JP6728186B2 - 脂質カプセル化ガスマイクロスフェア組成物および関連方法 - Google Patents
脂質カプセル化ガスマイクロスフェア組成物および関連方法 Download PDFInfo
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- JP6728186B2 JP6728186B2 JP2017535077A JP2017535077A JP6728186B2 JP 6728186 B2 JP6728186 B2 JP 6728186B2 JP 2017535077 A JP2017535077 A JP 2017535077A JP 2017535077 A JP2017535077 A JP 2017535077A JP 6728186 B2 JP6728186 B2 JP 6728186B2
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- lipid
- glycerol
- dppe
- dppa
- propylene glycol
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- VUFOSBDICLTFMS-UHFFFAOYSA-M ethyl-hexadecyl-dimethylazanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)CC VUFOSBDICLTFMS-UHFFFAOYSA-M 0.000 description 1
- KSCHLNBLIAOANF-UHFFFAOYSA-M ethyl-hexadecyl-dimethylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)CC KSCHLNBLIAOANF-UHFFFAOYSA-M 0.000 description 1
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- 150000002191 fatty alcohols Chemical class 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
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- WBCLXFIDEDJGCC-UHFFFAOYSA-N hexafluoro-2-butyne Chemical compound FC(F)(F)C#CC(F)(F)F WBCLXFIDEDJGCC-UHFFFAOYSA-N 0.000 description 1
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- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
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- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
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- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 description 1
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- 230000013011 mating Effects 0.000 description 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- DNMZJIGSDQVGSA-UHFFFAOYSA-N methoxymethane;hydrochloride Chemical compound Cl.COC DNMZJIGSDQVGSA-UHFFFAOYSA-N 0.000 description 1
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- BLLFVUPNHCTMSV-UHFFFAOYSA-N methyl nitrite Chemical compound CON=O BLLFVUPNHCTMSV-UHFFFAOYSA-N 0.000 description 1
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- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
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- 229910052754 neon Inorganic materials 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
