JP2016525123A - 熱安定性乾燥粉末医薬組成物及び方法 - Google Patents
熱安定性乾燥粉末医薬組成物及び方法 Download PDFInfo
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- JP2016525123A JP2016525123A JP2016527145A JP2016527145A JP2016525123A JP 2016525123 A JP2016525123 A JP 2016525123A JP 2016527145 A JP2016527145 A JP 2016527145A JP 2016527145 A JP2016527145 A JP 2016527145A JP 2016525123 A JP2016525123 A JP 2016525123A
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- dry powder
- oxytocin
- citrate
- peptide
- zinc
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Abstract
Description
FDKPマイクロ粒子の製造の最初の工程は、FDKPのpH誘導結晶化及びFDKP結晶の自己集合により全体として球状の形態を有するマイクロ粒子を形成する工程である(図2)。従って、マイクロ粒子の製造は実質的に結晶化処理である。過剰の溶媒は、遠心、デカンテーション、再懸濁を繰り返して懸濁液を洗うこと、又は、透析濾過をすることで除去できる。
以下の実施例は本明細書に記載のマイクロ粒子の実施形態を例示するためのものに過ぎない。当業者であれば、発明者が発見した技術を示す以下の実施例の技術が、本明細書の開示の実践に十分なものであり、好ましい実施態様をなし得ることを理解できるだろう。しかし、当業者であれば、本開示に基づいて、明細書に記載の特定の実施形態には種々の変更が可能であり、そうした変更によっても同等又は類似の結果が得られることを理解できるだろう。
(オキシトシン噴霧乾燥粉末の調製、特性解析、及び安定性)
1%(w/w)オキシトシンを含み、以下の表1に示すような様々な製造元から入手した、緩衝剤、塩類、担体、トレハロースをはじめとする賦形剤、PVP、イソロイシン、シスチン、トリロイシン、FDKP、クエン酸ナトリウム、及びクエン酸塩を異なる量含む14種の粉末を、以下の表2に示すように7gスケールで調製した。サンプルは、表2に記載の必要量を計り、脱イオン水に溶かして溶液又は懸濁液を形成し、噴霧乾燥前にオキシトシンを添加し混ぜた。クエン酸緩衝剤及び2価陽イオンを用いるサンプルでは、混合物中に残余の成分を添加する前に、オキシトシンをクエン酸緩衝剤中に溶かした。次に、溶液又は懸濁液を、以下の表3に記載のパラメータを用いて噴霧乾燥した。懸濁液は、噴霧乾燥前に、高剪断力ミキサーでホモゲナイズした。溶液は、噴霧乾燥前に、0.2μm膜を通して濾過した。
乾燥減量(LOD)は、加熱保温法(20℃/分、110℃等温線30分)を用いた熱重量分析(TGA)により測定した。得られた粉末は、平均収率73.8%、最小LOD4.63%であった。
粉末は、20mLガラス瓶に量り取り、蓋を閉めた後、ホイルで包装し、加熱密封した。ホイル包装は、40℃/75%RHで、安定室に置いた。サンプルは、2週及び4週目に抜き取り、その後は、インキュベーション後32週まで4週間毎に抜き取った。サンプルは、上述のようにHPLCで定量するまで、凍結保存した(−20℃)。
選択粉末での空気動力学的試験により、クエン酸ナトリウムと亜鉛をトレハロース、イソロイシン、及びPVPと組み合わせた場合の有益な効果が浮き彫りとなった。この効果は、クエン酸塩及び亜鉛の含量がそれぞれ4.8%及び1.3%程度でも観察された(表5のサンプルID番号4)。最大効果(60.3%RF/fill)は、クエン酸塩含量が12%且つ亜鉛が3.4%の場合に、観察された。クエン酸塩と亜鉛の量をこの2倍にして調整した粉末サンプルID番号2は59.1%のRF/fillを示した。サンプル粉末ID番号2及び4は共に、吸入器で試したところ、元の含量の約77%が吸入器から送り出された。トレハロース、イソロイシン、及びPVP(87:10:2)を製剤化した対照粉末(サンプルID番号1)のRF/fillは40.9%であり、亜鉛とクエン酸塩を含むサンプルよりもレートが低かった。
