CN105026030A - 充气微泡 - Google Patents
充气微泡 Download PDFInfo
- Publication number
- CN105026030A CN105026030A CN201380067383.8A CN201380067383A CN105026030A CN 105026030 A CN105026030 A CN 105026030A CN 201380067383 A CN201380067383 A CN 201380067383A CN 105026030 A CN105026030 A CN 105026030A
- Authority
- CN
- China
- Prior art keywords
- acid
- saturated
- suspension
- unrighted
- gas
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 claims abstract description 107
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 59
- 150000004671 saturated fatty acids Chemical class 0.000 claims abstract description 19
- 238000009472 formulation Methods 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims description 120
- 238000002360 preparation method Methods 0.000 claims description 51
- -1 ethyl phosphatid ylcholine Chemical compound 0.000 claims description 46
- 125000001931 aliphatic group Chemical group 0.000 claims description 28
- 239000000725 suspension Substances 0.000 claims description 27
- 235000021081 unsaturated fats Nutrition 0.000 claims description 23
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 claims description 20
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims description 17
- 235000021003 saturated fats Nutrition 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 12
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical group CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 12
- 229940124597 therapeutic agent Drugs 0.000 claims description 11
- BITHHVVYSMSWAG-KTKRTIGZSA-N (11Z)-icos-11-enoic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCC(O)=O BITHHVVYSMSWAG-KTKRTIGZSA-N 0.000 claims description 9
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 9
- 239000000654 additive Substances 0.000 claims description 9
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 9
- 210000002808 connective tissue Anatomy 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 229940067626 phosphatidylinositols Drugs 0.000 claims description 9
- 230000006641 stabilisation Effects 0.000 claims description 9
- 235000021355 Stearic acid Nutrition 0.000 claims description 8
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 8
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 claims description 8
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 8
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 8
- 239000008117 stearic acid Substances 0.000 claims description 8
- 230000000996 additive effect Effects 0.000 claims description 7
- 229940116226 behenic acid Drugs 0.000 claims description 7
- 229940108623 eicosenoic acid Drugs 0.000 claims description 7
- BITHHVVYSMSWAG-UHFFFAOYSA-N eicosenoic acid Natural products CCCCCCCCC=CCCCCCCCCCC(O)=O BITHHVVYSMSWAG-UHFFFAOYSA-N 0.000 claims description 7
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 6
- IJTNSXPMYKJZPR-UHFFFAOYSA-N parinaric acid Chemical compound CCC=CC=CC=CC=CCCCCCCCC(O)=O IJTNSXPMYKJZPR-UHFFFAOYSA-N 0.000 claims description 6
- LRYZPFWEZHSTHD-HEFFAWAOSA-O 2-[[(e,2s,3r)-2-formamido-3-hydroxyoctadec-4-enoxy]-hydroxyphosphoryl]oxyethyl-trimethylazanium Chemical class CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](NC=O)COP(O)(=O)OCC[N+](C)(C)C LRYZPFWEZHSTHD-HEFFAWAOSA-O 0.000 claims description 5
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 claims description 5
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- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 5
- 235000021357 Behenic acid Nutrition 0.000 claims description 4
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 239000008365 aqueous carrier Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 4
