JP4368198B2 - 肺送達用の改良された粒状組成物 - Google Patents
肺送達用の改良された粒状組成物 Download PDFInfo
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- JP4368198B2 JP4368198B2 JP2003545266A JP2003545266A JP4368198B2 JP 4368198 B2 JP4368198 B2 JP 4368198B2 JP 2003545266 A JP2003545266 A JP 2003545266A JP 2003545266 A JP2003545266 A JP 2003545266A JP 4368198 B2 JP4368198 B2 JP 4368198B2
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- A61K9/0012—Galenical forms characterised by the site of application
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- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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- Veterinary Medicine (AREA)
- Pulmonology (AREA)
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Description
出願人らは、以前、空気力学的に軽い粒子を含む乾燥粉末が薬物の肺への吸入に適していることを見出した。しかしながら、治療剤、診断剤、および/または予防剤(以後、集合的に薬物という)のエアロゾル送達に伴ういくつかの問題がある。例えば、静電気的荷電相互作用は、乾燥粉末吸入器(DPI)を介する乾燥粒子の送達の全体的な効率に影響する。なぜなら、そのような力は、粒子それ自体の間の、ならびに粒子およびデバイス表面の間の引力および接着に重要と考えられるからである。加えて、粒子サイズ分布、粒子形態、および水分含有量は、乾燥粉末の製剤のバルク特性およびその性能に大いに影響しかねない。
本発明は、薬物を肺系に送達するための改良された粒状組成物に関する。薬物は治療剤、診断剤、および/または予防剤であり得る。出願人らは、高度に分散性である空気力学的に軽い粒子の最適形態を同定する方法を開示する。本発明の粒子は、粒子形成のプロセスにおいて崩壊し、非常に低いエンベロープ密度のしわしわの薄い壁の薬物粒子に導く中空の球状薬物粒子(すなわち、原粒子)を創製することによって作製される。加えて、出願人らは、表面積パラメーター(σ)が2を超える、最適には3を超える場合に、そのような粒子は吸入されるエアロゾルに特に最適であることを見出した。
本明細書中で用いられる場合は、用語「壁厚み」とは、粒子の壁の平均厚みをいう。本発明の薄い壁の粒子では、壁厚みは約50〜150nm、好ましくは約75〜125nm程度であり、これは粒子の球状エンベロープ直径の約1%である。測定技術は当業者に公知であり、限定されるものではないが、肉眼での観察(例えば、SEM、TEM)が含まれるか、あるいは球状エンベロープ直径、タップ密度および表面積の関数として計算される。
本発明の好ましい態様の記載を以下に続ける。
として定義されるように、S=任意の形状の粒子の表面積とする。例えば、もし粒子が固体の球(ここに、壁厚み(h)=De/2、S=πDe 2)であれば、σ=1が得られる。しかしながら、もし粒子がゼロ(0)に近づく壁厚みを持つ中空の球であり、従って、S=2πDe 2であれば、σ=2が得られる。本発明は、折りたたまれてしわしわの粒子を形成し、それにより、表面積を2を超える値まで増加させる薄い壁を持ち(しかしながら、壁の崩壊を妨げるのに十分な剛性を有する)中空球の製造に関する。
実施例1.同一の組成および異なる形態を持つ粒子の製造(球状対しわしわの紙状)
60:20:20重量:重量のジパルミトイルホスファチジルコリン(DPPC,Avanti Polar Lipids, Alabaster, AL):ウシ血清アルブミン(BSA,Sigma Chemical Co., St.Louis, MO):ラクトース(Spectrum Chemical Co.)よりなる製剤を以下の様式で噴霧乾燥した。
