DE4127442C2 - Aqueous dispersion of fluorocarbon-containing phospholipid vesicles and a process for their preparation - Google Patents
Aqueous dispersion of fluorocarbon-containing phospholipid vesicles and a process for their preparationInfo
- Publication number
- DE4127442C2 DE4127442C2 DE4127442A DE4127442A DE4127442C2 DE 4127442 C2 DE4127442 C2 DE 4127442C2 DE 4127442 A DE4127442 A DE 4127442A DE 4127442 A DE4127442 A DE 4127442A DE 4127442 C2 DE4127442 C2 DE 4127442C2
- Authority
- DE
- Germany
- Prior art keywords
- fluoro
- phospholipid
- fluorocarbons
- transporting
- aqueous dispersion
- 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
- 150000003904 phospholipids Chemical class 0.000 title claims description 36
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 title claims description 21
- 239000006185 dispersion Substances 0.000 title claims description 20
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 3
- 229940067631 phospholipid Drugs 0.000 claims description 36
- 239000002245 particle Substances 0.000 claims description 17
- -1 fluoroalkyl halides Chemical class 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 125000001931 aliphatic group Chemical group 0.000 claims description 7
- GTNQBWBQOQZNCY-UHFFFAOYSA-N N-butyl-N-(fluoromethyl)butan-1-amine Chemical compound FCN(CCCC)CCCC GTNQBWBQOQZNCY-UHFFFAOYSA-N 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000003367 polycyclic group Chemical group 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- CNCUKGDUDOASDV-UHFFFAOYSA-N 1-bromo-6-fluorohexane Chemical compound FCCCCCCBr CNCUKGDUDOASDV-UHFFFAOYSA-N 0.000 claims description 3
- RTFARVWMEFHIKS-UHFFFAOYSA-N 1-bromo-8-fluorooctane Chemical compound FCCCCCCCCBr RTFARVWMEFHIKS-UHFFFAOYSA-N 0.000 claims description 3
- PNCADGVKAQUIHO-UHFFFAOYSA-N 1-butyl-1-fluorocyclohexane Chemical compound CCCCC1(F)CCCCC1 PNCADGVKAQUIHO-UHFFFAOYSA-N 0.000 claims description 3
- ICGUOIOKPHPFEE-UHFFFAOYSA-N 4a-fluoro-2-(methoxymethyl)-3,5,6,7,8,8a-hexahydro-2H-benzo[b][1,4]dioxine Chemical compound FC12OCC(OC2CCCC1)COC ICGUOIOKPHPFEE-UHFFFAOYSA-N 0.000 claims description 3
- GPLDLLBWLQHNBR-UHFFFAOYSA-N 4a-fluoro-3,5,6,7,8,8a-hexahydro-2H-benzo[b][1,4]dioxine Chemical compound FC12OCCOC2CCCC1 GPLDLLBWLQHNBR-UHFFFAOYSA-N 0.000 claims description 3
- ACQBVZAMLLRZGK-UHFFFAOYSA-N FCCCCC=CCCCCF Chemical compound FCCCCC=CCCCCF ACQBVZAMLLRZGK-UHFFFAOYSA-N 0.000 claims description 3
- LHAHSKRENHEOMW-UHFFFAOYSA-N FCCCCCCC=CCCCCCCF Chemical compound FCCCCCCC=CCCCCCCF LHAHSKRENHEOMW-UHFFFAOYSA-N 0.000 claims description 3
- 229920001774 Perfluoroether Polymers 0.000 claims description 3
- 125000002723 alicyclic group Chemical group 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- IVILBNIXEFKQHQ-UHFFFAOYSA-N 1-fluoro-1,2,3,4,4a,5,6,7,8,8a-decahydronaphthalene Chemical compound C1CCCC2C(F)CCCC21 IVILBNIXEFKQHQ-UHFFFAOYSA-N 0.000 claims description 2
- DHIVLKMGKIZOHF-UHFFFAOYSA-N 1-fluorooctane Chemical compound CCCCCCCCF DHIVLKMGKIZOHF-UHFFFAOYSA-N 0.000 claims description 2
- FLGIOHXLEHCGFP-UHFFFAOYSA-N 2-(ethoxymethyl)-4a-fluoro-3,5,6,7,8,8a-hexahydro-2H-benzo[b][1,4]dioxine Chemical compound FC12OCC(OC2CCCC1)COCC FLGIOHXLEHCGFP-UHFFFAOYSA-N 0.000 claims description 2
- OMOKZDMIEJKZMB-UHFFFAOYSA-N C(CC)N(CCC)CCC.[F] Chemical compound C(CC)N(CCC)CCC.[F] OMOKZDMIEJKZMB-UHFFFAOYSA-N 0.000 claims description 2
- VZGNSQIEHPIHBA-UHFFFAOYSA-N n,n-dibutyl-4-fluorobutan-1-amine Chemical compound CCCCN(CCCC)CCCCF VZGNSQIEHPIHBA-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- AVXHQHTVWBYGRM-UHFFFAOYSA-N 1-(fluoromethyl)-1,2,3,4,4a,5,6,7,8,8a-decahydronaphthalene Chemical compound C1CCCC2C(CF)CCCC21 AVXHQHTVWBYGRM-UHFFFAOYSA-N 0.000 claims 1
- DZYFBBJAYTVNSC-UHFFFAOYSA-N CCCCCCCCCCCC.[F] Chemical compound CCCCCCCCCCCC.[F] DZYFBBJAYTVNSC-UHFFFAOYSA-N 0.000 claims 1
- 239000000839 emulsion Substances 0.000 description 15
- 239000003995 emulsifying agent Substances 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 9
