CN1984708B - 微球体 - Google Patents
微球体 Download PDFInfo
- Publication number
- CN1984708B CN1984708B CN200580021966.2A CN200580021966A CN1984708B CN 1984708 B CN1984708 B CN 1984708B CN 200580021966 A CN200580021966 A CN 200580021966A CN 1984708 B CN1984708 B CN 1984708B
- Authority
- CN
- China
- Prior art keywords
- microsphere
- fluid
- manufacture method
- production fluid
- drop
- 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.)
- Expired - Fee Related
Links
- 239000004005 microsphere Substances 0.000 title claims abstract description 72
- 239000012530 fluid Substances 0.000 claims abstract description 58
- 238000004519 manufacturing process Methods 0.000 claims abstract description 53
- 238000000034 method Methods 0.000 claims description 21
- 229920000642 polymer Polymers 0.000 claims description 21
- 239000002775 capsule Substances 0.000 claims description 18
- 238000002347 injection Methods 0.000 claims description 11
- 239000007924 injection Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 9
- 238000001704 evaporation Methods 0.000 claims description 9
- 239000002872 contrast media Substances 0.000 claims description 8
- 230000008020 evaporation Effects 0.000 claims description 8
- 230000005855 radiation Effects 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000003381 stabilizer Substances 0.000 claims description 4
- 239000002131 composite material Substances 0.000 claims description 3
- 239000002405 nuclear magnetic resonance imaging agent Substances 0.000 claims description 3
- 239000004094 surface-active agent Substances 0.000 claims description 3
- 230000008602 contraction Effects 0.000 claims description 2
- 230000002285 radioactive effect Effects 0.000 claims description 2
- 230000002792 vascular Effects 0.000 claims description 2
- 125000003473 lipid group Chemical group 0.000 claims 1
- 239000007788 liquid Substances 0.000 abstract description 39
- 239000000463 material Substances 0.000 abstract description 6
- 239000000470 constituent Substances 0.000 abstract 1
- 239000002245 particle Substances 0.000 description 33
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 22
- 238000004108 freeze drying Methods 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 15
- 238000009826 distribution Methods 0.000 description 14
- 239000004372 Polyvinyl alcohol Substances 0.000 description 13
- KJZYNXUDTRRSPN-UHFFFAOYSA-N holmium atom Chemical compound [Ho] KJZYNXUDTRRSPN-UHFFFAOYSA-N 0.000 description 13
- 229920002451 polyvinyl alcohol Polymers 0.000 description 13
- 229910052689 Holmium Inorganic materials 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000004140 cleaning Methods 0.000 description 7
- LMGZGXSXHCMSAA-UHFFFAOYSA-N cyclodecane Chemical compound C1CCCCCCCCC1 LMGZGXSXHCMSAA-UHFFFAOYSA-N 0.000 description 6
- 229930012538 Paclitaxel Natural products 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000000879 optical micrograph Methods 0.000 description 5
