JP2012522018A - 肺疾患を治療するための乾燥粉末製剤および方法 - Google Patents
肺疾患を治療するための乾燥粉末製剤および方法 Download PDFInfo
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- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
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- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
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- PWQWICVUFSCLKH-UHFFFAOYSA-H triberyllium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Be+2].[Be+2].[Be+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PWQWICVUFSCLKH-UHFFFAOYSA-H 0.000 description 1
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
- NFMWFGXCDDYTEG-UHFFFAOYSA-N trimagnesium;diborate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]B([O-])[O-].[O-]B([O-])[O-] NFMWFGXCDDYTEG-UHFFFAOYSA-N 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- DFHAXXVZCFXGOQ-UHFFFAOYSA-K trisodium phosphonoformate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)P([O-])([O-])=O DFHAXXVZCFXGOQ-UHFFFAOYSA-K 0.000 description 1
- QGAPCDHPGCYAKM-UHFFFAOYSA-H tristrontium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Sr+2].[Sr+2].[Sr+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QGAPCDHPGCYAKM-UHFFFAOYSA-H 0.000 description 1
- JOPDZQBPOWAEHC-UHFFFAOYSA-H tristrontium;diphosphate Chemical compound [Sr+2].[Sr+2].[Sr+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O JOPDZQBPOWAEHC-UHFFFAOYSA-H 0.000 description 1
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229960002149 valganciclovir Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 229960004764 zafirlukast Drugs 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
Description
本明細書で使用される、「乾燥粉末」という用語は、吸入デバイス内で分散され、その後対象が吸入することができる微細に分散した吸入に適する乾燥粒子を含有する組成物を指す。そのような乾燥粉末もしくは乾燥粒子は、最大で約15%の水もしくは他の溶媒を含有するか、または実質的に水もしくは他の溶媒を含んでいないか、または無水であり得る。
本発明は、活性成分として、ベリリウム(Be2+)、マグネシウム(Mg2+)、カルシウム(Ca2+)、ストロンチウム(Sr2+)、バリウム(Ba2+)、ラジウム(Ra2+)、または鉄(第一鉄イオン、Fe2+)等の1つ以上の二価金属カチオン含有する吸入に適する乾燥粉末および乾燥粒子に関する。活性二価金属カチオン(例えば、カルシウム)は、概して、塩の形態で乾燥粉末および乾燥粒子中に存在し、結晶性または非晶質である。乾燥粉末および乾燥粒子は、任意で、追加の塩(例えば、ナトリウム塩、カリウム塩、およびリチウム塩等の一価塩)、治療的に活性な薬剤、または薬学的に許容される賦形剤を含むことができる。
乾燥粉末および乾燥粒子を調製するための方法