- 239000000787 lecithin Substances 0.000 description 7
- 235000010445 lecithin Nutrition 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229950011087 perflunafene Drugs 0.000 description 6
- UWEYRJFJVCLAGH-IJWZVTFUSA-N perfluorodecalin Chemical compound FC1(F)C(F)(F)C(F)(F)C(F)(F)[C@@]2(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[C@@]21F UWEYRJFJVCLAGH-IJWZVTFUSA-N 0.000 description 6
- 125000003709 fluoroalkyl group Chemical group 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000003633 blood substitute Substances 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 239000008347 soybean phospholipid Substances 0.000 description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 229940067606 lecithin Drugs 0.000 description 3
- JVNBJLUJOYZINW-UHFFFAOYSA-N 1-chloro-8-fluorooctane Chemical compound FCCCCCCCCCl JVNBJLUJOYZINW-UHFFFAOYSA-N 0.000 description 2
- BRKHZWFIIVVNTA-UHFFFAOYSA-N 4-cyclohexylmorpholine Chemical class C1CCCCC1N1CCOCC1 BRKHZWFIIVVNTA-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- VVMSRLPWMJZWBK-UHFFFAOYSA-N CC1CCCC2CCCCC12.[F] Chemical group CC1CCCC2CCCCC12.[F] VVMSRLPWMJZWBK-UHFFFAOYSA-N 0.000 description 2
- JPDVBFJZKJAKKA-UHFFFAOYSA-N FC(CCCC1)N1C1CCCCC1 Chemical class FC(CCCC1)N1C1CCCCC1 JPDVBFJZKJAKKA-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008344 egg yolk phospholipid Substances 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- 229950004354 phosphorylcholine Drugs 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- ASWBNKHCZGQVJV-UHFFFAOYSA-N (3-hexadecanoyloxy-2-hydroxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C ASWBNKHCZGQVJV-UHFFFAOYSA-N 0.000 description 1
- YHYBNVZCQIDLSQ-UHFFFAOYSA-N 1-fluorododecane Chemical group CCCCCCCCCCCCF YHYBNVZCQIDLSQ-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- UZFAMHCDHZHCEF-UHFFFAOYSA-N 3-fluoro-n,n-dipropylpropan-1-amine Chemical compound CCCN(CCC)CCCF UZFAMHCDHZHCEF-UHFFFAOYSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- FPMPBINKVBGAOK-UHFFFAOYSA-N C(CCC)N(C)CCCC.[F] Chemical group C(CCC)N(C)CCCC.[F] FPMPBINKVBGAOK-UHFFFAOYSA-N 0.000 description 1
- NFTATWYPMLQYMJ-UHFFFAOYSA-N C1CCCC2CCCCC12.[F] Chemical group C1CCCC2CCCCC12.[F] NFTATWYPMLQYMJ-UHFFFAOYSA-N 0.000 description 1
- DUPHBYMRRUVOKT-UHFFFAOYSA-N CCN(CCOC1)C1(OC1CCCCC1)F Chemical class CCN(CCOC1)C1(OC1CCCCC1)F DUPHBYMRRUVOKT-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 229910021583 Cobalt(III) fluoride Inorganic materials 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- LFJUYIZDMDUTPT-UHFFFAOYSA-N FC1N(CC2CCCCC2)CCOC1 Chemical group FC1N(CC2CCCCC2)CCOC1 LFJUYIZDMDUTPT-UHFFFAOYSA-N 0.000 description 1
- UYDYAGYQKVHKNI-UHFFFAOYSA-N FC1N(CCOC2CCCCC2)CCOC1 Chemical compound FC1N(CCOC2CCCCC2)CCOC1 UYDYAGYQKVHKNI-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- PRPAGESBURMWTI-UHFFFAOYSA-N [C].[F] Chemical compound [C].[F] PRPAGESBURMWTI-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- WZJQNLGQTOCWDS-UHFFFAOYSA-K cobalt(iii) fluoride Chemical compound F[Co](F)F WZJQNLGQTOCWDS-UHFFFAOYSA-K 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229940039231 contrast media Drugs 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 239000000112 cooling gas Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- SBOJXQVPLKSXOG-UHFFFAOYSA-N o-amino-hydroxylamine Chemical compound NON SBOJXQVPLKSXOG-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- JAJLKEVKNDUJBG-UHFFFAOYSA-N perfluorotripropylamine Chemical compound FC(F)(F)C(F)(F)C(F)(F)N(C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F JAJLKEVKNDUJBG-UHFFFAOYSA-N 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 239000006163 transport media Substances 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
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
- A61K9/0012—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
- A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
-
- 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
