JP5127466B2 - 医薬脂質組成物 - Google Patents
医薬脂質組成物 Download PDFInfo
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- JP5127466B2 JP5127466B2 JP2007551724A JP2007551724A JP5127466B2 JP 5127466 B2 JP5127466 B2 JP 5127466B2 JP 2007551724 A JP2007551724 A JP 2007551724A JP 2007551724 A JP2007551724 A JP 2007551724A JP 5127466 B2 JP5127466 B2 JP 5127466B2
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Description
a)5〜90%の少なくとも1つのホスファチジルコリン成分と、
b)5〜90%の少なくとも1つのジアシルグリセロール成分、少なくとも1つのトコフェロール、若しくはその混合物と、
c)1〜40%(好ましくは、2〜40%)の少なくとも1つの非イオン性安定化両親媒性物質と、を含み、
全ての部が、a+b+cの重量の合計に対する重量比であり、
前記組成物が、少なくとも1つの非ラメラ相構造の粒子を含むか、又は水性流体と接触すると少なくとも1つの非ラメラ相構造の粒子を形成する粒子組成物を提供する。
i)両親媒性物質/水性液晶相(水中における成分aなど)を細分化剤(成分b及び/又はcなど)の水溶液を添加し、その混合物を自然に細分化させるか、若しくは、例えば機械的攪拌、ボルテックス、回転ステータ混合、高圧均質化、ミクロ流体化、及び/又は超音波でプロセスを加速させること、又は
ii)a+b+cの混合物(必要に応じて、少なくとも1つの生物活性剤を含む)を溶媒(例えば、水溶液)に添加し、そのまま攪拌することが含まれる。
a)5〜90%の少なくとも1つのホスファチジルコリン成分と、
b)5〜90%の少なくとも1つのジアシルグリセロール成分、少なくとも1つのトコフェロール、若しくはその混合物と、
c)2〜40%の少なくとも1つの非イオン性安定化両親媒性物質と、
を含む混合物を形成し、全ての部がa+b+cの重量の合計に対する重量比であり、前記混合物を水性流体中に分散させることを含む、非ラメラ粒子の形成方法を提供する。この方法は、好ましくは、本明細書に記載されるように、少なくとも1つの加熱及び冷却サイクルを含み、水性流体は、水、注射に適した水溶液、体液、又は本明細書に示されるようなその他の任意の適切な流体であり得る。混合物は、純粋に両親媒性物質a〜cからなり、又は、以下の実施例に例示されるように、活性剤及び/又は水混和性溶媒などの他の成分を含んでいてもよい。方法はまた、必要に応じて、乾燥工程(噴霧乾燥若しくは凍結乾燥など)が伴われ、それによって、組成物は粉末状になる。
SPC=Lipoid GmbH(ドイツ)から入手できる大豆ホスファチジルコリン
GDO=Danisco(デンマーク)から入手できるグリセロールジオレエート
P80=Apoteket(スウェーデン)から入手できるポリソルベート80
ソルトール(登録商標)HS15=BASF(ドイツ)から入手できるマクロゴール15ヒドロキシステアレート
Cryo−TEM=低温透過型電子顕微鏡
PPF=Sigma−Aldrich(スウェーデン)から入手できるプロポフォール
EPC=Lipoid GmbH(ドイツ)から入手できる卵ホスファチジルコリン
DOPE−PEG(5000)=Avanti Polar Lipids(米国)から入手できるジオレオイルホスファチジルエタノールアミンポリ(エチレングリコール)5000
