JP2020073576A - 医薬製剤 - Google Patents
医薬製剤 Download PDFInfo
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- JP2020073576A JP2020073576A JP2020008235A JP2020008235A JP2020073576A JP 2020073576 A JP2020073576 A JP 2020073576A JP 2020008235 A JP2020008235 A JP 2020008235A JP 2020008235 A JP2020008235 A JP 2020008235A JP 2020073576 A JP2020073576 A JP 2020073576A
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Abstract
Description
水中のコルチコステロイド可溶性形態及び不溶性形態の双方を含む医薬組成物の形態で、この必要性の1つの解決策が、出された(PCT International Publication No.WO2014/116876)。コルチコステロイドの可溶性形態は、即時軽減をもたらし、一方、不溶性形態は、より長く持続する作用をもたらす。しかし、2014に、米国食品医薬品局(FDA)が、脊椎の硬膜外腔へのコルチコステロイドの注射の結果、視力喪失、脳卒中、麻痺、及び死亡などのまれであるが、重篤な有害作用が生じる可能性があるという警告を発した。これに応じて、経椎間孔注射に粒子状ステロイドを用いてはならないという勧告を含むMulti−Society Pain Workgroup(MPW)によって提案された17の安全勧告が承認された。経椎間孔注射は、注射部位の位置が炎症の推定される部位に最も近いため、鎮痛剤の投与の興味を引く経路である。したがって、作用の急速な開始及び長く持続する作用の双方をもたらすことができ、注射の3つの経路(経椎間孔、経椎弓間、及び仙骨)すべてが認められている、改善された医薬組成物の必要性が存在する。
本発明は、例えば、以下の項目を提供する。
(項目1)
可溶性コルチコステロイド及び少なくとも1つの粘度増強剤を含み、粘度が1kcP〜200kcPである水性医薬組成物。
(項目2)
前記可溶性コルチコステロイドが、デキサメタゾン、メチルプレドニゾロン、プレドニゾロン、及びトリアムシノロンアセトニドからなる群の塩及びエステルから選択される、項目1に記載の水性医薬組成物。
(項目3)
前記可溶性コルチコステロイドが、デキサメタゾンリン酸ナトリウム、メチルプレドニゾロンコハク酸ナトリウム、プレドニゾロンコハク酸ナトリウム、及びトリアムシノロンアセトニドリン酸エステルからなる群から選択される、項目2に記載の水性医薬組成物。
(項目4)
前記可溶性コルチコステロイドが、デキサメタゾンリン酸ナトリウムである、項目3に記載の水性医薬組成物。
(項目5)
前記の少なくとも1つの粘度増強剤が、ヒアルロン酸ナトリウム、ヒアルロン酸、架橋結合ヒアルロン酸、ポリビニルピロリドン、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルセルロース、及びグリセロールからなる群から選択される、項目1に記載の水性医薬組成物。
(項目6)
前記の少なくとも1つの粘度増強剤が、ヒアルロン酸ナトリウムである、項目5に記載の水性医薬組成物。
(項目7)
前記可溶性コルチコステロイドが、デキサメタゾンリン酸ナトリウムであり、前記少なくとも1つの粘度増強剤が、ヒアルロン酸ナトリウムである、項目1に記載の水性医薬組成物。
(項目8)
前記粘度増強剤が、2%w/v未満である、項目1に記載の水性医薬組成物。
(項目9)
さらに防腐剤及び/または麻酔剤を含む、項目1に記載の水性医薬組成物。
(項目10)
治療が必要な個体の炎症及び/または痛みを治療する方法であって、水性医薬組成物を前記個体に注射することを含み、前記製剤が、可溶性コルチコステロイド、及び少なくとも1つの粘度増強剤を含み、前記医薬組成物の粘度が1kcP〜200kcPである、前記方法。
(項目11)
前記水性医薬組成物が、硬膜外腔に注射される、項目10に記載の方法。
(項目12)
約0.5”/分の速度で前記硬膜外腔に前記水性医薬組成物を注射するために20N未満の力が用いられる、項目10に記載の方法。
(項目13)
1〜12週ごとに1回、前記水性医薬組成物が前記個体に注射される、項目10に記載の方法。
(項目14)
項目1に記載の水性医薬組成物を含むシリンジ。
可溶性コルチコステロイド
可溶性コルチコステロイドの非限定例としては、以下の塩またはエステル:デキサメタゾン、メチルプレドニゾロン、プレドニゾロン、及びトリアムシノロンアセトニドが挙げられる。可溶性コルチコステロイドは、一定範囲の溶解度を有してよいが、医薬製剤中で溶解することが十分な可溶性である。コルチコステロイドの溶解度は、塩またはエステルなどのその化学的形態によって、部分的に決定される。コルチコステロイドの可溶性形態としては、その塩、例えば、ナトリウム、リン酸塩、コハク酸塩、及びこれらの組み合わせが挙げられる。