- WBBQTNCISCKUMU-PDBXOOCHSA-N (13Z,16Z,19Z)-docosatrienoic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCCCCCC(O)=O WBBQTNCISCKUMU-PDBXOOCHSA-N 0.000 claims description 3
- OOJGMLFHAQOYIL-SQIWNDBBSA-N (2e,4e)-hexadeca-2,4-dienoic acid Chemical compound CCCCCCCCCCC\C=C\C=C\C(O)=O OOJGMLFHAQOYIL-SQIWNDBBSA-N 0.000 claims description 3
- ADHNUPOJJCKWRT-JLXBFWJWSA-N (2e,4e)-octadeca-2,4-dienoic acid Chemical compound CCCCCCCCCCCCC\C=C\C=C\C(O)=O ADHNUPOJJCKWRT-JLXBFWJWSA-N 0.000 claims description 3
- BBWMTEYXFFWPIF-CJBMEHDJSA-N (2e,4e,6e)-icosa-2,4,6-trienoic acid Chemical compound CCCCCCCCCCCCC\C=C\C=C\C=C\C(O)=O BBWMTEYXFFWPIF-CJBMEHDJSA-N 0.000 claims description 3
- FPRKGXIOSIUDSE-SYACGTDESA-N (2z,4z,6z,8z)-docosa-2,4,6,8-tetraenoic acid Chemical compound CCCCCCCCCCCCC\C=C/C=C\C=C/C=C\C(O)=O FPRKGXIOSIUDSE-SYACGTDESA-N 0.000 claims description 3
- ZVRMGCSSSYZGSM-CCEZHUSRSA-N (E)-hexadec-2-enoic acid Chemical compound CCCCCCCCCCCCC\C=C\C(O)=O ZVRMGCSSSYZGSM-CCEZHUSRSA-N 0.000 claims description 3
- ULNRTPCFRBIMKL-GHVJWSGMSA-N (e)-2-tetracosenoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCC\C=C\C(O)=O ULNRTPCFRBIMKL-GHVJWSGMSA-N 0.000 claims description 3
- ATNNLHXCRAAGJS-QZQOTICOSA-N (e)-docos-2-enoic acid Chemical compound CCCCCCCCCCCCCCCCCCC\C=C\C(O)=O ATNNLHXCRAAGJS-QZQOTICOSA-N 0.000 claims description 3
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 claims description 3
- PIFPCDRPHCQLSJ-WYIJOVFWSA-N 4,8,12,15,19-Docosapentaenoic acid Chemical compound CC\C=C\CC\C=C\C\C=C\CC\C=C\CC\C=C\CCC(O)=O PIFPCDRPHCQLSJ-WYIJOVFWSA-N 0.000 claims description 3
- YWWVWXASSLXJHU-UHFFFAOYSA-N 9E-tetradecenoic acid Natural products CCCCC=CCCCCCCCC(O)=O YWWVWXASSLXJHU-UHFFFAOYSA-N 0.000 claims description 3
- DPUOLQHDNGRHBS-UHFFFAOYSA-N Brassidinsaeure Natural products CCCCCCCCC=CCCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-UHFFFAOYSA-N 0.000 claims description 3
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 3
- PIFPCDRPHCQLSJ-UHFFFAOYSA-N Clupanodonic acid Natural products CCC=CCCC=CCC=CCCC=CCCC=CCCC(O)=O PIFPCDRPHCQLSJ-UHFFFAOYSA-N 0.000 claims description 3
- 235000021292 Docosatetraenoic acid Nutrition 0.000 claims description 3
- GZZPOFFXKUVNSW-UHFFFAOYSA-N Dodecenoic acid Natural products OC(=O)CCCCCCCCCC=C GZZPOFFXKUVNSW-UHFFFAOYSA-N 0.000 claims description 3
- 235000021297 Eicosadienoic acid Nutrition 0.000 claims description 3
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 claims description 3
- IJTNSXPMYKJZPR-WVRBZULHSA-N alpha-parinaric acid Natural products CCC=C/C=C/C=C/C=CCCCCCCCC(=O)O IJTNSXPMYKJZPR-WVRBZULHSA-N 0.000 claims description 3
- GWHCXVQVJPWHRF-UHFFFAOYSA-N cis-tetracosenoic acid Natural products CCCCCCCCC=CCCCCCCCCCCCCCC(O)=O GWHCXVQVJPWHRF-UHFFFAOYSA-N 0.000 claims description 3
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims description 3
- 235000020673 eicosapentaenoic acid Nutrition 0.000 claims description 3
- 229960005135 eicosapentaenoic acid Drugs 0.000 claims description 3
- IQLUYYHUNSSHIY-HZUMYPAESA-N eicosatetraenoic acid Chemical compound CCCCCCCCCCC\C=C\C=C\C=C\C=C\C(O)=O IQLUYYHUNSSHIY-HZUMYPAESA-N 0.000 claims description 3
- KYYWBEYKBLQSFW-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCC(O)=O KYYWBEYKBLQSFW-UHFFFAOYSA-N 0.000 claims description 3
- 235000021290 n-3 DPA Nutrition 0.000 claims description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- ZTUXEFFFLOVXQE-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCC(O)=O ZTUXEFFFLOVXQE-UHFFFAOYSA-N 0.000 claims description 3
