KR101076053B1 - 초음파 조영제 및 그것의 제조방법 - Google Patents
초음파 조영제 및 그것의 제조방법 Download PDFInfo
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- KR101076053B1 KR101076053B1 KR1020057013951A KR20057013951A KR101076053B1 KR 101076053 B1 KR101076053 B1 KR 101076053B1 KR 1020057013951 A KR1020057013951 A KR 1020057013951A KR 20057013951 A KR20057013951 A KR 20057013951A KR 101076053 B1 KR101076053 B1 KR 101076053B1
- Authority
- KR
- South Korea
- Prior art keywords
- emulsion
- aqueous
- gas
- phospholipids
- microbubbles
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 91
- 230000008569 process Effects 0.000 title claims description 13
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- 239000007788 liquid Substances 0.000 claims abstract description 28
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- 239000011159 matrix material Substances 0.000 claims abstract description 15
- 239000007900 aqueous suspension Substances 0.000 claims abstract description 14
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- 229930195729 fatty acid Natural products 0.000 claims description 27
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- 239000003446 ligand Substances 0.000 claims description 27
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- KLFKZIQAIPDJCW-HTIIIDOHSA-N Dipalmitoylphosphatidylserine Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCC KLFKZIQAIPDJCW-HTIIIDOHSA-N 0.000 claims description 25
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- 238000006243 chemical reaction Methods 0.000 claims description 21
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- 150000004665 fatty acids Chemical class 0.000 claims description 18
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 17
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- FVJZSBGHRPJMMA-IOLBBIBUSA-N PG(18:0/18:0) Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-IOLBBIBUSA-N 0.000 claims description 8
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 6
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- NEZDNQCXEZDCBI-UHFFFAOYSA-N 2-azaniumylethyl 2,3-di(tetradecanoyloxy)propyl phosphate Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCC NEZDNQCXEZDCBI-UHFFFAOYSA-N 0.000 claims description 5
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 5
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- 239000008194 pharmaceutical composition Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
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- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
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- HZLWUYJLOIAQFC-UHFFFAOYSA-N prosapogenin PS-A Natural products C12CC(C)(C)CCC2(C(O)=O)CCC(C2(CCC3C4(C)C)C)(C)C1=CCC2C3(C)CCC4OC1OCC(O)C(O)C1O HZLWUYJLOIAQFC-UHFFFAOYSA-N 0.000 description 1
