WO2015198456A1 - 安定性を改善したロクロニウム製剤 - Google Patents
安定性を改善したロクロニウム製剤 Download PDFInfo
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Abstract
Description
このように、本発明のロクロニウム製剤は、熱安定性に優れているため、特に、室温保存可能な製剤であってもよい。
また、前記の通り、本発明では、注射剤において、注入時痛や血管刺激も防止できる。そのため、本発明には、ロクロニウムと緩衝液とを含有するロクロニウム注射製剤のpHを3.5以下に調整することで、ロクロニウム注射製剤の注入時痛及び血管刺激を共に防止又は抑制し、かつ40℃で6ヶ月間保存後におけるロクロニウムの類縁物質Cの生成率が5%以下となるよう、ロクロニウム注射製剤の安定性を向上又は改善する方法も含む。
さらに、これらの方法では、製剤(ロクロニウム製剤又はロクロニウム注射製剤)を、さらに、室温保存可能としてもよい。
このように、本発明の製剤は、安定性及び安全性のいずれにおいても優れており、極めて実用性に優れる製剤である。
で示されるロクロニウム臭化物(化学名:(+)-(17β-acetoxy-3α-hydroxy-2β-morpholino-5α-androstan-16β-yl)-1-allyl-1-pyrrolidinium bromide)である。
本発明のロクロニウム製剤の投与経路は、特に限定されないが、注射剤を用いた非経口投与の場合、静脈内、動脈内、皮下、皮内、筋肉内、腹腔内投与等が好ましく、患者の年齢や病状その他の条件に応じて適宜選択することが好ましい。
また、ロクロニウム製剤を40℃で6ヶ月間保存したとき、ロクロニウムの類縁物質Cの生成率は、5%以下(例えば、0~4.9%)、好ましくは4%以下(例えば、0.01~3.9%)、さらに好ましくは3%以下(例えば、0.1~2.9%)程度とすることもできる。
なお、前記の類縁物質Cの生成率が5%以下であれば、医薬品として室温保存が可能になると判断される。ここで、室温とは1~30℃(日本薬局方)を指す。
このように、本発明のロクロニウム製剤は、類縁物質Cの生成率を、3ヶ月の保存では室温保存が可能な5%よりもはるかに低く抑えることができ、また、6ヶ月という長期保存によっても十分に室温保存に耐えうる5%以下とすることができ、極めて優れた安定性を有している。
日局pH測定法に従い、20~30℃で測定した。
USPのHPLC試験法に準じて測定した。
投与開始前にウサギ(雄性JW系、14週齢、6匹(1群:3匹))の投与部位を電気バリカンで刈毛し、左耳介後静脈の中央部付近で、小血管分枝の少ない部分を3cm選び(貯留部位)、その両端に油性マジックで印をつけ、この2ヶ所を心臓側及び末梢側止血部位とした。投与当日、セボフルラン麻酔下(導入:5%、維持:3%)で末梢側止血部位より末梢側へ5mmの所に油性マジックで印をつけ、注射針刺入部位とした。
投与時には注射針刺入部位の末梢側にクレンメを取付け、血流を止めて注射針を注射針刺入部位より心臓側に向けて末梢側止血部位まで刺入した。被験液を0.025mL注入し、局所血管が被験物質で満たされたことを確認した。続いて、心臓側止血部位をクレンメで止血し、さらに被験液を0.025mL注入し、末梢側止血部位をクレンメで止血した。次に2.5w/v%スガマデクス溶液0.2mLを右耳介静脈より急速投与した。被験液を3分間貯留させた後、クレンメをはずし、動物の自発呼吸を確認後に麻酔を解除した。なお、被験液の各投与日における貯留部位、注射針刺入部位はできる限り同一部位とした。
投与回数:1日1回、8日間連続
投与容量:0.05mL/site/日
なお、投与方法、投与回数、投与期間及び投与容量は、府川らの方法(日本薬理学雑誌71:307~315,1975)に従って選択した。
(血栓)
-:血栓なし(0mm)
+:小さい血栓(1~4mm)
++:中等度の血栓(5~14mm)
+++:大きい血栓(15mm以上)
-:変化なし
+:軽度の炎症(幅3cmの止血部位に限局)
++:中等度の炎症(止血部位を中心に耳介の1/3にわたる)
+++:強度の炎症(耳介の1/2~全体にわたる)
