JP2013513616A - 治療用粒子の凍結乾燥に対する安定製剤 - Google Patents
治療用粒子の凍結乾燥に対する安定製剤 Download PDFInfo
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- JP2013513616A JP2013513616A JP2012543308A JP2012543308A JP2013513616A JP 2013513616 A JP2013513616 A JP 2013513616A JP 2012543308 A JP2012543308 A JP 2012543308A JP 2012543308 A JP2012543308 A JP 2012543308A JP 2013513616 A JP2013513616 A JP 2013513616A
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- cyclodextrin
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- poly
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- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
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- 230000000699 topical effect Effects 0.000 description 1
- UWHZIFQPPBDJPM-BQYQJAHWSA-N trans-vaccenic acid Chemical compound CCCCCC\C=C\CCCCCCCCCC(O)=O UWHZIFQPPBDJPM-BQYQJAHWSA-N 0.000 description 1
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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Abstract
Description
a)疎水性ポリマー部分及び親水性ポリマー部分を有する共重合体をそれぞれ含む治療用粒子と、活性剤とを含む組成物を準備し、
b)二糖類、イオン性ハロゲン化物塩及び任意にシクロデキストリンを組成物に添加し、
c)組成物を凍結乾燥し、凍結乾燥組成物を形成し、
d)凍結乾燥組成物を溶解して非経口投与に適する製剤を形成する工程によって製造される非経口投与用の医薬的に許容される製剤を提供する。製剤は、さらにシクロデキストリンを含んでいてもよい。
a)疎水性ポリマー部分及び親水性ポリマー部分を有する共重合体を夫々含む治療用粒子及び活性剤を含む組成物を提供し、
b)二糖類及びシクロデキストリンを組成物に添加し、
c)組成物を凍結乾燥し、凍結乾燥組成物を形成し、
d)凍結乾燥組成物を溶解して非経口投与に適する製剤を形成する工程によって製造される非経口投与用の医薬的に許容される製剤を提供する。
一般に、組成物は活性剤を含むナノ粒子を含有していてもよい。ここに開示されるように、「ナノ粒子」は1000nm未満(例えば、約10nm〜約200nm)の直径を有する粒子である。開示された治療用ナノ粒子は、約60nmから約120nm、または約70nmから約130nm、または約60nmから約140nmの直径を有するナノ粒子を含んでいてもよい。