- IBYFOBGPNPINBU-UHFFFAOYSA-N tetradecenoic acid Natural products CCCCCCCCCCCC=CC(O)=O IBYFOBGPNPINBU-UHFFFAOYSA-N 0.000 claims description 3
- IBYFOBGPNPINBU-OUKQBFOZSA-N trans-2-tetradecenoic acid Chemical compound CCCCCCCCCCC\C=C\C(O)=O IBYFOBGPNPINBU-OUKQBFOZSA-N 0.000 claims description 3
- LKOVPWSSZFDYPG-WUKNDPDISA-N trans-octadec-2-enoic acid Chemical compound CCCCCCCCCCCCCCC\C=C\C(O)=O LKOVPWSSZFDYPG-WUKNDPDISA-N 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- XSXIVVZCUAHUJO-AVQMFFATSA-N (11e,14e)-icosa-11,14-dienoic acid Chemical compound CCCCC\C=C\C\C=C\CCCCCCCCCC(O)=O XSXIVVZCUAHUJO-AVQMFFATSA-N 0.000 claims 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 2
- 238000002405 diagnostic procedure Methods 0.000 claims 1
- 150000003904 phospholipids Chemical class 0.000 abstract description 8
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- 235000003441 saturated fatty acids Nutrition 0.000 abstract 1
- 239000007789 gas Substances 0.000 description 64
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 32
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- 239000000463 material Substances 0.000 description 23
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- HVVJCLFLKMGEIY-UHFFFAOYSA-N 2,3-dioctadecoxypropyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCCCOCC(COP([O-])(=O)OCC[N+](C)(C)C)OCCCCCCCCCCCCCCCCCC HVVJCLFLKMGEIY-UHFFFAOYSA-N 0.000 description 18
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- A—HUMAN NECESSITIES
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- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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
- A61K9/10—Dispersions; Emulsions
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Landscapes
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
用于制备充气微泡的制剂,所述制剂包括一种磷脂与一种饱和和不饱和脂肪酸的混合物。相对于仅包含一种饱和或一种不饱和脂肪酸的微泡,具有包含所述成分的稳定化层的充气微泡显示出增加的稳定性。
Description
技术领域
本发明涉及新的充气微泡,其制备以及在诊断和治疗方法中的用途。
背景技术
造影剂的在近几年快速发展已经产生了许多不同的组合物和制剂,它们在人体或动物体的器官和组织中的造影增强成像中和在治疗性处理中是有用的。
一类造影剂,特别是用于超声造影成像的造影剂,包括分散在水性介质中的纳米和/或微米尺寸的气体泡悬浮液。该气体通常是被夹带或包封在稳定化薄膜层中,所述稳定薄膜层包括,例如,乳化剂,油类,增稠剂或糖类。这些稳定化的气泡(分散在适宜的生理溶液中)通常涉及本领域中的各种术语,典型地取决于用于其制备的稳定化材料;这些术语包括,例如,“微球”,“微泡”,“微胶囊”或“微球”,在此全部被称为“充气微泡”(或“微泡”)。
特别令人感兴趣的是充气微泡的水悬浮液,其中气体的气泡通过非常薄的包络(膜)而被限定于气/液界面,该包络(膜)涉及配置在气液界面上稳定化两亲性材料(通常为磷脂)。这些悬浮液通过粉末状的两亲性材料接触空气或其它气体而有利的制备,例如冷冻干燥制备的脂质体或冷冻干燥或喷雾干燥的脂质溶液,然后接触含水的载体,同时搅拌以产生可以随后给药的充气微泡的悬浮液,优选在其制备后不久给药。充气微泡的水性悬浮液及其制备的实施例已经被公开,例如,US 5,271,928,US 5,445,813,US 5,413,774,US 5,556,610,US 5,597,549,US 5,827,504,WO97/29783和WO2004/069284,其通过参考而全文引入到本文中。稳定化层可以包含,除了上述所提及的磷脂类,还有其它的两亲性材料,如脂肪酸。例如,(由Bracco Suisse S.A.制造的商业化的超声造影剂)包括作为成膜稳定层的磷脂和脂肪酸的混合物。
最近,已经注意到所谓的“分子成像”,其中,适于靶点的特定成分被用在进行器官或组织选择性造影增强成像的造影剂的制剂中。此外,造影剂制剂的治疗性应用,任选与分子成像相联合,也已经被描述。
充气微泡的制剂可以被适当地修饰,或用于提高诊断效果(例如,通过分子成像)和/或用于治疗目的,例如药物递送和/或超声介导的溶栓治疗。例如,微泡可以与治疗剂和/或与特定的成分相关联(例如通过包含在它们边界外膜之中),其能够连接患者身体内确定的目标(称为“靶向配体”)。靶向配体的实例包括,例如,能够与在致病过程中由器官或组织表达的特异性受体结合的肽类,蛋白质,抗体,适体或碳水化合物,所述致病过程例如,血管生成,炎症或血栓形成。
本申请人现已发现,有可能通过在制剂的稳定层中包括饱和和不饱和脂肪酸的混合物,提高基于磷脂的充气微泡的某些特性。特别的是,已经观察到所述饱和/不饱和脂肪酸混合物的存在出人意料地增加了充气微泡的稳定性,相对于在形成稳定层的制剂中仅分别含有一种饱和或不饱和脂肪酸的相应微泡。
发明简述
因此,本发明的一个方面涉及在生理上可接受液体载体中的充气微泡的悬浮液,所述具有稳定化外膜的微泡含有磷脂、饱和脂肪酸和不饱和脂肪酸,其中饱和和不饱和脂肪酸的摩尔比是从2.5∶1至1∶8。
优选饱和和不饱和脂肪酸的摩尔比是从1.5∶1至1∶7.5,更优选从1∶1至1∶6,甚至更优选从1∶1.5至1∶4,特别优选的是从1∶2至1∶3的摩尔比。
根据优选的实施方案,磷脂与饱和/不饱和脂肪酸混合物的摩尔比是从3∶7至4∶1,优选从2∶3至7∶3,和甚至更优选从2.5∶3至3∶2。
在一个优选实施方案中,在生物相容性气体存在下,包括上述量的磷脂和脂肪酸的制剂(优选以冻干形式)与生理上可接受的液体载体混合而获得所述悬浮液。
本发明的另一个方面涉及一种密封小瓶,其含有药物制剂和生物相容性气体,所述制剂包含如上述定义的磷脂、饱和脂肪酸和不饱和脂肪酸。该制剂任选地还包含药学上可接受的添加剂和/或赋形剂。在一个优选实施方案中,所述制剂是在冷冻干燥(冻干)形式。
发明详述
本发明的制剂包含饱和和不饱和脂肪酸的混合物以及磷脂,其可以用于制造用于诊断成像和/或作为治疗剂的充气微泡。
本发明的制剂是特别有益于形成一个层,该层使在液体悬浮液中的气体的气泡稳定(稳定层)。该制剂可以包括额外的两亲性材料,以及通常是冷冻干燥(冻干)制剂的形式,优选包含冻干添加剂。本发明的充气微泡可以通过在生理上可接受的气体存在下,混合所述制剂与生理上可接受的液体载体而制备。