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- RKSFWNXSXBDVII-UHFFFAOYSA-N nonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(C(O)=O)CC(O)=O RKSFWNXSXBDVII-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
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- 239000003973 paint Substances 0.000 description 1
- QYZLKGVUSQXAMU-UHFFFAOYSA-N penta-1,4-diene Chemical compound C=CCC=C QYZLKGVUSQXAMU-UHFFFAOYSA-N 0.000 description 1
- XEIJMVGQZDKEPZ-UHFFFAOYSA-N perfluoroethanamine Chemical compound FN(F)C(F)(F)C(F)(F)F XEIJMVGQZDKEPZ-UHFFFAOYSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 229940067605 phosphatidylethanolamines Drugs 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 125000002525 phosphocholine group Chemical class OP(=O)(OCC[N+](C)(C)C)O* 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- 239000002244 precipitate Substances 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- JNYAEWCLZODPBN-CTQIIAAMSA-N sorbitan Polymers OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000008362 succinate buffer Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 150000007970 thio esters Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 1
- BPXRXDJNYFWRDI-UHFFFAOYSA-N trifluoro(trifluoromethylperoxy)methane Chemical compound FC(F)(F)OOC(F)(F)F BPXRXDJNYFWRDI-UHFFFAOYSA-N 0.000 description 1
- OFHCXWMZXQBQMH-UHFFFAOYSA-N trifluoro(trifluoromethylsulfanyl)methane Chemical compound FC(F)(F)SC(F)(F)F OFHCXWMZXQBQMH-UHFFFAOYSA-N 0.000 description 1
- DUXYWXYOBMKGIN-UHFFFAOYSA-N trimyristoyl-sn-glycerol Natural products CCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCC DUXYWXYOBMKGIN-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- NXHILIPIEUBEPD-UHFFFAOYSA-H tungsten hexafluoride Chemical compound F[W](F)(F)(F)(F)F NXHILIPIEUBEPD-UHFFFAOYSA-H 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
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- 238000012800 visualization Methods 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/225—Microparticles, microcapsules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
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- Pharmacology & Pharmacy (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Acoustics & Sound (AREA)
- Radiology & Medical Imaging (AREA)
- Physics & Mathematics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
Description