データによれば、調整した14種の粉末のうち3種が、40℃/75%RHでインキュベーションして32週間後で、元の合計オキシトシン含量の89%を維持していたことが示された(表4)。最も安定な粉末では、分解速度は、4週間までが最も高く、その後、頭打ちとなると考えられる。(図3)。この早発的分解はおそらく粉末中の残水量が中程度から高程度であるためである。最も安定な粉末は、pH6.5クエン酸緩衝剤及び亜鉛2価陽イオン源として塩化亜鉛を用いて調製した。全体として、クエン酸塩及び亜鉛塩の両方の存在下で調製した粉末は高い安定性を示した。この組み合わせの安定効果は低塩含量でも観察された(サンプルID番号1対サンプルID番号2、3、4)。『非緩衝』製剤では、FDKP二ナトリウムの添加又はイソロイシンからトリロイシン又はシスチンへの置換により、粉末の安定性が向上した。
(代替的実施形態に係るオキシトシン噴霧乾燥粉末の製造、特性解析、及び安定性)
オキシトシン噴霧乾燥粉末の調製は上記の実施例1と同様に行った。本実施形態では、1%(w/w)のオキシトシンを含み、以下の表6に示すような様々な製造元から入手した、緩衝剤、塩、担体、トレハロースをはじめとする賦形剤、PVP、イソロイシン、クエン酸ナトリウム、クエン酸、酒石酸ナトリウム、酒石酸、亜鉛塩を異なる量含む14種の粉末を、以下の表1に示すように2.5gスケールで調整した。以下の実験では、Alfa Aesarから入手したL−(+)−酒石酸及びL−(+)−酒石酸ナトリウム二水和物を使用した。実施例1とは異なり、クエン酸ナトリウム及びクエン酸のバルク固形物をクエン酸ナトリウム源として用いた。1%(w/w)のオキシトシンを含むサンプルを実施例1と同様に作り、その後、溶液及び懸濁液を以下の表6に記載のパラメータを用いて噴霧乾燥した。
噴霧乾燥粉末の空気動力学的性能は、Gen2C吸入器(21.6Lpm、4秒、マンカインド社)を用いたアンダーセンカスケードインパクション法により測定した。結果を表8に示す。高い%Rf/fill(>50%)が、低いピーク呼気圧下でも、観察された。表8のデータは、%RF/fillが約20から約60%の範囲であり、全含量のカートリッジ排出が77%まで(サンプルID番号22)であったことを示す。クエン酸亜鉛、塩化亜鉛を含み、さらに、PVPを任意で含む粉末で、最も高い%RF/fillが得られた。表8からわかるように、イソロイシンの添加により%RF/fillは改善した(サンプルID番号14及び20)。クエン酸亜鉛又は塩化亜鉛を単独で含むサンプル(サンプルID番号22、23、及び24)は、約50から60%の高い%RF/fillと70%を超えるカートリッジ排出を示した。
オキシトシン噴霧乾燥粉末の安定性試験は上記の実施例1と同様に行った。安定性試験は40週まで行った。オキシトシン安定性試験の定量結果を以下の表9及び図5に示す。データは、用いた出発材料に対するサンプル中に残存する百分率(%)として示した。表9からわかるように、試験した粉末製剤のうち3種のみ(サンプルID番号16、27、及び28)が、取り分けたサンプルを40週間インキュベーションした後に定量したときに、オキシトシンの約90%以上を維持できなかった。クエン酸塩及び亜鉛塩の組み合わせは、固体状態で最も高い安定性を示した(約90%超)。クエン酸ナトリウム14.6%及び塩化亜鉛6.8%の組み合わせで最も高い安定性が得られた(サンプルID番号18)。クエン酸亜鉛を最低でも9.1%含む粉末は、クエン酸ナトリウムの有無にかかわらず、40週間のインキュベーション後に、97%超のオキシトシンを維持した。図5は、2価亜鉛塩とクエン酸塩を種々の濃度で含む乾燥粉末サンプルの安定性試験の結果のグラフであり、40週に渡り、オキシトシンが徐々に分解するものの、試験サンプルにおいて、オキシトシン含量の90%超が維持されることを示している。
ある妊婦(35才、2回目の妊娠)は、最初の妊娠での軽度の産後出血の経歴があり、妊娠40週で陣痛発作を起こし病院に搬送された。担当産科医により陣痛が5分置きに生じることが観察された。妊婦は、出血は見られたが、健康な子供を産んだ。妊婦は、出産後直ぐ手術室で、100IUのオキシトシン、28%(w/w)のクエン酸塩、及び7%(w/w)の塩化亜鉛を一服分含む乾燥粉末製剤を、米国特許第8484129号明細書に記載の高抵抗吸入器を含む吸入システムを用いて、単回吸入投与された。これに関連する対象について、当該出願の内容を参照により本明細書で援用する。妊婦は、3日間入院したが、重度の出血はなく、新生児とともに退院した。
本出願は、合衆国法典第35編第119条(e)に基づき、2013年7月18日に出願された米国仮出願第61/847981号の優先権の利益を主張する。当該仮出願の内容を参照により本明細書で援用する。