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- 235000017709 saponins Nutrition 0.000 description 1
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- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
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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
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Acoustics & Sound (AREA)
- Radiology & Medical Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
- Measuring And Recording Apparatus For Diagnosis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
DPPS | 디팔미토일포스파티딜세린 (Genzyme) IUPAC: 1,2-디팔미토일-sn-글리세로-3-포스포콜린 |
DPPG | 디팔미토일포스파티딜글리세롤 나트륨 염 (Genzyme) IUPAC: 1,2 -디팔미토일-sn-글리세로-3-[포스포-rac-(1-글리세롤)] |
DSPA | 디스테아로일 포스파티드 산 나트륨 염 (Genzyme) IUPAC: 1,2 -디스테아로일-sn-글리세로-3-포스패이트 |
DSPG | 디스테아로일포스파티딜글리세롤 나트륨 염 (Genzyme) IUPAC: 1,2 -디스테아로일-sn-글리세로-3-포스포세린) |
DSPC | 디스테아로일포스파티딜콜린 (Genzyme) IUPAC: 1,2 -디스테아로일-sn-글리세로-3-포스포콜린 |
DSEPC | 디스테아로일에틸포스파티딜콜린 (Avanti Polar Lipids) IUPAC: 1,2 -디스테아로일-sn-글리세로-3-에틸포스포콜린 |
DAPC | 디아라키도일포스파티딜콜린 (Avanti Polar Lipids) IUPAC: 1,2 -디아라키도일-sn-글리세로-3-포스포콜린 |
DSTAP | 1,2 -디스테아로일-3-트리메틸암모늄-프로판 클로라이드 (Avanti Polar Lipids) |
DSPE-PEG2000 | PEG2000과 함께 변형된 디스테아로일포스파티딜에탄올아민, 나트륨 염 (Nektar Therapeutics) |
DSPE-PEG5000 | PEG5000과 함께 변형된 디스테아로일포스파티딜에탄올아민, 나트륨 염 (Nektar Therapeutics) |
DSPE-PEG2000-말레이미드 | PEG2000-말레이미드와 함께 변형된 디스테아로일포스파티딜에탄올아민 (Avanti Polar lipids) |
SATA | N-숙신이미딜-S-아세틸티오아세테이트 (Pierce) |
RGD-4C | H-Ala-Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys-Gly-NH2 (AnaSpec Inc.) |
실시예 |
에멀젼 | 기체 충전 마이크로버블 | ||||||
교반 (rpm) |
DV50 (㎛) |
DN (㎛) |
DV50 (㎛) |
DV (㎛) |
DN (㎛) |
DV50 /DN |
>3㎛ (%) |
|
1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l |
8000 9000 10000 11000 12000 12500 14000 14500 15000 15500 16000 17000 |
4.58 4.66 3.04 3.05 2.84 2.79 2.20 2.00 1.88 2.19 1.83 1.40 |
1.77 1.94 1.74 1.80 1.69 1.68 1.52 1.38 1.39 1.48 1.32 1.12 |
2.92 3.19 2.16 2.17 1.86 1.75 1.39 1.19 1.22 1.24 1.27 0.91 |
3.33 3.45 2.53 3.33 2.17 2.05 2.45 1.39 2.20 1.46 3.08 1.03 |
1.51 1.53 1.33 1.32 1.24 1.22 1.08 1.01 1.01 1.02 0.99 0.87 |
1.93 2.08 1.62 1.65 1.50 1.44 1.29 1.19 1.21 1.22 1.28 1.05 |
5.44 6.61 1.88 1.55 0.93 0.65 0.23 0.06 0.06 0.11 0.10 0.01 |
실시예 |
에멀젼 | 기체 충전 마이크로버블 | ||||||
교반 (rpm) |
DV50 (㎛) |
DN (㎛) |
DN (㎛) |
DV (㎛) |
DN (㎛) |
DV50 /DN |
>3㎛ (%) |
|
2a 2b 2c 2d 2e 2f 2g 2h 2i 2j |
6000 10000 12000 12500 13000 13500 14000 14500 15000 16000 |
8.75 3.54 3.04 2.85 2.98 2.91 2.45 2.18 1.94 1.81 |
3.07 1.90 1.83 1.76 1.83 2.05 1.67 1.55 1.42 1.38 |
7.55 3.00 2.45 2.21 2.25 1.88 1.82 1.58 1.34 1.35 |
