TW201831184A - 含有普多沙星(pradofloxacin)之液態組成物 - Google Patents
含有普多沙星(pradofloxacin)之液態組成物 Download PDFInfo
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- TW201831184A TW201831184A TW107104598A TW107104598A TW201831184A TW 201831184 A TW201831184 A TW 201831184A TW 107104598 A TW107104598 A TW 107104598A TW 107104598 A TW107104598 A TW 107104598A TW 201831184 A TW201831184 A TW 201831184A
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- podofloxacin
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- antioxidant
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Abstract
本發明係關於液態形式的醫藥組成物，其包含水性溶液中的普多沙星和作為抗氧化劑之檸檬酸或硫甘油。
Description
本發明係關於液態形式之醫藥組成物，其包含於水性溶液中之普多沙星(pradofloxacin)及作為抗氧化劑之檸檬酸或硫甘油。
溶液之化學安定性可藉由例如使用抗氧化劑增加。組成分之氧化性降解因而可被防止。此亦常用於注射用溶液，其中此特別為該情況。普多沙星通常已知是對氧化敏感。
又，普多沙星傾向由其溶液沉澱出。此過程有時極緩慢。因此判定特定普多沙星是否具儲存安定性並不容易且花費時間。
此等問題可例如藉由轉而選擇冷凍乾燥產品避免，該產品在使用前即時被重組(reconstituted)。 然而，冷凍乾燥產品在實務上難以操作且在重組後重組溶液常僅具不多於4週之儲存期，或因形成顆粒之可能性，必須被直接丟棄。因此，即用型(ready-to-use)溶液用作注射溶液是有利的。
又，投予後特定量之氟喹啉酮必須進入血清中，此亦述於WO 99/29322中。再次，這對可注射之氟喹啉酮組成物當然不是問題且可能同樣取決於所討論的動物物種。
此外，希望取得可容許高濃度普多沙星之組成物。對於動物的腸胃外製劑，皮下或肌內施用通常較佳。 皮下(s.c.)或肌內(i.m.)施用之體積無法擴大，並且每個注射部位注射小於10ml的體積是有利的。因此，如普多沙星之活性成分的濃度可能必須很高(例如10至30％）。
再者，發現液態可注射的普多沙星組成物可以顯示變色，其可通過抗氧化劑避免。進一步發現，找到合適的抗氧化劑並不容易，其不僅防止普多沙星的氧化，而且也不具有任何其他不利影響。
已發現包含普多沙星的即用型可注射組成物，其包含足夠濃度的氟喹啉酮，其在藥學條件下儲存時穩定並且無顆粒形成，特別是避免了普多沙星之氧化降解，並在儲存過程中保持溶液的顏色，耐受性良好及血清動力學良好。
因此，本發明係關於: 液態組成物，其包含: (a) 1至30 % (重量/體積)之普多沙星 (b) 1至30 % (重量/體積)之酸 (c) 0.01 至1 % (重量/體積)之抗氧化劑，其選自檸檬酸及硫甘油 (d) 若適當，另外之醫藥助劑及/或添加劑 (e) 及作為溶劑之水。
本發明又係關於上述液態組成物在治療動物細菌感染中的用途。