ペプチド、タンパク質、若しくは前記ペプチド若しくは前記タンパク質の誘導体若しくは類似体、クエン酸塩若しくは酒石酸塩、陽イオン塩、アミノ酸、及び/又は、医薬的に許容可能な担体若しくは賦形剤を含む乾燥粉末医薬製剤。
[付記2]
前記ペプチド、前記タンパク質、前記誘導体、又は前記類似体は、オキシトシン、オキシトシン誘導体、又はオキシトシン類似体である、付記1に記載の乾燥粉末医薬製剤。
[付記3]
前記クエン酸塩はクエン酸ナトリウム又はクエン酸亜鉛である、付記1に記載の乾燥粉末医薬製剤。
[付記4]
前記陽イオン塩は、2価陽イオン塩であり、塩化亜鉛、クエン酸亜鉛、酢酸亜鉛、塩化マグネシウム、又は塩化カルシウムである、付記1に記載の乾燥粉末医薬製剤。
[付記5]
前記医薬的に許容可能な担体又は賦形剤は、マンノース、マンニトール、トレハロース、又はソルビトールから選択される糖である、付記1に記載の乾燥粉末医薬製剤。
[付記6]
前記医薬的に許容可能な担体又は賦形剤は、ポリビニルピロリドン、ポリエチレングリコール、又はジケトピペラジンである、付記1に記載の乾燥粉末医薬製剤。
[付記7]
前記ジケトピペラジンは、フマリルジケトピペラジン又はスクシニルジケトピペラジンである、付記6に記載の乾燥粉末医薬製剤。
[付記8]
前記クエン酸塩は、オキシトシン、オキシトシン類似体、又はオキシトシン誘導体の1モル当たり100から20当量の範囲の量で存在する、付記1に記載の乾燥粉末医薬製剤。
[付記9]
前記陽イオン塩は、組成物中オキシトシン1モル当たり50から5当量の範囲の量で存在する、付記1に記載の乾燥粉末医薬製剤。
[付記10]
前記ペプチドは、内分泌ホルモン、成長因子、又は侵害受容ペプチドである、付記1に記載の乾燥粉末医薬製剤。
[付記11]
前記内分泌ホルモンは、インスリン、副甲状腺ホルモン、カルシトニン、グルカゴン、グルカゴン様ペプチド1、オキシントモジュリン、又は、前記内分泌ホルモンの類似体若しくは活性断片である、付記10に記載の乾燥粉末医薬製剤。
[付記12]
前記アミノ酸は、ロイシン、イソロイシン、トリロイシン、シスチン、リシン、グリシン、アルギニン、メチオニン、又はヒスチジンである、付記10に記載の乾燥粉末医薬製剤。
[付記13]
乾燥粉末製剤を製造する方法であって、
ペプチド、タンパク質、その断片、及び/又はその類似体を含む溶液を窒素ガス室内で噴霧乾燥することを含み、
前記乾燥粉末製剤は、pH4.5からpH6.5の範囲のpHで、前記ペプチド、前記タンパク質、その断片、及び/又はその類似体、クエン酸塩又は酒石酸塩、並びに陽イオン塩を含む混合物を含み、
前記陽イオン塩は二価陽イオン塩である、方法。
[付記14]
前記乾燥粉末製剤はオキシトシンを含む、付記13に記載の方法。
[付記15]
前記クエン酸塩はクエン酸ナトリウムである、付記13に記載の方法。
[付記16]
アミノ酸又は糖をさらに含む、付記13に記載の方法。
[付記17]
前記アミノ酸は、ロイシン、イソロイシン、トリロイシン、シスチン、リシン、グリシン、アルギニン、メチオニン、又はヒスチジンである、付記16に記載の方法。
[付記18]
前記糖は、トレハロース又はマンニトールである、付記16に記載の方法。
[付記19]
前記酒石酸塩は酒石酸ナトリウムである、付記13に記載の方法。
[付記20]
オキシトシン、オキシトシン類似体、又はオキシトシン類似体、クエン酸ナトリウム、塩化亜鉛、及び医薬的に許容可能な賦形剤を含む、吸入用医薬乾燥粉末製剤。
[付記21]
前記クエン酸ナトリウムは、前記乾燥粉末製剤中に、0.5%(w/w)より多く、5%(w/w)より多く、10%(w/w)より多く、又は20%(w/w)より多く存在する、付記20に記載の医薬乾燥粉末製剤。
[付記22]
前記噴霧乾燥は、前記溶液の流れを入口温度が約120℃から150℃である乾燥窒素ガス流中に霧化することを含む、付記13に記載の方法。
[付記23]
治療の必要な対象に200IUまでのオキシトシンを含む付記1に記載の乾燥粉末医薬製剤を投与することを含む、産後出血を治療又は予防する方法。
[付記24]
前記アミノ酸はイソロイシンである、付記17に記載の方法。
Claims (24)
- ペプチド、タンパク質、若しくは前記ペプチド若しくは前記タンパク質の誘導体若しくは類似体、クエン酸塩若しくは酒石酸塩、陽イオン塩、アミノ酸、及び/又は、医薬的に許容可能な担体若しくは賦形剤を含む乾燥粉末医薬製剤。
- 前記ペプチド、前記タンパク質、前記誘導体、又は前記類似体は、オキシトシン、オキシトシン誘導体、又はオキシトシン類似体である、請求項1に記載の乾燥粉末医薬製剤。