CMC=Sigma−Aldrich(スウェーデン)から入手できるカルボキシメチルセルロース(ナトリウム塩)
PVP=ISP(米国)から入手できるポリビニルピロリドン
PEG=Merck(米国)から入手できるポリエチレングリコール
1.1−非ラメラ分散液の調製
2.125gのSPC/GDO(40/60wt/wt)混合物(エタノール中に脂質を混合し、その後溶媒を蒸発させることによって形成される)と、0.3826gのP80とを混合することによって、非ラメラ粒子(80重量%より多くの両親媒性物質)及びラメラ粒子(20重量%より少量の両親媒性物質)の分散液を形成した。成分を70℃で5分間加熱し、ボルテックスすることによって、分子混合した。均質な溶融脂質(2.012g)を38.01gの脱イオン水に滴状添加した。得られた粗分散液を振盪テーブル(350rpm)上に置き、24時間振盪させ、混濁した均質分散液を得た。
熱処理の任意のサイクルを実施例1.1で調製された分散液に対して実施した。
成分:
a SPC
b GDO
c P80
さらに高濃度の安定化剤を添加することによって得られる効果を、実施例1.1及び1.2の方法で第2の組成物を調製することによって検討した。SPC及びGDO(40/60wt/wt)(2.017g)及びP80(0.514g)の溶液を70℃で5分間加熱し、ボルテックスすることにより分子混合した。均質な溶融脂質(2.006g)を38.00gの脱イオン水に滴状添加した。得られた粗分散液を振盪テーブル上に置き、24時間振盪させ、混濁した均質分散液を得た。その後、分散液を実施例1.2に従って熱処理した。
a SPC
b GDO
c P80
他のタイプの安定化剤を添加することによって得られる効果を、実施例1.1及び1.2の方法で他の組成物を調製することによって検討した。SPC及びGDO(40/60wt/wt)(2.004g)及びソルトール(登録商標)HS15(0.516g)の溶液を70℃で5分間加熱し、ボルテックスすることによって、分子混合した。均質な溶融脂質(2.042g)を38.00gの脱イオン水に滴状添加した。得られた粗分散液を振盪テーブル上に置き、24時間振盪させ、十分に分散していないマクロ粒子をいくつか含む混濁した分散液を得た。均質な分散液を得るために、5000PSIで動作するミクロ流動化装置を用いて室温で試料を均質化した。試料をホモジナイザーに5回通過させて乳状の均質な分散液を得た。その後、分散液を実施例1.2に従って熱処理した。
a SPC
b GDO
c ソルトール(登録商標)HS15
濃縮した非ラメラ粒子分散液を、実施例1.1及び1.2の方法によって調製した。SPC及びGDO(40/60wt/wt)(4.7958g)及びP80(0.8152g)の溶液を70℃で5分間加熱し、ボルテックスすることによって、分子混合した。均質な溶融脂質(5.001g)を44.999gの脱イオン水に滴状添加した。得られた粗分散液を振盪テーブル上に置き、48時間(350rpmで)振盪させ、混濁した均質分散液を得た。その後、分散液を実施例1.2に従って熱処理した。
a SPC
b GDO
c P80
実施例1.1及び1.2の方法に従って非ラメラ分散液を調製した。分散液の組成を以下の表に表示する。分散液を25℃で保存し、粒度分布を一定の間隔で測定した。粒度分布は、少なくとも2ヶ月の保存期間中、元の粒度分布と合致し、優れたコロイド及び保存安定性を有することが判明した。