- 229960001592 paclitaxel Drugs 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- 238000005507 spraying Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 5
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000011557 critical solution Substances 0.000 description 4
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 4
- 239000004914 cyclooctane Substances 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229920001432 poly(L-lactide) Polymers 0.000 description 4
- 238000006116 polymerization reaction Methods 0.000 description 4
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 3
- 229920002988 biodegradable polymer Polymers 0.000 description 3
- 239000004621 biodegradable polymer Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 229960004275 glycolic acid Drugs 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229920000747 poly(lactic acid) Polymers 0.000 description 3
- 239000013049 sediment Substances 0.000 description 3
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 229920001244 Poly(D,L-lactide) Polymers 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000002599 functional magnetic resonance imaging Methods 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000012798 spherical particle Substances 0.000 description 2
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical compound CCCCCCCCBr VMKOFRJSULQZRM-UHFFFAOYSA-N 0.000 description 1
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000004567 concrete Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000012809 cooling fluid Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229920006237 degradable polymer Polymers 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 229920000359 diblock copolymer Polymers 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 230000005670 electromagnetic radiation Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000010436 fluorite Substances 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 229920002313 fluoropolymer Polymers 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002412 holmium compounds Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 238000000710 polymer precipitation Methods 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000000287 tissue oxygenation Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229920000428 triblock copolymer Polymers 0.000 description 1
Images
Classifications
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1806—Suspensions, emulsions, colloids, dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
-
- 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
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
- A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
- B01J2/02—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops
- B01J2/06—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops in a liquid medium
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Radiology & Medical Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Physics & Mathematics (AREA)
- Nanotechnology (AREA)