9.05 3.71 3.73 3.24 3.04 2.46 2.66 3.04 1.96 2.30 |
2.27 1.47 1.32 1.27 1.28 1.20 1.16 1.09 1.04 1.03 |
3.33 2.04 1.85 1.74 1.76 1.57 1.57 1.44 1.28 1.31 |
21.81 5.05 2.15 1.57 1.76 0.87 0.57 0.38 0.31 0.14 |
실시예 |
DPPS /DSPC 비 |
에멀젼 | 기체 충전 마이크로버블 | |||||
교반 (rpm) |
DV50 (㎛) |
DN (㎛) |
DN (㎛) |
DN (㎛) |
DV50 /DN |
>3㎛ (%) |
||
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p |
80/20 75/25 60/40 60/40 60/40 50/50 40/60 40/60 40/60 40/60 40/60 30/70 30/70 25/75 10/90 5/95 |
12000 12000 11000 12000 14000 12000 11000 12000 13000 14000 14500 11000 12000 11000 11000 11000 |
2.44 2.53 3.53 2.62 2.36 2.81 3.00 2.88 2.61 2.06 2.39 3.12 3.08 3.15 3.72 4.53 |
1.54 1.66 1.86 1.60 1.60 1.68 1.72 1.75 1.69 1.43 1.67 1.75 1.81 1.85 2.26 2.23 |
1.68 1.73 2.75 1.78 1.59 2.28 2.44 2.07 1.76 1.41 1.64 2.64 2.38 2.46 3.14 4.08 |
1.19 1.18 1.45 1.21 1.13 1.30 1.32 1.27 1.16 1.07 1.15 1.37 1.34 1.31 1.47 1.54 |
1.41 1.47 1.90 1.47 1.41 1.75 1.85 1.63 1.52 1.31 1.43 1.93 1.78 1.88 2.13 2.65 |
0.48 0.62 4.00 0.72 0.36 2.05 2.31 1.45 0.57 0.23 0.49 2.76 2.45 2.15 4.60 6.35 |
실시예 |
DSPA/ DPPS 비 |
에멀젼 | 기체 충전 마이크로버블 | |||||
교반 (rpm) |
DV50 (㎛) |
DN (㎛) |
DV50 (㎛) |
DN (㎛) |
DV50 /DN |
>3㎛ (%) |
||
4a 4b 4c 4d |
25/75 50/50 50/50 75/25 |
12000 11000 12000 12000 |
2.61 2.81 2.35 2.50 |
1.63 1.86 1.57 1.65 |
1.94 2.35 1.84 2.11 |
1.24 1.39 1.19 1.27 |
1.56 1.69 1.55 1.66 |
1.07 2.67 0.74 1.45 |
실시예 |
에멀젼 | 기체 충전 마이크로버블 | |||||
교반 (rpm) |
DV50 (㎛) |
DN (㎛) |
DV50 (㎛) |
DN (㎛) |
DV50 /DN |
>3㎛ (%) |
|
5a 5b 5c 5d 5e 5f 5g 5h 5i |
6000 8000 9000 10000 10500 11000 12000 13000 14000 |
10.02 5.31 5.04 3.82 3.36 3.22 2.69 2.28 2.00 |
2.64 2.49 2.69 2.02 1.96 1.87 1.61 1.56 1.44 |
6.87 3.73 3.20 2.85 2.51 2.31 1.74 1.56 1.30 |
2.07 1.62 1.55 1.38 1.32 1.28 1.14 1.07 1.00 |
3.32 2.30 2.06 2.07 1.89 1.81 1.53 1.46 1.30 |
18.00 7.97 6.22 2.65 2.44 1.41 0.52 0.23 0.26 |
DV50 (㎛) |
DV (㎛) |
DV50/DN | > 3 ㎛ (%) |
1.65 | 1.11 | 1.49 | 0.30 |
실시예 | 용매 | DV50 (㎛) |
DN (㎛) |
DV50/DN |
7a | C6F14 | 2.77 | 1.44 | 1.92 |
7b | CF3-시클로-C6F11 | 2.24 | 1.30 | 1.72 |
7c | C7F16 | 2.48 | 1.40 | 1.77 |
7d | C9F20 | 2.46 | 1.36 | 1.81 |
7e | 퍼플루오로데칼린 | 3.76 | 1.52 | 2.47 |
7f | 시클로헥산 | 2.61 | 1.41 | 1.85 |
7g | 시클로옥탄 | 2.43 | 1.35 | 1.80 |
7h | 데칸 | 2.01 | 1.12 | 1.79 |
7i | 옥탄 | 2.87 | 0.96 | 2.99 |
7j | 메타 자일렌 | 2.45 | 1.21 | 2.02 |
7k | 디이소프로필 세톤 | 1.83 | 1.05 | 1.74 |
7l | CCl4 | 1.90 | 1.27 | 1.50 |
실시예 | 동결건조보호제 및 농도 (w/w) | DV50 (㎛) |
DN (㎛) |
DV50 /DN |
8a 8b 8c 8d 8e 8f 8g 8h 8j 8k 8i 8l |
만노스 5% 글루코스 5% 소르비톨 5% 만니톨 10% 만니톨 5% 만니톨 4% 말토스 5% 덱스트란 6000 7.5% 덱스트란 15000 5% 덱스트란 15000 7.5% 덱스트란 40000 7.5% 이뉼린 5% |
4.35 2.59 3.84 2.22 2.24 2.54 3.42 3.30 2.55 2.77 2.54 3.58 |