ラット(雄性SD系8週齢、1群:11匹)にウレタンを1.1g/kgの用量で腹腔内投与後、処置部付近の毛刈りを行い、皮膚を切開し大腿動脈付近の血管を露出した。あらかじめ先を細くしたPFAチューブを、浅後腹壁動脈に逆行性に大腿動脈との枝分かれ部分まで約2cm挿入した。左後部半腱様筋に同心針電極(26G)を挿入した。手術終了後、ラットは約37℃に保温した。投与前値(Baseline)を30秒間測定した後、PFAチューブを通して投与速度0.8mL/分で各被験液を50μL投与し、投与開始30秒間の筋電図(EMG)を測定した。各被験液は投与間隔を1時間以上あけて繰り返し投与した。なお、被験液投与前および全被験液投与後に1%プロポフォール「マルイシ」を投与し、筋収縮が認められた個体のみ、採用した。筋電図の解析はパワーラブ(16sp、ADInstruments)を用い、生波形を整流化したものを積分することで定量化した(μV・s)。結果は投与前値を100%としたときの割合で示した。
注射用水にグリシン0.06g、塩化ナトリウム0.67g、0.1M HCl 30g、ロクロニウム臭化物1.0gを加えて溶解させ、注射用水で容積を100mLに調節した。
得られた製剤のpHは2.0であった。この製剤を、40℃で3ヶ月及び6ヶ月保存した後、pHおよび類縁物質Cの生成率を測定したところ、pHはいずれも2.0、類縁物質Cの生成率は、それぞれ、1.24%(3ヶ月保存後)、2.52%(6ヶ月保存後)であった。
注射用水にグリシン0.55g、塩化ナトリウム0.50g、0.1M HCl 30g、ロクロニウム臭化物1.0gを加えて溶解させ、注射用水で容積を100mLに調節した。
得られた製剤のpHは3.0であった。この製剤を、40℃で3ヶ月及び6ヶ月保存した後、pHおよび類縁物質Cの生成率を測定したところ、pHはいずれも3.0、類縁物質Cの生成率は、それぞれ、0.77%(3ヶ月保存後)、1.58%(6ヶ月保存後)であった。
注射用水にグリシン4.58g、0.1M HCl 30g、ロクロニウム臭化物1.0gを加えて溶解させ、注射用水で容積を100mLに調節した。
得られた製剤のpHは4.0であった。この製剤を、実施例1と同様にして3ヶ月及び6ヶ月保存した後、pHおよび類縁物質Cの生成率を測定したところ、pHはいずれも4.0、類縁物質Cの生成率は、それぞれ、2.81%(3ヶ月保存後)、5.36%(6ヶ月保存後)であった。
市販のロクロニウム製剤(酢酸緩衝液、酢酸イオンとして0.15M、pH4.0)と同じ組成としたこと以外は、実施例1と同様の手順で調製した製剤を、実施例1と同様にして3ヶ月及び6ヶ月保存した後、pHおよび類縁物質Cの生成率を測定したところ、pHはいずれも4.0、類縁物質Cの生成率は、それぞれ、2.53%(3ヶ月保存後)、5.46%(6ヶ月保存後)であった。
注射用水にグリシン1.17g、塩化ナトリウム0.37g、0.1M HCl 45g、ロクロニウム臭化物1.0gを加えて溶解させ、注射用水で容積を100mLに調節した。
得られた製剤のpHは3.0であった。この製剤を、121℃で20分間熱処理した後、pHおよび類縁物質Cの生成率を測定したところ、pHは3.0、類縁物質Cの生成率は0.28%であった。
実施例2で得られた製剤(pH3.0)を、実施例3と同様にして熱処理した後、pHおよび類縁物質Cの生成率を測定したところ、pHは3.0、類縁物質Cの生成率は0.23%であった。
注射用水にグリシン0.18g、塩化ナトリウム0.64g、0.1M HCl 20g、ロクロニウム臭化物1.0gを加えて溶解させ、注射用水で容積を100mLに調節した。
得られた製剤のpHは3.0であった。この製剤を、実施例3と同様にして熱処理した後、pHおよび類縁物質Cの生成率を測定したところ、pHは3.1、類縁物質Cの生成率は0.23%であった。
比較例1で得られた製剤(pH4.0)を、実施例3と同様にして熱処理した後、pHおよび類縁物質Cの生成率を測定したところ、pHは4.0、類縁物質Cの生成率は0.75%であった。
注射用水に塩化ナトリウム0.90g、0.1M HCl 15g、ロクロニウム臭化物1.0gを加えて溶解させ、注射用水で容積を100mLに調節した。
得られた製剤のpHは3.0であった。この製剤を、実施例3と同様にして熱処理した後、pHを測定したところ、pHは3.3であった。