- 前記クエン酸塩はクエン酸ナトリウム又はクエン酸亜鉛である、請求項1に記載の乾燥粉末医薬製剤。
- 前記陽イオン塩は、2価陽イオン塩であり、塩化亜鉛、クエン酸亜鉛、酢酸亜鉛、塩化マグネシウム、又は塩化カルシウムである、請求項1に記載の乾燥粉末医薬製剤。
- 前記医薬的に許容可能な担体又は賦形剤は、マンノース、マンニトール、トレハロース、又はソルビトールから選択される糖である、請求項1に記載の乾燥粉末医薬製剤。
- 前記医薬的に許容可能な担体又は賦形剤は、ポリビニルピロリドン、ポリエチレングリコール、又はジケトピペラジンである、請求項1に記載の乾燥粉末医薬製剤。
- 前記ジケトピペラジンは、フマリルジケトピペラジン又はスクシニルジケトピペラジンである、請求項6に記載の乾燥粉末医薬製剤。
- 前記クエン酸塩は、オキシトシン、オキシトシン類似体、又はオキシトシン誘導体の1モル当たり100から20当量の範囲の量で存在する、請求項1に記載の乾燥粉末医薬製剤。
- 前記陽イオン塩は、組成物中オキシトシン1モル当たり50から5当量の範囲の量で存在する、請求項1に記載の乾燥粉末医薬製剤。
- 前記ペプチドは、内分泌ホルモン、成長因子、又は侵害受容ペプチドである、請求項1に記載の乾燥粉末医薬製剤。
- 前記内分泌ホルモンは、インスリン、副甲状腺ホルモン、カルシトニン、グルカゴン、グルカゴン様ペプチド1、オキシントモジュリン、又は、前記内分泌ホルモンの類似体若しくは活性断片である、請求項10に記載の乾燥粉末医薬製剤。
- 前記アミノ酸は、ロイシン、イソロイシン、トリロイシン、シスチン、リシン、グリシン、アルギニン、メチオニン、又はヒスチジンである、請求項10に記載の乾燥粉末医薬製剤。
- 乾燥粉末製剤を製造する方法であって、
ペプチド、タンパク質、その断片、及び/又はその類似体を含む溶液を窒素ガス室内で噴霧乾燥することを含み、
前記乾燥粉末製剤は、pH4.5からpH6.5の範囲のpHで、前記ペプチド、前記タンパク質、その断片、及び/又はその類似体、クエン酸塩又は酒石酸塩、並びに陽イオン塩を含む混合物を含み、
前記陽イオン塩は二価陽イオン塩である、方法。 - 前記乾燥粉末製剤はオキシトシンを含む、請求項13に記載の方法。
- 前記クエン酸塩はクエン酸ナトリウムである、請求項13に記載の方法。
- アミノ酸又は糖をさらに含む、請求項13に記載の方法。
- 前記アミノ酸は、ロイシン、イソロイシン、トリロイシン、シスチン、リシン、グリシン、アルギニン、メチオニン、又はヒスチジンである、請求項16に記載の方法。
- 前記糖は、トレハロース又はマンニトールである、請求項16に記載の方法。
- 前記酒石酸塩は酒石酸ナトリウムである、請求項13に記載の方法。
- オキシトシン、オキシトシン類似体、又はオキシトシン類似体、クエン酸ナトリウム、塩化亜鉛、及び医薬的に許容可能な賦形剤を含む、吸入用医薬乾燥粉末製剤。
- 前記クエン酸ナトリウムは、前記乾燥粉末製剤中に、0.5%(w/w)より多く、5%(w/w)より多く、10%(w/w)より多く、又は20%(w/w)より多く存在する、請求項20に記載の医薬乾燥粉末製剤。
- 前記噴霧乾燥は、前記溶液の流れを入口温度が約120℃から150℃である乾燥窒素ガス流中に霧化することを含む、請求項13に記載の方法。
- 治療の必要な対象に200IUまでのオキシトシンを含む請求項1に記載の乾燥粉末医薬製剤を投与することを含む、産後出血を治療又は予防する方法。
- 前記アミノ酸はイソロイシンである、請求項17に記載の方法。
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AU2020200290A1 (en) | 2020-02-06 |
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AU2014290438B2 (en) | 2019-11-07 |
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CN105451716A (zh) | 2016-03-30 |
BR112016000937A2 (pt) | 2017-07-25 |
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US9925144B2 (en) | 2018-03-27 |
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