JP2021536485A - 注射可能な徐放性の抗生物質製剤 - Google Patents
注射可能な徐放性の抗生物質製剤 Download PDFInfo
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- JP2021536485A JP2021536485A JP2021512900A JP2021512900A JP2021536485A JP 2021536485 A JP2021536485 A JP 2021536485A JP 2021512900 A JP2021512900 A JP 2021512900A JP 2021512900 A JP2021512900 A JP 2021512900A JP 2021536485 A JP2021536485 A JP 2021536485A
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Abstract
Description
フロルフェニコールとN−メチルピロリドン(NMP)は、Sigma−Aldrich社(イスラエル)から購入された。ポロキサマー407、188、338、及び237は、BASFの現地代理店から入手した。アモキシシリン、タイロシン、Klucel(登録商標)ポリマー(ヒドロキシプロピルセルロース)、PEG 400、及びプロピレングリコールは、製薬企業からの寄贈品である。水はカラムで精製し、使用前に蒸留した。塩化ナトリウムは、Merck社(イスラエル)から購入された。
ゲル化は、0.5〜1mLの製剤を含むガラスチューブを、温度を上げながら反転させることによって、測定した。反転時に製剤の流下が止まった温度を一次ゲル化点とした。或いは、予備スクリーニングのために、温度を40℃に上げ、製剤がゲル状になるまでの所要時間を記録した。
HPLC、HP1090装置、及び224nmでの吸光度を測定するUV検出器を使用して、フロルフェニコールを測定した。A C−18 250x4.6 5μmのカラムを使用し、1.2ml/minで溶出し、ACN:DDWが25:75の移動相を使用した。フロルフェニコールは、これらの条件下で4〜4.5分で溶出した。
A.中国特許出願CN103202802に開示された製剤の効率を評価するために、前記公報の実施例7(30%フロルフェニコール)を記載された条件下で再現して試験した。この公報には、使用したヒプロメロースのグレードに関するガイダンスがほとんどないため、試験では低濃度で見かけ粘度が20cP未満であった2つのグレード(HPMC K4M及びHPMC K15M)を別々に試験した。簡単に説明すると、ポロキサマーを正確に秤量し、冷却し、4℃の大容量の冷水中で溶解した後、ヒドロキシプロピルメチルセルロース(HPMC)を添加した。残りの賦形剤をストック溶液から提供し、残りの水分を添加して、完全に混合した。総量25gの製剤サンプルを調製し、HPMC K4Mを使用して調製したサンプルをサンプル調製物1.1とし、HPMC K15Mを使用して調製したサンプルをサンプル調製物1.2とした。
国際特許出願WO2012131678に開示されている別の既知のゲルベースの徐放性製剤と比較して、本発明の原理に係るフロルフェニコール徐放性製剤の利点を評価するために、30重量%のフロルフェニコールを含むゲルを作製した。共溶媒NMP、セルロース系物質であるヒドロキシプロピルセルロース、及びそれらの相乗的な組み合わせの効果を分離して検討した。全ての製剤は、25℃〜35℃の間でゲル化を示し(個々のデータは以下に示される)、上記方法に従って放出プロファイルを評価した。製剤は、それぞれの放出プロファイルデータとともに、以下の表にまとめた。
選択した共溶媒であるNMPが製剤に及ぼす影響を評価するために、調製物2.1に従ったゲルを作製し、NMP含有量を5から20重量%まで変化させて、調製物3.1(5重量%)及び3.2(20重量%)を得た。
追加の共溶媒が製剤に及ぼす影響を評価するために、調製物2.1に従ってゲルを作製し、NMPをDMSO(調製物4.1)、プロピレングリコール(調製物4.2)、PEG 400(調製物4.3)又はエタノール(調製4.4)のいずれかで置換した。
本発明の生体内での効果を実証するために、ブタに対するフロルフェニコールの単回投与により、長期かつ有効な血漿レベルを実証する薬物動態試験を行った。この試験は、エルサレムのヘブライ大学の動物研究に関する内部倫理委員会によって承認された。合計6匹の動物を、2匹の3〜4ヶ月齢の雌ブタと一緒に使用した。各ブタの頸静脈に20Gの中心静脈カテーテルを挿入して、採血を容易にした。全ての動物は、試験の第1の治療群において、調製物2.1の40mg/kgの単発治療を受け、そして、Nuflor(登録商標)(Merck Animal Health−NMPにおける、フロルフェニコールが30%の溶液)20mg/kgを48時間ごとに2回投与するか、2週間のウォッシュアウト期間の後に、第2の治療群において別の試験治療を行った。
超高負荷量の薬物を処理するシステムの能力を評価するために、フロルフェニコールの以下の製剤も本明細書に記載の方針に沿って調製した。調製物6.1は約33重量%、調製物6.2は約36重量%、調製物6.3は約39重量%のフロルフェニコールを含んでいた。