注射用水にグリシン0.55g、塩化ナトリウム0.50g、0.1M HCl 51g、ロクロニウム臭化物1.0gを加えて溶解させ、注射用水で容積を100mLに調節した。
得られた製剤のpHは2.5であった。この製剤を、実施例3と同様にして熱処理した後、pHおよび類縁物質Cの生成率を測定したところ、pHは2.5、類縁物質Cの生成率は0.10%であった。
注射用水にグリシン0.55g、塩化ナトリウム0.50g、0.1M HCl 38g、ロクロニウム臭化物1.0gを加えて溶解させ、注射用水で容積を100mLに調節した。
得られた製剤のpHは2.8であった。この製剤を、実施例3と同様にして熱処理した後、pHおよび類縁物質Cの生成率を測定したところ、pHは2.8、類縁物質Cの生成率は0.14%であった。
注射用水にグリシン0.55g、塩化ナトリウム0.50g、0.1M HCl 27g、ロクロニウム臭化物1.0gを加えて溶解させ、注射用水で容積を100mLに調節した。
得られた製剤のpHは3.2であった。この製剤を、実施例3と同様にして熱処理した後、pHおよび類縁物質Cの生成率を測定したところ、pHは3.2、類縁物質Cの生成率は0.27%であった。
注射用水にグリシン0.55g、塩化ナトリウム0.50g、0.1M HCl 21g、ロクロニウム臭化物1.0gを加えて溶解させ、注射用水で容積を100mLに調節した。
得られた製剤のpHは3.5であった。この製剤を、実施例3と同様にして熱処理した後、pHおよび類縁物質Cの生成率を測定したところ、pHは3.5、類縁物質Cの生成率は0.31%であった。
注射用水に0.1M塩酸15g、塩化ナトリウム0.45g、フタル酸水素カリウム0.42g、ロクロニウム臭化物0.50gを加えて溶解させ、注射用水で容積を50mLに調節した。
得られた製剤のpHは3.0であった。この製剤を、実施例3と同様にして熱処理した後、pHおよび類縁物質Cの生成率を測定したところ、pHは3.0、類縁物質Cの生成率は0.25%であった。
注射用水に塩化ナトリウム0.45g、クエン酸水和物0.34g、0.1M水酸化ナトリウム溶液2.46g、ロクロニウム臭化物0.50gを加えて溶解させ、注射用水で容積を50mLに調節した。
得られた製剤のpHは3.0であった。この製剤を、実施例3と同様にして熱処理した後、pHおよび類縁物質Cの生成率を測定したところ、pHは3.0、類縁物質Cの生成率は0.19%であった。
注射用水に塩化ナトリウム0.45g、酒石酸0.23g、0.1M水酸化ナトリウム溶液2.50g、ロクロニウム臭化物0.50gを加えて溶解させ、注射用水で容積を50mLに調節した。
得られた製剤のpHは3.0であった。この製剤を、実施例3と同様にして熱処理した後、pHおよび類縁物質Cの生成率を測定したところ、pHは3.0、類縁物質Cの生成率は0.28%であった。
実施例6で得られたロクロニウム製剤(pH2.5)及び市販のロクロニウム製剤[商品名:エスラックス(登録商標)静注50mg/5.0mL、酢酸緩衝液、酢酸イオンとして0.15M、pH4.0](比較例2)のそれぞれについて、血管刺激性を評価した。
実施例2で得られたロクロニウム製剤(pH3.0)、実施例6で得られたロクロニウム製剤(pH2.5)、及び比較例2のそれぞれについて、注入時痛を評価した。
Claims (13)
- ロクロニウムと緩衝液とを含有し、pHが3.5以下であるロクロニウム製剤。
- pHが2.5~3.5である請求項1記載のロクロニウム製剤。
- pHが2.8~3.2である請求項1又は2記載のロクロニウム製剤。
- 緩衝液が、ギ酸緩衝液、酢酸緩衝液、クエン酸緩衝液、酒石酸緩衝液、フタル酸緩衝液、リン酸緩衝液、クエン酸・リン酸緩衝液、及びグリシン緩衝液から選択された少なくとも1種である請求項1~3のいずれかに記載のロクロニウム製剤。
- 緩衝液が、クエン酸・水酸化ナトリウム緩衝液、酒石酸・水酸化ナトリウム緩衝液、フタル酸水素カリウム・塩酸緩衝液、及びグリシン・塩酸緩衝液から選択された少なくとも1種である請求項1~4のいずれかに記載のロクロニウム製剤。
- pHが2.5~3.5であり、緩衝液がグリシン・塩酸緩衝液であり、緩衝液の濃度が0.01M以上である請求項1~5のいずれかに記載のロクロニウム製剤。
- 40℃で6ヶ月間保存後、ロクロニウムの類縁物質Cの生成率が5%以下である請求項1~6のいずれかに記載のロクロニウム製剤。
