Halidor)
ジシノン(Dicynone)、エタンシラート(etamsylate)
ビンポセチン(Vinpocetini)、ビンポセチン-AKRI(vinpocetini-AKRI)、カビントン(cavinton)
トレンタル(Trental)、ペントキシフィリン(pentoxifylline)、ペンチリン(pentilin)、ペントマー(pentomer)
ソルコセリル(Solcoseryl)
タウフォン(Taufon)、タウリン(taurine)
セレブロリシヌム(Cerebrolysinum)
エモキシピン(Emoxypine)
ビシヌム(Viceinum)
ビタイオズロルム(Vitaiodurolum)、ビタファコール(vitaphacol)
キナックス(Qinax)
システイン(Cysteinum)
ATP、アデノシン三リン酸(Sol. Natrii adenosintriphosphatis)
コリン作動性調製物
ピロカルピン塩酸塩(Pilocarpini hydrochloridum)
カルバコール(Carbacholum)
アセクリジン(Aceclidinum)
アルミン(Arminum)
エゼリン(Eserinum)
プロセリン(Proserinum)
ホスファコルム(Phosphacolum)
トスミレン(Tosmilen)、臭化デメカリウム(Tosmilenum Demecarii bromidum)
アドレナリン(Adrenalinum)、エピー(eppy)、エピネフィリン、オフタン-ジピベフリン(Oftan-dipivefrin)
クロフェリン(Clophelin)(Clophelinum)、イソグラウコン(isoglaucon)
アプラクロニジン(Apraclonidin)、イオピジン(iopidine)
アルチモール(Arutimol)、マレイン酸チモロール(timolol maleate)、オクメド(ocumed)、オプティモール(optimol)、チモロール(timolol)(チモロルム(Timololum))、チモロール-POS(timolol-POS)、ブロカルデン(blocarden)、チモプティック(timoptic)
フォチル(Fotil)、フォチル-フォルテ(Fotil-forte)
プロキソドロール(Proxodolol)
ベタキソロール(Betaxolol)、ベトプティック(betoptic)
ラタノプロスト(Latanoprost)、キサラタン(xalatan)
チンピロ(Timpilo)
フォチル(Fotil)
フォチル-フォルテ(Fotil-forte)
ディアカルブ(Diacarb)、アセタゾラミド
トルソプト(Trusopt)、ドルゾラミド塩酸塩(Dorzolamide hydrochloridum)
レスクラ(Rescula)、ウノプロストン(unoprostone)
硫酸アトロピン(Atropini sulfas)
臭化水素酸スコポラミン(Scopolamini hydrobromidum)
臭化水素酸ホマトロピン(Homatropini hydrobromidum)
プラチフィリンハイドロタルトレート(Platiphyllini hydrotartras)
アドレナリン塩酸塩(Adrenalini hydrochloridum)
フェタノール(Phetanolum)
ミドリアシル、トロピカミド(tropicamid)
シクロムド(Cyclomed)
イリフリン(Irifrin)、フェニレフリン(Phenylephrine)
ビタミンA、レチノール(Vitaminum A、Retinolum)
魚油(Oleum Jecoris Aselli)
シトラール(Citralum)
チアミン臭化物(Thiamini bromidum)、ビタミンB1
ビタミンB2、リボフラビン、リボフラビン−モノヌクレオチド(Riboflavinum、Riboflavinum-mononucleotidum)
オフタゲル(Oftagel)、カルボマー(carbomer)
コルネルゲル(Corneregel)
ティアーズ ナチュレール(Tears naturale)
ビタシック(Vitacic)
ビディシック(Vidisic)
ラクリシン(Lacrysin)
A1−1〜25000 nM
黄斑変性症の原因は、以下:遺伝的又は身体的外傷、疾患、例えば糖尿病など、又は特に感染症、特に細菌性、を含むが、これに限定されない。
本発明の他の態様では、患者は家畜−イヌ、ネコ、ウマなどである。この場合、この組成物は、獣医学調製物として用いられる。
1. 医薬組成物(組成物1)における活性成分の安定性
250 nMまでの範囲の濃度におけるSkQ1の水溶液(10 mMリン酸ナトリウム、pH 6.5、0.9%NaCl)の安定性の試験は、0.01%塩化ベンザルコニウムの添加が、周囲温度で24時間の保管の間、活性成分の濃度の減少を防ぐことを示した。
獣医学臨床例1:
種、動物の品種:イヌ、クベルグシュナウザー(cverg schnauzer)
性別:雄性
年齢:2005年生まれ(4歳)
入院日:2008年12月4日
専門家への訪問は一度目か二度目か−一度目の訪問。
早期の調査の結果−調査は早期に行われなかった。
早期に与えられた疾患の診断−正確な診断はされなかった。
その期間の処置とその有効性(治療の詳細な記載と併せて)−処置は行われなかった。
この臨床例は、遺伝性である。
動物の一般的な状態は、申し分なかった。そのイヌは眼が見えなかった。外観試験:瞼は正常なボリュームを有し、瞼裂は正常であり、結膜はパールピンクであり、角膜は、輝き、球状で、透明であり、湿っており、血管を含まない。前房は深く、光に対する虹彩の反応は失っていた。
1. 重症度、疾患の形態、疾患の経過(急性、亜急性の、慢性の、再発性の、長期のなど)、病理学的進行活動の段階、機能障害の程度(段階)を含む、基礎疾患の診断−全身性進行性網膜萎縮症。
2. 基礎疾患の合併症の診断−なし。
3. 合併症の診断(得られる場合)−なし。
1. 特異性試験:迷路、綿球に対する反応、光に対する反応など−迷路を用いた試験において、イヌは、暗所及び明所で、障害物に躓き、近くに落ちる綿球に対して反応せず、光に対する虹彩の反応はなかった。
基礎疾患の詳細な診断:
1. −疾患の名称−全身性進行性網膜萎縮症。ステージ2。
2. −その臨床的、臨床形態学的又は病原性形態−失明、変性した脈絡層タペタム(t. Lucidum)の表面、過敏性、網膜の小血管は存在しない、網膜の大血管の薄化(thining)。疾患の経過−慢性的。
3.機能性障害又は疾患の重症度の程度(段階)−暗所及び明所での視野機能障害、動物は、固定された又は動く障害物が見えなかった。
1日2回、1滴の投与量での医薬的組成物(組成物1)
データは表に示される。
イヌ、クベルグシュナウザー(cverg schnauzer)種、ニックネーム ビンチク(Vintik)、4歳、は2008年12月4日に病院に入院した。既往歴データの取得の結果として、臨床試験は、全身性進行性網膜萎縮症を明らかにした。そのイヌは目が見えなかった。失明は、1年間観察され、脈絡層タペタム(t. Lucidum)のカーペット(carpet)領域は過敏性であり、網膜の小血管は存在せず、大血管の薄化(thining)、ODは白色であった。
A‐波−56.5マイクロボルト。
B‐波−9.5マイクロボルト。
左目:A‐波−9.4マイクロボルト、
B‐波−15マイクロボルト。
2009年4月13日、右目:
A‐波−56.5マイクロボルト。
B‐波−203.5マイクロボルト。
左目:A‐波−45マイクロボルト、
B‐波−45.5マイクロボルト。
1. イヌ、9歳、品種なし。イヌは、出血性脈絡網膜炎及び乳頭炎の症候を伴って2009年1月末に病院に入院した。検査の時点では、その動物は、眼が見えず、持続性の散瞳が見られた。
デキサメタゾン(メチル化フルオロプレドニゾロン)、0.1%点眼剤。
1滴、1日に4回
10分後
医薬組成物(組成物1)、点眼剤
1滴、1日に1回
10分後
エモキシピン(メチルエチルピリジノール)1%、点眼剤
1滴、1日に3回
そのイヌは、ブドウ膜皮膚症候群(自己免疫性皮膚炎により誘導された内因性ブドウ膜炎)の診断を伴って、2008年9月に病院に入院した。検査の時点で、動物は目が見えなかった。
1. シクロムド(Cyclomed)、点眼剤
1滴、1日に2回
10分後
2. ペレナシド(Prenacid)、点眼剤
1滴、1日に1回
10分後
3. インドコレイル(Indocollyre)、点眼剤
1滴、1日に2回
10分後
4. ベトプティック(Betoptic)、点眼剤
1滴、1日に3回
10分後
5. 医薬組成物(組成物1)、点眼剤
1滴、1日に1回
10分後
6. エモキシピン(Emoxypine) 1%、点眼剤
1滴、1日に3回
そのイヌは、レプトスピラ症により誘導された内因性ブドウ膜炎の診断を伴って、2008年9月に病院に入院した。視力は保存された。
1. プレナシド(prenacid)、点眼剤
1滴、1日に1回
10分後
2. インドコレイル(Indocollyre)、点眼剤
1滴、1日に2回
10分後
3. ベトプティック(Betoptic)、点眼剤
1滴、1日に3回
10分後
4. 医薬組成物(組成物1)、点眼剤
1滴、1日に1回
10分後
5. エモキシピン(Emoxypine) 1%、点眼剤
1滴、1日に3回
Claims (18)
- 眼病理の治療又は予防のための医薬組成物であって、以下の成分:
成分A1−ミトコンドリアに対処する(mitochondria-addressed)抗酸化剤
成分A3−塩化ベンザルコニウム、及び
成分A4−ヒドロキシプロピルメチルセルロース
を含み、
ここで、
成分A1は、標的化部分、リンカー基、及び抗酸化剤を含む化合物である、ミトコンドリアに対処する抗酸化剤であり、この化合物の一般的な化学構造は、下記の構造(I):