1.90 0.96 1.40 1.22 1.21 1.45 0.99 1.48 1.31 1.44 1.32 1.43 |
2.29 2.70 2.74 1.82 1.85 1.75 3.45 2.23 1.95 1.92 2.29 2.70 |
실시예 | Pluronic* (mg/ml) |
DV50 | DN | DV50/DN | 전환수율 (%) |
9a 9b 9c 9d 9e |
0 0.25 0.5 1.0 2.0 |
2.42 4.64 13.85 12.59 15.80 |
1.38 1.97 1.38 1.49 1.23 |
1.75 2.36 10.04 8.45 12.85 |
28.0 18.8 7.3 3.2 0.5 |
실시예 | 콜레스테롤* (mg/ml) |
DV50 | DN | DV50/DN | 전환수율 (%) |
10a 10b 10c 10d |
0 0.10 0.25 0.50 |
2.42 3.79 1.35 14.02 |
1.38 1.31 1.05 1.70 |
1.75 2.89 1.28 8.25 |
28.0 17.8 5.7 0.8 |
DV50 | DN | DV50/DN | |
파트 A | 1.71 | 1.12 | 1.53 |
파트 B | 1.65 | 1.12 | 1.47 |
파트 C | 1.57 | 1.09 | 1.44 |
에멀젼 방울 | 기체 충전 마이크로버블 | |||
DV50 | DN | DV50 | DN | >3㎛ |
2.36 | 1.48 | 2.10 | 1.12 | 0.63 |
에멀젼 | 마이크로버블 | |||||
실시예 | DV50 (㎛) |
DN (㎛) |
DV50 (㎛) |
DN (㎛) |
DV50/DN | 전환수율 (%) |
13a | 3.19 | 1.66 | 2.66 | 1.33 | 2.00 | 29.5 |
13b | 4.32 | 1.43 | 5.81 | 1.18 | 4.92 | 18.8 |
에멀젼 | 마이크로버블 | ||||
실시예 | DV50 (㎛) |
DN (㎛) |
DV50 (㎛) |
DN (㎛) |
DSPE-PEG (% w/w) |
14a | 2.6 | 2.3 | 1.9 | 1.1 | 0.0 |
14b | 2.5 | 2.3 | 3.4 | 1.3 | 35.5 |
14c | 2.5 | 2.3 | 2.2 | 1.2 | 37.9 |
가열 | DV50 | DN | DV50/DN | 에멀젼의 ml 당 마이크로버블의 개수 |
가열하지 않음 | 10.45 | 1.63 | 6.41 | 5.34 x 107 |
60℃ | 4.85 | 1.32 | 3.67 | 7.83 x 107 |
80℃ | 5.34 | 1.29 | 4.14 | 8.51 x 107 |
100℃ | 6.96 | 1.66 | 4.19 | 4.92 x 108 |
120℃ | 3.05 | 1.50 | 2.03 | 8.69 x 108 |
Claims (40)
- 수성 담체 액체 및 기체와 접촉하여, 인지질에 의해서 현저하게 안정화된 기체-충전 마이크로버블의 현탁액으로 복원되는 동결건조 매트릭스를 제조하는 방법으로서, 상기 방법은a) i) 물을 포함하는 수성 매질, ii) 물과 실질적으로 비혼화성인 유기 용매, iii) 50 중량% 이상의 인지질을 포함하는 양친매성 물질의 유화 조성물, 및 iv) 동결건조보호제를 포함하는 수성-유기 에멀젼을 제조하는 단계;b) 상기 인지질을 포함하는 동결건조된 매트릭스를 얻도록, 상기 유화된 혼합물을 동결건조하는 단계를 포함하는 것을 특징으로 하는 방법.
- 인지질에 의해서 현저하게 안정화된 기체-충전 마이크로버블의 액체 수성 현탁액을 포함하는 주사가능한 조영제를 제조하는 방법으로서,a) i) 물을 포함하는 수성 매질, ii) 물과 실질적으로 비혼화성인 유기용매; iii) 50 중량% 이상의 인지질을 포함하는 양친매성 물질의 유화 조성물 및 iv) 동결건조보호제를 포함하는 수성-유기 에멀젼을 제조하는 단계;b) 상기 인지질을 포함하는 동결건조된 매트릭스를 얻도록, 상기 에멀젼을 동결건조시키는 단계;c) 생적합성 기체를 가진 상기 동결건조된 매트릭스를 접촉시키는 단계;d) 상기 인지질에 의해서 현저하게 안정화된 기체-충전 마이크로버블의 현탁 액을 얻도록, 생성물을 생리학적으로 허용되는 수성 담체 액체에 용해시킴으로써 상기 동결건조된 매트릭스를 복원시키는 단계를 포함하는 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 에멀젼을 제조하는 단계 a)는 다음의 단계: a1) 수성 매질에서 유화 조성물 및 동결건조보호제를 분산시킴으로써 현탁액을 제조하는 단계; a2) 얻어진 현탁액과 유기 용매를 혼합시키는 단계; a3) 에멀젼을 얻도록, 혼합물을 제어된 교반을 시키는 단계를 포함하는 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 유기 용매는 10 g/l 이하의 용해도를 갖는 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 유기 용매는 1.0 g/l 또는 그 이하의 용해도를 갖는 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 유기 용매는 0.2 g/l 또는 그 이하의 용해도를 갖는 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 유기 용매는 0.01 g/l 또는 그 이하의 수용성을 갖는 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 유기 용매는 0.001 g/l 또는 그 이하의 용해도를 갖는 것을 특징으로 하는 방법.