- Dispersion Chemistry (AREA)
- Acoustics & Sound (AREA)
- Optics & Photonics (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
Abstract
一种包含组成材料的生产流体(23)的微球体制造***。该***包括用于容纳接收流体(11)的储液槽(1)。该***还设有喷射模块(2),具有至少一个用于将生产流体喷射到接收流体内的喷嘴(21)。该生产流体包含该组成材料的浓度范围为0.01至5%。最终微球体的成分溶解于该生产流体。由于喷嘴使用的喷墨头置于接收液体/空气界面的表面之下。在该配置中,喷墨液滴无需穿过空气-液体界面,而是将直接注射到接收流体内。
Description
技术领域
本发明涉及由生产流体(production fluid)制造微球体的***。
背景技术
这种***在D.Radulescu等的“Uniform Paclitaxel-loadedbiodegradable microspheres manufactured by ink-jettechnology”,Proc.Recent Adv.in Drug Delivery Sys.(March 2003)文献中已经公知。
这种已知***生产生物可降解的微球体,即,基于喷墨技术的微球体。具体而言,制造了窄尺寸分布和直径受控的装入了紫杉醇(paclitaxel)的PLGA微球体。该已知***采用按需供墨(drop-on-demand)工艺或压力辅助按需供墨,将紫杉醇PLGA喷射到聚乙烯醇水溶液中。已经生产了具有约60μm±1μm的窄尺寸分布的微球体。这些微球体由包含3%PLGA和1.5%紫杉醇的二氯乙烷溶液形成。在形成该溶液的液滴之后,除去二氯乙烷,留下包含PLGA和紫杉醇的混合物的固态粒子。
发明内容
本发明的目标是提供一种***,其能够制造尺寸远小于由已知***生产的微球体尺寸的微球体,并实现窄的尺寸分布。
本发明是基于以下理解,即,从低浓度即0.01%至5%范围开始,根据聚合物单分散,可通过喷墨和随后除去溶剂而形成紧密的聚合物粒子。在0.01至3%的聚合物浓度范围内实现了良好的结果。具体而言,在0.01至2.9%的聚合物浓度范围内实现了单分散微球体的可靠形成。该微球体泡的尺寸非常小,特别地,获得的微球体的尺寸范围为1至15μm,且体积变化小,约3%。典型地,生产的微球体尺寸为5μm。
该生产流体为组成材料(constituting material即,将在溶剂中制成的微球体的材料)的溶液。换而言之,最后的微球体的成分溶解在该生产流体中。例如,可将聚合物或单体溶解于该溶剂内。生产流体中的溶剂在接收流体(receiving fluid)中应该相对于该接收流体具有有限的溶解度。该溶剂将缓慢地扩散到接收流体内并随后蒸发,导致生产流体的液滴的收缩。在约1%的溶解度获得了良好的结果,正如二氯乙烷(DCE)或二氯甲烷(DCM)在水中的情况。
特别是当微球体形成稳定胶体时,可获得微球体的良好的尺寸维持以及尺寸分布,接收流体中存在的聚合物或表面活性剂有助于实现这一点。于是阻碍或防止液滴合并成更大的液滴。在优选实施方案中,该生产液体包含具有高密度的卤化溶剂,例如二氯乙烷,该接收溶液为水溶液。为了缓慢且受控地从液滴除去生产流体,在水中具有低溶解度(对于二氯乙烷,约0.8%)且具有高蒸气压力的卤化溶剂是优选的。最终微球体的成分被溶解于生产流体内。对于将用于活体内(通过静脉注射)的成分,生物可降解聚合物和(改性)磷脂优选作为载体材料,药品和成像剂可结合到该微球体内,并靶向至显示于血管壁上的疾病标记,例如与肿瘤相关的血管生成(angiogenesis)的标记以及易损性斑块(vulnerable plaque)的标记。喷射之后,通过一系列清洗步骤可以除去过量的稳定剂,通过冻干(lyophilization)(冷冻干燥)可以安排除去卤化溶剂的最后残余。
看上去可以获得小尺寸微球体的基本上单分散的分布。将生产流体喷射到接收流体内导致各个微液滴离开喷嘴时更优良的分离。这种制造涉及以相对高的喷射速率将生产流体喷射到接收流体内。发现当生产流体内聚合物浓度低时,液滴收缩成基本上无细孔的聚合物微球体。
由于上述方法形成紧密粒子,还可以形成紧密壳体,因此提供了牢固的液体或气体胶囊。为了实现这一点,还需要使用壳体形成材料的非溶剂改性该生产液体。该生产液体也可以改性成包括磷脂而非聚合物或磷脂与聚合物的组合。
根据本发明另一个方面,用于制造微球体的***设有控制***以控制所述喷射的喷射速率在0.1kHz至100kHz的范围内并以脉冲方式操纵该喷射。该控制***控制对喷射模块施加激励脉冲。矩形脉冲(blockshaped pulse)获得良好的结果,其原因在于可生产体积为零点几n1的略大尺寸的微球体。
根据本发明又一个方面,该喷射***设有几个喷嘴,可分别受控以调整来自相应喷嘴的微泡的尺寸。例如,这些喷嘴受到控制,使得这些喷嘴都产生落在窄尺寸分布内的泡。个别喷嘴的分别控制于是补 偿了喷嘴之间的微小差异。特别地,通过调整施加于喷嘴的电学激励脉冲而实现这一点。具体而言,体积分布的宽度可变窄为约3-5%。采用更多的喷嘴时,单位时间内可以生产更多的微球体。
根据本发明另一个方面,可以形成具有受控孔隙率的微球体。根据本发明又一个方面,储液槽设有温度控制,从而将接收流体冷却到其冷凝温度之下。当接收液体冷却到室温以下,即298K以下时,获得良好的结果。于是,该生产流体以液滴的形式喷射到冷却的接收液体内,并可被存储供稍后使用。当液滴温度上升时,接收流体蒸发并形成填充气体的微球体。另外,催化剂可用于接收液体以引发产生流体的聚合,从而促进形成稳定的微泡。作为使用电磁辐射的备选照射,例如可以采用通过照射模块对离开喷嘴的泡进行紫外线辐射,用于光引发聚合。
在本发明另一个方面,可以利用聚合物的最低临界溶解温度(lower critical solution temperature,LCST)或最高临界溶解温度(upper critical solution temperature,UCST)。当温度上升出现聚合物沉淀时观察到LCST。因此为了生产微球体,接收流体的温度上升到高于LCST,包含该聚合物的溶液在低于LCST的温度下喷射。由于严格定义的液滴内聚合物沉淀,于是形成微球体。当不允许使用卤化接收液体时,或者不期望冻干(冷冻干燥)时,这种方法尤其有利。具有LCST的公知聚合物的示例为聚(N-异丙基丙烯酰胺)(PNiPAAm)。根据所期望的LCST,通过与聚(丙烯酸)或更多的疏水丙烯酸脂共聚合,该聚合物的LCST(约32℃)可以容易地调整为临床应用的相关温度(例如低于或高于37℃)。
当液滴喷射到空气中而非直接喷射到接收液体内时,于是采用从液滴喷嘴的长的飞行路径,例如几厘米,也可以导致形成微球体。