脂肪酸
术语“脂肪酸”包括在其含义范围的羧酸,该羧酸包含一个相对长的脂肪族链,例如从10至28个碳原子(C10-C28)。脂肪族链优选是直链(直)链。用于根据本发明组合物的脂肪酸优选包括C10-C24脂肪族链,更优选C14-C22脂肪族链并且甚至更优选通过羧基封端的C16-C20脂肪族链。
脂肪酸可以是饱和的或不饱和的(即含有一个或多个不饱和度,通常是双键)。
饱和脂肪酸包括在脂肪族链中无不饱和度的脂肪酸,如,例如:羊蜡酸(正-癸酸),月桂酸(正-十二烷酸),肉豆蔻酸(正-十四烷酸),棕榈酸(正-十六烷酸),硬脂酸(正-十八烷酸),花生酸(正-二十烷酸),山嵛酸(正-二十二烷酸)和正-二十四烷酸。优选的饱和脂肪酸是肉豆蔻酸,棕榈酸,硬脂酸和花生酸。
不饱和脂肪酸可以包括在脂肪族链上有一个,两个,三个,四个或五个不饱和度(特别是双键)。优选的不饱和度是处于顺式构型。优选地,不饱和脂肪酸包括三个或更低的不饱和度,更优选的是两个或更低的不饱和度;特别优选的是包括在脂肪族链中单不饱和度的不饱和脂肪酸。为简便起见,不饱和脂肪酸有时用下列的烷基链中碳原子数和在链中不饱和度的位置表示;例如棕榈油酸,即顺式-9-十六碳烯酸,被称为C16,顺式-Δ9(或简单地:C16,Δ9)。不饱和脂肪酸的实例包括,例如,癸烯酸,十二碳烯酸,十四碳烯酸,十六碳烯酸,十六碳二烯酸,十八碳烯酸,十八碳二烯酸,十八碳三烯酸,十八碳四烯酸,二十碳烯酸,二十碳二烯酸,二十碳三烯酸,二十碳四烯酸,二十碳五烯酸,二十二碳烯酸,二十二碳二烯酸,二十二碳三烯酸,二十二碳四烯酸,二十二碳五烯酸和二十四碳烯酸。优选的不饱和脂肪酸包括肉豆蔻烯酸(顺式-9-十四碳烯酸),棕榈油酸(顺式-9-十六碳烯酸),棕榈酸(顺式-6-十六碳烯酸),油酸(顺式-9-十八烯酸),亚油酸(顺式-9,12-十八碳二烯酸),亚麻酸(顺式-9,12,15-十八碳三烯酸),巨头鲸鱼酸(顺式-11-二十碳烯酸),顺式-11,14-二十碳二烯酸,顺式-5,8,11-二十碳三烯酸,顺式-8,11,14-二十碳三烯酸,顺式-11,14,17-二十碳三烯酸,花生四烯酸(顺式-8,11,14,17-二十碳四烯酸)和芥酸(顺式-13-二十二碳烯酸),特别优选的是棕榈油酸,油酸和巨头鲸鱼酸。
饱和和不饱和脂肪酸的混合物优选包含具有相差至多四个碳原子烷基链长度的酸;更优选的饱和和不饱和酸在各自的链长度中,相差至多两个碳原子,和甚至更优选相差至多一个碳原子;特别优选的是包含具有相同烷基链长度的饱和和不饱和脂肪酸的混合物(例如棕榈酸/棕榈烯酸,硬脂酸/油酸,花生酸/巨头鲸鱼酸等)。
本申请人已经观察到,通过使用包括摩尔比从2.5∶1至1∶8的饱和/不饱和脂肪酸的组合物,相对于仅采用相同浓度的饱和或不饱和脂肪酸的微泡,可以制备具有增加稳定性的充气微泡。优选的是,组合物中饱和和不饱和脂肪酸的摩尔比是从1.5∶1至1∶7.5,更优选是从1∶1至1∶6,甚至更优选是从1∶1.5至1∶4,特别优选的是从1∶2至1∶3的摩尔比。
磷脂
本文所使用的,术语“磷脂”意欲涵盖包含至少一个磷酸基团和至少一个,优选两个,(C12-C22)烃链的两亲性化合物,其能够在最终的微泡悬浮液的气-水边界界面形成稳定的膜层(通常以单分子层的形式)。因此,这些材料也在本领域中被称为“成膜磷脂”。
术语磷脂包括天然存在的,半合成的或合成的产物,其可以单独的或作为混合物而使用。
适宜磷脂的实例包括具有一个或优选两个(相同或不同的)脂肪酸残基和磷酸残基的甘油酯,其中所述磷酸残基依次与亲水基团相结合,亲水基团如,例如,胆碱(磷脂酰胆碱-PC),丝氨酸(磷脂酰丝氨酸-PS),甘油(磷脂酰甘油-PG),乙醇胺(磷脂酰乙醇胺-PE),肌醇(磷脂酰肌醇)。仅具有一个脂肪酸残基的磷脂的酯通常在本领域中被称为“溶血”形式的磷脂或“溶血磷脂”。在磷脂中存在的脂肪酸残基通常是长链脂肪酸,通常包括从12到24个,优选从14到22个碳原子;该脂肪族链可以包含一个或多个不饱和度或优选是完全饱和的。包含在磷脂中的适宜脂肪酸的实例是,例如,月桂酸,肉豆蔻酸,棕榈酸,硬脂酸,花生酸,山萮酸,油酸,亚油酸,和亚麻酸。优选地,可以使用饱和脂肪酸,如肉豆蔻酸,棕榈酸,硬脂酸和花生酸。
磷脂的进一步实例是磷脂酸,即甘油磷酸与脂肪酸的二酯;鞘脂类,如鞘磷脂,即那些磷脂酰胆碱类似物,其中甘油二酯与脂肪酸的残基被替换为神经酰胺链;心磷脂类,即1,3-双磷脂酰甘油与脂肪酸的酯;糖脂类如神经节苷脂GM1(或GM2)或脑苷脂;糖脂;硫脂和糖(神经)鞘脂类。
天然存在的磷脂的实例是天然卵磷脂(磷脂酰胆碱(PC)的衍生物),例如,通常的,大豆或蛋黄卵磷脂。
半合成磷脂的实例是天然存在的卵磷脂的部分或完全氢化的衍生物。优选的磷脂是磷脂酰胆碱,乙基磷脂酰胆碱,磷脂酰甘油,磷脂酸,磷脂酰乙醇胺,磷脂酰丝氨酸,磷脂酰肌醇或鞘磷脂的脂肪酸二酯。
磷脂的具体实例是,例如,二月桂酰-磷脂酰胆碱(DLPC),二肉豆蔻酰基-磷脂酰胆碱(DMPC),二棕榈酰-磷脂酰胆碱(DPPC),二花生酰-磷脂酰胆碱(DAPC),二硬脂酰-磷脂酰胆碱(DSPC),二油酰-磷脂酰胆碱(DOPC),1,2-二硬脂酰-sn-甘油-3-乙基磷酸胆碱(乙基-DSPC),双十五酰-磷脂酰胆碱(DPDPC),1-肉豆蔻酰-2-棕榈酰-磷脂酰胆碱(MPPC),1-棕榈酰-2-肉豆蔻酰-磷脂酰胆碱(PMPC),1-棕榈酰-2-硬脂酰-磷脂酰胆碱(PSPC),1-硬脂酰-2-棕榈酰-磷脂酰胆碱(SPPC),1-棕榈酰-2-油基-磷脂酰胆碱(POPC),1-油酰-2-棕榈酰-磷脂酰胆碱(OPPC),二月桂酰-磷脂酰甘油(DLPG)及其碱金属盐,二花生酰磷脂酰甘油(DAPG)及其碱金属盐,二肉豆蔻酰磷脂酰甘油(DMPG)及其碱金属盐,二棕榈酰磷脂酰甘油(DPPG)及其碱金属盐,二硬脂酰磷脂酰甘油(DSPG)及其碱金属盐,二油酰磷脂酰甘油(DOPG)及其碱金属盐,二月桂酰磷脂酸(DLPA),二肉豆蔻酰磷脂酸(DMPA)及其碱金属盐,二棕榈酰磷脂酸(DPPA)及其碱金属盐,二硬脂酰磷脂酸(DSPA),二花生酰磷脂酸(DAPA)及其碱金属盐,二月桂酰-磷脂酰乙醇胺(DLPE),二肉豆蔻酰-磷脂酰乙醇胺(DMPE),二棕榈酰磷脂酰乙醇胺(DPPE),二硬脂酰磷脂酰-乙醇胺(DSPE),二油酰磷脂酰-乙醇胺(DOPE),二花生酰磷脂酰-乙醇胺(DAPE),二亚油醇磷脂酰乙醇胺,二月桂酰-磷脂酰-丝氨酸(DLPS),二肉豆蔻酰磷脂酰丝氨酸(DMPS),二花生酰-磷脂酰-丝氨酸(DAPS),二棕榈酰磷脂酰丝氨酸(DPPS),二硬脂酰磷脂酰丝氨酸(DSPS),二油酰磷脂酰丝氨酸(DOPS),二棕榈酰鞘磷脂(DPSP),二硬脂酰鞘磷脂(DSSP),二月桂酰-磷脂酰肌醇(DLPI),二花生酰磷脂酰肌醇(DAPI),二肉豆蔻酰磷脂酰肌醇(DMPI),二棕榈酰磷脂酰肌醇(DPPI),二硬脂酰磷脂酰肌醇(DSPI),二油酰-磷脂酰肌醇(DOPI)。
适宜的磷脂进一步包括通过连接亲水性聚合物而修饰的磷脂,亲水性聚合物例如聚乙二醇(PEG)或聚丙二醇(PPG)。优选的聚合物修饰磷脂包括“聚乙二醇化磷脂”,即磷脂结合于PEG聚合物。聚乙二醇化磷脂的实例是聚乙二醇化磷脂酰乙醇胺(简述为“PE-PEGs”)。即亲水性乙醇胺部分连接到可变分子量的PEG分子(例如,从300到20000道尔顿,优选从500至5000道尔顿)上的磷脂酰乙醇胺,例如DPPE-PEG(或DSPE-PEG,DMPE-PEG,DAPE-PEG或DOPE-PEG)。例如,DPPE-PEG2000是指连接具有约2000中平均分子量的PEG聚合物的DPPE。
特别优选的磷脂是DAPC,DSPC,DPPC,DMPA,DPPA,DSPA,DMPG,DPPG,DSPG,DMPS,DPPS,DSPS,DPPE,DSPE,DMPE,DAPE,乙基-DSPC和它们的混合物。最优选的是DSPG,DSPS,DSPE,DSPC,DAPC和它们的混合物。磷脂的混合物也可以使用,如,例如,DPPE和/或DSPE(包括聚乙二醇化的衍生物),DPPC,DSPC和/或DAPC与DSPS,DPPS,DSPA,DPPA,DSPG,DPPG,乙基-DSPC和/或乙基-DPPC的混合物。
磷脂相对于饱和或不饱和脂肪酸总量的摩尔比是从3∶7至4∶1,优选从2∶3至7∶3,和甚至更优选从2.5∶3至3∶2。
其他的两亲性材料