さらに、47.5重量%の負荷量で組成物を調製した。実施例6と同様に、篩にかけたフロルフェニコールを用いた。製剤及び結果を以下の表8にまとめた。
本発明の生体内での効果をさらに実証するために、別の薬物動態試験を実施して、ブタに対するフロルフェニコールの単回投与による長期かつ有効な血漿レベルを実証した。
本発明に係る組成物が他の抗生物質を放出する能力を実証するために、30重量%のアモキシシリンを含む製剤を調製した。調製物9.1は、共溶媒と、有機溶媒に少なくとも部分的に溶解するセルロース誘導体(ヒドロキシプロピルセルロース)との両方を含み、調製物9.2は、ヒドロキシプロピルセルロースのみを含み、調製物9.3は、追加の賦形剤を含まない。製剤は、フロルフェニコールについて記載された手順に沿って調製した。
本発明に係る組成物が他の抗生物質を放出する能力をさらに実証するために、タイロシン15重量%を含む製剤を調製した。調製物10.1は、共溶媒と、有機溶媒に少なくとも部分的に溶解するセルロース誘導体(ヒドロキシプロピルセルロース)との両方を含み、調製物10.2は、ヒドロキシプロピルセルロースのみを含み、調製物10.3は、追加の賦形剤を含まない。製剤は、フロルフェニコールについて記載された手順に沿って調製した。
Claims (18)
- 生物活性剤、ポロキサマー、水性担体及び有機共溶媒を含む医薬組成物であって、前記組成物は、室温で注射可能な組成物であり、ただし、前記活性剤の濃度が35重量%未満である場合、有機溶媒に少なくとも部分的に溶解するセルロース系物質をさらに含む、医薬組成物。
- 前記生物活性剤の濃度が10重量%〜35重量%である、請求項1に記載の医薬組成物。
- 前記生物活性剤の濃度が35重量%を超え、前記組成物は、有機溶媒に少なくとも部分的に溶解するセルロース系物質を含まない、請求項1に記載の医薬組成物。
- 前記生物活性剤の濃度が35重量%を超え、前記組成物は、有機溶媒に少なくとも部分的に溶解するセルロース系物質をさらに含む、請求項1に記載の医薬組成物。
- 前記生物活性剤の濃度が35重量%〜50重量%である、請求項3又は4のいずれか1項に記載の医薬組成物。
- 前記生物活性剤が、フロルフェニコール、リンコマイシン、タイロシン、メトロニダゾール、チルミコシン、スピラマイシン、エリスロマイシン、ツラスロマイシン、チアムリン、アンピシリン、アモキシシリン、クラブラン酸、ペニシリン、ストレプトマイシン、トリメトプリム、スルホンアミド、スルファメトキサゾール、プレウロムチリン、アビロシン、タイルバロシン、ドキシサイクリン及びオキシテトラサイクリンから選択される、請求項1〜5のいずれか1項に記載の医薬組成物。
- 前記生物活性剤がフロルフェニコールである、請求項1〜6のいずれか1項に記載の医薬組成物。
- 前記生物活性剤が前記組成物中に約25重量%〜約50重量%の負荷量で存在する、請求項6に記載の医薬組成物。
- 前記有機共溶媒が約5〜約15重量%の量で存在する、請求項1〜8のいずれか1項に記載の医薬組成物。
- 有機溶媒に少なくとも部分的に溶解する前記セルロース系物質がヒドロキシプロピルセルロースである、請求項1〜9のいずれか1項に記載の医薬組成物。
- 前記有機溶媒がN−メチルピロリドン(NMP)、ジメチルスルホキシド(DMSO)、PEG 400、プロピレングリコール及びエタノールからなる群から選択される、請求項1〜10のいずれか1項に記載の医薬組成物。
- 前記有機溶媒がN−メチルピロリドンである、請求項1〜11のいずれか1項に記載の医薬組成物。
- 前記有機溶媒がN−メチルピロリドンであり、有機溶媒に少なくとも部分的に溶解する前記セルロース系物質がヒドロキシプロピルセルロースであり、さらに、前記生物活性剤が25重量%〜50重量%の濃度のフロルフェニコールである、請求項1〜12のいずれか1項に記載の医薬組成物。
- 前記有機溶媒がN−メチルピロリドンであり、前記生物活性剤がフロルフェニコールであり、さらに、前記フロルフェニコールの濃度が35重量%〜50重量%である、請求項1〜13のいずれか1項に記載の医薬組成物。
- 請求項1〜14のいずれか1項に記載の医薬組成物であって、前記組成物中の薬理学的に有効な用量の抗生物質を非ヒト動物に投与することにより、前記動物の動物感染症の治療に使用するための、医薬組成物。
- 治療コースごとに前記非ヒト動物に単回投与される、請求項15に記載の医薬組成物。
- 前記投与が筋肉内注射又は皮下注射を含む、請求項15〜16のいずれか1項に記載の医薬組成物。
- 前記感染症がブタ病原体によって引き起こされる、請求項15〜17のいずれか1項に記載の医薬組成物。
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CN114306211B (zh) * | 2021-12-29 | 2023-12-22 | 中国药科大学 | 一种甘草酸超分子自组装温敏互穿网络凝胶及其制备方法和应用 |
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US3740421A (en) | 1966-09-19 | 1973-06-19 | Basf Wyandotte Corp | Polyoxyethylene-polyoxypropylene aqueous gels |