根据本发明的一个方面,喷墨头置于接收液体/空气界面的表面之下。在该配置中,喷射的液滴无需穿过该空气-液体界面,而是将直接注射到接收流体内。使用这种配置,接收液体中存在的聚合物或表面活性剂的稳定作用将被优化,从而导致生产流体液滴在接收液体中的稳定乳化。备选地,稳定剂可以添加到生产流体,合适的稳定剂为磷脂。浸渍喷墨的附加优点为,不会产生与接收液体的表面特性相关联的问题。良好的乳化和喷射稳定性由具有不同密度的生产流体与接 收液体支持。如果生产流体的密度高于接收液体且喷射沿重力的方向,则该液滴将继续以其沉降速度(sedimentation velocity)下沉到容器底部,从容器底部可以容易地收集该液滴。在备选设置中,生产流体密度小于接收液体,液滴沿一方向喷射使得液滴浮向接收液体表面而不返回朝向喷嘴。随后可在接收液体的表面收集形成的微球体。
本发明还涉及超声造影剂。使用非球面微液滴作为超声造影剂本身从美国专利US 5606973中已经公知。本发明的超声造影剂包括填充了气体的基本上单分散微泡或者填充了碳氟化合物液体的单分散微球体。该微泡不仅改变超声的反射,还能够在超声场内共振产生谐波。这种单分散造影剂以靶向造影剂的形式应用特别有利。靶向造影剂选择性地结合到特殊受体,例如粘附到管壁组织。选择性结合微泡的谐振频率相对于未结合微泡发生偏移。微泡的单分散分布导致这些谐振的谱线宽度窄,且因此该频移可被探测。因此,结合造影剂可以与未结合造影剂精确区分。
可以由包含卤化溶剂的生产流体、形成生物可降解聚合物的低浓度壳体、通过冻干可除去的分子量不太高的第二非极性液体来制备这种填充气体的泡。生物可降解聚合物选择为不溶于接收液体,而且如果卤化溶剂扩散到接收液体内之后通过蒸发而消失,则也不溶于生产流体。当冻干时,第二非极性溶剂通过升华被除去,留下空的粒子。
可用于本发明的典型生物可降解聚合物为生物高聚物,例如右旋糖酐和蛋白素,或者合成聚合物,例如聚(L-丙交酯酸)(PLA)以及特定的聚甲基丙烯酸甲脂,聚己内酯,聚羟基乙酸。其中尤其重要的是组合了两种聚合物嵌段(例如疏水和亲水嵌段)性能的所谓嵌段共聚物。随机共聚物实例为聚乳酸和乙醇酸的共聚物(poly(L-lactic-glycolic-acid),PLGA)和聚(d-乳酸-1-乳酸)[poly(d-lactic-1-lactic acid)Pd,1LA]。双嵌段共聚物的实例为聚(乙二醇)-聚(L-丙交酯)(PEG-PLLA)、聚(乙二醇)-聚(N-异丙基丙烯酰胺)(PEG-PNiPAAm)和聚环氧乙烷-聚环氧丙烷(PEO-PPO)。三嵌段共聚物的实例为聚环氧乙烷-聚环氧丙烷-聚环氧乙烷(PEO-PPO-PEO)。
当在生产流体中采用例如具有氟化端基(例如C6F14)的L-聚丙交酯(L-polylactide)的聚合物时,可获得良好的结果。对于制备中空胶囊,这是特别有利的。如果胶囊内部是疏水的,将不存在水蒸汽 冷凝在胶囊内壁上的趋势。因此,胶囊将不会被水填充,而是长时间保持被空气填充,对于超声造影剂这是期望的。将含氟的基团(fluorcontaing group)结合到聚合物中增大了胶囊内壁的疏水性,并因此抑制冷凝。此外,结合包含氟石的基团可形成水与极性溶质的更有效的扩散势垒。
从这种生产液体得到微球体具有非常良好的不透水性。这种氟化聚合物的合成本身从美国专利US 6329470已知。
通过改变聚合物性能、凝胶转变温度以及由该材料制成的膜发生破裂之前的最大延伸的重要参数,可以调整壳体的弹性。
填充了液体(例如氟化液体,诸如全氟溴-辛烷)的微球体,不仅可对于超声有益,而且对于功能磁共振成像(fMRI)有益。在Proc.Intl.Soc.mag.Reson.Med.9(2001)659-660中公开了fMRI技术。具体而言,基于核19F,可以进行组织充氧作用、氟化癌症药品的药物动力学的磁共振谱测量,其本身如Proc.Intl.Soc.mag.Reson.Med.9(2001)497所述。可以按照上述方法制备,不同的是选择包含氟基的非极性液体以及在冻干时不除去该液体。
微球体也可以被药品填充;药品可溶解于油中,并将形成具有液体核心的微球体,或者在冻干之后将微球体暴露于包含气体的气相药品,由此可以结合入气相药品。药品可用于受控释放,例如通过超声脉冲释放以实现局部供给。当使用靶向微球体时,将最为有效。
药品也可以结合到(另外的)紧密微球体。特别是,放射性化合物,例如用于治疗肝脏恶性肿瘤的(活性/螯合(activated/chelated))钬化合物是有用的。例如,钬起着磁共振造影剂的功能,其诱导T1与T2对比(contrast)。此外,通过使用中子照射可以使钬为放射性。钬的放射性同位素发射β辐射(高能电子)以及γ辐射。B辐射可在治疗上用于局部消灭肿瘤,而作为磁共振造影剂的活性使得可以监视该放射性钬的正确的局部应用。另外,γ发射可被伽马照相机探测以对施加了钬的解剖位置成像。具有非放射性钬的微球体首先形成,随后通过使用中子照射将钬转换成微球体内的放射性钬同位素。应当直到钬放射性消失才释放钬。粒子应该足够大以被俘获于毛细血管床中,且精细微球体不能在血液内循环。为此,需要严格控制的合成。
微球体的典型尺寸取决于具体应用。优选尺寸范围为1至100μm。例如,用于US成像作为血池剂的微球体的最优选直径为1至10μm。 用于钬胶囊微球体的最优选直径为15至40μm。
附图说明
参考详细示例并参考附图,将对本发明的这些与其他方面进行进一步的详细描述。
图1示出了本发明的微泡制造***的示意性图示;
图2示出了使用PVA清洗之后喷墨粒子的尺寸分布,给出了1μm类别粒子的百分比;
图3示出了根据下述示例1所述工艺获得的PLA粒子的SEM图片;以及
图4示出了来自示例7(0.1%PLGA)和8(0.1%PLGA,0.3%环辛烷)的尺寸分布;
图5示出了模型直径(model diameter)为4.7μm的由L聚丙交酯制成的微球体的示例;
图6示出了模型直径为4.5μm的由L聚丙交酯制成的微球体的示例。
具体实施方式
图1示出了本发明的微泡制造***的示意性图示。该微泡制造***包括容纳接收流体11的储液槽1。喷射***2包括喷嘴21,以将生产流体23的喷射液滴喷射到接收流体内。喷嘴21设有对喷嘴施加压力脉冲的压电***22以产生液滴24,微球体25由该液滴24形成且在本示例中聚集在储液槽1的底部。例如,喷嘴21可配置喷墨头。
喷射***2还设有对压电***22施加电学脉冲的控制单元3。控制单元按照这种方式控制喷射***的工作以产生生产流体的液滴。
此外,在本示例中以套筒4的形式提供冷却***4,冷却流体例如水通过该套筒从入口41流到出口42。冷却***工作以将接收液体冷却到室温以下。
此外,该微泡制造***设有紫外线辐射源5,对来自喷嘴的生产流体液滴发射紫外线辐射(脉冲)束以导致液滴内聚合的光引发,由此形成微球体。
示例:
示例1,制备10mm PLA粒子