氟喹啉酮抗生素普多沙星下式8-氰基-1-環丙基-7-((1S,6S)-2,8-二吖雙環[4.3.0]壬-8-基)-6-氟-1,4-二氫-4-側氧基-3-喹啉羧酸(普多沙星)揭示於WO 97/31001中。
普多沙星用語包括其鹽、水合物及鹽之水合物。
具光學活性之普多沙星可以其外消旋物形式或其鏡像異構物形式存在。根據本發明，不僅純鏡像異構物，其混合物亦可使用。通常用於醫藥用途之普多沙星為具有S,S–吡咯啶基-哌啶取代基之異構物。
適當的鹽是藥學上有用的酸加成鹽和鹼性鹽。
藥學上有用的鹽被認為是指例如鹽酸、硫酸、醋酸、乙醇酸、乳酸、琥珀酸、檸檬酸、酒石酸、甲磺酸、4-甲苯磺酸、半乳醣醛酸、葡萄糖酸、撲酸、麩胺酸或天冬胺酸。此外，根據本發明的化合物可以結合酸性或鹼性離子交換劑。可以提及的藥學上有用的鹼性鹽是鹼金屬鹽，例如鈉鹽或鉀鹽，鹼土金屬鹽，例如鎂鹽或鈣鹽；鋅鹽，銀鹽和胍鹽。
水合物不僅意謂氟喹啉酮本身的水合物，還意謂其鹽的水合物。可以提及的具體實例是安定的普多沙星三水合物（參見WO 2005/097789）。根據一個較佳的具體例，普多沙星三水合物用於製備根據本發明的液態組成物。
固體普多沙星，在某些情況下可以形成各種晶體變體；參見WO 00/31076（晶體變體B），WO 00/31075（晶體變體A），WO 00/52010（晶體變體C），WO 00/52010（晶體變體D），WO 00/31077（半鹽酸鹽）。普多沙星無水物變體B的晶型較佳。
本發明的液態組成物含有濃度為3至30％，較佳10至25％，更較佳15至25％的普多沙星。
根據另一個具體例，本發明的液態組合物含有濃度為5至15％，較佳10至15％的普多沙星。此另一具體例對於中等體重的動物較佳，例如，在治療時動物的體重高達約100kg。在體重大於約100kg的動物的情況下，氟喹啉酮的用量通常為5-30％，較佳10-25％，特別較佳15-25％。除非另有說明，在每種情況下，以百分數表示的重量/體積（即以g / 100ml溶液計）數值和 - 在鹽或水合物的情況下 - 計算為純普多沙星的含量。
本發明組合物應為略微至中等酸性。通常它們具有5或更低的pH，較佳pH 2至4.8，更較佳pH 3至4.8。
原則上，可以使用廣範圍的酸來調節本液態組成物的pH值。然而，已經發現，本領域中通常使用的某些酸導致不希望的效果，特別是普多沙星的沉澱。已經發現下述酸僅允許低濃度的活性成分，並且因此對於本發明組成物不是較佳的：天冬胺酸、麩胺酸、檸檬酸、酒石酸或鹽酸。
根據本發明較佳可使用的酸為：醋酸、葡萄糖酸、葡萄糖酸內酯、甲磺酸、乳酸、磷酸或丙酸。 葡萄糖酸或葡萄糖酸內酯和甲磺酸是特別較佳。上述酸在本發明組成物中的濃度為1至30 % (重量/體積)，較佳為5至20% (重量/體積)，更佳為5至15% (重量/體積)。
葡萄糖酸內酯特別是指葡萄糖酸δ-內酯。在水存在下，葡萄糖酸將δ-內酯水解成葡萄糖酸，其中內酯形式和酸形式之間的平衡確立為化學平衡。高濃度的水、熱量和高pH將平衡轉移到葡萄糖酸之側。
為了保護普多沙星不被氧化，需要使用抗氧化劑。如果沒有抗氧化劑，黃色溶液的顏色會變成棕色或甚至棕色，會出現結晶，並可能形成普多沙星形式的降解產物。發現適用於保護普多沙星不被氧化之抗氧化劑不多，例如，亞硫酸氫鈉、穀胱甘肽、酒石酸或抗壞血酸不適合，因為它們不能防止變色，導致在溶液中形成顆粒或降解產物。本發明組成物中的抗氧化劑選自檸檬酸和硫甘油，檸檬酸較佳。較佳的硫甘油是1-硫甘油。抗氧化劑在組成物中的濃度為0.01至1％（重量/體積），較佳為0.05至0.5％（重量/體積），更佳為0.05至0.3％（重量/體積）。
發現其它抗氧化劑在防止組成合物變色方面不太有效或甚至無效。