- A61K49/1812—Suspensions, emulsions, colloids, dispersions liposomes, polymersomes, e.g. immunoliposomes
-
- 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
- A61K49/227—Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
-
- 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
- A61K9/127—Liposomes
Description
Die vorliegende Erfindung betrifft eine wäßrige Dispersion Fluor carbon enthaltender Phospholipidvesikel und ein Verfahren zu ihrer Herstellung. Diese Phospholipidvesikeldispersion ist vor allem als gastransportierendes Medium und als Diagnostikum sowohl in biolo gischen Systemen in vivo als auch in vitro einsetzbar.The present invention relates to an aqueous dispersion of fluorine carbon-containing phospholipid vesicle and a process for their Manufacturing. This phospholipid vesicle dispersion is primarily as gas transport medium and as a diagnostic both in biolo systems can be used in vivo as well as in vitro.
Fluorcarbone sind in der Form wäßriger Emulsionen wegen ihrer che mischen Inertheit und des Gaslösevermögens geeignet, in biologi schen Systemen den Sauerstofftransport zu gewährleisten. In der geeigneten Form, d. h. im Gemisch mit Elektrolyten, Energieträgern und onkotisch wirkenden Substanzen können sie als Blutersatzstoffe und als spezielle O₂-transportierende pharmazeutische Präparate zur Behandlung des Schocks, des Herzinfarkts und der cerebralen Ischämie angewendet werden. Weitere Anwendungen sind die Unter stützung der Radio- und Chemotherapie maligner Tumoren und als Kontrastmittel in der Röntgen-, Magnetresonanz- und Ultraschall diagnostik.Fluorocarbons are in the form of aqueous emulsions because of their che mix inertness and gas solubility suitable, in biological systems to ensure oxygen transport. In the appropriate form, d. H. in a mixture with electrolytes, energy sources and oncotic substances can be used as blood substitutes and as special O₂-transporting pharmaceutical preparations for the treatment of shock, heart attack and cerebral Ischemia can be applied. Other applications are the sub support of radio and chemotherapy of malignant tumors and as Contrast media in X-ray, magnetic resonance and ultrasound Diagnosis.
Als Fluorcarbone werden bevorzugt cyclische bzw. polycyclische Fluorkohlenstoffe, z. B. Perfluordecalin und tertiäre aliphatische oder cyclische Amine eingesetzt. Wegen der Geschwindigkeit der Ex kretion der Fluorcarbone aus dem lebenden Organismus müssen Para meter wie Molekülmasse, Dampfdruck und kritische Löslichkeitstem peratur in n-Hexan (als ein Maß für die Lipidlöslichkeit) streng beachtet werden.Cyclic or polycyclic are preferred as fluorocarbons Fluorocarbons, e.g. B. perfluorodecalin and tertiary aliphatic or cyclic amines used. Because of the speed of the ex Cretion of fluorocarbons from the living organism must Para meters such as molecular weight, vapor pressure and critical solubility test strictly in n-hexane (as a measure of lipid solubility) get noticed.
Die Herstellung wäßriger, mit dem menschlichen Blut kompatibler Fluorcarbonemulsionen macht biokompatible Emulgatoren erforder lich. Zu einem gewissen Maße erfüllen Ethylenoxid-Propylenoxid- Blockpolymeremulgatoren (im folgenden EO-PO-Blockpolymeremulgato ren genannt) diese Anforderungen. Dessen ungeachtet werden einige grundlegende Nebenwirkungen bei der Applikation von Fluorcarbon emulsionen den Blockpolymeremulgatoren zugeschrieben (Anaphylak tische Reaktionen, Komplementaktivierung, Leukocytopenie). The production of watery, more compatible with human blood Fluorocarbon emulsions require biocompatible emulsifiers Lich. To a certain extent, ethylene oxide propylene oxide Block polymer emulsifiers (hereinafter EO-PO block polymer emulsifiers ren called) these requirements. Regardless, some will fundamental side effects when applying fluorocarbon emulsions attributed to block polymer emulsifiers (Anaphylak reactions, complement activation, leukocytopenia).