本発明の吸入に適する乾燥粉末および吸入に適する乾燥粒子は、気道への投与のためである。本発明の乾燥粉末および乾燥粒子を、喘息、気道過敏反応性、季節性アレルギー性アレルギー、気管支拡張症、慢性気管支炎、肺気腫、慢性閉塞性肺疾患、嚢胞性線維症等のようなの呼吸器(例えば、肺)疾患の治療のために、ならびにウイルス感染(例えば、インフルエンザウイルス、パラインフルエンザウイルス、呼吸器合胞体ウイルス、ライノウイルス、アデノウイルス、メタ肺炎ウイルス、コクサッキーウイルス、エコーウイルス、コロナウイルス、ヘルペスウイルス、サイトメガロウイルス等)、細菌感染(例えば、一般に肺炎球菌と称される肺炎連鎖球菌、黄色ブドウ球菌、バークホルデリア種、ストレプトコッカスアガラクティエ、インフルエンザ菌、パラインフルエンザ菌、肺炎桿菌、大腸菌、緑膿菌、カタラリス菌、肺炎クラミジア、肺炎マイコプラズマ、レジオネラニューモフィラ、セラチアマルセッセンス、ヒト型結核菌、百日咳菌等)、真菌感染(例えば、ヒストプラスマカプスラーツム、クリプトコックスネオフォルマンス、ニューモシスチスジロヴェチ、コクシジオイデスイミティス等)もしくは寄生虫感染(例えば、トキソプラズマ原虫、糞線虫等)、または環境アレルゲンおよび刺激物(例えば、花粉およびネコのフケ、浮遊粒子等を含む空気アレルゲン)によって引き起こされる悪化等のこれらの慢性疾患の急性増悪の治療および/または予防のために、それを必要とする対象に投与することができる。
以下の実施例で使用される物質およびそれらの供給源が以下に記載される。塩化カルシウム二水和物、乳酸カルシウム五水和物、塩化ナトリウム、L−ロイシン、マルトデキストリン、マンニトール、ラクトース、およびトレハロースをSigma−Aldrich Co.(St.Louis,MO)もしくはSpectrum Chemicals(Gardena,CA)から得、硫酸ナトリウムをEMD Chemicals(Gibbstown,NJ)、Sigma−Aldrich Co.(St. Louis, MO)、またはSpectrum Chemicals(Gardena,CA)から得、クエン酸ナトリウム二水和物をJ.T.Baker(Phillipsburg,NJ)、Mallinckrodt Baker(Phillipsburg,NJ)、またはSpectrum Chemicals(Gardena,CA)から得た。超純水は、水浄化システム(Millipore Corp.,Billerica,MA)からであった。
幾何学径または体積径。幾何学的体積中位径(VMGD)とも称され得る体積中位径(x50)を、レーザー回折技術を用いて判定した。装置は、HELOS回折計およびRODOS乾燥粉末分散機(Sympatec,Inc.,Princeton,NJ)から成った。RODOS分散機は、粒子の試料に剪断力を印加し、流入圧縮乾燥空気のレギュレータ圧(典型的には、7ミリバールで設定されたオリフィスリング圧を伴い1.0バールで設定される)によって制御される。圧力設定は、粉末を分散させるために使用されるエネルギーの量を変化させるために変化し得る。例えば、レギュレータ圧は、0.2バール〜4.0バールに変化し得、オリフィスリング圧は、5.00ミリバール〜115.00ミリバールに変化し得る。粉末試料は、マイクロスパチュラからRODOS漏斗に分注される。分散粒子は、典型的には、一連の検出器によるR2レンズを用いて、生成された回折光パターンが収集されるレーザー光を通って移動する。アンサンブル回折パターンは、次に、より小さい粒子がより大きな角度で光を回折するという前提で、フラウンホーファー回折モデルを用いて体積に基づく粒径分布に翻訳される。この方法を用いて、幾何学的体積中位径に対する幾何標準偏差(GSD)が判定された。
この反応は、カルシウム:ナトリウムイオンの1:2のモル比をもたらす。反応が完了へ進むためには、3モルの塩化カルシウムおよび2モルのクエン酸ナトリウムが必要とされる。グラムの質量および重量比に変換するために、塩のモル数に、1モル当たりのグラムとしての塩の分子量を乗じる。
塩化カルシウムにおいては、 3mol CaCl2×111g/mol=333g CaCl2
クエン酸ナトリウムにおいては、 2mol Na3C6H5O7×258g/mol=516g Na3C6H5O7
100重量パーセントのロイシンを含むプラセボ製剤を噴霧乾燥で産生した。バッチ処理のために、物質が室温で水に完全に溶解されるまで一定の撹拌で超純水中のロイシンを溶解することによって、水相を調製した。静的混合処理のために、超純水を半分に分割し、全体の所要のロイシンの半分をそれぞれの量の水に溶解した。次に、溶液をNiroまたはBuchi噴霧乾燥機を用いて噴霧乾燥させた。プラセボ製剤において、供給原料の2つのバッチ(AおよびB)を調製し、かつ噴霧乾燥させた。バッチAの全固体濃度は、15g/Lであり、バッチBは、5g/Lであった。Niro Mobile Minor噴霧乾燥機上でバッチA(プラセボ−A)を噴霧乾燥させるために使用された処理条件は、実施例1の製剤I−Aを噴霧乾燥させるために使用された条件と同様であった。バッチB(プラセボ−B)を噴霧乾燥させるために使用された処理条件は、製剤プラセボ−Bの出口温度が約82℃であったことを除いて、実施例1の製剤I−Cを噴霧乾燥させるために使用された条件と同様であった。この実施例で調製された製剤プラセボ−Aおよびプラセボ−B粉末ならびに/または粒子の処理条件ならびに特性に関する追加の情報を、図1A〜1Fおよび2〜4に示される表もしくはグラフに提供する。