本出願は、米国法典第35編第119条第(e)項の下、2014年12月31日出願の米国仮特許出願第62/098,453号明細書(その全体が参照により本明細書に組み込まれる)の利益を主張する。
こうした新しい配合物は、1種以上の脂質と、プロピレングリコール(PG)、またはグリセロール(G)、またはプロピレングリコールおよびグリセロール(PG/G)との非水性混合物を含む。こうした配合物は、既存の超音波コントラスト剤配合物を用いてこれまで可能であったよりも長い期間にわたりより高い温度で有意な分解を伴うことなく貯蔵しうることが本発明により見いだされた。したがって、こうした組成物は、配合物が使用前にどのように取り扱われたかに関して特に関心を払うことなく広範にわたる状況で使用しうる。
こうした新しい配合物は、1種、典型的には2種以上の脂質を含む。本明細書で用いられる場合、「脂質」または「全脂質」または「合わせた脂質」とは、脂質の混合物を意味する。
非水性混合物はガスと共に提供しうる。たとえば、非水性混合物は、ガスに接触した状態で提供しうるか、またはガスに接触せずにガスと同一の容器またはハウジング内に提供しうる(すなわち、非水性混合物およびガスは、互いから物理的に分離しうる)。
非水性混合物は、容器(またはハウジング)に入れて提供しうる。容器は、シングルチャンバー容器またはマルチチャンバー容器、たとえば、限定されるものではないが、デュアルチャンバー容器でありうる。
(i)以下のもの、すなわち、
(a)DPPA、DPPC、PEG5000−DPPEなどの脂質と、
(b)プロピレングリコールおよびグリセロール、またはプロピレングリコール、またはグリセロールと
を含む非水性混合物と、
(ii)パーフルオロカーボンガスなどのガスと
を含み、かつ第2のチャンバーは希釈水溶液を含む。
(i)以下のもの、すなわち、
(a)DPPA、DPPC、PEG5000−DPPEなどの脂質と、
(b)プロピレングリコールおよびグリセロール、またはプロピレングリコール、またはグリセロールと
を含む非水性混合物
を含み、かつ第2のチャンバーは、
(i)希釈水溶液と、
(ii)パーフルオロカーボンガスなどのガスと
を含む。
以上の組成物はいずれも、結果的に超音波コントラスト剤として使用可能な脂質カプセル化ガスマイクロスフェアを形成するために使用しうる。本明細書で用いられる場合、脂質カプセル化ガスマイクロスフェアとは、主にガスでありかつ脂質シェルによりカプセル化される内部体積を有するスフェアのことである。脂質シェルは、ユニラメラ層またはマルチラメラ二層を含めて単層または二層として配置しうる。こうしたマイクロスフェアは、超音波コントラスト剤として有用である。
本発明は、非水性溶液などの脂質溶液中の不純物含有率を評価する方法をさらに提供する。かかる方法は、任意選択的にHPLCなどの1種以上の分離技術と組み合わせた帯電エアロゾル検出(CAD)などのいくつかの分析方法のいずれかを用いて、不純物の存在に関して脂質溶液を分析する工程を含む。脂質溶液は、脂質とプロピレングリコールまたはグリセロールまたはプロピレングリコールおよびグリセロールとを含む非水性溶液でありうる。脂質溶液は、非リン酸緩衝液などの緩衝液をさらに含みうる。脂質溶液は、塩および/または水をさらに含みうる。閾値レベル超の不純物の存在は、脂質溶液が適正に貯蔵されなかったこと、その安定性が損なわれていること、およびそのために脂質溶液を被験体に投与せずに廃棄すべきであることを意味しうる。かかる方法は、品質管理の目的に使用しうる。
本発明は、マイクロスフェアおよびマイクロスフェア組成物の使用方法を提供する。マイクロスフェアは、超音波コントラスト剤であることが意図され、ヒトまたは非ヒト被験体においてin vivoまたはin vitroで使用しうる。本発明の組成物は、診断もしくは治療の目的でまたは診断と治療とを組み合わせた目的で使用しうる。
市販のFDA認可超音波コントラスト剤DEFINITY(登録商標)(Lantheus Medical Imaging)を比較のために使用した。各バイアルは、次のもの、すなわち、注射用水中の103.5mg/mLのプロピレングリコールと126.2mg/mLのグリセロールと2.34mg/mLの第一リン酸ナトリウム一水和物と2.16mg/mLの二塩基性リン酸ナトリウム七水和物と4.87mg/mLの塩化ナトリウムとのマトリックス中に、1,2−ジパルミトイル−sn−グルセロ−3−ホスファチジルコリン(DPPC、0.401mg/mL)と1,2−ジパルミトイル−sn−グルセロ−3−ホスファチジン酸(DPPA、0.045mg/mL)とN−(メトキシポリエチレングリコール5000カルバモイル)−1,2−ジパルミトイル−sn−グルセロ−3−ホスファチジルエタノールアミン(MPEG5000 DPPE、0.304mg/mL)とを含有する。pHは6.2〜6.8である。脂質溶液の公称充填体積は、3.80mLの近似体積を有する2ccWheatonガラスバイアル中の約1.76mLであり、そのため、パーフルオロプロパンガス(PFP、6.52mg/mL)を含有するヘッドスペースは、約2.04mLである。
