JP2018517777A - レファムリンの注射可能医薬組成物 - Google Patents
レファムリンの注射可能医薬組成物 Download PDFInfo
- Publication number
- JP2018517777A JP2018517777A JP2018517478A JP2018517478A JP2018517777A JP 2018517777 A JP2018517777 A JP 2018517777A JP 2018517478 A JP2018517478 A JP 2018517478A JP 2018517478 A JP2018517478 A JP 2018517478A JP 2018517777 A JP2018517777 A JP 2018517777A
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- JP
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- Prior art keywords
- formulation
- buffer
- pharmaceutically acceptable
- value
- citrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 238000001727 in vivo Methods 0.000 description 1
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- 229960002725 isoflurane Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
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- 239000007788 liquid Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/08—Solutions
-
- 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
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Emergency Medicine (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
a)S.Guptaら、Parenteral Formulation Development of Renin Inhibitor Abbott−72517、J.of Pharm.Sci.&Tech.48(2):86〜91(1994)
b)P.Simamoraら、「Studies in Phlebitis VIII:Evaluations of pH Solubilized Intravenous Dexverapamil Formulations」、PDA J.of Pharm.Sci.& Tech.50(2):123−128(1996)
c)L.Willemsら、Itraconazole oral solution and intravenous formulations:a review of pharmacokinetIcs and pharmacodynamics、Journal of Clinical Pharmacy and Therapeutics、2001、26、159。
API 医薬品有効成分
BID bis in die(1日2回)
EP ヨーロッパ薬局方
g グラム
JP 日本薬局方
kg キログラム
l リットル
M モル
mM ミリモル
min 分
ml ミリリットル
NF 国民医薬品集
q.s. 必要量
TID ter in die(1日3回)
USP アメリカ薬局方
w/v 重量/体積
a)医薬ビヒクルの調製/購入
医薬ビヒクルNSSの調製は、0.9%(w/v)NaClを溶解することにより確立される。D5WはFresenius Kabiから購入する。
薬学的に許容される塩、例えば、酢酸塩またはL−乳酸塩として存在する試験化合物14−O−{[(1R,2R,4R)−4−アミノ−2−ヒドロキシ−シクロヘキシルスルファニル]−アセチル}−ムチリン(BC−3781)を、緩衝溶液、NSSまたはD5Wに溶解し、6mg/ml(遊離塩基形態として計算)の濃度にする。
a)生理食塩水中のBC−3781濃縮液
BC−3781溶液の調製は、BC−3781酢酸塩を注射用水に溶解し、さらにNaClを溶解することにより達成された。滅菌濾過後、次いで溶液を無菌条件下でバイアルに充填した。
BC−3781生理食塩水バイアルの定量的組成
クエン酸緩衝溶液を別に調製する。クエン酸およびクエン酸三ナトリウムを注射用水に溶解し、次いでバイアルに充填する。
250mMクエン酸濃縮緩衝液のバッチ処方
250mMクエン酸緩衝液バイアルの定性的および定量的組成
540mMクエン酸濃縮緩衝液のバッチ処方
クエン酸緩衝液バイアルの定量的組成
BC−3781輸液の必要な体積および濃度に応じて、滅菌バッグに、必要量のi)生理食塩水中のBC−3781濃縮液(実施例2a)に記載の調製物)、ii)クエン酸濃縮緩衝液(実施例2b)に記載の調製物)およびiii)市販のNSSを充填した。
・ 1時間かけて注入される270ml中BC−3781 150mgの生理食塩水製剤
・ 1時間かけて注入される270ml中BC−3781 150mgの生理食塩水クエン酸緩衝液製剤
を、無作為化二重盲検プラセボ対照第1相臨床試験で調査した。
クエン酸緩衝生理食塩水バッグのバッチ処方
150mM濃縮緩衝液の調製は、適量のクエン酸一水和物とクエン酸三ナトリウム二水和物を水に溶解することにより行われた。得られたpHは約5である。