この実施例は、製剤I:10.0重量パーセントのロイシン、35.1重量パーセントの塩化カルシウム、および54.9重量パーセントのクエン酸ナトリウムの供給原料を用いた乾燥粉末の調製を説明する。
この実施例は、製剤II: 10.0重量パーセントのロイシン、58.6重量パーセントの乳酸カルシウム、および31.4重量パーセントの塩化ナトリウムの供給原料を用いた乾燥粉末の調製を説明する。
この実施例は、製剤III:10重量パーセントのロイシン、39.6重量パーセントの塩化カルシウム、および50.4重量パーセントの硫酸ナトリウムの供給原料を用いた乾燥粉末の調製を説明する。
この実施例は、室内および上昇温度および湿度条件での、乾燥粉末吸入器からの製剤バッチI−B、II−B、およびII−Bの粉末の用量放出を説明する。
この実施例は、表12に集約されるように、プラセボにおける製剤I−A、II−A、III−A、ならびにロイシン製剤の分散特性および密度特性を説明する。表12に見出される全てのデータを、図1A〜1Eに見出すこともできる。表12に示される結果によって証明されるように、全ての製剤は、極めて分散可能であり、それらの測定された体積サイズが、HELOS/RODOSにかかる圧力から比較的独立していることを意味する。表12に示されるように、低い分散圧(0.5バールまたは1.0バール)および高い分散圧(4.0バール)で得られた体積平均サイズの比率を、分散性の指標として使用することができる。これらの値は、0.5バール/4.0バール比または1.0バール/4.0バール比と称される。
この実施例は、下の表13に記載されるような供給原料製剤6.1〜6.9を用いた乾燥粉末の調製を説明する。
この実施例は、室内および上昇条件において、乾燥粉末吸入器からの供給原料製剤6.1〜6.9で調製された粉末の用量放出を説明する。このデータのいくつかは、上の実施例4にも示される。
この実施例は、供給原料製剤6.1、6.4、および6.7で調製された乾燥粉末のために行われた短期間安定性研究の結果を説明する。
この実施例は、供給原料製剤A〜Eを用いて調製された乾燥粉末を使用して実行された細菌通過アッセイを説明する。
この実施例は、ウイルス複製モデルを利用してウイルス複製を減少させる乾燥粉末の性能を説明する。
供給原料製剤10−1〜10−4から調製された乾燥粉末は、用量依存的様式でA型インフルエンザ/WSN/33/1(H1N1)感染を減少させる。
表19の供給原料製剤10−1〜10−4から調製された乾燥粉末は、用量依存的様式でA型インフルエンザ/Panama/2007/99(H3N2)感染を減少させる。
実施例11生体内インフルエンザモデル
この実施例は、異なる賦形剤から成る乾燥粉末製剤がインフルエンザ感染を減少させるが、ロイシンから成る製剤よりも高い用量で減少させることを示す。
この実施例は、インフルエンザ、パラインフルエンザ、またはライノウイルスに対するカルシウム塩、乳酸カルシウム、硫酸カルシウム、もしくはクエン酸カルシウム粉末を含む乾燥粉末製剤の効力を示す。
インフルエンザモデルにおいて、3つ全ての粉末は、最高用量で試験する時に、同程度までウイルス力価を著しく減少させる。製剤I、製剤III、および製剤IIは、それぞれ、3.25、3.80、および3.95log10 TCID50/mLまでウイルス力価を減少させた(図13A)。最高用量で試験した時に、これらの粉末がインフルエンザに対して同様の活性を示した一方で、データは、低用量で、最も効果的な粉末が製剤II(ロイシン、乳酸カルシウム、および塩化ナトリウムから成る)であることを示唆することに留意するのが重要である。製剤IIは、低用量および中用量でウイルス力価を3.70および3.75log10 TCID50/mLに減少させた一方で、製剤Iおよび製剤IIIの低用量は、それぞれ、ウイルス力価を2.50および2.95log10 TCID50/mLに減少させ、かつ製剤Iおよび製剤IIIの中用量は、それぞれ、ウイルス力価を2.65および3.30log10 TCID50/mLに減少させた。
製剤I、製剤II、および製剤IIIを、パラインフルエンザに対して同様の用量範囲で試験した。製剤IIIで処理された細胞培養中のパラインフルエンザ力価は、インフルエンザ実験で使用した用量と同様のカルシウムの用量で、対照細胞(図13B)に相当し、硫酸カルシウムベースの製剤が、特定の病原体に対してのみ活性を示すことを示す。対照的に、製剤Iおよび製剤II処理は、パラインフルエンザ感染において用量依存的減少をもたらした。高用量で、製剤Iおよび製剤IIは、対照細胞と比較して、それぞれ、感染を2.70および4.10log10 TCID50/mL減少させた。同様に、製剤IIは、中用量で試験した時に、製剤Iよりも大きな効力を示したが、しかしながら、どの製剤も中用量で試験した時には感染を減少させなかった(図12B、表25)。集合的に、これらのデータは、カルシウムベースの乾燥粉末製剤は、パラインフルエンザの感染性を効率的に減少させることを示す。これらの効果は、ある特定のカルシウム塩に特定され、効果的な用量範囲は、インフルエンザにおいて観察された範囲とは著しく異なる。