粘度増強剤が、医薬組成物に含まれる。粘度増強剤は、医薬組成物が標的部位(例えば、個体の硬膜外腔)に投与される場合、製剤が、標的部位中の粘性のある製剤の循環の程度が低いため、標的部位により長くとどまるという利点をもたらす。粘度増強剤は、また、標的部位への活性薬剤の結合を促進し、局所的に薬剤吸収及び生物学的利用性を向上させる可能性がある。
本明細書に開示された医薬組成物と用いられる好適な緩衝剤としては、クエン酸、アスコルビン酸、グルコン酸、炭酸、酒石酸、コハク酸、酢酸またはフタル酸などの塩の有機酸塩;トリス、トメタミン(thomethamine)塩酸塩、またはリン酸緩衝剤が挙げられるが、これらに限定されない。いくつかの実施形態では、緩衝剤が生理学的に相溶性がある。
製剤のpHは、製剤中に存在する賦形剤によって本質的に与えてよい;代わりに、pH調整剤を用いてよい。医薬組成物に緩衝剤または単純酸もしくは塩基などのpH調整剤を添加し、pHを6〜8に維持することができる。例えば、pH調整剤の量は、一般に0.1〜10%である。いくつかの実施形態では、製剤のpHが、生理学的範囲内である。
製剤のオスモル濃度は、200mOsm/kg〜350mOsm/kg、250mOsm/kg〜300mOsm/kg、280mOsm/kg〜290mOsm/kgである。いくつかの実施形態では、製剤のオスモル濃度が、生理学的範囲内である。いくつかの実施形態では、医薬組成物が、ヒト中で等張である。
1つの実施形態では、医薬組成物が、さらにリドカイン、ブピバカイン、またはベンゾカインなどの麻酔剤を含む。
本製剤は、好ましくは界面活性剤を含まない。しかし、いくつかの実施形態では、医薬組成物が、1つ以上の非イオン性界面活性剤を含む。界面活性剤を含むと、薬剤粒子の溶解度及び湿潤性が増す。好適な非イオン性界面活性剤としては、ポリソルベート(例えば、TWEEN(登録商標)−80、TWEEN(登録商標)−20)、チロキサポール、ポリオキシルヒマシ油、ポラキサマー、ポリエチレングリコール、カプリル酸トリグリセリド、ステアリン酸ポリオキシル(例えば、オキシエチレンモノステアレート)、ポリオキシエチレン化植物油及びグリセリルモノステアレートが挙げられる。好ましい非イオン性界面活性剤は、TWEEN(登録商標)−80などのポリソルベートである。医薬組成物中の非イオン性界面活性剤の量は、存在する場合、一般に、医薬組成物の0.001〜10、または0.01〜1%(w/v)である。
用語「保存寿命」は、医薬組成物が力価及び/または性能特性を失わずに保存される可能性がある時間の量を指す。いくつかの実施形態では、保存寿命は、医薬組成物が力価及び/または性能の2%、5%、8%または10%超を失わずに保存される可能性がある時間の量を指す。本明細書に提供される防腐剤を含まない医薬組成物の保存寿命が、少なくとも12、24または36ヶ月となるように設計される。いくつかの実施形態では、医薬組成物の保存寿命が、12〜24ヶ月である。いくつかの実施形態では、医薬組成物が室温で保存され、少なくとも12、24または36ヶ月の保存安定性がある。いくつかの実施形態では、医薬組成物が、室温以下で保存され、少なくとも12、24、または36ヶ月の保存寿命がある。
本製剤は、好ましくは防腐剤を含まない。しかし、いくつかの実施形態では、医薬組成物が、1つ以上の防腐剤を含む。抗微生物防腐剤などの防腐剤を含むと、医薬組成物の保存寿命が増す。活性薬剤または賦形剤のいずれとも有害に相互作用しない任意の防腐剤を用いてよい。例えば、防腐剤としては、エタノール、ベンジルアルコール、塩化ベンザルコニウム、塩化ベンゼトニウム、安息香酸、ブロノポール、ブチルパラベン、セトリミド、クロルヘキシジンが挙げられる。防腐剤の量は、例えば、約0.01〜1%の範囲としてよい。
1つの実施形態では、水性医薬組成物が、可溶性コルチコステロイド及び少なくとも1つの粘度増強剤を含み、当該水性医薬組成物の粘度は、1kcP〜200kcPである。いくつかの実施形態では、水性医薬組成物が単位用量中にあり、その容積は1mL、2mL、3mL、4mL、5mL、6mL、7mL、8mL、または10mLである。いくつかの実施形態では、粘度増強剤濃度が、0.05%w/v〜1.5%w/v;0.05%w/v〜0.5%w/v;0.1%w/v〜1.5%w/v;0.1%w/v〜1.0%w/v;0.5%w/v〜1%w/v;0.5%w/v〜2.5%w/v;1.0%w/v〜1.5%w/v;1.0%w/v〜1.25%w/v;または1.25%w/v〜1.5%w/vである。