SPC(32重量%の両親媒性物質)、GDO(48重量%の両親媒性物質)、及びP80(20%の両親媒性物質)を含む組成物と、PPFとを以下の表に示される割合で混合することによって、麻酔活性剤PPFを含有する非ラメラ粒子分散液を形成した。成分を70℃で5分間加熱し、ボルテックスすることによって、分子混合した。均質な脂質/PPF融液を(総製剤の重量に基づき)2.5%のグリセロールを含む水溶液に滴状添加した。得られた粗分散液を振盪テーブル(350rpm)上に置き、12時間振盪させ、均質分散液を得た。その後、分散液を実施例1.2の方法で熱処理した。図9に示されるように、得られた分散液の粒度分布は狭く、平均粒度140〜150nmの単峰型であった。PPFが充填された分散液は、少なくとも2ヶ月室温で保存するのに安定していることが判明した。
PPFを含有する非ラメラ粒子の分散液を、実施例6と同じ組成物を用い、実施例6と同じ方法で調製した。但し、この場合、PPFの濃度は、10mg/mLであり、両親媒性物質の濃度は、25mg/mL(PPF:両親媒性物質=1:2.5wt/wt)であった。ラット(雄のSPF Sprague−Dawleyのラット(Mol:SPRD HAN,M&B Taconic,Lille Skensved,デンマーク))における麻酔期間について、非ラメラ粒子PPF分散液と、参照用の市販のプロポフォールフレゼニウスカビ(Fresenius Kabi)エマルジョン製剤(10mgのPPF/mL)とを比較した。動物に、体重1kg当たり10mgのPPFを1回だけボーラス静脈注射した(麻酔の誘導は、両ケースにおいて注射の直後発生した)。薬力学パラメーターについては、回復時間(立ち上がろうとすることによって示される復原(righting)応答時間)を記録した。この結果を以下の表にまとめる。表は、非ラメラ粒子PPF分散液が、必要な麻酔効果を高効率で維持することを示している。
以下の成分を用いて、非ラメラ分散液を実施例1.1及び1.2の方法によって調製した。
a)SPC
b)GDO
c)P80
10重量%の総両親媒性物質の濃度に対して重量比a:b:c=34:51:15で水中に分散されている。塩化ナトリウム(NaCl)を分散液に添加して9mgのNaCl/mLを達成した。その後、ラットのモデルに静脈注射した後の急性毒性について、分散液をテストした。
水溶性の高い着色料であるパテントブルーをカプセル化する非ラメラ粒子を以下のように調製した。3.0gのSPC/GDO/P80(34/51/15重量%)の製剤を実施例1に従って調製した。この溶液に、0.15gのエタノールを添加し、製剤をボルテックス混合によって混合した。0.20gのパテントブルー(20mg/mL)の水溶液を3.0gのSPC/GDO/P80/EtOH製剤に添加した。得られた試料をボルテックス混合によって混合し、均質な低粘度の製剤を生成した。2.55gのこの製剤を22.5gの脱イオン水に添加し、得られた製剤を350rpmで18時間振盪させて青色に着色した均質な分散液を得た。分散液を限外濾過(30000MWCOフィルター)後、カプセル化効率を元の分散液の吸光度(640nm)から濾液(カプセル化されていない画分)の吸光度を差し引き、その差を元の分散液の吸光度によって除算して測定した(すべての吸光度測定の前にTritonX100(脱イオン水中10重量%)を添加して透明な溶液を得た)。
水溶性ペプチドであるオクトレオチドをカプセル化する非ラメラ粒子を以下のようにして調製した。1.0gのSPC/GDO/P80(34/51/15重量%)の製剤を実施例1に従って調製した。この溶液に、0.10gのエタノールを添加し、製剤をボルテックス混合によって混合した。その後、0.054gのオクトレオチド(35.5mg/mL)の水溶液を添加し、得られた試料をボルテックス混合によって混合して低粘度の均質な製剤を生成した。1.0gのこの製剤を9.0gの生理的食塩水(9mgのNaCl/mL)に添加し、得られた製剤を350rpmで18時間振盪させて均質な分散液(平均粒度:約100nm)を得た。カプセル化されたオクトレオチドを2.5mLの分散液をセファデックスG25(PD−10)カラムに通し、脂質画分及び遊離したオクトレオチド画分を別個のガラス瓶に収集することによってカプセル化されていないペプチドから分離した。TritonX100を添加後、HPLCによって脂質画分及び遊離オクトレオチド画分の濃度を分析した。