インフルエンザおよびパラインフルエンザは、エンベロープウイルスである。カルシウム乾燥粉末製剤の広範なスペクトル活性を試験し、かつこれらの所見を非エンベロープウイルスに拡張するために、同一の粉末をライノウイルスに対して試験した。3つ全ての製剤は、ライノウイルスをある程度減少させ、製剤II粉末が最大の活性を示した(図13C)。製剤II処理は、最大用量で試験した時に、著しい2.80log10 TCID50/mLのウイルス減少をもたらした。この粉末の低用量および中用量は、対照細胞と比較して、それぞれ、力価を1.15および2.10log10 TCID50/mLに減少させた。製剤IIよりも小さい程度であったが、製剤Iおよび製剤III処理もライノウイルス感染を減少させた。最高用量で試験された時に、製剤Iは、感染を1.70log10 TCID50/mLに減少させ、製剤IIIは、感染を1.60log10 TCID50/mLに減少させた。併せて、これらの結果は、カルシウムベースの乾燥粉末製剤が、多様なウイルス感染に広範に適用され得ることを示す。
この実施例は、製剤XIV:10.0重量パーセントのマルトデキストリン、58.6重量パーセントの乳酸カルシウム、および31.4重量パーセントの塩化ナトリウムの供給原料を用いた乾燥粉末の調製を説明する
この実施例は、様々な吸入手技で異なる乾燥粉末吸入器から送達される時に、かつ同様に分散される従来の微粒薬物産物と比較して、乳酸カルシウム、硫酸カルシウム、またはクエン酸カルシウム粉末を含む乾燥粉末製剤の分散性を示す。
A.X線粉末回折
製剤I、II、III、およびXIVを、高分解能X線粉末回折(XRPD)ならびに示差走査熱量測定を用いて、非晶質/結晶性含有量および多形形態において分析した。XRPDにおいて、各々のXRPDパターンで観察された任意の結晶相を特定するために、相同定を実行した。PANalytical X'Pert Pro回折計(Almelo,The Netherlands)を用いてXRPDパターンを収集した。Optix長焦点微小焦点線源を使用して産生されたCu放射を用いて標本を分析した。標本を通して検出器上の供給源のCu KαX線の焦点を合わせるために、楕円形に勾配した多層膜鏡を使用した。標本を3ミクロン厚のフィルムの間に挟み、透過幾何学で分析し、かつ標定統計を最適化するために回転させた。光線停止を、空気散乱によって生み出されるバックグラウンドを最小化するために、いくつかの場合においてヘリウムパージとともに使用した。突発事象のためにSollerスリットを使用し、軸分岐を最小化するために光線を回折した。回折パターンを、標本から240mmの位置に設置された走査位置感度検出器(X'Celerator)を用いて収集した。各回折パターンのデータ収集パラメータが、付録Cの各パターンの画像の上に示される。分析の前に、シリコン111ピークの位置を検証するために、シリコン標本(NIST標準参照物質640c)を分析した。可能性のある結晶成分(無水および水和形態を含む)において計算されたパターンを、ケンブリッジ結晶構造データベースまたは国際回析データセンター(ICDD)データベースのいずれかから生成し、かつ実験的パターンと比較した。結晶成分を質的に判定した。上昇した湿度への短期間の曝露時に、該粉末の再結晶化における傾向を評価するために、XRPDを、Dynamic Vapor Sorptionシステム内で3〜4時間、75%のRHで調整された粉末で実行した。
これらの製剤を含む粒子の表面における化学組成物の性質を判定するために、製剤I〜IIIおよびXIVの試料で表面マッピングラマン実験を行った。ラマンマップスペクトルを、Leica DM LM顕微鏡(Wetzlar,Germany)を装備したRenishaw inVia Ramascope(Gloucestershire,UK)上で取得した。器具をシリコンウエハ標準を用いて較正した。試料を、分析のためにアルミニウム被覆の顕微鏡スライド上で調製した。高出力近赤外ダイオードレーザ源を用いて、励起波長は785nmであった。製剤I、製剤III、および製剤XIVに関するデータ収集は、30秒の曝露時間および10回の蓄積を伴う静的スキャンであった。製剤IIに関するデータ収集は、60秒の曝露時間および1回の蓄積を伴う拡大スキャンであった。画像収集のために、50倍の対物レンズを有するPhilips ToUcam Pro IIカメラ(モデルPCVC 840K)(Amsterdam,the Netherlands)を使用した。Renishaw WiRE 3.1(service pack 9)ソフトウェア(Gloucestershire,.UK)をデータ収集および処理のために使用した。
含水硫酸カルシウムまたはクエン酸カルシウムの飽和もしくは過飽和原料を、出発物質として塩化カルシウムおよび硫酸ナトリウムまたは塩化カルシウムもしくはクエン酸カルシウムを使用して、噴霧乾燥させるために調製した。5〜30g/Lの範囲の全固体濃度を、(i)両方の塩を水に予混合すること、および(ii)噴霧乾燥の直前にインライン静的混合して別々の水溶液に保存することの両方によって調製した。調製された液体供給原料の全ては、飽和または過飽和硫酸カルシウム量(水中の硫酸カルシウムの溶解限度は2.98g/Lである)および飽和または過飽和クエン酸カルシウム量(水中のクエン酸カルシウムの溶解限度は0.96g/Lである)を含有した。塩化カルシウムおよび硫酸ナトリウム沈殿反応が完了(CaCl2+Na2SO4→CaSO4+2 NaCl)へ進むことを考慮して、硫酸カルシウムの対応する最終濃度が、表24に記載される。塩化カルシウムおよびクエン酸ナトリウム沈殿反応(3 CaCl2+2 Na3C6H5O7→Ca3(C6H5O7)2+6 NaCl)における同様の結果も表28に示される。