US5035891A (en) | 1987-10-05 | 1991-07-30 | Syntex (U.S.A.) Inc. | Controlled release subcutaneous implant |
DE69636626T2 (de) | 1995-07-28 | 2007-08-30 | Genzyme Corp., Cambridge | Biologische abbaubare multiblokhydrogene und ihre verwendung wie trägerstoffe fur kontrollierte freisetzung pharmakologisch activen werstoffe und gewebekontaktmaterialen |
US6316011B1 (en) | 1998-08-04 | 2001-11-13 | Madash, Llc | End modified thermal responsive hydrogels |
JP4644397B2 (ja) * | 2001-09-05 | 2011-03-02 | 信越化学工業株式会社 | 難溶性薬物を含む医薬用固形製剤の製造方法 |
GB0205253D0 (en) * | 2002-03-06 | 2002-04-17 | Univ Gent | Immediate release pharmaceutical granule compositions and a continuous process for making them |
US6790867B2 (en) * | 2002-05-20 | 2004-09-14 | Schering-Plough Animal Health Corporation | Compositions and method for treating infection in cattle and swine |
US20040247672A1 (en) | 2003-05-16 | 2004-12-09 | Alkermes Controlled Therapeutics, Inc. | Injectable sustained release compositions |
NZ555774A (en) * | 2004-12-21 | 2010-09-30 | Intervet Int Bv | Injectable veterinary composition comprising florfenicol, a pyrrolidone solvent and a cosolvent selected from diethyleneglycol monoethyl ether and / or tetrahydrofurfuryl alcohol polyethylene glycol ether |
US9107815B2 (en) | 2008-02-22 | 2015-08-18 | Allergan, Inc. | Sustained release poloxamer containing pharmaceutical compositions |
US8614315B2 (en) * | 2009-12-25 | 2013-12-24 | Mahmut Bilgic | Cefdinir and cefixime formulations and uses thereof |
CN104997803B (zh) * | 2010-07-22 | 2019-07-09 | 雷文制药有限公司 | 包含使用磁偶极子稳定化溶液的治疗或改善疾病并增强表现的方法和组合物 |
US11052043B2 (en) * | 2011-03-28 | 2021-07-06 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Sustained-release injectable formulation |
CN103202802A (zh) * | 2013-04-22 | 2013-07-17 | 南京农业大学 | 氟苯尼考注射用原位凝胶及其制备方法 |
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EP3846781A1 (en) | 2021-07-14 |
EA202190672A1 (ru) | 2021-07-01 |
CA3111385A1 (en) | 2020-03-12 |
CL2021000536A1 (es) | 2021-08-20 |
BR112021004192A2 (pt) | 2021-05-25 |
US20210315803A1 (en) | 2021-10-14 |
MX2021002492A (es) | 2021-09-08 |
KR20210099553A (ko) | 2021-08-12 |
WO2020049570A1 (en) | 2020-03-12 |
PH12021550477A1 (en) | 2021-11-22 |
CO2021004131A2 (es) | 2021-07-30 |
PE20211334A1 (es) | 2021-07-22 |
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