液態組成物含有水作為溶劑。根據一個實施方案，水是唯一的溶劑。根據另一個實施方案，可以將水混溶性物質作為共溶劑加入，可以提及的實例為甘油，丙二醇，聚乙二醇，耐受的醇如乙醇，苯甲醇或正丁醇，乳酸乙酯，醋酸乙酯，甘油三醋酸酯(triacetin)，N-甲基吡咯烷酮，碳酸丙烯酯，丙二醇，乙二醇呋喃(glycofurol)，二甲基乙醯胺，2-吡咯烷酮，二甲基亞碸，亞異丙基甘油或甘油縮甲醛。較佳之共溶劑是乙醇，苯甲醇或正丁醇。也可以使用超過一種共溶劑的混合物。通常，共溶劑以高達50％，較佳1至30％，特別較佳5至20％的濃度存在。
根據本發明的一個實施方案，液態組成物除了水或與水混溶的物質外，還可以含有乳液形式的油作為溶劑。其中，可提及的物質是植物油、動物油和合成油，如棉籽油，芝麻油，豆油，鏈長為C12-C18的中鏈三酸甘油酯，丙二醇辛酸酯/癸酸酯或石蠟。
在本液態組成物中，溶劑通常以約98至35％，98至40％或98至45％，較佳約90至60％的濃度使用，或者在另一個較佳實施方案中約95至75％，或特別較佳80至60％，或者在替代性特別較佳的實施方式中，94至80％。百分比數據在每種情況下都以重量/體積表示。
液態組成物可含有防腐劑，例如脂族醇如芐醇，乙醇，正丁醇，苯酚，甲酚，氯丁醇，對羥基苯甲酸酯（特別是甲基和丙基酯），羧酸的鹽或游離酸，如山梨酸，苯甲酸，乳酸或丙酸，苯扎氯銨(benzalkonium chloride)，芐索氯銨(benzethonium chloride)或氯化十六烷基吡啶鎓(cetylpyridinium chloride)。醫藥領域中使用的典型濃度（技術人員已知）通常為0.01至30％（重量/體積）。對於乙醇，較佳的濃度是10至30％（重量/體積），特別較佳15至25％（重量/體積）。對於丁醇，較佳的濃度為0.1至10重量/體積，較佳1至5％（重量/體積）。對於乙醇或丁醇以外的防腐劑，較佳的濃度範圍為0.01至5％（重量/體積）。
取決於配製物的類型和投予形式，根據本發明的醫藥組成物可含有其他常規的醫藥上可接受的添加劑和佐劑。可以提到的例子是：乳化劑，特別是用於乳液例如Tween80（聚山梨酸酯80），CremophorEL（聚乙氧基化蓖麻油），Solutol HS15（聚乙二醇15羥基硬脂酸酯）或Poloxamer188（泊洛沙姆）是環氧乙烷嵌段共聚物的國際非專有名稱和甲基環氧乙烷）。等滲劑，例如氯化鈉，葡萄糖或甘油。
除了氟喹啉酮之外，根據本發明的組成物還可以包含其他藥物活性成分。例如，氟喹啉酮也可與例如止痛劑組合使用，特別是所謂的NSAID（非甾體抗炎物質）。這樣的NSAID可以是例如美洛昔康(meloxicam)，氟尼辛(flunixin)，酮洛芬(ketoprofen)，咔洛芬(carprofen)，安乃明(metamizole)或（乙醯基）水楊酸。
根據本發明的藥物可以通過將成分溶解在水相中來製備。較佳地，首先將酸溶於水中，然後加入抗氧化劑，然後是普多沙星和 - 如果合適的話 - 加入其他成分以形成溶液。或者，抗氧化劑先溶於水中，然後再加入普多沙星，如果適用的話 - 其他成分在普多沙星之後添加，抑或與普多沙星一起加入以形成溶液。另一種製備方法是一次性將所有成分加入到水相中，並一個步驟中將它們全部溶解。
為確保提供普多沙星抗氧化的最佳保護，可在惰性氣體條件下進行製造，例如，可以在製造溶液期間施加氮氣或氬氣充氣。較佳在添加普多沙星之前，將諸如氬氣或氮氣的惰性氣體施加至水相。
該溶液是滅菌的，例如，藉由過濾。然後可以將組成物填充到適當的初級包裝容器中。視情況地，該過程的一個或多個步驟可以在惰性氣體氣氛下進行，例如，使用氮氣。