Aはエフェクター部分−下記の構造:
及び/又はその還元された形態を随意的に有する抗酸化剤であり、
L−リンカー基は、以下:
a) 一つ若しくはそれ以上の置換基により随意的に置換され、一つ若しくはそれ以上の二重又は三重結合を随意的に含む、直線又は分枝の炭化水素鎖;
b) 天然のイソプレン鎖;
を含み、
nは1〜40の整数であり;
B−標的化基は、以下:
a) スクラチェフ(Skulachev)‐イオン Sk:
Sk+Z-
[式中、Sk+は脂溶性陽イオン、Z-は薬理学的に許容される陰イオンである]
を含む}
により表される、医薬組成物。 - 成分A1がSkQ1-臭化物である、請求項1又は2に記載の医薬組成物。
- 眼病理及び疾患の治療及び予防のための、請求項1〜4のいずれか一項に記載の組成物。
- 前記病理が網膜の黄斑変性症である、請求項5に記載の組成物。
- 前記病理が、白内障である、請求項5に記載の組成物。
- 前記白内障が、老人性白内障、及び糖尿病性白内障から選択される、請求項7に記載の組成物。
- 前記病理が、網膜症;網膜剥離;網膜血管、脈絡膜、若しくは視神経の病理;中枢性及び末梢性脈絡網膜性ジストロフィー;又はブドウ膜炎である、請求項5に記載の組成物。
- 前記病理が、眼内出血、又は外傷性出血である、請求項5に記載の組成物。
- 前記病理が、炎症性疾患である、請求項5に記載の組成物。
- 前記炎症性疾患が、結膜炎、眼潰瘍、角膜炎、及び乾性角結膜炎から選択される、請求項11に記載の組成物。
- 前記病理が緑内障である、請求項5に記載の組成物。
- 患者の眼病理の予防及び/又は治療のための組成物であって、この予防及び/又は治療が、この治療又は予防を必要とする患者への、請求項1〜4のいずれか一項に記載の医薬組成物の有効量の投与を含むことを条件とする、組成物。
- 医薬組成物を用いた疾患の治療又は予防を必要とする患者が、ヒトである、請求項5〜14のいずれか一項に記載の組成物。
- 前記組成物を用いた疾患の治療又は予防を必要とする対象が、動物である場合に、請求項5〜14のいずれか一項に記載の組成物を用いて動物対象を治療又は予防する獣医学的方法。
- 前記動物が、家畜である、請求項16に記載の方法。
- 前記家畜が、イヌ、ネコ、及びウマから選択される、請求項17に記載の方法。
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EP (2) | EP2441453B1 (ja) |
JP (1) | JP5659388B2 (ja) |
KR (1) | KR101478728B1 (ja) |
CN (2) | CN102548548B (ja) |
AU (1) | AU2009347921B8 (ja) |
BR (1) | BRPI0924460A2 (ja) |
CA (1) | CA2764481C (ja) |
EA (1) | EA025414B1 (ja) |
ES (1) | ES2527791T3 (ja) |
IL (1) | IL216702A0 (ja) |
MX (1) | MX2011013150A (ja) |
UA (1) | UA104320C2 (ja) |
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US9308165B2 (en) * | 2013-08-22 | 2016-04-12 | Therapeutic Vision, Inc. | Composition for treating ocular effects of diabetes |
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US9314427B2 (en) | 2013-08-28 | 2016-04-19 | Presbyopia Therapies Llc | Compositions and methods for the improvement of distance vision and the treatment of refractive errors of the eye |
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US11179327B2 (en) | 2013-08-28 | 2021-11-23 | Lenz Therapeutics, Inc. | Compositions and methods for the treatment of presbyopia |
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US9968594B2 (en) | 2013-08-28 | 2018-05-15 | Presbyopia Therapies Llc | Compositions and methods for the treatment of presbyopia |