小さい分散可能な粒子を、ロイシンを含むカルシウム含有製剤および含まないカルシウム含有製剤、ならびにマグネシウム含有製剤およびナトリウムのみの製剤から作製する。
18−2) 63.4%の乳酸マグネシウム、36.6%の塩化ナトリウム、カルシウム:ナトリウムの比率=1:2
18−3) 10.0%のロイシン、58.4%の乳酸マグネシウム、31.6%の塩化ナトリウム、カルシウム:ナトリウムの比率=1:2
18−4) 50.0%のロイシン、50%の乳酸カルシウム
18−5) 10%のロイシン、90%の塩化ナトリウム
18−6) 60%のロイシン、40%の塩化ナトリウム
18−7) 10.0%のアルブテロール、58.6%の乳酸カルシウム、31.4%の塩化ナトリウム
18−8) 90.0%のアルブテロール、5.9%の乳酸カルシウム、3.1%の塩化ナトリウム
純粋な塩化カルシウムを、Labplant噴霧乾燥システム内で180℃の入口温度にて噴霧乾燥させた。液体フィードは、D.I.水中の塩化カルシウム二水和物の20g/Lの固体濃度から成った。塩化カルシウムが潮解する時に水は収集容器内で凝縮し、粉末を収集することができなかった。排出乾燥ガス中の高い含水量を有する水溶液からの純粋な塩化カルシウムは、噴霧乾燥には吸湿性が高すぎると見なされた。次に、排出ガス中の湿度を低下させるために、固体濃度を20g/L、入口温度を200℃、出口温度を69℃に保って、液体フィードを70%のエタノールに変えた。水は収集容器内でさらに凝縮し、粉末は湿ったように見えた。塩化カルシウムは、最終粉末内の塩化カルシウム含有量を減少させるために他の塩または賦形剤と混合することなしでは、噴霧乾燥させるには吸湿性が高すぎると結論付けられた。
乾燥粉末を、30℃および相対湿度75%と定義される、極端な温度および湿度条件(ICH,Climatic Zone XIV)下で、使用中の安定性のために試験した。約25mgの製剤I、製剤II、および製剤IIIをカプセル内に充填した。カプセルを開けたままにし、次に定義される条件で15〜30分間安定チャンバ内に設置した。カプセルを適切な時点で取り除き、閉鎖し、破壊的2−段階ACIを用いてaPSDに関して、かつMalvernスプレーテックを用いてgPSDに関して試験した。両試験を2秒間60LPMで行った。各時点をn=2で繰り返した。結果を室温および相対湿度25〜30%での粉末からのaPSD/gPSDデータと比較した。
噴霧乾燥した粉末を室温、約30%〜40%の相対湿度で1週間保存し、粒径分布に関して定期的に試験した。サイズ3のHPMCカプセル(Quali−V,Qualicaps,Whitsett,NC)を各々の乾燥粉末で半分充填した。1つの試料を、乾燥粉末が吸入器セル設定を用いて吸入器から分散することができるスプレーテック(Malvern Instruments Inc.,Westborough,MA)、レーザー回折噴霧粒子定寸システムで即座に試験した。約16個のカプセルを各粉末で充填した。カプセルの半分を、制御された湿度および温度条件(約23〜28%の相対湿度)で研究室内に保存し、一方、他の半分を異なる温度および相対湿度(約38〜40%の相対湿度)で研究室外に保存した。特定の時点(t=1時間、2時間、4時間、24時間、48時間、1週間)で、環境制御された部屋からの1個のカプセルおよび研究室外からの1個のカプセルを体積粒径分布のためにスプレーテックで試験した。
噴霧乾燥した粉末を室温、約30%〜40%の相対湿度で1週間保存し、粒径分布に関して定期的に試験した。サイズ3のHPMCカプセル(Quali−V,Qualicaps,Whitsett,NC)を各々の乾燥粉末で半分充填した。1つの試料を、乾燥粉末が吸入器セル設定を用いて吸入器から分散することができるスプレーテック(Malvern Instruments Inc.,Westborough,MA)、レーザー回折噴霧粒子定寸システムで即座に試験した。約16個のカプセルを各粉末で充填した。カプセルの半分を、制御された湿度および温度条件(約23〜28%の相対湿度)で研究室内に保存し、一方、他の半分を異なる温度および相対湿度(約38〜40%の相対湿度)で研究室外に保存した。特定の時点(t=1時間、2時間、4時間、24時間、48時間、1週間)で、環境制御された部屋からの1個のカプセルおよび研究室外からの1個のカプセルを体積粒径分布のためにスプレーテックで試験した。