形成充气微泡稳定化层的成分可以进一步包括也可有助于稳定层形成的两亲性成分,例如:带有聚合物的脂类,如壳聚糖,透明质酸,聚乙烯吡咯烷酮或聚乙二醇(PEG),也被称为“聚乙二醇化脂类”;带有磺酸化单-,二-,低聚-或多糖的脂类;胆固醇,胆固醇硫酸酯或胆固醇半琥珀酸酯;生育酚半琥珀酸酯;用醚或酯连接的脂肪酸的脂类;聚合脂类;双乙酰磷酸酯;双十六烷基磷酸酯;神经酰胺;聚氧乙烯脂肪酸酯(如聚氧乙烯脂肪酸硬脂酸酯),聚氧乙烯脂肪醇,聚氧乙烯脂肪醇醚,聚氧乙基化脱水山梨醇脂肪酸酯,甘油聚乙二醇蓖麻醇酸酯,乙氧基化大豆甾醇,乙氧基化蓖麻油或环氧乙烷(EO)和环氧丙烷(PO)嵌段共聚物;甾醇脂肪酸酯,包括胆固醇丁酸酯,胆固醇异丁酸盐,胆甾醇棕榈酸酯,胆甾醇硬脂酸酯,羊毛甾醇乙酸酯,麦角甾醇棕榈酸酯,或植物甾醇正丁酸酯;糖酸的甾醇酯包括葡糖苷酸胆固醇,葡糖苷酸羊毛甾醇,葡糖苷酸7-脱毛氢胆固醇,葡糖苷酸麦角甾醇,胆固醇葡糖酸酯,羊毛甾醇葡糖酸酯或麦角甾醇葡糖酸酯;糖酸和醇的酯包括月桂基葡糖苷酸,硬脂酰葡糖苷酸,肉豆蔻酰葡糖苷酸,月桂基葡糖酸酯,肉豆蔻酰葡糖酸酯,或硬脂酰葡糖酸酯;具有脂肪酸的糖酯类,包括蔗糖月桂酸酯,果糖月桂酸酯,蔗糖棕榈酸酯,蔗糖硬脂酸酯,葡糖醛酸,葡糖酸或聚糖醛酸;皂苷包括菝葜皂苷元,菝葜配基,常春配基,或洋地黄毒甙配基;甘油或甘油酯,包括甘油三棕榈酸酯,甘油二硬脂酸酯,甘油三硬脂酸酯,甘油二肉豆蔻酸酯,甘油三肉豆蔻酸酯,甘油二月桂酸酯,甘油三月桂酸酯,甘油二棕榈酸酯;长链醇,包括正-癸醇,月桂醇,肉豆蔻醇,鲸蜡醇,或正-十八烷基醇;6-(5-胆甾烯-3β-基氧基)-1-硫代-β-D-吡喃半乳糖苷;双半乳糖甘油二酯;6-(5-胆甾烯-3β-基氧基)己基-6-氨基-6-脱氧-1-硫代-β-D-吡喃半乳糖苷;6-(5-胆甾烯-3β-基氧基)己基-6-氨基-6-脱氧-1-硫代-β-D-吡喃甘露糖苷;1,2-二油基-sn-甘油;1,2-二棕榈酰基-sn-3-琥珀酰甘油;1,3-二棕榈酰-2-琥珀酰甘油;棕榈酰基高半胱氨酸;烷基胺或烷基铵盐,包括至少一个(C10-C20),优选(C14-C18)烷基链,如,例如,N-硬脂酰胺,N,N′-二硬脂酰胺,N-十六烷基胺,N,N′-双十六烷基胺,N-十八烷基氯化铵,N,N′-双十八烷基氯化铵,N-十六烷基氯化铵,N,N′-双十六烷基氟化铵,二甲基双十八烷基溴化铵(DDAB),十六烷基三甲基溴化铵(CTAB);叔或季铵盐,包括一个或优选两个通过(C3-C6)亚烷基桥连接N原子的(C10-C20),优选(C14-C18)的酰基链,如,例如,1,2-二硬脂酰-3-三甲基铵-丙烷(DSTAP),1,2-二棕榈酰-3-三甲基铵-丙烷(DPTAP),1,2-油酰基-3-三甲基铵-丙烷(DOTAP),1,2-二硬脂酰-3-二甲基铵-丙烷(DSDAP);以及它们的混合物或组合。
这些进一步的两亲性化合物,如果存在,可以以不同的数量存在,例如为形成稳定层的组合物摩尔数量的至多25%,优选至多10%。
添加剂和赋形剂
因为充气微泡的制备可能涉及冷冻干燥或喷雾干燥步骤,在制剂中包含冻干添加剂可能是有利的,如有冷冻保护性和/或溶解保护性效果的试剂和/或填充剂,例如,如甘氨酸的氨基酸;碳水化合物,即,糖如蔗糖,甘露醇,麦芽糖,海藻糖,葡萄糖,乳糖或环糊精,或者多糖如葡聚糖,壳聚糖及其衍生物(例如:羧甲基壳聚糖,三甲基壳聚糖);或聚氧亚烷基乙二醇,如聚乙二醇。例如,在制剂冻干制备的情况下,添加剂(如聚乙二醇)的数量可以从冻干制剂总量的约90%变化至约99.99%(以重量计)。
其它赋形剂或添加剂可以存在于或用于微泡制备的干制剂中或可能与用于重构它们的含水载体一起加入,而不一定参与(或仅部分参与)微泡稳定化外膜的形成。这些包括pH调节剂,渗透压调节剂,粘度增强剂,乳化剂,填充剂等,并且可以以常规用量使用。例如化合物如聚氧化亚丙基二醇和聚氧化亚乙基二醇以及它们的共聚物可以被应用。粘度增强剂或稳定剂的实例是选自线性和交联的聚糖和寡糖,糖和亲水性聚合物如聚乙二醇的化合物。
靶向配体
根据本发明的组合物和微泡可以任选地包含靶向配体。
术语“靶向配体”包括在其含义内的任何化合物,部分或残基,其具有或能够促进本发明组合物微泡朝向活体中任何生物或病理部位的靶向活性(例如,包括选择性结合)。可能与靶向配体相关联的靶点包括组织如,例如,心肌组织(包括心肌细胞和心脏肌细胞),膜组织(包括内皮和上皮),板,层,结缔组织(包括间质组织)或肿瘤;血块;和受体,如,例如,肽激素的细胞表面受体,神经递质,抗原,补体片段和免疫球蛋白和类固醇激素的细胞质受体。
靶向配体可以是合成的,半合成的,或天然存在的。可以作为靶向配体的材料或物质包括,例如,但不限于蛋白质,包括抗体,抗体片段,受体分子,受体结合分子,糖蛋白和凝集素;肽类,包括寡肽和多肽;多肽模拟物;糖类,包括单糖和多糖;维生素;类固醇,类固醇类似物,激素,辅助因子,生物活性剂和遗传物质,包括核苷,核苷酸和多核苷酸。
靶向配体可以是与微泡的其它成分混合的化合物本身,或者可以是与用于微泡形成的两亲性分子(通常是磷脂)相连的化合物。
在一个优选的实施方案中,所述靶向配体可以通过共价键结合形成微泡稳定化外膜的两亲性分子(例如磷脂)。在这样的情况下,需要存在于所述两亲性分子上的特定反应部分将取决于被连接到其上的特定靶向配体。作为一个实例,如果该靶向配体可以通过氨基而连接到所述两亲性分子,用于两亲性分子的适宜的反应基团可以是异硫氰酸酯基团(即将形成硫脲键),反应性酯类(以形成酰胺键),醛基(用于将被还原成烷基胺键的亚胺键的形成)等;如果靶向配体可以通过硫醇基团而连接到两亲性分子,用于两亲性分子的适宜的互补反应部分包括卤代乙酰衍生物或马来酰亚胺(以形成硫醚键);并且如果靶向配体可以通过羧基基团而连接到两亲性分子,用于两亲性分子的适宜的反应性部分可以是胺类和酰肼(以形成酰胺或烷基酰胺键)。为了共价结合所期望的靶向配体,形成微泡外膜的至少部分两亲化合物因此应包含适宜的反应基团并且含有互补官能团的靶向配体将根据现有技术与其连接,例如通过将其加入到含有微泡两亲性成分的分散体中。优选地,两亲性化合物是如前面所提到的那些带有亲水聚合物的脂类,优选聚乙二醇化磷脂。在这种情况下,靶向配体连接到亲水性聚合物上的适宜的反应性部分。在制备微泡之前,两亲性化合物可以与所需的靶向配体进行组合,并且如此获得的组合可以用于微泡的制备。可替代地,所述靶向配体可以在微泡制备过程中连接到各自的两亲性化合物。
根据一个替代性实施方案,所述靶向配体还可以通过物理和/或静电相互作用而适当地与微泡相连。作为一个实例,对互补部分具有高亲和力的和选择性的功能部分可以被引入到两亲性分子中,而互补部分将与靶向配体连接。例如,抗生物素蛋白(或链霉亲和素)部分(具有对生物素的高亲和力)可以共价连接到磷脂(或聚乙二醇化的磷脂),而互补的生物素部分可以引入到适宜的靶向配体,例如肽类或抗体。生物素标记的靶向配体将因此通过抗生物素蛋白-生物素偶联系统而与微泡中的抗生物素蛋白标记的磷脂相关联。可替换的是,磷脂和靶向配体两者均可以有生物素部分,并且随后通过抗生物素蛋白(其是能够桥接两个生物素部分的双官能组分)彼此偶联。偶联磷脂和肽的生物素/抗生物素蛋白的实例也在上述引用的US6,139,819中公开。可替代的是,范德华相互作用,静电相互作用和其他关联过程可以与相关联或结合靶向配体至两亲性分子。
可替代的是,所述磷脂可以用适合于特定偶联到免疫球蛋白(Ig)上Fc结构域的蛋白质修饰,如蛋白质A,蛋白质G,蛋白质A/G或蛋白质L。根据一个可替代的实施例,靶向配体可以是与形成微泡的成分相混合的化合物,该化合物最终要掺入微泡结构中,如脂肽,例如,在国际专利申请WO 98/18501或99/55383中公开的脂肽,两者通过引用而并入本文。
可替代的是,一个微泡可以首先被制造,其包含具有能够与靶向配体的相应互补部分相互作用的适宜部分的化合物(脂质或聚合物修饰的脂质);此后,所期望的靶向配体加入到微泡悬浮液中,以结合微泡相应的互补部分。
微泡可以涉及的适宜的特定靶点的实例是,例如,纤维蛋白和活化血小板上的GPIIbIIIa结合受体。纤维蛋白和血小板实际上通常存在于“血栓”中,即可以在血流中形成并且导致血管阻塞的凝块。适宜的结合肽已经被公开,例如,在上述引用的US 6,139,819中。纤维蛋白靶向特异性的进一步结合肽已经被公开,例如,在国际专利申请WO 02/055544中,其通过引用而并入本文。
重要靶点的其他实例包括在易损斑块中的受体和肿瘤特异性受体,例如激酶结构域区(KDR)和VEGF(血管内皮生长因子)/KDR复合物。适宜用于KDR或VEGF/KDR复合物的结合肽已经被公开,例如,在国际专利申请WO03/74005和WO 03/084574中,均通过引用而并入本文。