- 제 1 항에 있어서, 유기 용매는 분지형 또는 선형 알칸, 알켄, 시클로-알칸, 방향족 탄화수소, 알킬 에테르, 케톤, 할로겐화 탄화수소, 퍼플루오르화 탄화수소 및 그것의 혼합물 중에서 선택되는 것을 특징으로 하는 방법.
- 제 9 항에 있어서, 유기 용매는 펜탄, 헥산, 펩탄, 옥탄, 노난, 데칸, 1-펜텐, 2-펜텐, 1-옥텐, 시클로펜탄, 시클로헥산, 시클로옥탄, 1-메틸-시클로헥산, 벤젠, 톨루엔, 에틸벤젠, 1,2-디메틸벤젠, 1,3-디메틸벤젠, 디-부틸 에테르 및 디-이소프로필케톤, 클로로포름, 사염화탄소, 2-클로로-1-(디플루오로메톡시)-1,1,2-트리플루오로에탄 (엔플루란), 2-클로로-2-(디플루오로메톡시)-1,1,1-트리플루오로에탄 (이소플루란), 테트라클로로-1,1-디플루오로에탄, 퍼플루오로펜탄, 퍼플루오로헥산, 퍼플루오로헵탄, 퍼플루오로노난, 퍼플루오로벤젠, 퍼플루오로데칼린, 메틸플루오로부틸에테르, 메틸플루오로이소부틸에테르, 에틸퍼플루오로부틸에테르, 에틸퍼플루오로이소부틸에테르 및 그것의 혼합물 중에서 선택되는 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 유기 용매의 양은 물의 양에 대하여 1 부피% 내지 50 부피%인 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 동결건조보호제는 탄수화물, 당 알코올, 폴리글리콜 및 그것의 혼합물 중에서 선택되는 것을 특징으로 하는 방법.
- 제 12 항에 있어서, 동결건조보호제는 글루코스, 갈락토스, 프룩토스, 슈크로스, 트레할로스, 말토스, 락토스, 아밀로스, 아밀로펙틴, 시클로덱스트린, 덱스트란, 이뉼린, 가용성 전분, 히드록시에틸 전분(HES), 에리쓰리톨, 만니톨, 소르비톨, 폴리에틸렌글리콜 및 그것의 혼합물 중에서 선택되는 것을 특징으로 하는 방법.
- 제 12 항에 있어서, 물의 중량에 대하여 1 중량% 내지 25 중량%의 동결건조보호제의 양을 갖는 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 인지질은 디라우로일-포스파티딜콜린 (DLPC), 디미리스토일-포스파티딜콜린 (DMPC), 디팔미토일-포스파티딜콜린 (DPPC), 디아라키도일-포스파티딜콜린 (DAPC), 디스테아로일-포스파티딜콜린 (DSPC), 디올레오일-포스파티딜콜린 (DOPC), 1,2 디스테아로일-sn-글리세로-3-에틸포스포콜린 (에틸-DSPC), 디펜타데카노일-포스파티딜콜린 (DPDPC), 1-미리스토일-2-팔미토일-포스파티딜콜린 (MPPC), 1-팔미토일-2-미리스토일-포스파티딜콜린 (PMPC), 1-팔미토일-2-스테아로일-포스파티딜콜린 (PSPC), 1-스테아로일-2-팔미토일-포스파티딜콜린 (SPPC), ), 1-팔미토일-2-올레일포스파티딜콜린 (POPC), 1-올레일-2-팔미토일-포스파티딜콜린 (OPPC), 디라우로일-포스파티딜글리세롤 (DLPG) 및 그것의 알칼리 금속 염, 디아라키도일포스파티딜-글리세롤 (DAPG) 및 그것의 알칼리 금속 염, 디미리스토일포스파티딜글리세롤 (DMPG) 및 그것의 알칼리 금속 염, 디팔미토일포스파티딜글리세롤 (DPPG) 및 그것의 알칼리 금속 염, 디스테아로일포스파티딜글리세롤 (DSPG) 및 그것의 알칼리 금속 염, 디올레오일-포스파티딜글리세롤 (DOPG) 및 그것의 알칼리 금속 염, 디미리스토일 