ある実施形態では、開示のナノ粒子は、約0.2〜約10重量%のターゲティング・リガンドで官能化されたPLA−PEGをさらに含んでいてもよく、及び/又は約0.2〜約10重量%のターゲティング・リガンドで官能化されたポリ(乳酸)−コ−ポリ(グリコール酸)ブロック−PEG−を含んでいてもよい。そのようなターゲティング・リガンドは、ある実施形態では、例えば、PEGに共有結合されていてもよく、例えば、PLA−PEG−アルキレン−GL2のようなアルキレン・リンカーを介してPEGに結合されていてもよい。例えば、開示のナノ粒子は、約0.2〜約10モルパーセントのPLA−PEG−GL2またはポリ(乳酸)−コ−ポリ(グリコール酸)−PEG−GL2を含んでいてもよい。PLA−PEG−GL2又はPLGA−PEG−GL2は、PEGがGL2に結合するアルキレン・リンカー、例えば、C1−C20、例えば(CH2)5)を含むことができる部分をさすと理解される。
ある実施形態では、本発明のナノ粒子は、ポリマー及び治療剤のマトリクスを含む。いくつかの実施形態では、治療剤及び/又はターゲティング部分(すなわち、低分子量のPSMAリガンド)は、高分子マトリックスの少なくとも一部と結合することができる。例えば、いくつかの実施形態では、ターゲティング部分(例えば、リガンド)は、高分子マトリックスの表面と共有結合によって結合していることがある。ある実施形態では、共有結合は、リンカーによって仲介される。治療剤は、高分子マトリックスで封止され、取り囲まれ及び/又は全体にわたって分散して、その表面と結合することができる。
式中、Rは、それぞれ独立にC1〜C30アルキルを表す。
式Vの一実施形態では、脂質は、1,2−ジステアロイル−sn−グリセロ−3−ホスホエタノールアミン(DSPE)及びそれらの塩、例えば、ナトリウム塩である。
他の実施形態では、本発明は治療剤、ポリマーマトリクス、DSPE及び低分子量PSMAターゲティングリガンドを含むターゲット特異性ナノ粒子を提供する。リガンドは、例えば、共有結合によって、DSPEに結合されている。例えば、本発明のナノ粒子は、PLGA−DSPE−PEG−リガンドを含むポリマーマトリックスを含むことができる。
例えば、そのような方法は、脂質と反応する第1のポリマーを準備し、ポリマー/脂質複合体を形成することを含む。ポリマー/脂質複合は、次いで、低分子量リガンドと反応し、リガンド結合ポリマー/脂質複合体を形成し、ナノ粒子を形成するように、リガンド結合ポリマー/脂質複合体と第2の非官能化ポリマー及び治療剤と混合する。ある実施形態では、第1のポリマーは、PEGであり、脂質終端かPEGが形成される。一実施形態では、脂質は、式V、例えば、2ジステアロイル−sn−グリセロ−3−ホスホエタノールアミン(DSPE)及びその塩類(例えば、ナトリウム塩)である。続いて、脂質終端化PEGは、例えば、PLGAと混合して、ナノ粒子を形成する。
任意にターゲティング部分、つまり、生物学的構成要素(例えば、膜成分、細胞表面レセプター、前立腺特異的膜抗原等)と結合するか、さもなければそれと結びつくことができる部分を含んでいてもよいナノ粒子が提供される。粒子表面に存在するターゲティング部分は、粒子を、特定のターゲティング・サイト、例えば、腫瘍、疾病サイト、組織、器官、細胞型等に局所化させることを可能にするかもしれない。そのため、ナノ粒子は、「ターゲット特異性」となり得る。薬物又は他のペイロードは、場合によっては、粒子から放出し、特異的ターゲティング・サイトで局所的に相互作用させることを可能にする。
及び鏡像異性体、立体異性体、回転異性体、互変異性体、ジアステレオマーの混合物又はそのラセミ化合物である。特に、ブチルアミン化合物が、ベンゼン環を有さないため、合成しやすいという長所がある。
式中、R1は、H及びハロゲンで置換されていてもよいC1〜C20アルキル基からなる群から選択され、
R2は、結合手、エステル結合又はアミド結合、
R3は、C1〜C10アルキレン又は結合手、
xは、50から約1500、例えば、約170から約260、
yは0〜約50、例えば、yは0及び
zは約30から約456又は約30から約200、例えば、zは約80から約130である。