粉末流動性の特徴付けのために、製剤I、II、III、およびXIV粉末の流動性も、当分野の従来の方法を用いて評価した。各粉末の流動性指数をFlodex粉末流動性試験器具(Hanson Research Corp.,モデル21−101−000)を用いて判定した。任意の所与の実行のために、シリンダ内のトラップドア穴の中心に向けられたステンレス漏斗を用いて全ての試料を装填した。シリンダ内の粉末の列を妨害しないように注意を払った。羊斑の電位形成を約30秒間待った後に、装置にできるだけ小さい振動を引き起こしながら、トラップドアを解放した。粉末がトラップドアを通って落ち、その結果、上からシリンダを通して見下ろせるように穴が可視的であり、かつシリンダ内の残渣が逆円錐型を形成した場合に、試験は合格と見なされ、穴が可視的ではないか、または粉末が円錐型の残渣を残すことなく穴を通って真直に落ちた場合には、試験は失敗であった。粉末が通過するであろう最小の大きさの穴を見出すために、十分な流動ディスクを試験し、肯定的な試験をもたらした。3回の試み中、3回の肯定的な試験を得るために、最小の流動ディスクをさらに2回試験した。流動性指数(FI)をこの最小穴径として報告する。
製剤I、II、III、およびXIV粉末の含水量を、熱重量分析(TGA)およびカールフィッシャー分析の両方を介して決定した。TA器具Q5000 IR熱重量測定分析器(New Castle,DE)を用いて、熱重量分析(TGA)を実行した。試料を、アルミニウム試料皿内に置き、TG炉内に挿入した。データ収集および処理パラメータを各サーモグラム上に表示した。Nickel and Alumel(商標)をキャリブレーション標準として使用した。TGAのために、含水量を、150℃の温度に加熱した時に、試料の質量の損失から決定した(TGAのために、用いた噴霧乾燥溶媒は100%の水であり、水のみがこれらの粉末中の揮発性成分として存在すると想定された)。粉末製剤Iの代表的なTGAサーモグラムが図34に示される。水判定のために、Mettler Toledo DL39 KF滴定装置(Greifensee,Switzerland)を用いてカールフィッシャー(KF)電量分析を実行した。試料をHydranal-Coulomat ADを含有するKF滴定容器内に置き、溶解を確保するために10秒間混合した。次に、電気化学的酸化によってヨウ素を生成する発生電極の手段で試料を滴定した。2 I−=>I2+2e。概して、再現性を確保するために、1つの距離測定走行および2つの反復を得た。これらの方法を用いた粉末含水量に関する要約データが表36に示される。
(i)30%の塩化カルシウム、31.6%の塩化ナトリウム、および38.4%のロイシンから成る対照粉末、(ii)未加工塩化カルシウム二水和物、ならびに(iii)未加工ロイシンと比較して、HBSS緩衝剤中での製剤I〜IIIの試料の溶解時に、溶解熱を得た。表38に示されるように、カルシウム含有試料に関して、同等のカルシウムイオンのモルを含有する製剤I(PUR111)、II(PUR113)、およびIII(PUR112)粉末の質量を試験した。結果は図35に示される。図35に示されるデータから見られるように、製剤I〜IIIは、未加工塩化カルシウム二水和物および対照カルシウム粉末の両方と比較して、著しく減少した溶解熱をもたらした。塩化カルシウム二水和物は、高い溶解発熱を有し、水と接触した時に著しい量の熱を放出することで知られている。大量の塩化カルシウム二水和物または高い溶解発熱を有する他の塩を迅速に溶解する時等のある特定の状況下で、熱傷を引き起こす可能性がある大量の熱を放出する。したがって、粘膜表面を塩化カルシウム二水和物と接触させることに関する安全性の懸念が存在する。これらの安全性の懸念を、高い溶解発熱を有さない製剤I〜III等の粉末を産生することによって軽減することができ、したがって、望ましくない発熱効果の可能性を減少させた。
37℃および5%CO2で一晩培養物をトリプシン大豆寒天(TSA)血液プレート上で成長させることによって、細菌を調製した。単一コロニーを無菌PBS中でOD600約0.3に再懸濁し、その後無菌PBS中で1:4に希釈した(約2×107コロニー形成単位(CFU)/mL)。麻酔にかかっている間、気道内注入によって、マウスを50μLの細菌懸濁液(約1×106CFU)に感染させた。
サイズ3のHPMCカプセル(Shionogi Qualicaps,Madrid,Spain)内に装填され、以下の条件、(i)2〜8oCの冷蔵保存、(ii)25oC/相対湿度60%、乾燥剤下で保管されたカプセル、および(iii)40oC/相対湿度75%、乾燥剤下で保管されたカプセルで、設置された製剤I〜IIIの代表的な試料を利用して、3ヶ月間の物理的安定性の研究を行った。FPF<5.6および3.4、ならびにDv50(スプレーテック)および含水量(カールフィッシャー)を3ヶ月時点まで監視した。表40に示されるように、製剤I〜IIIの各々は、これらの条件の各々で評価された物理的特性に関して、良好な安定性を示した。
Claims (55)