微泡的制备
根据本发明的微泡可以根据本领域中任何已知的方法从本发明的组合物而制造。通常的是,该制造方法涉及含有本发明组合物的干燥粉末材料的制备,优选通过包含所述组合物的含水或有机悬浮液的冻干(冷冻干燥)。然后可以在气体存在下,经温和搅拌,通过冻干制剂在水性载体中重构而获得所述微泡。
优选地,例如在国际专利申请WO2004/069284中公开的,包含磷脂和脂肪酸的混合物的组合物可以在搅拌下分散在水和与水不混溶的有机溶剂(例如支链或直链烷烃,烯烃,环烷烃,芳族烃,烷基醚,酮,卤代烃,全氟化烃或它们的混合物)的乳液中,优选有冻干保护剂(如前面所列出的那些,特别是碳水化合物,糖醇,聚(乙)二醇,聚氧亚烷基二醇和它们的混合物)的混合物中。该乳液可以通过在磷脂和脂肪酸存在下,采用水性介质和溶剂以本领域中已知的任何适当的乳液产生技术而获得,如,例如,超声处理,摇动,高压均质化,微观混合,膜乳化,高速搅拌或高剪切混合。如此获得的微滴乳液,其中含有由磷脂和脂肪酸包围和稳定的溶剂的微滴(和任选由其它两亲性成膜化合物和/或添加剂),然后根据常规技术冻干以获得冻干材料。
干燥的或冻干的产物通常是粉末或饼的形式,并且可以存储(通常在小瓶中)在与所需的气体相接触下。在生物相容性气体存在和该悬浮液温和搅拌下,该产品是在适宜的生理上可接受的水性液体载体中容易的重构,以形成充气微泡的悬浮液,该产品通常是可注射的。适宜的生理上可接受的液体载体是无菌水,水性溶液例如盐水(其可以有利地被平衡而使得用于注射的最终产物不是低渗的),或一种或多种张力调节物质的溶液,所述张力调节物质例如盐或糖,糖醇,二醇类或其它非离子多元醇材料(例如葡萄糖,蔗糖,山梨醇,甘露醇,甘油,聚乙二醇,丙二醇等),壳聚糖衍生物,例如羧甲基壳聚糖,三甲基壳聚糖或凝胶化的化合物,如羧甲基纤维素,羟乙基淀粉或葡聚糖。
气体
任意的生物相容性气体,气体前体或它们的混合物可以用于形成本发明的微泡(以下,也确定为“微泡-形成气体”)。术语“生物相容性气体”(或气体前体)包括任何气体(或其前体),其在有关的诊断或治疗应用中的通常剂量不会导致对患者的任何显著副作用或毒性作用。
所述气体可以包括,例如,空气;氮气;氧气;二氧化碳;氢气;一氧化二氮;一氧化氮;稀有气体或惰性气体如氦,氩,氙或氪;低分子量烃(例如含有至多7个碳原子),例如烷烃,如甲烷,乙烷,丙烷,丁烷,异丁烷,戊烷或异戊烷,环烷烃如环丁烷或环戊烷,烯烃如丙烯,丁烯或异丁烯,或炔如乙炔;醚;酮;酯;卤化气体,优选如氟化气体,或卤化,氟化或全氟化的低分子量烃(例如含有至多7个碳原子);或任何前述物质的混合物。当使用卤化烃时,在所述化合物中的卤原子优选至少部分,更优选全部,是氟原子。
氟化气体是优选的是,特别是全氟化气体。氟化气体包括含有至少一个氟原子的材料,如,例如氟化烃(含有一个或多个碳原子和氟原子的有机化合物);六氟化硫;氟化,优选全氟化的,酮如全氟丙酮;和氟化,优选全氟化的,醚如全氟乙醚。优选的化合物是全氟化气体,例如SF6或全氟化碳(全氟化烃),即烃类,其中所有氢原子被氟原子所替换,这是众所周知的以形成特别稳定的微泡悬浮液,如例如在EP 0554 213中所公开的,其通过参考而引入本文。
术语全氟化碳包括饱和,不饱和,和环状全氟化碳。生物相容性的,生理学上可接受的全氟化碳的实例是:全氟烷烃,如全氟甲烷,全氟乙烷,全氟丙烷,全氟丁烷(例如全氟-正-丁烷,任选混合有其他异构体如全氟-异丁烷),全氟戊烷,全氟己烷或全氟庚烷;全氟烯烃,如全氟丙烯,全氟丁烯(例如全氟-2-丁烯)或全氟丁二烯;全氟炔烃(例如全氟丁-2-炔);和全氟环烷烃(例如全氟环丁烷,全氟甲基环丁烷,全氟二甲基环丁烷,全氟三甲基环丁烷,全氟环戊烷,全氟甲基环戊烷,全氟二甲基环戊烷,全氟环己烷,全氟甲基环戊己烷和全氟环庚烷)。优选的饱和全氟化碳包括,例如,CF4,C2F6,C3F8,C4F8,C4F10,C5F12和C6F12。
以任何比例使用任何上述气体的混合物也可能是有利的。例如,该混合物可以包含常规的气体,如氮气,空气或二氧化碳和形成稳定的微泡悬浮液的气体,例如如上所示的六氟化硫或全氟化碳。适宜的气体混合物的实例可以,例如,在WO 94/09829中被发现,其通过参考而引入本文。以下的组合是特别优选的:气体(A)和(B)的混合物,其中气体(B)是一种氟化气体,其选自在先所示的那些氟化气体,包括它们的混合物,和(A)选自空气,氧气,氮气,二氧化碳或它们的混合物。气体(B)的数量可以是总混合物的约0.5%至约95%v/v,优选从约5%至80%。
特别优选的气体是SF6,C3F8,C4F10或者它们的混合物,任选地是与空气,氧气,氮气,二氧化碳或其混合物混合。
在某些情况下,可能希望包括一种气态物质的前体(即能够在体内被转化成气体的材料)。优选的气态前体和由其衍生的气体是生理上可接受的。气态前体可以是pH活化的,光激活的,温度活化的,等等。例如,某些全氟化碳可以用作温度活化的气态前体。这些全氟化碳,例如全氟戊烷或全氟己烷,具有高于室温(或药物生产和/或储存的温度)但是低于体温的一个液体/气体的相变温度;因此,它们经历一个液体/气体的相变,并且在人体内转化成气体。
与微泡相关的试剂或成分
根据本发明的微泡可以任选进一步包含诊断剂和/或治疗剂,或者包含在微泡结构中或与其相关联。
术语“诊断剂”包括在其含义范围内的任何化合物,组合物或颗粒,它们是可以与成像患者的内部区域和/或诊断患者的疾病存在或不存在的方法相结合使用的。具体地,掺入到或与本发明组合物的微泡相关联的诊断剂是任何化合物,组合物或颗粒,其可以允许与诊断技术相关的成像增强,包括磁共振成像,X-射线,特别是计算机断层扫描,光学成像,核成像或分子成像。适宜的诊断剂的实例是,例如,磁性纳米颗粒,碘化化合物,如或顺磁性离子络合物,如疏水钆络合物。
术语“治疗剂”包括在其含义范围内的任何物质,组合物或颗粒,它们可以在任何治疗应用中使用,例如用于处理(包括诊断,预防,减轻,缓解疼痛或治愈)患者疾病的方法,以及能够施加或负责施加在体外和/或体内的生物效应的任何物质。治疗剂因此包括能够在患者任何病理状态(包括疾病,痛苦,疾病病变或损伤)的治疗中应用以及在任何这种病理状态的预防(例如疫苗)中应用的任何化合物或材料。治疗剂的实例是药物,药品,生物活性剂,细胞毒性剂,化疗剂,放射治疗剂,蛋白质,天然或合成的肽,包括寡肽和多肽,维生素,类固醇和遗传物质,包括核苷,核苷酸,寡核苷酸,多核苷酸和质粒。
本发明的微泡也可以与其它组分结合,如,例如,脂质体或微胶粒。所述组分可以简单地与微泡一起混合,或者可以通过与微泡稳定化外膜的物理和/或化学相互作用而形成一个组合体件,例如通过共价结合,静电或离子相互作用,范德华相互作用,疏水或亲水相互作用。这些相关联的微泡组合物和其制备的实例已经被公开,例如,在US专利号6,258,378和国际专利申请WO2005/063305和WO2005/063306中公开,所有通过引用而并入本文。这些与微泡相联合的或相关联的组分可以依次与任何上述所列的靶向配体诊断试剂或治疗剂相连,其将因此通过所述成分而与微泡相关联。例如,磁性纳米粒子可以与如前面提到的那些带电的两亲性材料混合,以稳定所述颗粒和保持它们分散于水性溶液中(如例如在US 5,545,395中所公开的,其通过引用而并入本文),以便于将其与微泡相关联。可替代地,钆复合物可以与适宜的胶束形成性化合物混合,例如在欧洲专利EP 804 251中公开的(通过引用而并入本文),并且所形成的胶束可以与微泡相关联。类似地,治疗剂可以制备为胶束或脂质体混悬液,并且因此与微泡相关联。
药物试剂盒和给药
根据本发明的微泡被优选存储为干燥粉末形式,并且因此可以有利地以双组分包装在诊断和/或治疗试剂盒中,优选用于注射给药。所述试剂盒优选地包括一个第一容器,其包含与选定的生物相容性气体相接触的冻干组合物和第二容器,其包含药理学上可接受的水性载体。适宜载体的实例是水,通常是无菌的,无热原的水(以尽可能的防止在中间冻干产品可能的污染),水性溶液如盐水(其可以有利地平衡而使得用于注射的最终产物不是低渗的),或一种或多种张力调节物质的水性溶液如盐或糖,糖醇,二醇或其它非离子多元醇材料(如葡萄糖,蔗糖,山梨醇,甘露醇,甘油,聚乙二醇,丙二醇等)。所述双组分试剂盒可以包括两个分离的容器或一种双室容器。在前者的情况下,该容器最好是常规的隔膜密封的小瓶,其中含有冻干残余物的小瓶用隔膜密封,通过所述隔膜使用任选的预装填注射器可以注射该载体液体。在这样的情况下作为第二组分容器的注射器然后也用于注射造影剂。在后一种情况下,该双室容器最好是一种双室注射器,并且一旦冻干物已经被重构和然后适当地混合或轻轻摇动,该容器可直接用于注射造影剂。