即使在高達40℃的高溫下，根據本發明的液態組成物也表現出極佳之化學和物理穩定性。
通常，根據本發明的藥物製劑適用於人和動物。它們較佳用於家畜，育種動物，動物園動物，實驗室動物，實驗動物和寵物中的動物飼養和畜牧業。
家畜和育種動物包括哺乳動物，例如牛，馬，綿羊，豬，山羊，駱駝，水牛，驢，兔，黇鹿(fallow deer)，馴鹿，帶皮毛動物，例如水貂，栗鼠，浣熊和鳥類，諸如雞，鵝，火雞，鴨子，鴿子和鳥物種，以飼養在家用處所和動物園中。
實驗室和實驗動物包括小鼠，大鼠，豚鼠，金倉鼠，狗和貓。
寵物包括兔子，倉鼠，豚鼠，小鼠，馬，爬行動物，適宜的鳥物種，狗和貓。
根據一個實施方案，根據本發明的液態組成物可用於寵物，較佳它們可以用於貓或狗。
根據一個較佳實施方案，本發明組成物用於家畜，如牛，綿羊，豬，山羊，馬和水牛。特別較佳的家畜是牛和豬。
因此，根據另一個特別較佳的實施方案，本發明組成物用於豬。
根據一個特別較佳的實施方案，本發明組成物用於牛。
該投予可以預防性或以其他治療性方式進行。
原則上，本文所述的組成物可以通過不同的途徑施用於標的生物體。然而較佳地，它們可以腸胃外給藥，特別是通過注射（例如皮下，肌內，靜脈內，腦內，腹膜內）給藥。皮下或肌肉注射是較佳的。
典型劑量在約5至20mg / kg目標動物的範圍內。關於治療方案，一次施用可能已經足夠，但可能需要兩天或更多天的施用，取決於個別狀況和疾病。通常，施用是連續幾天。
根據本發明的藥物的特徵在於活性物質的良好溶解性和在醫藥相關儲存條件下的良好的化學和物理穩定性。此外，它們在動物中具有良好的耐受性和合適的血清動力學，特別是在胃腸外給藥時。
實施例
所有實施例中的百分比均以％（重量/體積）表示。在所有實施例中，用所需量的酸(標示為“q.s.”)將pH值調整至pH 4.4至4.8。
實施例1 20% 普多沙星 (使用22.73% 普多沙星三水合物) q.s. (7 至3%) 葡萄糖酸內酯 0.1% 檸檬酸 加至100% 水
實施例2 20% 普多沙星 (使用22.73% 普多沙星三水合物) q.s. (7至13%) 葡萄糖酸內酯 0.3% 檸檬酸 加至100% 水
實施例3 10% 普多沙星 (使用22.73% 普多沙星三水合物) q.s. (4至8%) 葡萄糖酸內酯 0.1% 檸檬酸 加至100% 水
實施例4 5% 普多沙星 (使用22.73% 普多沙星三水合物) q.s. (1至5%) 葡萄糖酸內酯 0.1% 檸檬酸 加至100% 水
實施例5 20% 普多沙星 (使用22.73% 普多沙星三水合物) q.s. (7至13%) 葡萄糖酸內酯 0.1% 硫甘油 加至100% 水
實施例6 20% 普多沙星 (使用22.73% 普多沙星三水合物) q.s. (7至13%) 葡萄糖酸內酯 0.3% 硫甘油 加至100% 水
實施例7 20% 普多沙星 (使用22.73% 普多沙星三水合物) q.s. (7至13%) 葡萄糖酸內酯 0.1% 檸檬酸 0.1% 硫甘油 加至100% 水
實施例8 20% 普多沙星 (使用22.73% 普多沙星三水合物) q.s. (3至5%) 甲磺酸 0.1% 檸檬酸 加至100% 水
實施例9 15% 普多沙星 (使用22.73% 普多沙星三水合物) q.s. (2至4%) 甲磺酸 0.1% 檸檬酸 加至100% 水
實施例10 5% 普多沙星 (使用22.73% 普多沙星三水合物) q.s. (0.5至2%) 甲磺酸 0.1% 檸檬酸 加至 100% 水
穩定性試驗
:
1. 顏色:
配製物在不同溫度下儲存。目視觀察各溶液的顏色並拍攝照片以供記錄：
表1