BC−3781酢酸塩の150mg遊離塩基等価物を150mMクエン酸緩衝液20mlに溶解し、濃度を7.5mg/mlにする。溶液を、例えば、ガラスバイアルに充填してもよい。
BC−3781をラット背部尾静脈に注入するための注入忍容性モデル部位を開発し、BC−3781の可能性のある臨床静脈内製剤を調査した。このために、雌のSprague Dawley(SD)ラットに、永久静脈カテーテル(BD(登録商標)G21)を挿入し、6mg/mlの濃度のBC−3781からなる様々な製剤を、最終用量75mg/kgになるまで1ml/分の一定の注入速度で注入した。血漿および尿を溶血徴候について5〜30分間チェックした。注入部位(尾静脈)での局所忍容性を、適用の24時間後にチェックした。血漿および/または尿の溶血に関する情報と共に開発されたスコアシステムを回収し、分析に使用した。
a)局所忍容性モデル
静脈内製剤の局所忍容性を決定するために、ラット尾静脈注入モデルを開発し、実施例1に従って調製したBC−3781製剤を試験した。このために、スコアシステムを使用して、注射部位の臨床兆候を説明した。
24時間後ラット尾静脈で異常が認められなかった場合の評価 0点
若干の赤色の斑点(斑状出血) 1点
中程度の斑点 2点、および
より重度の青から暗赤色の斑点 3点。
壊死の場合は3点とした。
血液を、注入終了の15分後に舌下静脈から採取し、2g、4℃で5分間遠心分離した。血漿を採取し、溶血の徴候を視覚的にチェックし、その後−20℃で貯蔵した。様々な製剤の薬物動態(PK)に対する影響を評価するために、BC−3781の血漿濃度を決定し、比較した。
注入終了後、麻酔を除去した。動物は、麻酔からの覚醒中、白いティッシュのシート上の個々のケージに入れたままにした。ティッシュ上に認められたわずかな赤血球尿滴を、溶血の徴候として記録した。
各製剤についての局所忍容性モデルからのスコアを合計し、次いで対応する動物の数(n=3〜12)で割った。さらに、血漿および尿中の溶血の徴候を、製剤のランク付けで考慮した。
a)ラット尾静脈注入モデルで試験したBC−3781製剤
製剤の調製は実施例1に記載されている。活性製剤において、酢酸塩またはL−乳酸塩のいずれかとして存在する、必要量のBC−3781を、上の表に列挙した緩衝溶液、NSSまたはD5W各々に溶解した。完全な溶解後、必要な希釈物を動物に直ちに投与した。BC−3781 75mg/kg用量は、BC−3781の遊離塩基含量を指す。
尾を加熱ランプ下で5分間加熱した後、背部尾静脈に永久静脈カテーテル(BD insyte(商標)、24GA)を挿入した。カテーテル挿入後、開始用に5%、麻酔維持用(マスク)に3.5%の濃度のイソフルランをラットに麻酔した。様々なBC−3781製剤を、プログラム可能なシリンジポンプから、カテーテルが挿入されたラット背部尾静脈に注入した(1ml/分、6mg/ml、約2分)。注入終了後、カテーテルを生理食塩水0.1〜0.2mlで洗い流した。カテーテルおよびシリンジは廃棄し、接続チューブは再利用のためにエタノールで洗い流し、乾燥した。注入設定毎のグループサイズは3であった。
ラット尾モデルでの試験した製剤の結果(局所忍容性スコア、ならびに血漿および尿中の溶血)
実施例2で調製したNSS中のBC−3781(270ml中BC−3781 150mg)製剤とクエン酸緩衝生理食塩水中のBC−3781(270ml中BC−3781 150mg)製剤とを比較すると、BC−3781緩衝化製剤の局所忍容性の向上が、第1相臨床試験でも確認された。試験は無作為化二重盲検プラセボ対照(生理食塩水をプラセボとして使用)であった。男性25人および女性35人の健康な対象合計60人を処置した。試験の主要エンドポイントは、最初の3日以内での中程度の疼痛および紅斑であった。製剤は1時間かけて注入され、クエン酸緩衝生理食塩水中のレファムリンを投与したとき、驚くべきことに、最初の3日間での中程度の疼痛および/または紅斑の発生は、ほぼ半減した。例えば、生理食塩水治療群では、合計150回の注入のうち、中程度の疼痛が生じたのは13回の注入(8.7%)であったが、クエン酸緩衝生理食塩水治療群では、150回の注入のうち中程度の疼痛と関連していたのはわずか6回(4%)であった。
Claims (14)
- 式(I)
- 緩衝液が、式Iの化合物を緩衝化するために用いられ、前記緩衝液が、2〜6の範囲内のpKa値を有する少なくとも1つの成分を含有し、結果得られた前記緩衝液のpH値が前記pKa値以下であることを特徴とする、請求項1に記載の製剤。
- 緩衝液が、クエン酸緩衝液、リン酸緩衝液およびそれらの混合物からなる群から選択される、請求項1または2に記載の製剤。
- 緩衝液が、クエン酸緩衝液、好ましくは10〜20mMクエン酸緩衝液、特に好ましくは10mMクエン酸緩衝液である、請求項3に記載の製剤。
- 緩衝化された製剤が、生理食塩水、5%ブドウ糖液およびそれらの混合物からなる群から好ましくは選択される、薬学的に許容されるビヒクルを含む、請求項2から4のいずれか一項に記載の製剤。
- 緩衝液が、10mM〜20mMクエン酸緩衝液であり、製剤のpH値が3〜5.5、好ましくはpH5であり、式(I)の化合物の濃度が0.2〜3mg/ml(遊離塩基形態として計算)であり、製剤が薬学的に許容されるビヒクルを含む、請求項2から5のいずれか一項に記載の製剤。
- 緩衝液が、10mMクエン酸緩衝液であり、製剤のpH値が3〜5.5、好ましくはpH5であり、式(I)の化合物の濃度が0.3〜1.2mg/ml(遊離塩基形態として計算)であり、製剤が薬学的に許容されるビヒクルを含む、請求項6に記載の製剤。
- 緩衝液が、10mMクエン酸緩衝液であり、製剤のpH値が3〜5.5、好ましくはpH5であり、式(I)の化合物の濃度が0.3〜0.6mg/ml(遊離塩基形態として計算)であり、製剤が薬学的に許容されるビヒクルを含む、請求項7に記載の製剤。
- 式(I)の化合物が、薬学的に許容される塩として、特に酢酸塩および/またはL−乳酸塩として、特に好ましくは酢酸塩として用いられる、請求項1から8のいずれか一項に記載の製剤。