喷射1%PLA(聚-DL-丙交酯,Aldrich)的二氯乙烷溶液,在将喷墨头浸渍到荧光液池(fluorescence cuvet)内1%PVA(15/79)水溶液后立即开始。穿过液池观察到初始液滴直径约为50μm,对应于6.5×10-14m3的液滴体积。以1500Hz喷墨20分钟之后,停止该工艺。沉淀物再分散并转移到玻璃样品瓶,并搅拌一小时以除去二氯乙烷。使用滤过(200nm)的去离子水清洗粒子三次。取样品进行显微检查,显示出直径约10μm的严格分散的球形粒子。使用20×物镜以及IMAGE PROPLUS软件分析平均直径,从显微检查获得的尺寸分布示于图2。将该样品冷冻干燥48小时,并存储于-20℃。在再分散在过滤的去离子水中且干燥并沉积3nm Pd/Pt层之后得到的SEM图片示出了10.2±0.3μm的粒子尺寸,对应于5.6×10-16m3的粒子体积。由于二氯乙烷和PLA的密度近似相等,初始和最后尺寸之间的体积比率证明已经以低的孔隙率制备成了PLA粒子。所生产的粒子的SEM图片示于图3。
示例2,制备18mm PLA粒子
喷射3%PLA(聚-DL-丙交酯,Aldrich)的二氯乙烷溶液,在将喷墨头浸渍到荧光液池内1%PVA水溶液后立即开始。以1500Hz喷墨20分钟之后,停止该工艺。沉淀物再分散并转移到玻璃样品瓶,并搅拌一小时以除去二氯乙烷。使用滤过(200nm)的去离子水清洗粒子三次。取样品进行显微检查,显示出直径约18μm的严格分散的单分散球形粒子。冷冻干燥不改变粒子尺寸。初始液滴体积和最后粒子尺寸之间的体积比率为20,该比率为形成完全紧密的聚合物粒子时5%溶液的期望值。这表明由3%溶液制成的这种制备粒子中存在残余孔隙率。
示例3,制备PLGA粒子
喷射3%PLGA(poly(DL-lactic-co-glycolic(75∶25),Aldrich)的二氯乙烷溶液,在将喷墨头浸渍到荧光液池内1%PVA水溶液后立即开始。以1500Hz喷墨20分钟之后,停止该工艺。沉淀物再分散并转移到玻璃样品瓶,并搅拌一小时以除去二氯乙烷。使用滤过(200nm)的去离子水清洗粒子三次。取样品进行显微检查,显示出直径约18μm的严格分散的单分散球形粒子。冷冻干燥不改变粒子尺寸。初始液滴体积和最后粒子尺寸之间的体积比率为20,该比率为形成完 全紧密的聚合物粒子时5%溶液的期望值。这表明由3%溶液制成的这种制备粒子中存在残余孔隙率。
示例4,使用连续喷墨制备PLGA粒子
制备1%PLA的二氯乙烷溶液,并以14kHz的频率使用50μm的喷嘴将其喷墨到1%PVA 15/79的水溶液中。在蒸发二氯乙烷、清洗和冷冻干燥之后,使用光学显微图片进行图像分析定量时,形成的粒子的平均直径为15.3μm,标准偏差为2.7μm。
示例5,制备装入有乙酰丙酮化钬的PLA粒子
以14kHz的频率使用50μm的喷嘴将1%PLA,0.02%乙酰丙酮化钬的二氯乙烷溶液喷墨到1%PVA(15/79)的水溶液中。在蒸发二氯乙烷、清洗和冷冻干燥之后,使用光学显微图片进行图像分析定量时,形成的粒子的平均直径为15.7μm,标准偏差为2.6μm。
示例6,通过连续喷墨制备12mm PLGA粒子
制备1%PLGA(75%乳酸,25%羟基乙酸)的二氯乙烷溶液,并以14kHz的频率使用50μm的喷嘴将其喷墨到1%PVA 15/79溶液中。在蒸发二氯乙烷、清洗和冷冻干燥之后,使用光学显微图片进行图像分析定量时,形成的粒子的平均直径为12.5μm,标准偏差为2.3μm。
示例7,通过连续喷墨制备7mm PLGA粒子
制备0.1%PLGA(75%乳酸,25%羟基乙酸)的二氯乙烷溶液,并以14kHz的频率使用50μm的喷嘴将其喷墨到1%PVA 15/79溶液中。在蒸发二氯乙烷、清洗和冷冻干燥之后,使用光学显微图片进行图像分析定量时,形成的粒子的平均直径为6.8μm,标准偏差为1.3μm。尺寸分布示于图4。
示例8,制备11微米聚合物壳体胶囊
制备0.1%PLGA和0.3%环辛烷的二氯乙烷溶液,并以14kHz的频率使用50μm的喷嘴将其喷墨到0.1%PVA 40/88溶液中。蒸发二氯乙烷,使用预先使用环辛烷饱和的水清洗样品,并冷冻干燥样品。使 用光学显微图片进行图像分析定量时,形成的胶囊的直径为11.2μm,标准偏差为1.8μm,其尺寸分布示于图4。从SEM图片推知,胶囊具有包含单一腔体的平滑表面。
示例9,制备脂质糖衣胶囊
将0.1%PLGA、0.3%环辛烷、0.005%粗磷脂(asolectin)的二氯乙烷溶液以12kHz的频率使用50μm的喷嘴喷墨到PVA 15/79水溶液中。蒸发二氯乙烷,清洗样品并冷冻干燥样品,使用SEM观察到直径为7.5μm的平滑胶囊,呈现单个中空核。
示例10
具有C6F14端基的L-聚丙交酯在存在0.01%环癸烷时以0.01%的浓度溶解于二氯乙烷。以23,000Hz的频率使用50μm的喷嘴通过在0.3%PVA中浸渍喷墨,形成了初始直径约85μm的液滴。通过一夜的反复清洗和搅拌,液滴收缩形成填充了环癸烷的胶囊,模型直径为4.7μm。在Coulter Counter上测量尺寸分布,结果示于图5。样品被冻干以除去环癸烷的核。在除去以及再分散之后的尺寸分布未改变,如图5所示。对再分散样品的显微检查示出了填充了气体的胶囊。曝光于超声时,可以探测到该气体的逃逸。
示例11
具有C6F14端基的L-聚丙交酯在存在0.01%环癸烷时以0.005%的浓度溶解于二氯乙烷。以23,000Hz的频率使用50μm的喷嘴通过在0.3%PVA中浸渍喷墨,形成了初始直径约85μm的液滴。通过一夜的反复清洗和搅拌,液滴收缩形成填充了环癸烷的胶囊,模型直径为4.5μm。在Coulter Counter上测量尺寸分布,结果示于图6。样品被冻干以除去环癸烷的核。在除去以及再分散之后的尺寸分布几乎没有改变,如图6所示。对再分散样品的显微检查示出了填充了气体的胶囊。曝光于超声时,可以探测到该气体的逃逸。
Claims (13)
1.一种微球体制造方法,所述微球体为包含组成材料的生产流体(23)的微球体,所述方法包括:
由储液槽(1)容纳接收流体(11),
通过具有至少一个喷嘴(21)的喷射模块(2)将所述生产流体的液滴喷射到所述接收流体内,其中
所述生产流体包含所述组成材料的浓度范围为0.01%至5%,并且所述生产流体中的溶剂在接收流体中相对于该接收流体具有有限的溶解度,并适于扩散到接收流体内并随后蒸发,导致所述生产流体的液滴的收缩。
2.如权利要求1所述的微球体制造方法,包括通过控制***控制所述喷射的喷射速率在0.1kHz至100kHz的范围内。
3.如权利要求2所述的微球体制造方法,其中所述喷射被控制成以脉冲方式操作。
4.如权利要求2所述的微球体制造方法,其中:
所述喷射模块包括数个喷嘴,以及
所述控制***布置成调整个别喷嘴的液滴尺寸。
5.如权利要求1所述的微球体制造方法,其中所述储液槽设有温度控制***。
6.如权利要求1所述的微球体制造方法,包括通过照射模块以使用紫外辐射照射所述微球体。
7.如权利要求1所述的微球体制造方法,其中所述微球体的飞行路径经过一定距离从所述喷嘴延伸到所述接收流体。
8.如权利要求1所述的微球体制造方法,其中所述接收流体和/或所述生产流体包含选自脂质、表面活性剂、聚合物的组的稳定剂。
9.一种超声造影剂,包括根据权利要求1-8之任一的微球体制造方法制造的单分散微球体。
10.如权利要求9所述的超声造影剂,靶向至脉管***内的具***置。
11.一种磁共振造影剂,包括根据权利要求1-8之任一的微球体制造方法制造的单分散微球体。