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RU2528912C1 (ru) * | 2013-10-09 | 2014-09-20 | Станислав Анатольевич Кедик | Глазные капли на основе композиции фармацевтически приемлемой аддитивной соли кислоты и метилэтилпиридинола, содержащие композицию витаминов группы в |
US20160361245A1 (en) * | 2014-02-25 | 2016-12-15 | Mitotech Sa | Cosmetic compositions of mitochondrially targeted antioxidants |
EP3148520A4 (en) * | 2014-05-30 | 2018-01-10 | Friedhoff, Lawrence, T. | Antimicrobial pharmaceutical compositions with multiple drug resistance inhibiting properties |
WO2016013993A1 (en) | 2014-07-25 | 2016-01-28 | Imuneks Farma Llac Sanayi Ve Ticaret A.Ş. | Stable preservative free ophthalmic formulations of opioid antagonists |
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CN107312194A (zh) * | 2017-07-13 | 2017-11-03 | 温州嘉泰乳胶制品有限公司 | 乳胶固化配方工艺 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2018035182A (ja) * | 2011-06-03 | 2018-03-08 | ミトテック ソシエテ アノニム | ミトコンドリアを標的とする抗酸化剤の経口製剤ならびにそれらの調製および使用 |
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KR20130082069A (ko) | 2013-07-18 |
EP2441453A1 (en) | 2012-04-18 |
US20170304225A1 (en) | 2017-10-26 |
CA2764481C (en) | 2015-11-24 |
WO2010143990A1 (ru) | 2010-12-16 |
ZA201200111B (en) | 2012-09-26 |
CN102548548B (zh) | 2017-09-01 |
EP2441453A4 (en) | 2013-04-10 |
CA2764481A1 (en) | 2010-12-16 |
CN107362157A (zh) | 2017-11-21 |
ES2527791T3 (es) | 2015-01-29 |
AU2009347921A1 (en) | 2012-01-19 |
AU2009347921B8 (en) | 2014-07-24 |
KR101478728B1 (ko) | 2015-01-02 |
AU2009347921B2 (en) | 2014-07-17 |
US20120094962A1 (en) | 2012-04-19 |
US10213392B2 (en) | 2019-02-26 |
EA201101518A1 (ru) | 2012-04-30 |
CN107362157B (zh) | 2022-08-26 |
EP2823814A1 (en) | 2015-01-14 |
IL216702A0 (en) | 2012-02-29 |
EP2441453B1 (en) | 2014-11-26 |
EA025414B1 (ru) | 2016-12-30 |
UA104320C2 (ru) | 2014-01-27 |
US9724313B2 (en) | 2017-08-08 |
JP2012529504A (ja) | 2012-11-22 |
BRPI0924460A2 (pt) | 2018-03-27 |
MX2011013150A (es) | 2012-03-14 |
CN102548548A (zh) | 2012-07-04 |
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