SPC、α−トコフェロール、及びエタノール(27/63/10重量%)(1.34g)の溶液をd−αトコフェリルポリエチレングリコール1000コハク酸エステル(ビタミンE TPGS)(0.30g)と混合した。試料を40℃で15分間加熱し、ボルテックスすることによって、分子混合した。均質な脂質融液(1.0g)を19gの脱イオン水に滴状添加した。得られた粗分散液を振盪テーブル上に置き、20時間(350rpm)振盪させ、混濁した均質な非ラメラ粒子分散液を得た。
EPC(1.539g)、GDO(2.302g)、P80(0.685g)をエタノール(0.501g)と混合した。試料を3時間にわたるボルテックス混合及び転倒型回転によって混合し、均質且つ透明な液体を得た。液体製剤(1.665g)を滅菌水(28.335g)に添加し、得られた粗分散液を振盪テーブルにおいて400rpmで18時間混合した。図12に示されるように、得られた分散液は均質であり、粒度分布は狭く、平均粒度114nmの単峰型であることが判明した。
非ラメラナノ粒子の容易な製造に対する、脂質組成物の変化の影響を調べるために、SPC/GDOの比が変化し、P80の比が一定である試料を調製した。48時間振盪させた試料#1128以外は実施例13に記載されるように、成分をエタノールと混合し、その後、滅菌水に分散させた。試料の最終組成、振盪(400rpm)後の平均粒度及び多分散性指数(PI)、並びに(実施例1.2による)加熱処理後の平均粒度及び多分散性指数を以下の表に示す。
SPC(1.45g)、GDO(2.15g)、P80(0.90g)、及びEtOH(0.50g)を混合することによって液体非ラメラ粒子前駆体を調製し、5時間にわたる転倒型回転によって、均質且つ透明な脂質を得た。
以下の表に示される割合(製剤1g当たり0.6mgのオクトレオチド)で、SPC、GDO、P80、EtOH、及びOCTを混合することによって、実施例15に記載されるように、オクトレオチドを含む液体非ラメラ粒子前駆体を調製した。得られた試料を、転倒型回転によって混合し、透明且つ均質な液体製剤を得た。
SPC(0.918g)、GDO(1.377g)、P80(0.405g)、及びEtOH(0.30g)をガラス瓶中で混合し、15時間にわたる転倒型回転によって、液体脂質保存溶液を調製した。OCT(5mg)を滅菌水(0.095g)に溶解させ、2.2gの脂質保存溶液をオクトレオチド水溶液に添加した。得られた混合物を、試料が均質になるまでボルテックスした。脂質/オクトレオチド混合物(1.85g)を生理食塩水(18.15g)に添加し、得られた分散液(0.2mgのOCT/mL)を振盪テーブルにおいて400rpmで15時間混合した。その後、分散液を滅菌濾過(0.22μmのフィルター)で滅菌した。得られた分散液は、混濁から乳状であり、レーザ回折で測定したところ、平均粒度約100nmで、均質であった。
OCT(0.2mgのOCT/mL)を含む非ラメラ粒子分散液を、実施例17に記載されるように、生理食塩水中で調製した。得られた分散液は、混濁から乳状であり、レーザ回折で測定したところ、平均粒度約100nmで、均質であった。製剤の組成を以下の表に示す。
以下の表に示される割合(製剤1g当たり0.5mgのsCT)で、SPC、GDO、P80、EtOH、及びsCTを混合することによって、実施例14に記載されるように、sCTを含む液体非ラメラ粒子前駆体を調製した。得られた試料を、転倒型回転によって混合し、透明且つ均質な液体製剤を得た。