포스파티드 산 (DMPA) 및 그것의 알칼리 금속 염, 디팔미토일 포스파티드 산 (DPPA) 및 그것의 알칼리 금속 염, 디스테아로일 포스파티드 산 (DSPA), 디아라키도일포스파티드 산 (DAPA) 및 그것의 알칼리 금속 염, 디미리스토일-포스파티딜에탄올아민 (DMPE), 디팔미토일포스파티딜에탄올아민 (DPPE), 디스테아로일 포스파티딜-에탄올아민 (DSPE), 디올레일포스파티딜-에탄올아민 (DOPE), 디아라키도일포스파티딜에탄올아민 (DAPE), 디리놀에일포스파티딜에탄올아민 (DLPE), 폴리에틸렌글리콜 변형 디미리스토일-포스파티딜에탄올아민 (DMPE-PEG), 폴리에틸렌글리콜 변형 디스테아로일 포스파티딜-에탄올아민 (DSPE-PEG), 폴리에틸렌글리콜 변형 디올레일포스파티딜-에탄올아민 (DOPE-PEG), 폴리에틸렌글리콜 변형 디아라키도일포스파티딜에탄올아민 (DAPE-PEG), 폴리에틸렌글리콜 변형 디리놀에일포스파티딜에탄올아민 (DLPE-PEG), 디미리스토일 포스파티딜세린 (DMPS), 디아라키도일 포스파티딜세린 (DAPS), 디팔미토일 포스파티딜세린 (DPPS), 디스테아로일포스파티딜세린 (DSPS), 디올레오일포스파티딜세린 (DOPS), 디팔미토일 스핑고미엘린 (DPSP) 및 디스테아로일스핑고미엘린 (DSSP) 및 그것의 혼합물 중에서 선택되는 것을 특징으로 하는 방법.
- 제 1 항에 있어서, 양친매성 물질의 유화 조성물은, 총실전하를 갖는 인지질 또는 양친매성 물질을 포함하는 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 인지질의 양은, 유화된 혼합물의 총 중량에 대하여 0.005 중량% 내지 1.0 중량%인 것을 특징으로 하는 방법.
- 제 17 항에 있어서, 인지질의 양은, 유화된 혼합물의 총 중량에 대하여 0.01 중량% 내지 1.0 중량%인 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 인지질은 표적화하는 리간드, 또는 표적화하는 리간드와 함께 반응할 수 있는 보호된 반응기를 포함하는 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 에멀젼은, 리소지질; 지방산 및 그것의 알칼리 또는 알칼리 금속과의 각각의 염; 폴리머를 갖는 지질; 술폰화 단당, 이당, 올리고당, 또는 다당을 갖는 지질; 에테르 또는 에스테르-결합 지방산을 갖는 지질; 중합된 지질; 디아세틸 포스페이트; 디세틸 포스페이트; 스테아릴아민; 세라미드; 폴리옥시에틸렌 지방산 에스테르; 폴리옥시에틸렌 지방 알코올; 폴리옥시에틸렌 지방 알코올 에테르; 폴리옥시에틸화 소르비탄 지방산 에스테르; 글리세롤 폴리에틸렌 글리콜 리시놀레이트; 에톡실화 대두 스테롤; 에톡실화 캐스터 오일; 에틸렌 옥시드 (EO) 및 프로필렌 옥시드 (PO) 블록 코폴리머; 당산의 스테롤 에스테르; 지방산과 당과의 에스테르; 글리세롤과 (C12-C24) 디카르복실 지방산과의 에스테르 및 그것 각각의 알칼리 또는 알칼리-금속 염; 사포닌; 긴 사슬 (C12-C24) 알코올; 6-(5-콜레스텐-3β-일옥시)-1-티오-β-D-갈락토피라노시드; 디갈락토실디글리세라이드; 6-(5-콜레스텐-3β-일옥시)헥실-6-아미노-6-데옥시-1-티오-β-D-갈락토피라노시드; 6-(5-콜레스텐-3β-일옥시)헥실-6-아미노-6-데옥실-1-티오-β-D-만노피라노시드; 