- 二価金属カチオン塩を含む吸入に適する乾燥粒子を含む吸入に適する乾燥粉末であって、前記二価金属カチオン塩は、前記乾燥粒子の約5重量%以上の量の二価金属カチオンを供給し、前記吸入に適する乾燥粒子は、レーザー回折(RODOS/HELOSシステム)で測定して、約10ミクロン以下の幾何学的体積中位径(VMGD)および約2未満の分散性比率(1/4バール)を有する、吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、約5.0ミクロン以下の幾何学的体積中位径(VMGD)を有する、請求項1に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、レーザー回折(RODOS/HELOSシステム)で測定して、約1.5未満の分散性比率(1/4バール)を有する、請求項1または2に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、前記粒子の約6重量%以上の量の一価カチオンを提供する一価塩をさらに含む、請求項1または2のいずれかに記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、少なくとも45%の5.6ミクロン未満の細粒分(FPF)を有する、請求項1〜4のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、少なくとも30%の3.4ミクロン未満の細粒分(FPF)を有する、請求項1〜4のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、少なくとも45%の5.0ミクロン未満の細粒分(FPF)を有する、請求項1〜4のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、約5ミクロン以下の空気力学的質量中位径(MMAD)を有する、請求項1または7のいずれかに記載の吸入に適する乾燥粉末。
- 前記二価金属カチオン塩は、水中で0.5g/L以上の溶解度を有する、請求項1〜8のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粒子は、リン酸カルシウムを含有しない、請求項1〜9のいずれかに記載の吸入に適する乾燥粉末。
- 二価金属カチオンの前記二価金属カチオン塩に対する分子量比は、約0.1より大きい、請求項1〜10のいずれか1項に記載の吸入に適する乾燥粉末。
- 二価金属カチオンの前記二価金属カチオン塩に対する分子量比は、約0.16より大きい、請求項1〜10のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、少なくとも1つの薬学的に許容される賦形剤をさらに含む、請求項1〜12のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記少なくとも1つの賦形剤は、約20重量%以下の量で存在し、かつロイシンを含む、請求項13に記載の吸入に適する乾燥粉末。
- 前記少なくとも1つの賦形剤は、約50重量%以下の量で存在し、かつロイシンを含む、請求項13に記載の吸入に適する乾燥粉末。
- 前記少なくとも1つの賦形剤は、約20重量%以下の量で存在し、かつマルトデキストリンまたはマンニトールを含む、請求項13に記載の吸入に適する乾燥粉末。
- 前記少なくとも1つの賦形剤は、約50重量%以下の量で存在し、かつマルトデキストリンまたはマンニトールを含む、請求項13に記載の吸入に適する乾燥粉末。
- 前記二価金属塩は、マグネシウム塩およびバリウム塩から成る群から選択される、請求項1〜17のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記二価金属カチオン塩は、カルシウム塩である、請求項1〜17のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記カルシウム塩は、硫酸カルシウム、クエン酸カルシウム、塩化カルシウム、酢酸カルシウム、グルコン酸カルシウム、またはそれらの任意の組み合わせである、請求項19に記載の吸入に適する乾燥粉末。
- 前記カルシウム塩は、乳酸カルシウムである、請求項19に記載の吸入に適する乾燥粉末。
- 前記一価塩は、リチウム塩またはカリウム塩である、請求項1〜21のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記一価塩は、ナトリウム塩である、請求項1〜21のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記ナトリウム塩は、塩化ナトリウムである、請求項23に記載の吸入に適する乾燥粉末。
- 前記ナトリウム塩は、クエン酸ナトリウム、乳酸ナトリウム、または硫酸ナトリウムである、請求項23に記載の吸入に適する乾燥粉末。
- 二価金属カチオン塩および一価塩を含む吸入に適する乾燥粒子を含む吸入に適する乾燥粉末であって、非晶質二価金属カチオン相および結晶性一価塩相を含む、吸入に適する乾燥粉末。
- 前記非晶相のガラス転移温度は、少なくとも約120℃である、請求項26に記載の吸入に適する乾燥粉末。
- 前記非晶相は、賦形剤をさらに含む、請求項26または27に記載の吸入に適する乾燥粉末。