例えば、治療剤(例えば、抗がん剤)、診断薬(例えば、造影剤、放射性核種、蛍光体、発光体、磁気分子)、予防剤(例えば、ワクチン)及び/又は栄養補助食品(例えば、ビタミン、ミネラルなど)を含む剤が、本発明のナノ粒子の一部を構成する。本発明によって供給される典型的な剤は、限定されないが、小分子(例えば、細胞障害性剤)、核酸(例えば、siRNA、RNAi及びマイクロRNA剤)、タンパク質(例えば、抗体)、ペプチド、脂質、炭水化物、ホルモン類、金属、放射性元素及び化合物、薬物、ワクチン、免疫学的剤など、及び/又はこれらの組み合わせを含む。いくつかの実施形態では、供給される剤は、ガン(例えば、前立腺ガン)の治療に有用な剤である。
この発明の他の側面は開示のナノ粒子製造する方法及びシステムに指向する。いくつかの実施形態では、2以上の異なる比率で異なるポリマー(例えば、共重合体、例えば、ブロック共重合体)を使用し、ポリマー(例えば、共重合体、例えば、ブロック共重合体)から粒子を製造し、粒子の特性が制御される。例えば、1つのポリマー(例えば、共重合体、例えば、ブロック共重合体)は、低分子量PSMAリガンドを含んでいてもよく、他のポリマー(例えば、共重合体、例えば、ブロック共重合体)は、得られる粒子のその生体適合性及び/又は免疫の制御能のために選択することができる。
本発明の別の側面によれば、ここに開示のナノ粒子は、医薬組成物を形成するために、薬理学的に許容できるキャリアと組み合わることができる。当業者には、後述するような投与経路、標的組織の位置、供給薬物、薬物供給の時間的経過等に基づいて、キャリアを選択することができることはいうまでもない。
a)疎水ポリマー部分と親水性ポリマー部分とを有する共重合体を各々含有する複数の治療用粒子と、活性剤とを含む組成物を準備し、
b)二糖類及びイオン性ハロゲン化物塩をこの組成物に添加し、
c)組成物を凍結乾燥して、凍結乾燥組成物を形成し、
d)凍結乾燥組成物を溶解して非経口投与に適する製剤を形成する。一実施形態では、シクロデキストリンがこの製剤に含まれる。いくつかの実施形態では、そのような溶解は、2、3分間の簡便な手動の混合によって有利に管理することができる。溶解物の特性(例えば、薬物純度及び放出プロフィール)は、凍結乾燥前の組成物(例えば、懸濁剤)から実質的に不変かもしれない。
a)各々疎水ポリマー部分と親水性ポリマー部分とを有する共重合体を含有する複数の治療用粒子と、活性剤とを含む組成物を準備し、
b)二糖類及びシクロデキストリンをこの組成物に添加し、
c)組成物を凍結乾燥して、凍結乾燥組成物を形成し、
d)凍結乾燥組成物を溶解して非経口投与に適する製剤を形成する。一実施形態では、シクロデキストリンがこの製剤に含まれる。いくつかの実施形態では、そのような溶解は、2、3分間の簡便な手動の混合によって有利に管理することができる。溶解物の特性(例えば、薬物純度及び放出プロフィール)は、凍結乾燥前の組成物(例えば、懸濁剤)から実質的に不変かもしれない。
一般的に示す本発明は、以下の実施例を参照することにより、より理解しやすくなるであろうが、これらの実施例は、単に例示の目的で含まれるものであり、これらに限定されるものではない。
以下に示すように、合成は、マクロ開始剤であるα−ヒドロキシ−コ−メトキシポリ(エチレングリコール)でのd,l−ラクチドの開環重合を、触媒として2−エチルヘキサン酸錫(II)を用いて高温で行うことにより行われる(PEG Mn:〜5,000Da、PLA Mn:〜16,000Da、PEG−PLA Mn:〜21,000Da)。
有機相を、ドセタキセル(DTXL)とポリマー(ホモポリマ、コポリマー及びリガンドとも共重合体)の混合物から構成するように形成する。有機相は、約1:2(油相:水相)の比率で水相と混合し、水相が界面活性剤(0.25%のナトリウム・コール酸塩)と多少溶解した溶媒(4%の酢酸エチル、2%のベンジルアルコール)から構成される。高い薬物充填を達成するために、有機相中約30%の固形分を用いる。