SPC(0.3046g)、GDO(0.4570g)、P80(0.1344g)、EtOH(0.100g)、及びOCT(0.004g)を混合することによって液体非ラメラ粒子前駆体を調製し、15時間にわたる転倒型回転によって、透明な均質液体を得た。OCTを含む液体前駆体(0.50g)を9.5gの滅菌水に添加し、得られた分散液を振盪テーブルにおいて400rpmで20時間混合し、製剤1g当たり0.2mgのOCTを含む均質な非ラメラ粒子分散液を得た。非ラメラ粒子分散液(9.0g)に対して、9.0gの1重量%のCMC水溶液及び18gの5重量%のPVP溶液を添加した。得られた混合物を丸底フラスコに添加し、EtOH/ドライアイス混合物上で凍結させ、一晩凍結乾燥させた。得られた粉末は、白色から淡黄色の乾燥状態(dry consistency)であり、2重量%未満の残留水を含み、OCT含有量は、粉末1g当たり1.3mgであった。粉末は、ボルテックス混合によって生理食塩水中に容易に再分散され、乳状の白色(混濁)非ラメラ粒子分散液を得た。
実施例1.1に記載されるように調製された6gのSPC/GDO/P80(31/54/15重量%)の予め形成された非ラメラ粒子分散液(5重量%の両親媒性物質)と、12gの1重量%のCMC水溶液及び12gの5重量%のPVP水溶液とを混合することによって、噴霧乾燥された非ラメラ粒子前駆体を得た。得られた混合物は、BUCHIミニスプレードライヤー B−290を用いて噴霧乾燥し、乾燥状態で、且つ、2重量%未満の残留水を含む白色から淡黄色の粉末を得た。噴霧乾燥された粉末は、ボルテックス混合によって生理食塩水中に容易に再分散され、乳状から白色(混濁)の非ラメラ粒子分散液を得た。
SPC(0.918g)、GDO(1.377g)、P80(0.574g)、及びEtOH(0.319g)をガラス瓶中で混合し、15時間にわたる転倒型回転によって、液体脂質保存溶液を調製した。インスリン(10mg)を滅菌水(0.190g)に添加し、1.80gの脂質保存溶液をインスリン水溶液(製剤1g当たり5mgのインスリン)に添加した。得られた混合物を試料が均質になるまでボルテックスした。
SPC(0.918g)、GDO(1.377g)、P80(0.574g)、及びEtOH(0.319g)をガラス瓶中で混合し、15時間にわたる転倒型回転によって、液体脂質保存溶液を調製した。GLP−1(10mg)を滅菌水(0.190g)に添加し、1.80gの脂質保存溶液をインスリン水溶液(製剤1g当たり5mgのインスリン)に添加した。得られた混合物を試料が均質になるまでボルテックスした。
Claims (22)
- 粒子組成物であって、
a)5〜50%の少なくとも1つのホスファチジルコリン成分と、
b)20〜85%の少なくとも1つのジアシルグリセロール成分、少なくとも1つのトコフェロール、若しくはその混合物と、
c)8000amu未満の分子量を有するポリオキシエチレン及び/又はポリオキシプロピレン鎖(又はそのコポリマー)がグラフトした非イオン性脂質を含む、1〜40%の少なくとも1つの非イオン性安定化両親媒性物質と、を含み、
全ての部が、a+b+cの重量の合計に対する重量比であり、前記組成物が、少なくとも1つの非ラメラ相構造の粒子を含むか、又は水性流体と接触すると少なくとも1つの非ラメラ相構造の粒子を形成する粒子医薬組成物。 - 前記成分a)が、卵ホスファチジルコリン(PC)、心臓PC,脳PC、肝臓PC、及び大豆PCから選択される少なくとも1つのPCを含む請求項1に記載の組成物。
- 前記成分b)が、炭素14〜18のアシル鎖を有するジアシルグリセロールを含む請求項1又は2に記載の組成物。
- 前記成分b)が、グリセロールジオレート(GDO)、又はGDOとトコフェロールの混合物である請求項1〜3のいずれか一項に記載の組成物。
- 前記成分a)及び/又は前記成分b)が、天然供給源から得られる請求項1〜4のいずれか一項に記載の組成物。