*類似組成物含0.05、0.1或0.15 % (重量/體積)之各別抗氧化劑
2. 儲存穩定性(HPLC):
製備含有檸檬酸或硫甘油作為抗氧化劑的配製物，置於高溫儲存並藉由HPLC（普多沙星和副產物的含量）分析。
表2: 實施例1 (0.1% 檸檬酸)之結果
NK =未界定之雜質(% 相對於活性成分); RT = 滯留時間(分鐘)
根據實施例1製備的配製物在檸檬酸和普多沙星的含量方面保持穩定。8週後普多沙星濃度的變化在分析方法的容許範圍內，8週後的濃度完全在預期的規格範圍內。然而，在8週後，在40℃下可以發現低的雜質含量。儲存在40°C的配製物保持黃色，顏色不變（不變色），顯示所選抗氧化劑的適用性。
表5: 實施例5 (0.1 % 硫甘油)之結果
NK=未界定之雜質(% 相對於活性成分)；RT=滯留時間(分鐘) “硫甘油2” = 硫甘油之氧化產物
根據實施例5製備的配製物在普多沙星的含量方面保持穩定，但如對於抗氧化劑所預期的，硫甘油1從0.1％降低至0.02％。8週後，40°C時可發現低含量雜質。儲存在40℃的配方保持黃色，顏色不變（無變色），顯示所選抗氧化劑的適用性。
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Claims (11)
- 一種液態組成物，其包含: (a) 1至30 % (重量/體積)之普多沙星 (b) 1至30 % (重量/體積)之酸 (c) 0.01至1 % (重量/體積)之抗氧化劑，其選自檸檬酸及硫甘油 (d) 若適當，其他醫藥助劑及/或添加劑 (e) 及作為溶劑之水。
- 根據請求項1之液態組成物，其中抗氧化劑為檸檬酸。
- 根據請求項1之液態組成物，其中抗氧化劑為硫甘油。
- 根據前述請求項中任一項之液態組成物，其中抗氧化劑以0.05至 0.5 % (重量/體積)之濃度存在。
- 根據請求項4之液態組成物，其中抗氧化劑以0.05 至0.3 % (重量/體積)之濃度存在。
- 根據前述請求項中任一項之液態組成物，其中該酸選自下列組成之群組：葡糖酸、葡萄糖酸內酯、甲磺酸、乳酸、丙酸。
- 根據前述請求項中任一項之液態組成物，其中該酸為葡糖酸或葡萄糖酸內酯。
- 根據前述請求項中任一項之液態組成物，其為溶液。
- 根據前述請求項中任一項之液態組成物，其具有pH 2 至5。
- 根據前述請求項中任一項之液態組成物，其用作可注射之藥物。
- 根據請求項11之液態組成物，其用於治療動物之細菌感染。
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| DE19854357A1 (de) | 1998-11-25 | 2000-05-31 | Bayer Ag | Semi-Hydrochlorid von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo/4.3.0/ -nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
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| DE102004015981A1 (de) | 2004-04-01 | 2005-10-20 | Bayer Healthcare Ag | Neue kirstalline Form von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
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