12-(((7'-디에틸아미노쿠마린-3-일)카르보닐)메틸아미노)옥타데칸 산; N-[12-(((7'-디에틸아미노쿠마린-3-일)카르보닐)메틸아미노)옥타데카노일]2-아미노팔미트 산; N-숙신일-디올레일포스파티딜에탄올아민; 1-헥사데실-2-팔미토일글리세로-포스포에탄올아민; 팔미토일호모시스테인; 적어도 하나의 (C10-C20) 알킬 사슬을 포함하는 알킬암모늄 염; (C3-C6) 알킬렌 다리를 통해서 N-원자에 결합된, 적어도 하나의 (C10-C20) 아실 사슬을 포함하는 제3차 또는 제4차 암모늄 염: 및 혼합물 또는 그것의 조합물로부터 선택된 양친매성 물질을 더 함유하는 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 단계 a)의 수성-유기 에멀젼은, 동결건조 단계 b) 이전에 세척 단계를 거치는 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 단계 a)의 수성-유기 에멀젼은, 동결건조 단계 b) 이전에 미세여과 단계를 거치는 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 동결 건조 단계 b)이전에 단계 a)에 따라서 얻어진 수성-유기 에멀젼에 양친매성 화합물을 더 포함하는 수성 현탁액을 첨가하여, 상기 양친매성 화합물을 더 포함하는 제 2 수성-유기 에멀젼을 얻는 단계를 더 포함하는 것을 특징으로 하는 방법.
- 제 23 항에 있어서, 상기 수성 현탁액 및 상기 수성-유기 에멀젼의 혼합물을 가열하는 것을 더 포함하는 것을 특징으로 하는 방법.
- 제 23 항에 있어서, 상기 혼합물을 40℃ 내지 80℃의 온도에서 가열하는 것을 특징으로 하는 방법.
- 제 23 항에 있어서, 상기 양친매성 화합물은, PEG-변형 인지질, 반응 부분을 갖는 PEG-변형 인지질, 또는 표적화하는 리간드를 갖는 PEG-변형 인지질인 것을 특징으로 하는 방법.
- 제 1 항 또는 제 2 항에 있어서, 동결건조 단계 b) 이전에 수성-유기 용매를 제어하여 가열하는 것을 더 포함하는 것을 특징으로 하는 방법.
- 제 27 항에 있어서, 상기 제어된 가열은 60℃ 내지 125℃의 온도에서 수행되는 것을 특징으로 하는 방법.
- 제 28 항에 있어서, 상기 제어된 가열은 80℃ 내지 120℃의 온도에서 수행되는 것을 특징으로 하는 방법.
- 제 28 항에 있어서, 상기 에멀젼은 밀폐된 바이알에 담겨있는 것을 특징으로 하는 방법.
- 제 2 항에 있어서, 생적합성 기체는, 공기; 질소; 산소; 이산화탄소; 수소; 일산화질소; 비활성 기체; (C1-C7) 알칸, (C4-C7) 시클로알칸, (C2-C7) 알켄 및 (C2-C7) 알킨을 포함하는 저분자량 탄화수소; 에테르; 케톤; 에스테르; 할로겐화 (C1-C7) 탄화수소, 케톤 또는 에테르; 또는 앞서 언급한 것의 임의의 혼합물 중에서 선택되는 것을 특징으로 하는 방법.
- 제 31 항에 있어서, 할로겐화 탄화수소 기체는 브로모클로로디플루오로-메탄, 클로로디플루오로메탄, 디클로로디플루오로-메탄, 브로모트리플루오로메탄, 클로로트리플루오로메탄, 클로로펜타플루오로에탄, 디클로로테트라플루오로에탄 및 그것의 혼합물 중에서 선택되는 것을 특징으로 하는 방법.
- 제 31 항에 있어서, 할로겐화 탄화수소 기체는 퍼플루오르화 탄화수소인 것을 특징으로 하는 방법.