- 微生物が介在する疾患の治療での使用のための、請求項1から9のいずれか一項に記載の製剤。
- 製剤が、静脈内適用により投与されることを特徴とする、請求項10に記載の使用のための製剤。
- 請求項1〜9のいずれか一項に記載の注射可能製剤を含む医薬品提示形態。
- 請求項1〜9のいずれか一項に記載の製剤が、それを必要とする対象に投与される、微生物が介在する疾患の治療方法。
- 前記製剤が、静脈内適用により投与される、請求項13に記載の方法。
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CN115397407A (zh) | 2020-04-17 | 2022-11-25 | 纳布里瓦治疗有限责任公司 | 截短侧耳素类化合物的新治疗用途 |
BR112022020007A2 (pt) | 2020-04-17 | 2022-11-22 | Nabriva Therapeutics GmbH | Uso terapêutico de pleuromutilinas |
WO2023004327A1 (en) * | 2021-07-19 | 2023-01-26 | Jbc Science Inc. | Methods for isolating circulating nucleic acids from urine samples |
WO2023152115A1 (en) | 2022-02-09 | 2023-08-17 | Nabriva Therapeutics GmbH | Lefamulin and its derivatives for use in the treatment of a spiral shaped bacteria |
EP4338732A1 (en) | 2022-09-16 | 2024-03-20 | Nabriva Therapeutics GMBH | Lefamulin and its derivatives for use in the treatment of tularemia |
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GB2228412B (en) * | 1989-02-28 | 1993-04-14 | Syntex Inc | Nicardipine pharmaceutical composition for parenteral administration |
FR2772272B1 (fr) | 1997-12-16 | 2000-01-14 | Rhone Poulenc Rorer Sa | Compositions pharmaceutiques a base de dalfopristine et de quinupristine et leur preparation |
MXPA02009816A (es) * | 2000-04-04 | 2003-03-27 | Smithkline Beecham Plc | Derivados de carbamato de 2-hidroxi-multilina para uso antibacteriano. |
GB0308114D0 (en) * | 2003-04-08 | 2003-05-14 | Glaxo Group Ltd | Novel compounds |
TWI427077B (zh) * | 2004-12-30 | 2014-02-21 | Astex Therapeutics Ltd | 吡唑化合物及其用途和含有彼之藥學組成物 |
EP1896404B1 (en) * | 2005-06-27 | 2014-09-17 | Nabriva Therapeutics AG | Pleuromutilin derivatives containing a hydroxyamino- or acyloxyaminocycloalkyl group |
EP1972618A1 (en) * | 2007-03-20 | 2008-09-24 | Nabriva Therapeutics AG | Pleuromutilin derivatives for the treatment of diseases mediated by microbes |
WO2011002776A1 (en) * | 2009-06-29 | 2011-01-06 | Nitric Biotherapeutics, Inc. | Pharmaceutical formulations for iontophoretic delivery of an immunomodulator |
EP2399904A1 (en) * | 2010-05-26 | 2011-12-28 | Nabriva Therapeutics AG | Process for the preparation of pleuromutilins |
CN103204787B (zh) * | 2012-01-17 | 2014-10-01 | 北京艾百诺科技有限公司 | 含有取代方酸的乙酸妙林酯及其应用 |
CN103626693B (zh) * | 2012-08-28 | 2016-09-14 | 中国科学院上海药物研究所 | 一类截短侧耳素衍生物、其药物组合物及其合成方法与用途 |
US9993469B2 (en) * | 2013-05-28 | 2018-06-12 | Morphochem Aktiengesellschaft Für Kombinatorishe Chemie | Combination therapy comprising oxazolidinone-quinolones for use in treating bacterial infections |
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