プロピレングリコール中の実施例1の新しい配合物脂質ブレンドサンプルを2ccWheatonガラスバイアルに入れ、ヘッドスペースをPFPガスで置き換え、Westグレイブチルライオストッパーを挿入し、アルミニウムシールでバイアルをクリンプした。室温貯蔵に対応するように25℃の環境チャンバー内にバイアルを貯蔵するか、または最終滅菌に対応するように乾燥オーブン内で130℃に加熱した。適切な時間点でサンプルバイアルを貯蔵域から取り出し、デクリンプし、生理食塩水をバイアルに添加し、均一溶液が確保されるように混合した。サンプルをHPLCバイアルに移して、逆相HPLC分離およびコロナ帯電エアロゾル検出(CAD;HPLC With Charged Aerosol Detection for the Measurement of Different Lipid Classes,I.N.Acworth,P.H.Gamache,R.McCarthy and D.Asa,ESA Biosciences Inc.,Chelmsford,MA,USA;J.Waraska and I.N.Acworth,American Biotechnology Laboratory,January 2008)により不純物を分析した。
プロピレングリコール/グリセロール中の実施例1の新しい配合物脂質ブレンドサンプルを2ccWheatonガラスバイアルに入れ、ヘッドスペースをPFPガスで置き換え、Westグレイブチルライオストッパーを挿入し、アルミニウムシールでバイアルをクリンプした。室温貯蔵に対応するように25℃の環境チャンバー内にバイアルを貯蔵するか、または最終滅菌に対応するようにオーブン内で130℃に加熱した。25℃で貯蔵したバイアルを準備し、実施例2に記載されるように分析した。130℃で加熱したバイアルを実施例2に記載されるように準備したが、実施例2でDEFINITY(登録商標)に対して記載したHPLC系を用いて分析した。表3および4は、25℃および130℃でバイアル中の全脂質内容物に対するパーセントとして全不純物を提供する。実施例2に記載されるように分析したDEFINITY(登録商標)の結果を比較のために提供する。
0.005Mの酢酸(75/25酢酸ナトリウム/酢酸)緩衝液、安息香酸(75/25安息香酸ナトリウム/安息香酸)緩衝液、またはサリチル酸(90/10サリチル酸ナトリウム/サリチル酸)緩衝液を含有する1:1(v:v)プロピレングリコール/グリセロール中の実施例1の新しい配合物脂質ブレンドサンプルを2ccWheatonガラスバイアルに充填し、ヘッドスペースをPFPガスで置き換え、Westグレイブチルライオストッパーを挿入し、アルミニウムシールでバイアルをクリンプした。25℃でバイアルを貯蔵して準備し、実施例2に記載されるように分析した。実施例2に記載されるように分析したDEFINITY(登録商標)の結果を比較のために提供する。25℃でのバイアルで全脂質内容物に対するパーセントとして全不純物を表5に示す。
グリセロール中の実施例1の新しい配合物脂質ブレンドサンプルを2ccHPLCガラスバイアルに充填し、ヘッドスペースをPFPガスで置き換え、セプタムを含有するスクリューキャップでバイアルをシールした。25℃でバイアルを貯蔵して準備し、実施例2に記載されるように分析した。
PTFEでライニングされたキャップを備えたアンバーボトルにLB粉末を入れて25℃で貯蔵した。メタノール(50%)とプロピレングリコール(10%)とグリセリン(10%)と酢酸アンモニウム(30%、5mM)との溶液でサンプルを調製した。溶液をHPLCバイアルに移して、C18カラムと、水、メタノール、酢酸アンモニウム、およびトリエチルアミンを含有する移動相とを用いて、蒸発光散乱検出(ELSD)を備えたグラジエント逆相HPLCで分析した。
VIALMIX(登録商標)を用いてPFP/脂質溶液の機械的振盪(米国特許第6,039,557号明細書(その内容は参照により本明細書に組み込まれる)に記載されており、本プロセスで使用しうる)を行って、市販のFDA認可超音波コントラスト剤DEFINITY(登録商標)(Lantheus Medical Imaging,Inc.)を活性形態にした(「活性化」)。この結果、脂質マイクロスフェア中にガスが取り込まれて活性生成物を生じる(DEFINITY(登録商標)処方情報を参照されたい)。DEFINITY(登録商標)の最適VIALMIX(登録商標)活性化によりガス充填マイクロスフェアが一貫して生成され、1および40ミクロンの下側および上側カットオフを有する適切なシース溶液(表8参照)中に希釈すると粒子サイザー(Malvern FPIA−3000 Sysmex)を用いて数およびサイズ分布を分析することが可能である。
実施例1に記載の脂質ブレンドの新しい配合物を2ccWheatonガラスバイアルに秤取し、所要により希釈剤を添加し、ヘッドスペースをPFPガスで置き換え、Westグレイブチルライオストッパーを挿入し、アルミニウムシールでバイアルをクリンプした。所要によりストッパーを介して希釈剤を注入し、ある時間にわたりVIALMIX(登録商標)を用いてバイアルを機械的に振盪し、最適な生成物活性化をもたらした。マイクロスフェアの数および分布を決定し、実施例7に記載の方法によりいくつかの活性化配合物の超音波減衰を調べた。