12.一种胶囊药品,包括根据权利要求1-8之任一的微球体制造方法制造的单分散微球体,其装有药物活性化合物。
13.一种胶囊治疗化合物,包括根据权利要求1-8之任一的微球体制造方法制造的单分散微球体,其装有放射性化合物或者具有放射性同位素的化合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04103038 | 2004-06-29 | ||
EP04103038.8 | 2004-06-29 | ||
PCT/IB2005/052098 WO2006003581A1 (en) | 2004-06-29 | 2005-06-24 | System for manufacturing micro-spheres |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1984708A CN1984708A (zh) | 2007-06-20 |
CN1984708B true CN1984708B (zh) | 2014-01-29 |
Family
ID=34970671
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200580021966.2A Expired - Fee Related CN1984708B (zh) | 2004-06-29 | 2005-06-24 | 微球体 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20080019904A1 (zh) |
EP (1) | EP1763397A1 (zh) |
JP (1) | JP5068646B2 (zh) |
CN (1) | CN1984708B (zh) |
WO (1) | WO2006003581A1 (zh) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007014876A (ja) * | 2005-07-07 | 2007-01-25 | Nippon Kayaku Co Ltd | 微粒体型硬化触媒の製造方法 |
US8257338B2 (en) * | 2006-10-27 | 2012-09-04 | Artenga, Inc. | Medical microbubble generation |
JP2009524602A (ja) * | 2006-01-24 | 2009-07-02 | コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ | ガスコア及びシェルを含む粒子の製造方法、並びにその方法で得られる粒子 |
AU2007226258A1 (en) * | 2006-03-10 | 2007-09-20 | Mcgill University | Ultrasound molecular sensors and uses thereof |
JP5628037B2 (ja) * | 2007-10-12 | 2014-11-19 | フィオ コーポレイション | 濃縮されたミクロビーズを形成するためのフローフォーカシング方法及びシステム、並びにそのシステムに形成されたミクロビーズ |
EP2055299A1 (en) | 2007-10-23 | 2009-05-06 | Koninklijke Philips Electronics N.V. | Methods for preparing polymer microparticles |
WO2009053885A2 (en) | 2007-10-23 | 2009-04-30 | Koninklijke Philips Electronics N.V. | Methods for preparing polymer microparticles |
GB2455143A (en) * | 2007-11-30 | 2009-06-03 | Ct Angewandte Nanotech Can | Preparation of emulsions using inkjet technology |
EP2103313A1 (en) * | 2008-03-19 | 2009-09-23 | Koninklijke Philips Electronics N.V. | Method for the synthesis of hollow spheres |
EP2318086B1 (en) * | 2008-07-23 | 2016-04-13 | Koninklijke Philips N.V. | Ultrasound mediated drug delivery |
GB2469087A (en) * | 2009-04-02 | 2010-10-06 | Ct Angewandte Nanotech Can | Preparation of colloidal dispersion |
WO2011135275A1 (en) * | 2010-04-29 | 2011-11-03 | Imperial Innovations Limited | Method and microbubbles for detecting atherosclerotic plaque |
GB201016436D0 (en) | 2010-09-30 | 2010-11-17 | Q Chip Ltd | Method of making solid beads |
GB201016433D0 (en) | 2010-09-30 | 2010-11-17 | Q Chip Ltd | Apparatus and method for making solid beads |
JP2014517371A (ja) * | 2011-04-11 | 2014-07-17 | インテル コーポレイション | 個人向け広告を選択するシステム及び方法 |
US20140294944A1 (en) | 2013-03-28 | 2014-10-02 | Kimberly-Clark Worldwide, Inc. | Microencapsulation of oxygen liberating reactants |
GB2551944B (en) * | 2015-12-18 | 2021-09-01 | Midatech Pharma Wales Ltd | Microparticle production process and apparatus |
EP3471705A1 (en) | 2016-06-20 | 2019-04-24 | Virbac | Method and apparatus for preparing a micro-particles composition |