- 前記賦形剤は、ロイシン、マルトデキストリン、マンニトール、またはそれらの組み合わせである、請求項28に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、2.0以下の1/4バールまたは0.5/4バールを有する、請求項26〜29のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、1.5以下の1/4バールまたは0.5/4バールを有する、請求項26〜29のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、約5ミクロン以下のMMADを有する、請求項26〜31のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、0.5〜約5ミクロンのVMGDを有する、請求項26〜31のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、約5ミクロン〜約20ミクロンのVMGDを有する、請求項26〜31のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、約−10kcal/mol〜10kcal/molの溶解熱を有する、請求項26〜34のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記二価金属カチオンは、前記吸入に適する乾燥粉末の少なくとも約5重量%で存在する、請求項26〜35のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記二価金属カチオン塩は、カルシウム塩である、請求項36に記載の吸入に適する乾燥粉末。
- 前記カルシウム塩は、クエン酸カルシウム、乳酸カルシウム、硫酸カルシウム、塩化カルシウム、またはそれらの任意の組み合わせである、請求項37に記載の吸入に適する乾燥粉末。
- 前記一価塩は、ナトリウム塩である、請求項26〜38のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記ナトリウム塩は、塩化ナトリウムである、請求項39に記載の吸入に適する乾燥粉末。
- 二価金属塩を含む吸入に適する乾燥粒子を含む吸入に適する乾燥粉末であって、前記二価金属塩は、前記乾燥粒子の約5重量%以上の量のカチオンを提供し、前記吸入に適する乾燥粉末は、1.5より大きいハウスナー比および2以下の1/4バールまたは0.5/4バールを有する、吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、1.5以下の1/4バールまたは0.5/4バールを有する、請求項41に記載の吸入に適する乾燥粉末。
- 前記ハウスナー比は、1.7より大きい、請求項41に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、約5ミクロン以下のMMADを有する、請求項41〜43のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記吸入に適する乾燥粉末は、約−10kcal/mol〜10kcal/molの溶解熱を有する、請求項41〜44のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記二価金属カチオン塩は、カルシウム塩である、請求項41〜45のいずれか1項に記載の吸入に適する乾燥粉末。
- 前記カルシウム塩は、クエン酸カルシウム、乳酸カルシウム、硫酸カルシウム、塩化カルシウム、またはそれらの任意の組み合わせである、請求項46に記載の吸入に適する乾燥粉末。
- クエン酸カルシウムまたは硫酸カルシウムを含有する吸入に適する乾燥粒子を含む吸入に適する乾燥粉末であって、前記吸入に適する乾燥粒子は、
a)塩化カルシウムの水溶液を含む第1の液体供給原料と、硫酸ナトリウムまたはクエン酸ナトリウムの水溶液を含む第2の液体供給原料とを提供することと、
b)前記第1の液体供給原料および前記第2の液体供給原料を混合して、アニオン交換反応が起こる混合物を産生し、硫酸カルシウムおよび塩化ナトリウム、またはクエン酸カルシウムおよび塩化ナトリウムを含む飽和もしくは過飽和溶液を産生することと、
c)b)で産生された前記飽和もしくは過飽和溶液を噴霧乾燥して、吸入に適する乾燥粒子を産生することと、を含む過程で産生される、吸入に適する乾燥粉末。 - b)において、前記第1の液体供給原料および前記第2の液体供給原料は、バッチ混合される、請求項48に記載の吸入に適する乾燥粉末。
- b)において、前記第1の液体供給原料および前記第2の液体供給原料は、静的混合される、請求項48に記載の吸入に適する乾燥粉末。
- 静的混合後、得られた混合物は、5分以内に霧化される、請求項50に記載の吸入に適する乾燥粉末。
- 静的混合後、得られた混合物は、30秒以内に霧化される、請求項50に記載の吸入に適する乾燥粉末。
- 呼吸器疾患を治療するための方法であって、それを必要とする患者の気道に、請求項1〜52のいずれか1項に記載の有効量の吸入に適する乾燥粉末を投与することを含む、方法。
- 呼吸器疾患の急性増悪を治療するための方法であって、それを必要とする患者の気道に、請求項1〜52のいずれか1項に記載の有効量の吸入に適する乾燥粉末を投与することを含む、方法。
- 気道の感染性疾患を治療または予防するための方法であって、それを必要とする患者の気道に、請求項1〜52のいずれか1項に記載の有効量の吸入に適する乾燥粉末を投与することを含む、方法。
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