0.045:0.401:0.304(w:w:w)比(脂質ブレンドの比と同一)で個別リン脂質(DPPA、DPPCおよびMPEG5000 DPPE)をプロピレングリコール中に混合することにより配合物(個別脂質配合物)を調製した。得られた7.5mg/mLの個別脂質プロピレングリコール配合物を希釈剤(DEFINITY(登録商標)バイアル組成物に一致するようにグリセロール、リン酸緩衝液、および生理食塩水を含有する)に添加し、かつ混合して0.75mg/mLの最終全脂質濃度を得た。1.7mLのアリコートを2ccWheatonガラスバイアルに添加し、ヘッドスペースをPFPガスで置き換え、Westグレイブチルライオストッパーを挿入し、アルミニウムシールでバイアルをクリンプした。VIALMIX(登録商標)でバイアルを活性化し、Sysmex FPIA3000を用いてマイクロスフェア数および平均マイクロスフェアサイズを分析した。
実施例1に記載の脂質ブレンドを用いて、プロピレングリコール(PG)または1:1v/vプロピレングリコール/グリセロール(PG/G)のいずれかにさまざまな量のLB粉末を混合することにより、さまざまな全脂質ブレンド濃度で配合物を作製した。各脂質配合物を2ccWheatonガラスバイアルに秤取し、所要により希釈剤を添加し、ヘッドスペースをPFPガスで置き換え、Westグレイブチルライオストッパーを挿入し、アルミニウムシールでバイアルをクリンプした。VIALMIX(登録商標)を用いてバイアルを機械的に振盪して生成物を活性化し、所要により、針を備えたシリンジを用いてストッパーを介して希釈剤を添加した。実施例7に記載されるようにマイクロスフェアの数および分布を決定した。
バイアル、シリンジ、および可撓性プラスチックチューブを含む種々の容器に新しい脂質配合物またはDEFINITY(登録商標)を充填してから活性化した。すべての研究で、適切量の脂質配合物を容器に入れ、ヘッドスペースをPFPと交換し、容器をシールし、および配合物を活性化した。
VIALMIX(登録商標)を使用する以外のいくつかの方法を用いてDEFINITY(登録商標)を活性化する能力を実証する研究を行った。こうした方法は、表25に報告された結果と共に以下に記載されている。
Claims (16)
- (a)プロピレングリコールおよびグリセロール
(b)プロピレングリコール、または
(c)グリセロール
中に、DPPA、DPPC、およびPEG5000−DPPEを含む非水性混合物と、
パーフルオロカーボンガスと
を含む、超音波を用いた診断イメージングおよび/または治療において用いられる薬剤の形成に用いるための組成物。 - (a)DPPA、DPPC、およびPEG5000−DPPE対プロピレングリコール対グリセロールの比が、約1:100:100〜約1:600:700の範囲内であるか、
(b)DPPA、DPPC、およびPEG5000−DPPE対プロピレングリコールの比が、約1:100〜約1:600の範囲内であるか、または
(c)DPPA、DPPC、およびPEG5000−DPPE対グリセロールの比が、約1:100〜約1:700である、請求項1に記載の組成物。 - 前記非水性混合物が、
(a)5w/w(重量/重量)%以下の水、
(b)1〜4w/w%の水、または
(c)1w/w%以下の水
を含む、請求項1または2に記載の組成物。 - (a)脂質の対イオンであるイオンを含むか、
(b)塩化ナトリウムを含まないか、
(c)塩化物イオンを含まないか、
(d)緩衝液をさらに含むか、
(e)非リン酸緩衝液をさらに含み、適宜、前記非リン酸緩衝液が、酢酸緩衝液、安息香酸緩衝液、またはサリチル酸緩衝液であってもよく、
(f)約3ヶ月間室温で貯蔵した場合、2%以下の不純物を含むか、および/または
(g)室温で貯蔵した場合、DEFINITY(登録商標)より少ない不純物を含む、
請求項1〜3のいずれか一項に記載の組成物。 - DPPA、DPPC、およびPEG5000−DPPEの合計が、
(a)非水性混合物に対して約0.9〜約7.5mg/mlの濃度、または
(b)非水性混合物に対して約0.9〜約4mg/mlの濃度
で存在する、請求項1〜4のいずれか一項に記載の組成物。 - (a)前記パーフルオロカーボンガスが、パーフルオロプロパンガスであるか、
(b)PEG5000−DPPEが、MPEG5000−DPPEであるか、および/または
(c)DPPA、DPPC、およびPEG5000−DPPEが、10対82対8(10:82:8)のモル%比で存在する、
請求項1〜5のいずれか一項に記載の組成物。 - (i)バイアルであって、適宜、
(a)約3.8mlまたはそれ以下の実体積を有するバイアル、
(b)V底バイアル、
(c)平底バイアル、
(d)丸底バイアル
であって、適宜、前記バイアルは、ガラスバイアルであってもよいもの、
(ii)2mLのWheatonバイアルであって、前記非水性混合物が、プロピレングリコールおよびグリセロールの約3.75mg/mLの脂質濃度を有するもの、
(iii)シングルチャンバー、
(iv)マルチプルチャンバーであって、適宜、前記マルチプルチャンバーが、第1および第2のチャンバーを含み、前記組成物が、前記第1のチャンバーに存在し、かつ希釈水溶液が、前記第2のチャンバーに存在し、適宜、前記希釈水溶液が、
(a)生理食塩水溶液、または
(b)緩衝生理食塩水溶液
であってもよいもの
の中で提供される、請求項1〜6のいずれか一項に記載の組成物。 - 容器中に請求項1〜7のいずれか一項に記載の組成物を含む、超音波を用いた診断イメージングおよび/または治療において用いられる薬剤の形成に用いるためのキットであって、適宜、前記容器が、シングルチャンバー容器またはマルチチャンバー容器である、キット。