前記実施例1から方法iおよびiiによって製造した粉末を、それらの幾何学的および空気力学的特性について特徴付けた。(後記する)粉末分散性指標もまた幾何学的および空気力学的分析方法によって得た。幾何学的サイズはレーザー回折(Sympatec RODOSシステム)によって得られ、種々の分散圧力で得た測定値を、粉末分散性の指標として用いた(実験は0.25〜4バールまでの範囲の分散圧力で行った)。また、RODOSシステムを吸入器付属システムと組み合わせて用い、吸入器を通過する流速(30〜90L/分)の関数として粒子サイズを測定し、粉末分散性の別の指標を提供した。粒子の空気力学的サイズ分布は、Aerodisperser(API, Amherst, MA)を利用するAerosizerシステムによって得た。幾何学的、空気力学的および分散性特徴付け測定の結果(全てのデータはミクロンで得られる)を表1に示す。
SEM顕微鏡を利用して、しわしわの紙状粉末試料と球状形態の粉末試料の間の形態の差を解明すると共に、しわしわの紙状形態の粉末試料が球状形態の試料よりも薄い壁を保有することを確認した。不変粉末の試料のSEM画像を図1(製剤i)および2(製剤ii)に示す。壁厚さの観察のため、球状粉末を3''直径のサイクロンの使用によって粉砕して、粒子のいくらかを破砕して壁断面の画像化を可能とし、他方、(壁厚さは密に折り畳まれた領域のおよそ1/2の幅であると仮定して)密に折り畳まれた領域の観察によってしわしわの紙状形態粉末について壁厚さを概算した。壁厚さについての推定値は球状粒子についてはおよそ150〜200ナノメートルであり、しわしわの紙状形態粒子については80〜120ナノメートルであった。
BET等温方法(Autosorb System, Quantachrome Instruments, Boynton Beach, FL)を用いて、代表的な製剤i(球状)およびii(しわしわの紙状形態)粉末試料の外部表面積を測定した。試料から室温にて24時間ガス抜きし、その後、吸着体として窒素ガスを利用する3点方法を介して等温線を得た。この方法によって得られた比表面積は製剤iについては5.16m2/グラム、製剤ii粉末については8.10m2/グラムであった。AFM結果は、AFMによって測定した表面積がBET等温方法によって得られたものと等しい場合、BET等温方法が外部粒子表面積の尺度を提供するという仮定を支持した(データは示さず)。各製剤について表面積定数(factor)(σ)を計算するために、4バールの分散圧力でRODOSによって測定した幾何学的直径と概算した粒子密度を用いて、以下の方程式:
しわしわの紙状形態を有しているブランクおよび薬物を含有する粉末双方について前記とは異なる賦形剤を利用して同様の結果を得ることができる。前記実施例1に記載したのと同様の噴霧乾燥方法を利用し、しわしわの紙状形態を有している以下の薬物を含有する粉末を製剤化した:
a.68:20:10:2のDPPC:クエン酸ナトリウム:塩化カルシウム:硫酸アルブテロール
b.58:20:20:2のDPPC:DPPE:ラクトース:エストラジオール。
用いた70/20/10重量%のDPPC/クエン酸ナトリウム/塩化カルシウムよりなるプラセボ粉末は以下の特徴を有していた:Dg=6.7um;=0.06g/cm3;Da=1.6um。一次空気力学的粒子サイズの特徴は時間飛行(AeroSizer/AeroDisperser)を用いて得られ、幾何学的粒子サイズ特徴は、1および2バールで操作したレーザー回折(本明細書中に記載したRODOS乾燥粉末分散器およびHELOSレーザー回折計を用いて測定される)を用いて得られた。噴出した空気力学的粒子のサイズ特徴は、2Lの合計空気容量にて、28.3L/分で操作したAndersenカスケードインパクション(重力分析)を用いて得られた。幾何学的粒子のサイズ特徴は、60L/分で操作した吸入器付属品を備えるレーザー回折(RODOS/HELOS, Sympatec, NJ)を用いて得られた。
高度に分散性の粉末は、効果的に噴出し呼吸活性化乾燥粉末吸入器(DPI)の区域から肺に達し得る。クエン酸ナトリウム、DPPC、塩化カルシウム緩衝液および微量のローダミン蛍光標識よりなる噴霧乾燥粉末を調製した。該粉末は2.1μmのメジアン空気力学的直径(AeroDisperserおよびAerosizerによって測定される)および11.0μmの幾何学的直径(本明細書中に記載したようなRODOS乾燥粉末分散器およびHELOSレーザー回折計を用いて測定される)を有しており、優れた脱凝集特性を呈した。
乾燥条件に応じて種々の程度に折り畳むことができる薄い乾燥殻の形成を促進する入口温度および乾燥速度にて薬物および薬学的賦形剤のエタノール/水共溶媒溶液を噴霧乾燥することによって、ナノ薄粒子(すなわち、100nm程度の壁厚さを持つ中空粒子)を形成した。このプロセスにより、インスリン、硫酸アルベテロール、エストラジオール、ヒト成長ホルモンおよび免疫グロブリンを含めた薬物、および脂質、糖およびアミノ酸を含めた賦形剤を用いて、頑強なナノ薄粒子の形成が可能であることを証明した。