本发明的微泡可能在各种诊断和/或治疗技术中使用,特别是包括超声和磁共振。
诊断技术包括任意方法,其中充气微泡的应用允许增强动物(包括人类)体内的一部分或局部的可视化,包括为临床前和临床研究目的而成像。多种成像技术可以用于超声应用中,例如包括基波和谐波B-模式成像,脉冲或倒相成像和基波和谐波多普勒成像;如果需要,可以使用三维成像技术。
根据本发明的微泡通常可以以每kg患者约0.01至约1.0μL气体的浓度给药,这取决于例如它们各自的组合物(组分),将更进行成像的所述组织或器官和/或所选择的成像技术。当然,这种通常的浓度范围可能依赖于特定的成像应用而变化,即当信号可以在非常低的剂量观察到时,例如在彩色多普勒或功率反向脉冲(power pulse inversion)中。
可能的其他诊断成像应用包括闪烁显像,光成像,和X射线成像,包括X射线相位衬度成像。
治疗技术包括治疗(如上述定义)患者的任何方法,其包括使用充气微泡其本身(例如超声介导的溶栓)或者使用与治疗剂(例如,用于传递生物活性化合物到所选择的部位或组织,如在基因治疗中或在用作疫苗中)组合的充气微泡,并且其能够通过其自身或者通过各种物理方法(包括例如超声介导的递送)的特异性激活,施加或负责施加在体内和/或在体外的生物效应。
根据本发明的微泡通常可以以每kg患者体重约0.01至约5.0μL气体的浓度给药,这取决于例如它们各自的组合物(组分),所治疗的患者类型,治疗的组织或器官和/或应用的治疗方法。
下面的实施例将有助于进一步阐明本发明。
实施例
材料
通过Coulter counter Multisizer3(孔径:30μm)确定微泡的尺寸和浓度。
在下列实施例中制备的编号标识具有缩写NxXn的磷脂的各种组合,其中:
-N是一个数字,标识所述组合物是否仅包含饱和脂肪酸(1),仅包含不饱和脂肪酸(2)或两者的混合物(3或更高,其中高于3的编号标识两种脂肪酸之间不同的摩尔比)
-x是一个字母,标识脂肪酸的链长度(a=C16;b,b′,b″=C18;c,c′=C20;其中b′(和c′)和b″分别标识具有两个或三个不饱和度的不饱和脂肪酸);
-X是一个字母(大写),标识磷脂的类型(A=DSPC,B=DSPG,C=DSPS,D=DPPC和E=DAPC);和
-n是另一个数字,标识在不同制剂中磷脂的类似的相对摩尔量。
例如,3b′A1标识混合物,其中有C18脂肪酸混合物和DSPC,所述C18脂肪酸混合物是饱和脂肪酸与不饱和脂肪酸摩尔比(N=3)为1/2.5的C18脂肪酸混合物(b),其中含有两个不饱和度(x=b′)的不饱和脂肪酸,DSPC为相对于3b′A1标识的混合物按摩尔计(n=1)的52%相对含量的DSPC(X=A);同样的,3aC1标识混合物,其中有C16脂肪酸混合物和DSPS,所述C16脂肪酸混合物是饱和脂肪酸与不饱和脂肪酸摩尔比(N=3)为1/2.5的C16脂肪酸混合物(x=a),其中DSPS为相对于3aC1标识的混合物按摩尔计(n=1)的52%相对含量的DSPS(X=C)。
实施例1(比较的)
含有饱和或不饱和脂肪酸的微泡的制备
15.6mg的DSPC(按摩尔计52%)和4.4mg的棕榈酸(按摩尔计45.5%)混合在THF中,在60℃下蒸发和在真空下(0.2mbar)25℃干燥过夜;在70℃将残余物溶解在环辛烷(1.6mL)中直至获得澄清的,均匀的溶液。
DSPE-PEG2000(2.6mg)与200μL蒸馏水混合。在加热(50℃)和混合后,获得澄请的胶束溶液,并且加入到20mL的10%(w/v)PEG 4000的蒸馏水溶液。
在高速均化器Polytron搅拌下(1分钟9′000rpm),将有机相加入水相中。在轻微搅拌下,将所得乳液在80℃下放置1小时,并且冷却至室温。用10%(w/v)PEG 4000溶液稀释该乳液两次,并且在DIN4R小瓶中等分(每小瓶0.5mL乳液)。冷冻干燥小瓶中的乳液并且C4F10/空气(35%-65%)的混合物被引入到小瓶中。小瓶在-50℃冷冻1小时(Telstar冻干机),然后在-25℃和0.2mbar下冷冻干燥12小时。然后小瓶中的内容物在轻微搅拌下再分散在0.9%NaCl(1mL)中,以得到充气微泡的悬浮液。
通过用类似摩尔量的其它饱和和不饱和脂肪酸替代棕榈酸,重复上述制备过程,如下表1中所示。
表1:包含饱和或不饱和脂肪酸的微泡
实施例2
包含饱和的和不饱和脂肪酸混合物的微泡
通过用类似摩尔量(约45.5%)的包含饱和脂肪酸(按摩尔计约13%;1.5至1.8mg)和不饱和脂肪酸(按摩尔计约32.5%;3.7至4.4mg)的混合物替代棕榈酸,重复实施例1的制剂1a,如下表2中所示,混合18.2至18.5mg的DSPC(总计为20mg的饱和脂肪酸数量)和3.0mg的DSPE-PEG2000。
表2:具有饱和/不饱和脂肪酸混合物的微泡
制剂 | 饱和脂肪酸(mg) | 不饱和脂肪酸(mg) | 微泡浓度(颗粒/mL) |
3aA1 | 棕榈酸-1.5 | 棕榈油酸-3.7 | 2.9×109 |
3bA1 | 硬脂酸-1.7 | 油酸-4.1 | 3.2×109 |
3b′A1 | 硬脂酸-1.7 | 亚油酸-4.1 | 2.9×109 |
3b″A1 | 硬脂酸-1.7 | 亚麻酸-4.0 | 2.8×109 |
3cA1 | 花生酸-1.8 | 二十碳烯酸-4.5 | 3.3×109 |
3c′A1 | 花生酸-1.8 | 二十碳二烯酸-4.4 | 3.7×109 |
3ab′A1 | 棕榈酸-1.5 | 亚油酸-4.1 | 3.2×109 |
3ab″A1 | 棕榈酸-1.5 | 亚麻酸-4.1 | 2.6×109 |
实施例3
包含饱和/不饱和脂肪酸混合物的微泡对比于包含饱和或不饱和脂肪酸的
微泡的稳定性
在37℃下经24小时在上述确定的培养基中测定实施例1和2中制备的微泡的稳定性。每个制剂的两个小瓶再分散在1mL培养基中并且在i)刚刚重构之后和ii)在静态条件下37℃孵育24小时之后,通过Coulter Counter表征样品。维持微泡的比例(相对于在重构后测得的初始量)报告在下表3中。
表3:微泡的稳定性
*=对比的
从上表可推知,饱和和不饱和脂肪酸混合物(摩尔比约1∶2.5)提供了增加的微泡的稳定性,相对于仅含有相同摩尔数量的饱和或不饱和脂肪酸的微泡。
实施例4
具有各种摩尔比的花生酸与二十碳烯酸的微泡的制备和稳定性测量
重复实施例2中的制剂3c,但是饱和脂肪酸相对于不饱和脂肪酸的摩尔比是如表4所示的变动(同时保持饱和+不饱和脂肪酸的总摩尔数量维持在约45.5%摩尔),其余成分是DSPC(52%摩尔)和DSPE-PEG2000(2.5%摩尔)。
如上所述测定所获得的微泡在培养基中的稳定性,并且与仅具有花生酸或二十碳烯酸的每一种微泡进行对比(制剂1c和2c,每一种脂肪酸总数是约45.5%摩尔)。结果报告在下表4中。
表4:包含花生酸和二十碳烯酸混合物的微泡的稳定性
*=对比的
从上表可推知,针对包含从2.5/1至1/7.3摩尔的饱和/不饱和脂肪酸混合物的微泡,观察到增加的稳定性。
实施例5
具有各种摩尔比的棕榈酸与棕榈油酸的微泡的制备和稳定性测量
重复实施例2中的制剂3a,但是饱和脂肪酸相对于不饱和脂肪酸的摩尔比是如表5所示的变动(同时保持饱和+不饱和脂肪酸的总摩尔数量在约45.5%摩尔),其余成分是DSPC(52%摩尔)和DSPE-PEG2000(2.5%摩尔)。
如上所述测定所获得的微泡在培养基中的稳定性,并且与每一个仅具有棕榈酸或棕榈油酸的微泡进行对比(制剂1a和2a,每一个脂肪酸总数是约45.5%摩尔)。结果报告在下表5中。
表5:具有棕榈酸棕榈油酸不同比例的微泡
制剂 | 棕榈酸 | 棕榈油酸 | 摩尔比 | (颗粒/mL) | 稳定性(24h |
(mg) | (mg) | 之后%) | |||
1a*A1 | 4.4 | 0 | - | 2.9×109 | 32.5 |
4aA1 | 4.0 | 0.5 | 7.3/1 | 2.7×109 | 33 |
5aA1 | 2.9 | 1.9 | 1.5/1 | 2.4×109 | 50 |
6aA1 | 2.5 | 2.5 | 1/1 | 3.0×109 | 48 |
3aA1 | 1.5 | 3.7 | 1/2.5 | 2.9×109 | 86 |
7aA1 | 0.7 | 4.8 | 1/7.3 | 2.6×109 | 58 |