本製剤は、単位用量バイアルまたはシリンジ中にパッケージすることができる。それは、また、2つのコンパートメントバイアルまたはシリンジ中に、分離コンパートメント中の可溶性ステロイド及び粘度増強剤それぞれとパッケージすることができる。いくつかの実施形態では、単位用量が、1mL〜10mL;2mL〜8mL;2mL〜5mLである。いくつかの実施形態では、単位用量が、約1mL、約2mL、約2.5mL、約3mL、約3.5mL、約4mL、約4.5mL、約5mL、または約5.5mLである。上記の実施形態のいずれかでは、単位用量が、ゲル医薬組成物である。他の上記の実施形態では、単位用量が、水性医薬組成物である。本開示は、また、本明細書に開示された医薬製剤及び使用のための指示書を含むキットを提供する。
本出願は、また、本明細書に開示された水性医薬組成物のいずれかで、リウマチ性関節炎、変形性関節症、腰痛、腱炎、脊椎管狭窄症、椎間板ヘルニア、脊髄神経根炎及び慢性椎間板性腰痛と関係するものなどの炎症及び/または痛みを治療する方法を提供する。
病変内注射では、医薬品が皮膚病変へ経皮的に直接送達される。病変内注射は、病変に導入される、または病変内で実施される。皮膚は、貯臓器としての役割を果たし、一定の期間にわたり真皮に沈着した医薬品の送達を可能にし、その結果、全身的治療法の有害作用を阻止する、または最少化すると同時に、治療法が延長される。
シリンジ通過能力は、注射前のバイアルからの移動の際に、皮下針を通して容易に通過するための注射可能治療の能力である。シリンジ通過能力としては、抜取りの容易さ、目詰り及び泡立ち傾向、及び用量測定の精度などの要素が挙げられる。注射能力は、注射中の製剤の性能を指す。注射能力としては、注射に必要な圧力または力、流れの均一性、及び目詰りの解消(すなわち、シリンジ針の詰りがないこと)が挙げられる。シリンジ通過能力及び注射能力は、医薬組成物の粘度、注射または移動流速、及び針特性(長さ及びゲージなど)によって部分的に影響を受ける。
本実施例は、実施例2〜5に詳細を記載した物理的及び化学的分析、溶解、in vivo、及び病理組織学的試験に用いられるデキサメタゾンリン酸ナトリウム(SP−102)の製剤を示す。
本実施例は、0.5%、0.75%、1.0%、及び1.25%ヒアルロン酸ナトリウムを含有するSP−102製剤の物理的及び化学的分析を示す。試料の外観及び測定したpHを表4に示している。また、HPLCによる試料中のデキサメタゾンリン酸ナトリウムの分析を表4に示している。
本実施例は、0.5%、0.75%、1.0%、及び1.25%ヒアルロン酸ナトリウムを含有するSP−102製剤の溶解を示す。
カラム:Waters XTerra RP18カラム、3.5μm、4.6×150mm
移動相(無勾配):水中の0.1%リン酸:アセトニトリル(70:30)
カラム温度:40℃
オートサンプラ温度:周囲
検出:UV242nm
流速:1mL/分
注射容積:10μL
実行時間:10分
希釈剤:溶解媒質
本実施例は、SP−102(1.25%HA)製剤の安定性を示す。
カラム:Waters XTerra RPC18カラム、5μm、4.6×250mm移動相A(MP A):0.02M ギ酸アンモニウム
移動相B(MP B):アセトニトリル
カラム温度:40℃
検出:UV242nm
勾配条件:
実行時間:30分
希釈剤:0.02M ギ酸アンモニウム中の30%アセトニトリル
本実施例は、0.5%、1.0%、及び1.25%ヒアルロン酸ナトリウムを含有するSP−102製剤のin vivo試験を示す。
動物#1に3つの分離製剤を注射した。製剤は、以下のとおりであった。注射1(対照):2mLのデキサメタゾンリン酸ナトリウム(4mg/mL)及び647イオヘキソール(造影剤)。注射2:2mL SP−102(0.5%HA)及び647mgイオヘキソール。注射3:2mL SP−102(1.25%HA)及び647mgイオヘキソール。
全体の病理学及び病理組織学によって、市販のデキサメタゾン及び実施例4からのSP−102(1.25%HA)の注射を分析した。簡潔にいうと、剖検は、身体の外表面、全開口部ならびに胸腔及び腹腔の検査を含み、その内容物を含んだ。また、脳の全体検査を実施した。脳を採集し、少なくとも24時間、10%NBF(中性緩衝ホルマリン)に浸した。その後、4μmで切片を切り、ヘマトキシリン及びエオシン(H&E)で染色し、光学顕微鏡を用いて検査した。出血及び/または壊死/塞栓の観察を表9にまとめている。病理学データは、市販のデキサメタゾンまたはSP−102(1.25%HA)のいずれかの注射後に、感染または出血の徴候がないことを示す。
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JPH11279065A (ja) * | 1998-03-25 | 1999-10-12 | Shiseido Co Ltd | 局所投与炎症治療剤 |
JP6829201B2 (ja) * | 2015-01-21 | 2021-02-10 | セムヌール ファーマシューティカルズ, インコーポレイテッド | 医薬製剤 |
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