KR102613626B1 (ko) * | 2017-05-21 | 2023-12-15 | 엘지전자 주식회사 | 유체조성물 제조 장치 |
CN110833802A (zh) * | 2018-08-15 | 2020-02-25 | 漯河医学高等专科学校 | 一种γ射线辐照制备磁性淀粉微球的方法 |
CN114082376B (zh) * | 2022-01-10 | 2022-04-22 | 烟台科立化工设备有限公司 | 一种聚合物微球生产装置及生产方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6110444A (en) * | 1994-03-01 | 2000-08-29 | Nycomed Imaging As | Gas-containing microcapsules useful as contrast agents for diagnostic imaging |
US6368586B1 (en) * | 1996-01-26 | 2002-04-09 | Brown University Research Foundation | Methods and compositions for enhancing the bioadhesive properties of polymers |
US20020160109A1 (en) * | 2000-12-13 | 2002-10-31 | Yoon Yeo | Microencapsulation of drugs by solvent exchange |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4389330A (en) * | 1980-10-06 | 1983-06-21 | Stolle Research And Development Corporation | Microencapsulation process |
JPS607931A (ja) * | 1983-06-24 | 1985-01-16 | Suriibondo:Kk | マイクロカプセルの製造方法 |
JPS61274738A (ja) * | 1985-05-29 | 1986-12-04 | Mitsui Toatsu Chem Inc | マイクロカプセル |
JPH0558882A (ja) * | 1991-09-04 | 1993-03-09 | Yoshiaki Kawashima | ナノカプセルの製造法 |
GB9221329D0 (en) * | 1992-10-10 | 1992-11-25 | Delta Biotechnology Ltd | Preparation of further diagnostic agents |
JPH0775728A (ja) * | 1993-06-18 | 1995-03-20 | Suzuki Yushi Kogyo Kk | 無機質均一微小球体の製造方法 |
US5540909A (en) * | 1994-09-28 | 1996-07-30 | Alliance Pharmaceutical Corp. | Harmonic ultrasound imaging with microbubbles |
US6139819A (en) * | 1995-06-07 | 2000-10-31 | Imarx Pharmaceutical Corp. | Targeted contrast agents for diagnostic and therapeutic use |
US5606973A (en) | 1995-06-07 | 1997-03-04 | Molecular Biosystems, Inc. | Liquid core microdroplets for ultrasound imaging |
US5873811A (en) * | 1997-01-10 | 1999-02-23 | Sci-Med Life Systems | Composition containing a radioactive component for treatment of vessel wall |
WO1998048783A1 (en) * | 1997-04-30 | 1998-11-05 | Point Biomedical Corporation | Microparticles useful as ultrasonic contrast agents and for delivery of drugs into the bloodstream |
DE19800294A1 (de) * | 1998-01-07 | 1999-07-08 | Mueller Schulte Detlef Dr | Induktiv aufheizbare magnetische Polymerpartikel sowie Verfahren zur Herstellung und Verwendung derselben |
DE19925311B4 (de) * | 1999-05-27 | 2004-06-09 | Schering Ag | Mehrstufen-Verfahren zur Herstellung von gasgefüllten Mikrokapseln |
US6329470B1 (en) * | 1999-09-30 | 2001-12-11 | The Research Foundation Of State University Of New York | Fluorocarbon end-capped polymers and method of synthesis |
JP4029252B2 (ja) * | 2000-02-24 | 2008-01-09 | セイコーエプソン株式会社 | マイクロカプセルの製造方法、および表示デバイスの製造方法 |
DE10105156A1 (de) * | 2001-02-06 | 2002-08-22 | Bruske Frank | Verfahren und Vorrichtung zur Herstellung von Teilchen aus flüssigen Ausgangsmedien |
US6919068B2 (en) * | 2002-05-17 | 2005-07-19 | Point Biomedical Corporation | Method of preparing gas-filled polymer matrix microparticles useful for echographic imaging |
-
2005
- 2005-06-24 CN CN200580021966.2A patent/CN1984708B/zh not_active Expired - Fee Related