- 前記成分a)が、少なくとも50%のC18:1及び/又はC18:2のアシル基を有し、前記成分b)が、少なくとも50%のC18:1及び/又はC18:2のアシル基を有するジアシルグリセロールである請求項1〜5のいずれか一項に記載の組成物。
- 前記成分c)が、PEG−ソルビタン−モノラウレート、PEG−ソルビタン−モノオレエート、PEG−(4−ヒドロキシステレート)、d−αトコフェリルポリエチレングリコール1000コハク酸エステル(ビタミンE TPGS)、並びにポリオキシエチレンヒマシ油から選択される少なくとも1つの非イオン性安定化両親媒性物質を含む請求項1〜6のいずれか一項に記載の組成物。
- さらに活性剤を含む請求項1〜7のいずれか一項に記載の組成物。
- 前記活性剤が、オクトレオチド及び他のソマトスタチン関連ペプチド、インスリン、二グルコン酸クロルヘキシジン、二塩酸クロルヘキシジン、ビスホスホネート、非ステロイド抗炎症剤、コルチコステロイド、メトトレキサート、アザチオプリン、6−メルカプトプリン、及びホスホリパーゼ阻害剤から選択される少なくとも1つである請求項8に記載の組成物。
- 前記組成物が、I2及び/又はL2相構造の粒子を含み、及び/又は水性流体と接触するとI2及び/又はL2相構造の粒子を形成する請求項1〜9のいずれか一項に記載の組成物。
- 前記組成物を含むか、又は水性流体と接触すると形成される粒子の平均粒度が0.1〜0.6μmである請求項1〜10のいずれか一項に記載の組成物。
- 前記組成物が、少なくとも3ヶ月間、相挙動、粒度、及び粒度分布に関して実質的に安定している請求項1〜11のいずれか一項に記載の組成物。
- 1〜6個の炭素原子、及び/又はその水溶性ポリマーを有する少なくとも1つの有機溶媒を20%までさらに含む請求項1〜12のいずれか一項に記載の組成物。
- a)分散液、
b)補助溶媒中の予備濃縮物、
c)乾燥粉末、又は生物学的に許容可能なポリマーを含む固化混合物の形態である請求項1〜13のいずれか一項に記載の組成物。 - 請求項1〜14のいずれか一項に記載の少なくとも1つの組成物、及び少なくとも1つの生物学的に許容可能な担体又は賦形剤を含む医薬製剤。
- 液体の懸濁液、粉剤、錠剤、カプセル剤、コーティングされたカプセル剤、コーティングされた錠剤、エアロゾル、坐薬、ドロップ、クリーム、経皮パッチ、及び噴霧剤から選択される形態の請求項15に記載の医薬製剤。
- 非経口投与に適する請求項15又は16に記載の製剤。
- a)5〜50%の少なくとも1つのホスファチジルコリン成分と、
b)20〜85%の少なくとも1つのジアシルグリセロール成分、少なくとも1つのトコフェロール、若しくはその混合物と、
c)8000amu未満の分子量を有するポリオキシエチレン及び/又はポリオキシプロピレン鎖(又はそのコポリマー)がグラフトした非イオン性脂質を含む、1〜40%の少なくとも1つの非イオン性安定化両親媒性物質と、を含み、
全ての部が、a+b+cの重量の合計に対する重量比である混合物を形成すること、及び
前記混合物を水性流体に分散させることを含む非ラメラ粒子医薬組成物の製造方法。 - 懸濁液の形態で請求項1〜14のいずれか一項に記載の組成物を調製するためのキットであって、粉末の形態の請求項1〜14に記載の少なくとも1つの組成物を含むキット。
- 体腔における炎症及び/又は痛みを治療するための請求項15〜17のいずれか一項に記載の医薬製剤。
- 炎症性の腸疾患を治療するための請求項15〜17のいずれか一項に記載の医薬製剤。
- 請求項1〜14のいずれか一項に記載の組成物及び少なくとも1つの活性剤を含む製剤をヒトを除く動物被検体に投与することを含む、1〜30日の期間にわたる活性剤の持続放出方法。
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