表B:クエンチ・プロセスのパラメータの要約
2 安定性のデータは、スラリーにおける結晶形成(顕微鏡検査によって視認)の前に、25℃で、10〜50mg/mlのナノ粒子濃度で最終製品を維持した時間を意味する。
3 インビトロバーストは、薬物が最初の時点(基本的にすぐに)で放出された薬物を示す。
図3で示すように、>40mg/mLのナノ粒子濃度のナノ粒子懸濁液(実施例として形成されたナノ粒子、ポリマーとして16/5のPLA−PEGで)を、10%の蔗糖及び添加剤:NaCl、CaCl2又はPBSの存在下で凍結乾燥する。この実験は、マイクロ凝集なしに溶解しることができる、高い(>40mg/ml)ナノ粒子濃度で、ナノ粒子懸濁液を処方する。3つの全てのCaCl2製剤は、崩壊した凍結乾燥品を生成した、中濃度(150mM)及び高濃度(200mM)の濃度範囲であっても、<100粒子/ml(10μ+)で溶解ケーキを生成する。
ナノ粒子懸濁液を、糖(例えば、蔗糖又はトレハロース)、塩(例えば、NaCl又はCaCl2)及び/又はシクロデキストリン(例えば、ヒドロキシプロピルβ−シクロデキストリン:HPbCD)の存在下で凍結乾燥する。例えば、製剤は250mM又は500mMのNaCl又はCaCl2及び/又は15%、20%又は25重量%の蔗糖又はトレハロース(例えば、20重量%のトレハロース、500mMのCaCl2、5%のHPbCd)で製造される。代表的な製剤を、表Fに示す。
ナノ粒子懸濁液を、糖(例えば、トレハロース)、シクロデキストリン(例えばヒドロキシプロピルβシクロデキストリン:HPbCD)及び/又は塩(例えば、CaCl2)の存在下で、凍結乾燥する。Design of Experiment(DOE)を用いた製剤をスクリーンするための賦形剤及びレベルを以下の表Gに示す。トールバイアルを、5mLのフル容量にて、全製剤で用いる(n=5〜6バイアル/製剤)。第1の乾燥を−37℃の棚温度で行う。
ナノ粒子懸濁液を、糖(例えば、トレハロース又は蔗糖)及びシクロデキストリン(例えば、ヒドロキシプロピルβシクロデキストリン:HPbCD)の存在下で凍結乾燥する。試験した製剤を表Hに示す。トールバイアルを、5mLのフル容量にて、全製剤で用いる(n=10バイアル/製剤)。
当業者であれば、単なる慣例の実験を用いて、本明細書に記載の本発明の特定の実施形態の多くの等価物を理解されるであろう、あるいは確かめることができるであろう。かかる等価物は、以下の特許請求の範囲によって包含されることが意図される。
本明細書に記載のすべての特許、公開特許出願、ウェブサイト、および他の参考文献の内容全体が、参照によりその全体が本明細書に明示的に援用される。
Claims (53)
- 約100mL以下の水性媒体での凍結乾燥医薬組成物の溶解において、非経口投与に適した溶解組成物が、
10ミクロン以上の微粒子を6000未満及び
25ミクロン以上の微粒子を600未満含有するポリマーナノ粒子を含有する凍結乾燥医薬組成物。 - 溶解組成物は、10ミクロン以上の微粒子を3000未満及び25ミクロン以上の微粒子をが300未満含有する請求項1の凍結乾燥医薬組成物。
- 微粒子の数は、USP32<788>に準じた光掩蔽粒子計数試験によって測定される請求項1又は2の凍結乾燥医薬組成物。
- 微粒子の数は、USP32<788>に準じた顕微鏡粒子計数試験によって測定される請求項1又は2の凍結乾燥医薬組成物。
- 微粒子の数は、USP32<788>に準じた単一粒子光学検出によって測定される請求項1又は2の凍結乾燥医薬組成物。
- ナノ粒子は、ポリ(乳酸)ブロック−ポリ(エチレン)グリコール共重合体又はポリ(乳酸)−コ−ポリ(グリコール酸)−ブロック−ポリ(エチレン)グリコール共重合体を含む請求項1〜6のいずれか1つの凍結乾燥医薬組成物。
- 溶解組成物は、約10〜100mg/mLのナノ粒子濃度を有する請求項1〜6のいずれか1つの凍結乾燥医薬組成物。
