JP2021523893A - 高吸入性粒子の調製のためのシステアミンの新規な塩 - Google Patents
高吸入性粒子の調製のためのシステアミンの新規な塩 Download PDFInfo
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- JP2021523893A JP2021523893A JP2020561907A JP2020561907A JP2021523893A JP 2021523893 A JP2021523893 A JP 2021523893A JP 2020561907 A JP2020561907 A JP 2020561907A JP 2020561907 A JP2020561907 A JP 2020561907A JP 2021523893 A JP2021523893 A JP 2021523893A
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- cysteamine
- hyaluronic acid
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Abstract
Description
本発明の目的のために、「呼吸性能」(「respirability」)という用語は、エアロゾル化される粉末の量に関して、肺に堆積した薬剤の量を意味する。
用語「微細粒子投与」(「Fine Particle Dose」 FPD)とは、空気力学的直径が5μm以下の粒子の送達された投与における薬剤の量のことである。これらの粒子は、吸入時に肺を通過することができる。用語「微細粒子割合」(「Fine Particle Fraction」 FPF)とは、吸入器から出る粉末の量である送達された用量のパーセンテージで表されたFPDである。
用語「中央値粒子径」は、粒子径分布が2つの母集団で均等に分割されている場合の粒子径をμm単位で記述する。本発明の目的のために、中央値粒子径は、体積分布(DV50)に基づいて計算される。
イオン交換樹脂を指す場合、用語「総容量」とは、対イオンがイオン交換のために連結できる重量単位あたりの利用可能なサイトの総数を意味する。それは、グラム当たりのミリグラム当量(meq/g)で表される。
用語「肺疾患」には、例えば、嚢胞性線維症およびCOPDのような肺に影響を及ぼす任意の呼吸器疾患が含まれる。
なお、「NaHA」とはヒアルロン酸ナトリウムを意味し、「HA」とはヒアルロン酸を意味する。また、「約」とは、値を指す場合には、記載された値のプラスマイナス5%を意味し、範囲を指す場合には、最も外側の値のプラスマイナス5%を意味する。
これまで、ヒアルロン酸のような高分子物質を新規システアミン塩の調製に用いたことはなかった。
a. ヒアルロン酸ナトリウムを溶解させるステップ。
b. イオン交換樹脂を添加するステップ。
c. 得られた溶液をフィルタリング(濾過)するステップ。
d. システアミン塩基を追加するステップ。
e. 得られた溶液を噴霧乾燥するステップ。
10〜30%w/wのシステアミン、
50〜80%w/wのヒアルロン酸、および
6〜20%w/wのロイシン。
本明細書に記載された実施形態は、例示的な目的のみを有するものであり、本発明の範囲を限定することを意図したものではない。さらに、当業者には明らかな、以下の実施形態の修正および変更は、添付の特許請求の範囲に包含されることを意図している。
ヒアルロン酸ナトリウム0.35MDa(#2−#6)または0.9MDa(#1)から出発して、添加剤(複数可)の有無にかかわらず、ヒアルロン酸システアミンの噴霧乾燥粉末を本発明に従って調製した(表1)。異なる分子量のヒアルロン酸ナトリウムの使用は、噴霧乾燥粉末のシステアミンアッセイ、嵩密度および粒度分布の点で、最終製品の特性に悪影響を及ぼさない。
表1.システアミンの噴霧乾燥粉末の組成
ヒアルロン酸溶液の塩基との反応能力
63.25mgのNaHA 0.35MDaを含むヒアルロン酸溶液25mlを、指示薬のブロモチモールブルー(bromothymol blue)を用いて滴定した。指示薬が黄色から青色(pH7.0付近)に変色するまで滴定液(0.01 N NaOH溶液)をゆっくりと添加した。HA溶液の中和には12.13mlの0.01N NaOHを必要とした(すなわち、0.1213meq);したがって、平均63.25mgのNaHA 0.35MDaは、0.1213ミリグラム当量のHAを含んでいる。したがって、63.25mgのヒアルロン酸ナトリウムから得られるヒアルロン酸と反応可能なシステアミン塩基(MW 77.15)の量は、以下のように計算された。0.1213×77.15=9.358mg。