に唯一関連した。よって、該方程式によると、粒子壁厚さ(h)は一定の質量密度(p)およびサイズ(d)の中空粒子粉末についての粒子表面積(σ)または表面形態を規定する。psは比重びん法(pynonometry)によって測定され(ps=1.2g/cm3)、σは原子間力顕微鏡(AFM)によって測定され(σA=2.6;σB=5.0)、これにより、球状粒子Aについてはh=200nm、およびしわしわの粒子Bについてはh=50nmの粒子壁厚さの推定値を得た。これらの推定値を、透過型電子顕微鏡(TEM)画像によって肉眼で確認し、前記方程式の結果として推定した粒子構造を間接的に証明した。
Claims (8)
- 0.4g/cm3未満のタップ密度および5μmより大きなメジアン幾何学的直径、および5m2/gより大きな外表面積を有する、しわしわの紙状形態の粒子を含有してなる、肺系への送達のための改良された粒状組成物。
- 薬物をさらに含有してなる請求項1記載の粒子。
- 薬学的賦形剤をさらに含有してなる請求項2記載の粒子。
- レーザー回折(RODOS/HELOSシステム)により測定した場合、1.0〜1.5のメジアン幾何学的直径の比をさらに含む請求項1記載の粒子。
- 少なくとも1g/cm3の骨格密度を有する請求項4記載の粒子。
- 0.4g/cm3未満のタップ密度および5μmより大きな幾何学的直径を有する粒子を含有してなる、肺系への薬物の送達のための改良された粒状組成物であって、該粒子が連続した崩壊した中空球状壁を有し、該壁が150ナノメートル未満の壁厚さおよび少なくとも5m2/gの外表面積を有する、しわしわの紙状形態の粒子である、粒状組成物。
- 少なくとも70%の粒子が5.6μm未満の微粒子画分を有する請求項6記載の粒状組成物。
- a)薬物および薬学的に許容され得る賦形剤を含有してなる混合物を噴霧乾燥して噴霧乾燥粒子を形成すること;
b)噴霧乾燥粒子の平均壁厚さを測定すること;
c)噴霧乾燥条件を調整して平均壁厚さを最小にすること;ならびに
d)最小の平均壁厚さを有する噴霧乾燥粒子を収集すること
を含む、肺系への薬物送達のための粒状組成物の製造方法。
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2002
- 2002-11-20 WO PCT/US2002/037333 patent/WO2003043585A2/en active IP Right Grant
- 2002-11-20 EP EP02789792.5A patent/EP1455755B1/en not_active Expired - Lifetime
- 2002-11-20 US US10/300,657 patent/US7182961B2/en not_active Expired - Lifetime
- 2002-11-20 ES ES02789792T patent/ES2415654T3/es not_active Expired - Lifetime
- 2002-11-20 DK DK02789792.5T patent/DK1455755T3/da active
- 2002-11-20 PT PT2789792T patent/PT1455755E/pt unknown
- 2002-11-20 AU AU2002352836A patent/AU2002352836B2/en not_active Expired
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US20030129139A1 (en) | 2003-07-10 |
AU2002352836A1 (en) | 2003-06-10 |
EP1455755A4 (en) | 2007-05-09 |
ES2415654T3 (es) | 2013-07-26 |
US7182961B2 (en) | 2007-02-27 |
CA2465675A1 (en) | 2003-05-30 |
EP1455755B1 (en) | 2013-04-17 |
JP2005511628A (ja) | 2005-04-28 |
DK1455755T3 (da) | 2013-07-15 |
AU2002352836B2 (en) | 2005-09-29 |
CA2465675C (en) | 2008-06-10 |
PT1455755E (pt) | 2013-06-18 |
WO2003043585A3 (en) | 2003-11-13 |
US20070104657A1 (en) | 2007-05-10 |
EP1455755A2 (en) | 2004-09-15 |
WO2003043585A2 (en) | 2003-05-30 |
US7384649B2 (en) | 2008-06-10 |
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