- (a)第2の容器をさらに含み、適宜、前記第2の容器が、
(i)希釈水溶液を含むか、
(ii)プレ充填シリンジであるか、
(iii)プロピレングリコールを含むか、または
(iv)グリセロールを含み、適宜、
(b)希釈水溶液を含む第3の容器をさらに含む、請求項8に記載のキット。 - (a)前記容器が、プロピレングリコール中にDPPA、DPPC、およびPEG5000−DPPEを含む非水性混合物と、パーフルオロカーボンガスとを含む、請求項1〜7のいずれか一項に記載の組成物を含む第1のチャンバーと、グリセロールおよび/または希釈水溶液を含む第2のチャンバーとを含むマルチチャンバー容器であり、
(b)前記容器が、プロピレングリコールおよびグリセロール中にDPPA、DPPC、およびPEG5000−DPPEを含む非水性混合物と、パーフルオロカーボンガスとを含む、請求項1〜7のいずれか一項に記載の組成物を含む第1のチャンバーと、希釈水溶液を含む第2のチャンバーとを含むマルチチャンバー容器であり、または
(c)前記容器が、グリセロール中にDPPA、DPPC、およびPEG5000−DPPEを含む非水性混合物と、パーフルオロカーボンガスとを含む、請求項1〜7のいずれか一項に記載の組成物を含む第1のチャンバーと、プロピレングリコールおよび/または希釈水溶液を含む第2のチャンバーとを含むマルチチャンバー容器である、請求項8に記載のキット。 - VIALMIX(登録商標)デバイスをさらに含む、請求項8〜10のいずれか一項に記載のキット。
- (1)プロピレングリコール中にDPPA、DPPC、およびPEG5000−DPPEを含む非水性混合物と、パーフルオロカーボンガスとを含む、請求項1〜7のいずれか一項に記載の組成物にグリセロールおよび/または希釈水溶液を添加し、
次いで前記組成物を活性化して脂質カプセル化ガスマイクロスフェアを形成する工程、 (2)プロピレングリコールおよび/またはグリセロール中にDPPA、DPPC、およびPEG5000−DPPEを含む非水性混合物と、パーフルオロカーボンガスとを含む、請求項1〜7のいずれか一項に記載の組成物を活性化して脂質カプセル化ガスマイクロスフェアを形成する工程であって、適宜、希釈水溶液を前記組成物に添加した後に活性化される工程、
(3)プロピレングリコールおよび/またはグリセロール中にDPPA、DPPC、およびPEG5000−DPPEを含む非水性混合物と、パーフルオロカーボンガスとを含む、請求項1〜7のいずれか一項に記載の組成物に希釈水溶液を添加し、
次いで前記組成物を活性化して脂質カプセル化ガスマイクロスフェアを形成する工程、あるいは
(4)グリセロール中にDPPA、DPPC、およびPEG5000−DPPEを含む非水性混合物と、パーフルオロカーボンガスとを含む、請求項1〜7のいずれか一項に記載の組成物にプロピレングリコールおよび/または希釈水溶液を添加し、
次いで前記組成物を活性化して脂質カプセル化ガスマイクロスフェアを形成する工程、
とを含む、超音波を用いた診断イメージングおよび/または治療において用いられる薬剤を形成する方法であって、
適宜、前記組成物が、
(i)20〜45秒間、または
(ii)60〜120秒間
にわたり活性化される、方法。 - 追加の希釈水溶液で前記脂質カプセル化ガスマイクロスフェアを希釈する工程をさらに含む、請求項12に記載の方法。
- コントラスト超音波イメージングを必要とする非ヒト被験体に前記脂質カプセル化ガスマイクロスフェアを投与する工程をさらに含む、請求項13に記載の方法。
- 超音波を用いた診断イメージングおよび/または治療において用いるための、脂質カプセル化ガスマイクロスフェアを含む組成物であって、
前記脂質カプセル化ガスマイクロスフェアを含む組成物が、DPPA、DPPC、およびPEG5000−DPPE、並びにパーフルオロカーボンガスを、ポリエチレングリコールおよび/またはグリセロールを含む非水性溶媒中に含み、かつ
(a)(1)DPPA、DPPC、およびPEG5000−DPPE、ポリエチレングリコールおよび/またはグリセロールを含む非水性溶媒、並びにパーフルオロカーボンガスを含む非水性混合物に希釈水溶液を添加して、混合物を生成し、次いで(2)前記混合物を活性化する工程、
(b)DPPA、DPPC、およびPEG5000−DPPE、ポリエチレングリコールおよび/またはグリセロールを含む非水性溶媒、並びにパーフルオロカーボンガスを含む非水性混合物を活性化し、次いで希釈水溶液で希釈する工程、または
(c)DPPA、DPPC、およびPEG5000−DPPE、ポリエチレングリコールおよび/またはグリセロールを含む非水性溶媒、並びにパーフルオロカーボンガスを含む非水性混合物を活性化する工程
によって形成されるものであって、
適宜、前記パーフルオロカーボンガスがパーフルオロプロパンガスであってもよい、組成物。 - 前記脂質カプセル化ガスマイクロスフェアが、
(a)約1.0ミクロン〜約2.0ミクロンの範囲の平均直径を有するか、
(b)約1.2ミクロン〜約2.0ミクロンの範囲の平均直径を有するか、
(c)約1.4〜1.8ミクロンの平均直径を有するか、および/または
(d)10 8 個/mL以上の濃度で前記組成物中に存在する、
請求項15に記載の組成物。
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