2a*A1 | 0 | 4.4 | - | 2.1×109 | 31 |
*=对比的
从上表可推知,针对包含从1.5/1至1/7.3摩尔的饱和/不饱和脂肪酸混合物的微泡,观察到增加的稳定性。
实施例6
具有饱和/不饱和脂肪酸混合物和不同量磷脂酰胆碱的微泡
重复实施例2中的制剂3a,但是相对于脂肪酸混合物摩尔数量,DSPC的摩尔数量是如下表6所示变化的(饱和/不饱和脂肪酸的摩尔比维持在1∶2.5)。用于每个制剂的摩尔总数(DSPC+棕榈酸+棕榈油酸)固定维持在约45μ摩尔。
如上所述测定所获得的微泡在培养基中的稳定性,并且结果报告在下表6中。
表6:包含不同摩尔比的磷脂与饱和/不饱和脂肪酸混合物的微泡的稳定性
*=对比的
从上表可推知,当磷脂相对于饱和和不饱和脂肪酸混合物的摩尔数量比是从约1/3至约2/1时,微泡具有增加的稳定性。
实施例7
包含磷脂酰甘油与饱和/不饱和脂肪酸混合物的组合的微泡
重复制剂1a,2a(实施例1)和3a(实施例2),但是用磷脂酰甘油(DSPG)替代磷脂酰胆碱(DSPC)。如上所述测定所获得的微泡的稳定性,并且结果报告在下表7中。
表7:包含DSPG的微泡的稳定性
*=对比的
从上表可推知,当与仅包含相同摩尔数量的饱和或不饱和脂肪酸的组合物相比时,饱和/不饱和脂肪酸混合物为含有磷脂酰甘油的微泡提供增加的稳定性。
实施例8
包含磷脂酰丝氨酸与饱和/不饱和脂肪酸混合物的组合的微泡
重复实施例7,但是用磷脂酰丝氨酸(DSPS)替代磷脂酰甘油(DSPG)。如上所述测定所获得的微泡的稳定性,并且结果报告在下表8中。
表8:包含DSPS的微泡的稳定性
*=对比的
从上表可推知,当与仅包含相同摩尔数量的饱和或不饱和脂肪酸的组合物相比时,饱和/不饱和脂肪酸混合物为含有磷脂酰丝氨酸的微泡提供增加的稳定性。
实施例9
包含磷脂酰胆碱饱和/不饱和脂肪酸混合物的组合的微泡
重复实施例7,但是用磷脂酰胆碱(DPPC)替代磷脂酰甘油(DSPG),并且用硬脂酸和油酸替代脂肪酸。如上所述测定所获得的微泡的稳定性,并且结果报告在下表9中。
表9:包含DPPC的微泡的稳定性
*=对比的
从上表可推知,当与仅包含相同摩尔数量的饱和或不饱和脂肪酸的组合物相比时,饱和/不饱和脂肪酸混合物为含有磷脂酰胆碱的微泡提供增加的稳定性。
实施例10
包含磷脂酰胆碱与饱和/不饱和脂肪酸混合物的组合的微泡
重复实施例9,但是用DAPC替代DPPC。如上所述测定所获得的微泡的稳定性,并且结果报告在下表10中。
表10:包含DAPC的微泡的稳定性
*=对比的
上述数据确定,当与仅包含相同摩尔数量的饱和或不饱和脂肪酸的组合物相比时,饱和/不饱和脂肪酸混合物为含有磷脂酰胆碱的微泡(具有不同脂肪酸链)提供增加的稳定性。
实施例11
包括饱和和不饱和脂肪酸混合物的微泡在体内的超声波图像
根据制剂1aA1(DSPC和棕榈酸-PA)制备的充气微泡与根据制剂3aA1(DSPC+棕榈酸和棕榈油酸混合物-PA/POA)制备的微泡相比较,以比较它们分别的体内灌注性能(大鼠肾脏)。
通过使用装配有15L8线性换能器的西门子Sequoia 512扫描器(西门子医疗系统,Issaquah,WA)进行超声波成像,评价微泡制剂各自的灌注性能。使用Cadence Pulse Sequencing(CPS)模式在低声功率(MI 0.25)下进行间歇性肌肉成像,以在微泡制剂给药(随机注射)之后,跟踪微泡在大鼠肾脏中的洗入(washin)/洗出(washout)。
使用内部开发的软件(Bracco Suisse SA,日内瓦,瑞士)进行微泡灌注的定量分析,该软件旨在定量所感兴趣的区域(AOI)内对比度回波功率的幅度。在AOI中对比度增强表示为相对的回波功率值(rms2),其正比于在所选择的AOI中微泡的数量。基于rms2值,评价在大鼠肾脏中的最大强度(Imax,至多注射后30秒)和后期阶段增强(注射后5和10分钟)。微泡的持久性被确定为标准化值,该值为在后期阶段(在5分钟和10分钟)测量的rms2值和Imax值之间比例的百分比。
表11:在体内微泡的持久性
脂肪酸组合物 | 持久性(5min) | 持久性(10min) |
3aA1 | 21.3% | 12.5% |
1aA1 | 5.9% | 1.8% |
从上表可推知,相比于仅包含相同摩尔数量的饱和脂肪酸的微泡,根据本发明的微泡(具有饱和和不饱和脂肪酸混合物)表现出在注射5和10分钟之后增加的持久性。
Claims (25)
1.一种在生理上可接受液体载体中的充气微泡的悬浮液,所述微泡具有稳定化外膜,所述外膜含有磷脂,饱和脂肪酸和不饱和脂肪酸,其中饱和和不饱和脂肪酸的摩尔比是从2.5∶1至1∶8。
2.根据权利要求1的悬浮液,其中所述摩尔比是从1.5∶1至1∶7.5。
3.根据权利要求2的悬浮液,其中所述摩尔比是从1∶1.5至1∶4。
4.根据前述权利要求中任一项的悬浮液,其中饱和或不饱和脂肪酸是包括C10-C28脂肪族链的羧酸。
5.根据权利要求4的悬浮液,其中所述饱和脂肪酸选自羊蜡酸(正-癸酸),月桂酸(正-十二烷酸),肉豆蔻酸(正-十四烷酸),棕榈酸(正-十六烷酸),硬脂酸(正-十八烷酸),花生酸(正-二十烷酸),山嵛酸(正-二十二烷酸),正-二十四烷酸和它们的混合物。
6.根据权利要求4或5的悬浮液,其中所述不饱和脂肪酸选自癸烯酸,十二碳烯酸,十四碳烯酸,十六碳烯酸,十六碳二烯酸,十八碳烯酸,十八碳二烯酸,十八碳三烯酸,十八碳四烯酸,二十碳烯酸,二十碳二烯酸,二十碳三烯酸,二十碳四烯酸,二十碳五烯酸,二十二碳烯酸,二十二碳二烯酸,二十二碳三烯酸,二十二碳四烯酸,二十二碳五烯酸和二十四碳烯酸和它们的混合物。
7.根据前述权利要求中任一项的悬浮液,其中在悬浮液中磷脂与饱和/不饱和脂肪酸混合物的摩尔比是从3∶7至4∶1。
8.根据权利要求7或8的悬浮液,其中所述磷脂选自磷脂酰胆碱,乙基磷脂酰胆碱,磷脂酰甘油,磷脂酸,磷脂酰乙醇胺,磷脂酰丝氨酸,磷脂酰肌醇或鞘磷脂和它们的混合物。
9.根据前述权利要求中任一项的悬浮液,其中所述充气微泡进一步包含靶向配体和/或治疗剂。
10.根据前述权利要求中任一项的悬浮液,其中所述气体包含氟化气体。
11.根据前述权利要求中任一项的充气微泡的悬浮液,用于在诊断方法或治疗处理中的用途。
12.一种密封小瓶,包括:
a)一种药物制剂,包括磷脂,饱和脂肪酸和不饱和脂肪酸,其中饱和与不饱和脂肪酸的摩尔比是从2.5∶1到1∶8;和
b)一种生物相容性气体。
13.根据权利要求12的小瓶,其中饱和与不饱和脂肪酸的摩尔比是从1.5∶1至1∶7.5。
14.根据权利要求13的小瓶,其中饱和与不饱和脂肪酸的摩尔比是从1∶1.5至1∶4。
15.根据权利要求12至14中任一项的小瓶,其中饱和或不饱和脂肪酸是包括C10-C28脂肪族链的羧酸。
16.根据权利要求15的小瓶,其中所述饱和脂肪酸选自羊蜡酸(正-癸酸),月桂酸(正-十二烷酸),肉豆蔻酸(正-十四烷酸),棕榈酸(正-十六烷酸),硬脂酸(正-十八烷酸),花生酸(正-二十烷酸),山嵛酸(正-二十二烷酸),正-二十四烷酸和它们的混合物。
17.根据权利要求15或16中任一项的小瓶,其中所述不饱和脂肪酸选自癸烯酸,十二碳烯酸,十四碳烯酸,十六碳烯酸,十六碳二烯酸,十八碳烯酸,十八碳二烯酸,十八碳三烯酸,十八碳四烯酸,二十碳烯酸,二十碳二烯酸,二十碳三烯酸,二十碳四烯酸,二十碳五烯酸,二十二碳烯酸,二十二碳二烯酸,二十二碳三烯酸,二十二碳四烯酸,二十二碳五烯酸和二十四碳烯酸和它们的混合物。
18.根据权利要求13至17中任一项的小瓶,其中在制剂中磷脂与饱和/不饱和脂肪酸混合物的摩尔比是从3∶7至4∶1。
19.根据权利要求18的小瓶,其中所述磷脂选自磷脂酰胆碱,乙基磷脂酰胆碱,磷脂酰甘油,磷脂酸,磷脂酰乙醇胺,磷脂酰丝氨酸,磷脂酰肌醇或鞘磷脂和它们的混合物。
20.根据前述权利要求中任一项的小瓶,其中所述制剂进一步包含靶向配体和/或治疗剂。
21.根据前述权利要求中任一项的小瓶,其中所述制剂是冷冻干燥形式。
22.根据前述权利要求中任一项的小瓶,其中所述制剂进一步包含药学上可接受的添加剂和/或赋形剂。
23.根据权利要求22的小瓶,其中所述添加剂是冻干剂。
24.根据前述权利要求中任一项的小瓶,其中所述气体包括含氟化气体。
25.一种用于充气微泡悬浮液制备的药物试剂盒,包括根据前述权利要求中任一项的小瓶和含有生理上可接受的水性载体的容器。
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