JP6189437B2 - 注射用抗生物質製剤およびその使用方法 - Google Patents
注射用抗生物質製剤およびその使用方法 Download PDFInfo
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- JP6189437B2 JP6189437B2 JP2015523049A JP2015523049A JP6189437B2 JP 6189437 B2 JP6189437 B2 JP 6189437B2 JP 2015523049 A JP2015523049 A JP 2015523049A JP 2015523049 A JP2015523049 A JP 2015523049A JP 6189437 B2 JP6189437 B2 JP 6189437B2
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- Endocrinology (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pregnancy & Childbirth (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description
この研究において、100mLの透明なPETバイアルに充填され室温に保存されたペネタマート懸濁液(好ましい薬剤処方に準拠)は、16Gの皮下注射針を備えた10mLの使い捨ての滅菌注射器を使用して、四週間の各週ごとに口を開けた。そのたびごとにサンプルの適当な量を取り出し、28日後に物理的、化学的および微生物学的特性について残りのサンプルを分析した。その結果は、ペネタマート懸濁液が室温で28日の期間にわたり頻回の口開け後に物理的および化学的に安定なままであることを示す。
本発明の他の態様によれば、微生物感染症の治療または予防用の実質的に本明細書に記載された組成物による動物の治療方法が提供され、ここで該方法には必要とする動物への該組成物の筋肉内または皮下注射が含まれる。
本発明のさらなる態様によれば;
a)均質な油の混合物を形成するために(i)容器中に油を供給するか、または(ii)容器中で油と界面活性剤を混合するかによって、油性ビヒクルを調製する段階;
b)油性ビヒクル中に有効剤を分散させる段階、
を含む、実質的に上述した組成物の製造方法が提供される。
短い休薬期間の例示
驚いたことに、組成物OT11PNTRTU‐aおよび‐bの粘度を制御することによって注射部位での組成物からの薬剤放出は、60時間と同等もしくは60時間より短い、または規制当局から要請されている信頼区間を考慮すれば72時間までの、乳中におけるWHPを達成するために十分なほど速いことが図3に示す通り見出だされた。
生物学的利用能の例示
図3は、種々の試験組成物、Mamyzin(登録商標)およびPenethaject(登録商標)についてのPNT10g投与後の乳中BP濃度を示す。再び、組成物OT11PNTRTU‐aおよび‐bは、Mamyzin(登録商標)の放出特性と一致することが見て取られる。
保存安定性の例示
PNTは、特許文献US4,446,144においてなされた主張にもかかわらず、すべての非水性製剤においては化学的に安定でないことが見出だされた。図14は、温度40℃および湿度無規制の条件において、プロピレングリコール中のPNT(OT11PNTRTU‐l)は、約二か月後に約30%(w/w)だけ分解するが、一方でPNTは、組成物OT11PNTRTU‐dおよび‐m中で約六か月間化学的に安定であることを示す。
物理的に安定な非水性PNT懸濁液の例示
ウシ乳房炎の治療にとって、注射用組成物中のPNT濃度は20%(w/v)以上になり得る。任意のさらなる賦形剤を含まないPNTと油のこのような懸濁液は、制御された実験室条件下または保存中に物理的に安定に思える一方で、典型的な運送および取扱い下で懸濁液は、固結する性質を示し得る。沈降および/または固結特性に関する初期の試験は、サンプルを現実の輸送条件に置くことによって実施した。より制御され簡便な試験は、特設の撹拌装置を使用して実施した。制御された実験室内実験は、実世界の条件の結果と一致することが見出だされた。
最終製剤の安定性はまだ完了していないが、しかし室温でのシェルフライフは少なくとも12月であると思われる。