- 2005-06-24 US US11/570,787 patent/US20080019904A1/en not_active Abandoned
- 2005-06-24 WO PCT/IB2005/052098 patent/WO2006003581A1/en active Application Filing
- 2005-06-24 JP JP2007518767A patent/JP5068646B2/ja not_active Expired - Fee Related
- 2005-06-24 EP EP05749229A patent/EP1763397A1/en not_active Ceased
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6110444A (en) * | 1994-03-01 | 2000-08-29 | Nycomed Imaging As | Gas-containing microcapsules useful as contrast agents for diagnostic imaging |
US6368586B1 (en) * | 1996-01-26 | 2002-04-09 | Brown University Research Foundation | Methods and compositions for enhancing the bioadhesive properties of polymers |
US20020160109A1 (en) * | 2000-12-13 | 2002-10-31 | Yoon Yeo | Microencapsulation of drugs by solvent exchange |
Also Published As
Publication number | Publication date |
---|---|
EP1763397A1 (en) | 2007-03-21 |
JP5068646B2 (ja) | 2012-11-07 |
US20080019904A1 (en) | 2008-01-24 |
JP2008504950A (ja) | 2008-02-21 |
CN1984708A (zh) | 2007-06-20 |
WO2006003581A1 (en) | 2006-01-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1984708B (zh) | 微球体 | |
Yeo et al. | AC electrospray biomaterials synthesis | |
US7537803B2 (en) | Polymer coating/encapsulation of nanoparticles using a supercritical antisolvent process | |
JP5984903B2 (ja) | 微粒子を調製する乳剤基調プロセス、及び、プロセスで利用されるワークヘッド構造体 | |
KR100477857B1 (ko) | 이미지형성제로사용되는마이크로캡슐화된불소첨가가스 | |
ES2223080T5 (es) | Gases microencapsulados en un polimero y un lipido para utilizacion como agentes de visualizacion. | |
Böhmer et al. | Preparation of monodisperse polymer particles and capsules by ink-jet printing | |
Chang et al. | Controlling the thickness of hollow polymeric microspheres prepared by electrohydrodynamic atomization | |
Pareta et al. | A novel method for the preparation of biodegradable microspheres for protein drug delivery | |
JP6117699B2 (ja) | 固体ビーズを作製するための方法 | |
JP5733981B2 (ja) | ポリマー微粒子を調製する方法及びデバイス | |
TWI246426B (en) | Microencapsulated fluorinated gases for use as imaging agents | |
JP2009502772A (ja) | 生体内の薬物の送達用の方法及びシステム | |
JP4967101B2 (ja) | 中空マイクロカプセルの製造方法 | |
JP5220263B2 (ja) | 集束音響エネルギーを使用して形成される液滴からの固体粒子の沈殿 | |
US6998074B1 (en) | Method for forming polymer microspheres | |
JP2004532102A (ja) | 集中音響エネルギーを使用する薬剤粒子の生成 | |
Kim et al. | Golf ball-shaped PLGA microparticles with internal pores fabricated by simple O/W emulsion | |
JP2005538835A5 (zh) | ||
US20050191357A1 (en) | Method of manufacturing chemical-containing composite particles | |
WO2005061095A9 (ja) | 微小球体の製造方法およびその製造装置 | |
US20100221190A1 (en) | Method for producing a particle comprising a gas core and a shell and particles thus obtained | |
JP2006193518A (ja) | 新規なコア−シェル構造体 | |
KR20150083841A (ko) | 치료제의 서방을 위한 다층 생분해성 미세입자 | |
Zhang | Investigation of single-needle and multi-needle electrohydrodynamic processes for the preparation of drug loaded particles |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140129 Termination date: 20170624 |