- 共重合体のポリ(乳酸)部分は、約16kDaの重量平均分子量を有しており、共重合体のポリ(エチレン)グリコール部分は約5kDaの重量平均分子量を有している請求項6又は7の凍結乾燥医薬組成物。
- ナノ粒子は治療剤を含む請求項1〜8のいずれか1つの凍結乾燥医薬組成物。
- 治療剤はドセタキセルである請求項9の凍結乾燥医薬組成物。
- 凍結乾燥医薬品組成物は、さらに、糖とイオン性ハロゲン化物塩を含む請求項1〜10のいずれか1つの凍結乾燥医薬組成物。
- 凍結乾燥医薬品組成物は、さらに、二糖類とイオン性ハロゲン化物塩を含む請求項1〜11のいずれか1つの凍結乾燥医薬組成物。
- さらに、シクロデキストリンを含む請求項12の凍結乾燥医薬組成物。
- 凍結乾燥医薬品組成物は、さらに、二糖類及びシクロデキストリンを含む請求項1〜10のいずれか1つの凍結乾燥医薬組成物。
- 二糖類は、蔗糖又はトレハロースあるいはそれらの混合物である請求項12〜14のいずれか1つの凍結乾燥医薬組成物。
- イオン性ハロゲン化物塩は、塩化ナトリウム、塩化カルシウム及び塩化亜鉛ならびにそれらの混合物から選択される請求項11〜15のいずれか1つの凍結乾燥医薬組成物。
- シクロデキキストリンは、α−シクロデキストリン、β−シクロデキストリン、γ−シクロデキストリン又はこれらの混合物からなる群から選択される請求項13〜16のいずれか1つの凍結乾燥医薬組成物。
- 凍結乾燥医薬品組成物は、約1〜約15重量%の蔗糖を含む請求項15〜17のいずれか1つの凍結乾燥医薬組成物。
- 凍結乾燥医薬品組成物は、約1〜約15重量%のトレハロースを含む請求項14〜16のいずれか1つの凍結乾燥医薬組成物。
- 凍結乾燥医薬品組成物は、約10から約100mMの塩化ナトリウムを含む請求項12〜19のいずれか1つの凍結乾燥医薬組成物。
- 凍結乾燥された医薬品組成物は、約100から約500mMの二価のイオン性塩化物塩を含む請求項12〜19のいずれか1つの凍結乾燥医薬組成物。
- 凍結乾燥医薬品組成物は、約100から約500mMの塩化カルシウム又は塩化亜鉛を含む請求項21の凍結乾燥医薬組成物。
- 凍結乾燥医薬品組成物は、約1から約25重量%のβ―シクロデキストリンを含む請求項14〜21のいずれか1つの凍結乾燥医薬組成物。
- 溶解組成物は、イオン性ハロゲン化物塩を含有しない溶解組成物に比較して最小限の凝集体しか含有しない請求項14〜23のいずれか1つの凍結乾燥医薬組成物。
- 溶解組成物は、シクロデキストリンを含有しない溶解組成物に比較して最小限の凝集体しか含有しない請求項14〜23のいずれか1つの凍結乾燥医薬組成物。
- 溶解組成物は、0.2未満のポリ分散インデックスを有する請求項1〜25のいずれか1つの凍結乾燥医薬組成物。
- ナノ粒子は約40〜60mg/mlの濃度を有する請求項1〜26のいずれか1つの凍結乾燥医薬組成物。
- 溶解して非経口用途に適する医薬組成物であって、
複数の治療用粒子を含み、各粒子は、親水性ポリマーと疎水性ポリマーとを含むコポリマーと、活性剤と、糖と、イオン性ハロゲン化物塩とを含有する医薬組成物。 - さらにシクロデキストリンを含む請求項28の医薬組成物。
- イオン性ハロゲン化物塩は、塩化ナトリウム、塩化カルシウム及び塩化亜鉛あるいはそれらの混合物からなる群から選択される請求項28又は29の医薬組成物。
- 約10から約100mMの塩化ナトリウムを含む請求項30の医薬組成物。
- 約100から約500mMの塩化カルシウム又は塩化亜鉛を含む請求項30の医薬組成物。
- 溶解して非経口用途に適する医薬組成物であって、
複数の治療用粒子を含み、各粒子は、親水性ポリマーと疎水性ポリマーとを含むコポリマーと、活性剤と、糖と、シクロデキストリンとを含有する医薬組成物。 - シクロデキストリンは、α−シクロデキストリン、β−シクロデキストリン、γ−シクロデキストリン又はこれらの混合物から選択される請求項33の医薬組成物。