実施例#1
ヒアルロン酸ナトリウム(MW 0.9MDa)500mgを170mlの浄化水を入れたフラスコに磁気撹拌下50℃で導入した。次いで、Dowex社製Monosphere650C(H)樹脂の容量が2meq/ml(密度1.22g/ml)であることを考慮して、ヒアルロン酸溶液に500mgの樹脂を添加し、pH値が安定する(pH3.03)まで磁気攪拌下で室温で約2時間接触させた。得られたヒアルロン酸を含む溶液をブフナー漏斗でフィルタリング(濾過)し、200mlの容積式フラスコに回収した。フィルター上に残った樹脂を10mlの浄化水で洗浄し、樹脂と漏斗上に残ったヒアルロン酸を抽出した。その後、混合下のHAフラスコにシステアミン塩基74mgを溶解してシステアミン/ヒアルロン酸の塩水溶液を得、容積フラスコを使って浄化水で容量調整した。
Tinlet(℃) 150
Toutlet(℃) 75
吸引率(%) 100
供給速度(ml/min) 5
空気流量(L/h) 600
添加剤を含むヒアルロン酸システアミン噴霧乾燥微粒子を、システアミン塩基の添加前に、上記開示のようにして得られたヒアルロン酸溶液に添加剤をさらに添加するという唯一の違いをもって、実施例1に準じて調製した。
実施例5で報告した方法を改変して調製したシステアミン/ヒアルロン酸塩溶液を噴霧乾燥することにより、添加剤ロイシンを含むヒアルロン酸システアミン噴霧乾燥微粒子を製造した。具体的には、ヒアルロン酸ナトリウムを80mlの浄化水を含むフラスコに50℃で磁気撹拌下で導入した。次いで、このヒアルロン酸溶液に樹脂を添加し、pH値が安定するまで磁気攪拌下で室温で約2時間接触させた。得られたヒアルロン酸を含む溶液をブフナー漏斗でフィルタリング(濾過)し、100mlの容積式フラスコに回収した。フィルター上に残った樹脂を10mlの浄化水で洗浄し、樹脂と漏斗上に残ったヒアルロン酸を抽出した。その後、HAフラスコにシステアミン塩基を溶解し、混合下でシステアミン/ヒアルロン酸の塩水溶液を得て、容積フラスコを使って浄化水で容量調整した。
Claims (15)
- 以下のステップを含む、ヒアルロン酸システアミン微粒子を調製するための方法。
a. ヒアルロン酸ナトリウムを溶解させるステップ。
b. イオン交換樹脂を添加するステップ。
c. 得られた溶液をフィルタリングするステップ。
d. システアミン塩基を追加するステップ。
e. 得られた溶液を噴霧乾燥するステップ。 - ステップdで得られた溶液は、システアミン塩基:ヒアルロン酸が重量比で1:3と1:10の間、好ましくは1:5と1:8の間、より好ましくは1:7である、請求項1に記載の方法。
- ステップdが、薬学的に許容される添加剤の添加をさらに含む、請求項1に記載の方法。
- ステップeは、ヒアルロン酸システアミンからなる溶液をノズルに対して内側(内側オリフィス)に、添加剤からなる溶液をノズルに対して外側(外側オリフィス)にして同時に噴霧することを提供する、請求項1に記載の方法。
- 前記添加剤は、ロイシン、トレハロース、アスコルビン酸および酢酸からなる群から選択される、請求項3または4に記載の方法。
- 前記添加剤は、ロイシンである、請求項5に記載の方法。
- ヒアルロン酸システアミン塩を含む微粒子。
- 5μm以下の平均粒子径を有する、請求項7に記載の微粒子。
- 60%以上のFPFを有する、請求項7に記載の微粒子。
- 請求項7〜9のいずれかに記載の微粒子を含む医薬組成物。
- 粉末吸入器における請求項7〜9のいずれかに記載の微粒子の使用。
- 前記塩は、ヒアルロン酸システアミンであるシステアミン塩。
- 薬剤として使用するためのヒアルロン酸システアミン。
- 肺疾患の治療に使用するためのヒアルロン酸システアミン。
- シスチン症の治療に使用するためのヒアルロン酸システアミン。
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EP18425038.9A EP3572068A1 (en) | 2018-05-22 | 2018-05-22 | New salt of cysteamine for the preparation of highly respirable particles |
EP18425038.9 | 2018-05-22 | ||
PCT/EP2019/062872 WO2019224130A1 (en) | 2018-05-22 | 2019-05-17 | New salt of cysteamine for the preparation of highly respirable particles |
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