- 제 33 항에 있어서, 퍼플루오르화 탄화수소 기체는, 퍼플루오로메탄, 퍼플루오로에탄, 퍼플루오로프로판, 퍼플루오로부탄, 퍼플루오로펜탄, 퍼플루오로헥산 또는 퍼플루오로헵탄; 퍼플루오로프로펜, 퍼플루오로부텐, 퍼플루오로부타디엔, 퍼플루오로부트-2-인, 퍼플루오로시클로부탄, 퍼플루오로메틸시클로부탄, 퍼플루오로디메틸시클로부탄, 퍼플루오로트리메틸시클로-부탄, 퍼플루오로시클로펜탄, 퍼플루오로메틸시클로펜탄, 퍼플루오로디메틸시클로-펜탄, 퍼플루오로메틸시클로헥산, 퍼플루오로메틸시클로헥산, 퍼플루오로메틸시클로헥산 또는 그것의 혼합물인 것을 특징으로 하는 방법.
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- 2004-02-03 EP EP04707586A patent/EP1590006B1/en not_active Expired - Lifetime
- 2004-02-03 CN CNB2004800029752A patent/CN100374165C/zh not_active Expired - Lifetime
- 2004-02-03 JP JP2006502384A patent/JP4670083B2/ja not_active Expired - Lifetime
- 2004-02-03 DK DK04707586.6T patent/DK1590006T3/da active
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- 2004-02-03 AT AT04707586T patent/ATE480263T1/de active
- 2004-02-03 RU RU2005127634/15A patent/RU2345793C2/ru active
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Cited By (6)
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KR20150003221A (ko) * | 2012-04-30 | 2015-01-08 | 지이 헬스케어 에이에스 | 용기를 발포성 조성물로 충전시키는 방법 |
KR102157909B1 (ko) * | 2012-04-30 | 2020-09-18 | 지이 헬스케어 에이에스 | 용기를 발포성 조성물로 충전시키는 방법 |
US11045748B2 (en) | 2012-04-30 | 2021-06-29 | Ge Healthcare As | Method for filling a container with a foamable composition |
WO2020138886A1 (ko) * | 2018-12-24 | 2020-07-02 | 서강대학교 산학협력단 | 세포외 소포 기반의 초음파 조영제용 마이크로버블 및 이의 제조방법 |
KR20200079364A (ko) * | 2018-12-24 | 2020-07-03 | 서강대학교산학협력단 | 세포외 소포 기반의 초음파 조영제용 마이크로버블 및 이의 제조방법 |
KR102180629B1 (ko) * | 2018-12-24 | 2020-11-20 | 서강대학교 산학협력단 | 세포외 소포 기반의 초음파 조영제용 마이크로버블 및 이의 제조방법 |
Also Published As
Publication number | Publication date |
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AU2004210221B2 (en) | 2008-11-20 |
RU2005127634A (ru) | 2006-01-20 |
JP4670083B2 (ja) | 2011-04-13 |
IL169677A (en) | 2011-07-31 |
US9364569B2 (en) | 2016-06-14 |
EP1590006B1 (en) | 2010-09-08 |
DE602004029010D1 (de) | 2010-10-21 |
CA2512454C (en) | 2012-10-30 |
ES2352087T3 (es) | 2011-02-15 |
DK1590006T3 (da) | 2010-12-20 |
MXPA05007730A (es) | 2006-01-31 |
CN1744921A (zh) | 2006-03-08 |
RU2345793C2 (ru) | 2009-02-10 |
NO20054089D0 (no) | 2005-09-02 |
KR20050096959A (ko) | 2005-10-06 |
EP1590006A2 (en) | 2005-11-02 |
US20110236320A1 (en) | 2011-09-29 |
CA2512454A1 (en) | 2004-08-19 |
WO2004069284A2 (en) | 2004-08-19 |
ATE480263T1 (de) | 2010-09-15 |
AU2004210221A1 (en) | 2004-08-19 |
US20060034770A1 (en) | 2006-02-16 |
NO331966B1 (no) | 2012-05-14 |
US20130101522A1 (en) | 2013-04-25 |
WO2004069284A3 (en) | 2004-11-25 |
NO20054089L (no) | 2005-10-05 |
US20060051297A1 (en) | 2006-03-09 |
CN100374165C (zh) | 2008-03-12 |
JP2006520754A (ja) | 2006-09-14 |
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