- 医薬組成物は、約1から約25重量%のβ―シクロデキストリンを含む請求項34の医薬組成物。
- コポリマーは、ポリ(乳酸)−ブロック−ポリ(エチレン)グリコールである請求項28〜35のいずれか1つの医薬組成物。
- 溶解において、100mlの水性サンプルが、10ミクロン以上の微粒子を6000未満で、25ミクロン以上の微粒子を600未満で含む請求項28〜36のいずれか1つの医薬組成物。
- 溶解において、100mlの水性サンプルは、10ミクロン以上の微粒子を600未満で、25ミクロン以上の微粒子が60未満で含む請求項28〜36のいずれか1つの医薬組成物。
- 溶解して、ナノ粒子は、約40〜60mg/mLの濃度を有する請求項37又は38の医薬組成物。
- a)疎水ポリマー部分と親水性ポリマー部分とを有する共重合体を各々含有する複数の治療用粒子と、活性剤とを含む組成物を準備し、
b)二糖類、イオン性ハロゲン化物塩及び任意にシクロデキストリンをこの組成物に添加し、
c)組成物を凍結乾燥して、凍結乾燥組成物を形成し、
d)凍結乾燥組成物を溶解して非経口投与に適する製剤を形成する工程を含んで製造される非経口投与用の薬理学的に許容される製剤。 - a)疎水性ポリマー部分と親水性ポリマー部分とを有する共重合体を各々含有する複数の治療用粒子と、活性剤とを含む組成物を準備し、
b)二糖類及びシクロデキストリンをこの組成物に添加し、
c)組成物を凍結乾燥して、凍結乾燥組成物を形成し、
d)凍結乾燥組成物を溶解して非経口投与に適する製剤を形成する工程を含んで製造される非経口投与用の薬理学的に許容される製剤。 - 凍結乾燥組成物が約40mg/mlより高濃度の治療用粒子を有する請求項40又は41の製剤。
- 非経口投与に適する製剤が、10ml用量中、10ミクロンより大きなサイズの粒子を600個未満で含有する請求項40〜42のいずれか1つの製剤。
- 二糖類及びイオン性ハロゲン化物塩の添加が、
約5〜15重量%の蔗糖又は約10〜20重量%のトレハロースと、約10〜500mMのイオン性ハロゲン化物塩の添加を含む請求項40〜43のいずれか1つの製剤。 - 二糖類、イオン性ハロゲン化物塩及びシクロデキストリンの添加が、
約5〜15重量%の蔗糖と、約5〜20重量%のトレハロースと、約10〜500mMのイオン性ハロゲン化物塩と、約1〜25重量%のシクロデキストリンの添加を含む請求項40、42又は43の製剤。 - イオン性ハロゲン化物塩は、塩化ナトリウム、塩化カルシウム及び塩化亜鉛あるいはそれらの混合物からなる群から選択される請求項40、41又は45の製剤。
- 二糖類及びシクロデキストリンの添加が、
約5〜15重量%の蔗糖又は約10〜20重量%のトレハロースと、約1〜25重量%のシクロデキストリンの添加を含む請求項40、41又は45の製剤。 - シクロデキストリンは、α−シクロデキストリン、β−シクロデキストリン、γ−シクロデキストリン又はこれらの混合物からなる群から選択される請求項45〜47のいずれか1つの製剤。
- 凍結乾燥は、約−30℃未満の温度で組成物を凍結し、
凍結組成物を形成し、及び
凍結組成物を乾燥して凍結乾燥組成物を形成する薬理的に許容される製剤。 - 乾燥を、約−30℃から−40℃のプロダクト温度で約50mTorrで行う請求項49の製剤。
- 糖及び塩を、ナノ粒子を含有する凍結乾燥製剤に添加し、
凍結乾燥製剤を溶解し、溶解組成物は実質的にナノ粒子の凝集体を含まないことを含む溶解医薬ナノ粒子組成物における粒子の凝集を実質的に防止する方法。 - さらにシクロデキストリンの添加を含む請求項51の方法。
- 糖及びシクロデキストリンを、ナノ粒子を含有する凍結乾燥製剤に添加し、
凍結乾燥製剤を溶解し、溶解組成物は実質的にナノ粒子の凝集体を含まないことを含む溶解医薬ナノ粒子組成物における粒子の凝集を実質的に防止する方法。
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