好ましい実施形態の休薬期間を測定するために研究、すなわち実施例6を実施した。該研究では22頭の乳牛を使用し、それらに三日連続でペネタマート5g(15mL)を筋肉内注射した。最終の注射120時間後まで日に二回、全頭の乳牛より乳サンプルを採取した。搾乳12、36、48、60および72時間由来の乳は、残留ペニシリンについて分析した。図16に示された結果は、乳中残留ベンジルペニシリンが最終の注射約41時間後に、0.004mg/kgのMRL(最大残留基準値)よりも少なくなることを示す。これは、毎日二回の搾乳に基づけば、48時間の休薬期間を提供するであろう。
実施例6のMamyzin(登録商標)との生物学的同等性を判定するために研究を実施した。
製剤化プロセス
・トリアセチンの56%を適当な大きさの製造容器に添加する
・ベンジルアルコールとポリソルベート80を撹拌しながら添加する
・混合液を0.2μmの滅菌フィルテーを通して滅菌タンクの中にろ過する
・約55℃に加熱し、温度を点検しかつ温度を維持する
・Phospholipon H90を添加し、懸濁して十分に均質化する。均質性を点検する
・ペネタマートヨウ化水素酸塩(微粉化、無菌)を添加し、懸濁して十分に均質化する。均質性を点検する
・懸濁液を約25℃に冷却する。温度を点検する
・トリアセチンにより規定の容量にする
・均質な懸濁液に均質化し、均質性を点検する
この製剤処方およびプロセスは、少なくとも従来のPNT治療と同様に作用する、安定で固結しない注射用製品を製造した。
Claims (26)
- ペネタマート(PNT)またはその薬学的に許容される塩と、トリアセチンとを含む、筋肉内または皮下注射用のすぐに使える(RTU)急速放出性組成物。
- 固結防止剤を含む、請求項1に記載の組成物。
- 該固結防止剤が乳化剤または分散剤を含む、請求項2に記載の組成物。
- 該固結防止剤が界面活性剤を含む、請求項2に記載の組成物。
- 該界面活性剤が7〜16の親水親油バランス(HLB)を有する化合物より選択される、請求項4に記載の組成物。
- 該界面活性剤がポリソルベート80である、請求項5に記載の組成物。
- 乳化剤または分散剤が非脂溶性レシチンである、請求項3ないし5のいずれか一項に記載の組成物。
- 該非脂溶性レシチンがphospholipon H90である、請求項7記載の組成物。
- 該固結防止剤がトリアセチンを含む、請求項2ないし8のいずれか一項に記載の組成物。
- 該固結防止剤が非増粘性である、請求項2ないし9のいずれか一項に記載の組成物。
- 粘度が、温度20℃およびせん断速度1/sでカップシリンダー法により測定された3000mPas未満である、請求項1ないし10のいずれか一項に記載の組成物。
- 該ペネタマート(PNT)またはその薬学的に許容される塩が該組成物の55%(w/v)以下を構成する、請求項1ないし11のいずれか一項に記載の組成物。
- ペネタマート(PNT)またはその薬学的に許容される塩の濃度が15〜55%(w/v)である、請求項12に記載の組成物。
- 該組成物中のペネタマートまたはその薬学的に許容される塩の濃度が20〜35%(w/v)である、請求項13記載の組成物。
- 該組成物が液体形態である、請求項1ないし14のいずれか一項に記載の組成物。
- 該ペネタマート(PNT)またはその薬学的に許容される塩の粒径d50が8〜30ミクロンである、請求項1ないし15のいずれか一項に記載の組成物。
- 保存料を含む請求項1ないし16のいずれか一項に記載の組成物。
- 該保存料がベンジルアルコールである、請求項17に記載の組成物。
- 請求項1ないし18のいずれか一項に記載の組成物を含む注射器。
- ペネタマートまたはその薬学的に許容される塩5gを含む請求項19に記載の注射器。
- 微生物感染症の治療または予防のために、請求項1ないし18のいずれか一項に記載の組成物により非ヒト動物を治療する方法であって、それを必要とする動物に対する該組成物の筋肉内または皮下注射を含む方法。
- 該微生物感染症が前臨床または臨床乳房炎である、請求項21に記載の方法。
- 約三日間繰り返される一日当たりペネタマートまたはその薬学的に許容される塩5gの投与計画を含む、請求項21または22のいずれかに記載の方法。
- a)(i)トリアセチンを用意する段階、または、(ii)容器中でトリアセチンと固結防止剤とを混合して均質な混合液を形成する段階:および
b)ペネタマート(PNT)またはその薬学的に許容される塩を、前記トリアセチンまたは均質な混合液に分散する段階
を含む、請求項1ないし18のいずれか一項に記載の組成物の製造方法。 - 段階a)において保存料が前記トリアセチンまたは均質な混合液に添加される、請求項24に記載の製造方法。
- 段階b)において高せん断分散装置が使用される、請求項24または25に記載の製造方法。
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