- 注射剤である請求項1~7のいずれかに記載のロクロニウム製剤。
- 40℃で6ヶ月間保存後、ロクロニウムの類縁物質Cの生成率が5%以下であり、かつ注入時痛及び血管刺激が共に防止又は抑制された請求項8記載のロクロニウム製剤。
- 室温保存可能である請求項1~9のいずれかに記載のロクロニウム製剤。
- ロクロニウムと緩衝液とを含有するロクロニウム製剤のpHを3.5以下に調整することで、40℃で6ヶ月間保存後におけるロクロニウムの類縁物質Cの生成率が5%以下となるよう、ロクロニウム製剤の安定性を向上又は改善する方法。
- ロクロニウムと緩衝液とを含有するロクロニウム注射製剤のpHを3.5以下に調整することで、ロクロニウム注射製剤の注入時痛及び血管刺激を共に防止又は抑制し、かつ40℃で6ヶ月間保存後におけるロクロニウムの類縁物質Cの生成率が5%以下となるよう、ロクロニウム注射製剤の安定性を向上又は改善する方法。
- 製剤を、さらに、室温保存可能とする請求項11又は12に記載の方法。
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CN108676052B (zh) * | 2018-08-16 | 2020-05-22 | 北京市新里程医药科技有限公司 | 一种罗库溴铵的制备方法及其药物组合物 |
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CN106950314A (zh) * | 2017-04-17 | 2017-07-14 | 南京健友生化制药股份有限公司 | 一种检测罗库溴铵或其注射液中烯丙基溴含量的方法 |
WO2023275157A1 (en) | 2021-07-02 | 2023-01-05 | Fresenius Kabi Austria Gmbh | Aqueous, room-temperature stable rocuronium composition |
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KR101692884B1 (ko) | 2017-01-04 |
CN107073007A (zh) | 2017-08-18 |
KR20160086953A (ko) | 2016-07-20 |
NZ725625A (en) | 2018-10-26 |
US10869876B2 (en) | 2020-12-22 |
BR112016026042B1 (pt) | 2022-11-16 |
CA2950873C (en) | 2022-08-23 |
CN113350274A (zh) | 2021-09-07 |
IL249217A0 (en) | 2017-02-28 |
IL249217B (en) | 2021-10-31 |
PH12016502418A1 (en) | 2017-03-06 |
JPWO2015198456A1 (ja) | 2017-04-20 |
US20170128463A1 (en) | 2017-05-11 |
EP3162370A1 (en) | 2017-05-03 |
BR112016026042A8 (pt) | 2021-07-20 |
JP5684954B1 (ja) | 2015-03-18 |
RU2017102325A3 (ja) | 2018-07-31 |
RU2017102325A (ru) | 2018-07-31 |
CA2950873A1 (en) | 2015-12-30 |
EP3162370A4 (en) | 2017-11-15 |
AU2014398349B2 (en) | 2020-08-06 |
RU2705996C2 (ru) | 2019-11-13 |
MX2016016148A (es) | 2017-04-25 |
SG11201609790SA (en) | 2017-01-27 |
BR112016026042A2 (ja) | 2017-08-15 |
AU2014398349A1 (en) | 2016-12-01 |
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