Zusätzlich sind einige physikalische Parameter der Emulsionsbil dung und Emulsionsstabilisierung mit Blockpolymeremulgatoren nicht optimal gelöst. So ist die Stabilität entsprechender Fluorcarbon emulsionen bei Raumtemperatur und die notwendige Langzeitstabili tät der Lagerung unbefriedigend; eine thermische Sterilisierung der medizinischen Präparate ist nicht möglich.In addition, some physical parameters of the emulsion are dung and emulsion stabilization with block polymer emulsifiers not optimally solved. So is the stability of corresponding fluorocarbon emulsions at room temperature and the necessary long-term stability storage unsatisfactory; thermal sterilization medical preparations are not possible.
Probleme, die die Resttoxizität des Blockpolymeremulgators betref fen, können überwunden werden, wenn an dessen Stelle Phospholipi de, z. B. Ei- oder Sojalecithine, eingesetzt werden.Problems related to the residual toxicity of the block polymer emulsifier fen can be overcome if in its place Phospholipi de, e.g. B. egg or soy lecithins can be used.
YOKOYAMA (Green Cross Corp., Osaka) beansprucht mit US-Patent 3.962.439 (1976) eine Fluorcarbonemulsion als Blutersatzmittel, die ein Fluorcarbon mit 9 bis 11 Kohlenstoffatomen mit einer Kon zentration von 10 bis 40% enthält und durch ein Phospholipid in Verbindung mit langkettigen Fettsäuren, deren Salzen oder Mono glyceriden als Emulgatorgemisch stabilisiert wird.YOKOYAMA (Green Cross Corp., Osaka) claims US patent 3.962.439 (1976) a fluorocarbon emulsion as a blood substitute, which is a fluorocarbon with 9 to 11 carbon atoms with a con contains concentration of 10 to 40% and in by a phospholipid Connection with long-chain fatty acids, their salts or mono glycerides is stabilized as an emulsifier mixture.
H. SLOVITER schützt mit US-P 4.397.870 einen Prozeß zur Erhöhung der intravasalen Verweilzeit von Fluorcarbonemulsionen im Blut kreislauf des lebenden Organismus, indem in das zirkulierende Blut Lecithin als Emulgator zur Aufrechterhaltung einer hohen Blut lipidkonzentration injiziert wird. Der gleiche Erfinder beschreibt in US-P 4.497.829 ein Verfahren zur Herstellung stabiler Fluorcar bonemulsionen, wonach durch Ultraschalleinwirkung Phospholipide in physiologischen Lösungen mit Perfluordecalin, F-Methyldecalin, F- Tripropylamin oder F-Tributylamin in Konzentrationen von 30 bis 75% emulgiert werden. Die Teilchengrößen betragen im Durchschnitt 200 nm.H. SLOVITER protects a process for increasing with US-P 4,397,870 the intravascular residence time of fluorocarbon emulsions in the blood circulation of the living organism by putting in the circulating blood Lecithin as an emulsifier to maintain high blood lipid concentration is injected. The same inventor describes in U.S. Patent 4,497,829 discloses a process for making stable fluorocars bonemulsions, after which by ultrasound exposure to phospholipids physiological solutions with perfluorodecalin, F-methyldecalin, F- Tripropylamine or F-tributylamine in concentrations from 30 to 75% can be emulsified. The particle sizes are on average 200 nm.
Fluorcarbonemulsionen mit extrem hohen Fluorcarbongehalten von 30 bis 125% w/v in Form des F-Octylbromids werden von D. LONG jr mit EP 307.087 (1988) beansprucht. Das Wesen der Erfindung ist, daß als Emulgatoren Lecithin, anionische Tenside oder Fluortenside An wendung finden. Als onkotisch wirkende Komponente wird Mannitol eingesetzt, und zur Emulgierung dient ein spezieller Prozeß unter Einbeziehung einer Druckhomogenisierung. Fluorocarbon emulsions with extremely high fluorocarbon contents of 30 up to 125% w / v in the form of F-octyl bromide are used by D. LONG jr EP 307.087 (1988) claims. The essence of the invention is that as emulsifiers lecithin, anionic surfactants or fluorosurfactants find application. Mannitol is used as an oncotic component used, and a special process is used for emulsification Inclusion of pressure homogenization.
Ein weiteres Beispiel für konzentrierte stabile wäßrige Fluorcar bonemulsionen wird von SCHWEIGHART und KAYHART von Air Products and Chemicals in EP 282.949 (1988) gegeben. Die Erfinder erzielen stabile Fluorcarbonemulsionen größer 60% w/v Fluorcarbon, indem neben einem Phospholipid-Emulgator 5 bis 30% Triglyceride lang kettiger Fettsäuren als Co-surfactant angewendet werden. Eine be vorzugte Komposition besteht demnach aus 75% Perfluordecalin, 1 bis 2% Phospholipid und 20% Fettsäuretriglycerid. Bei einer optimalen Zusammensetzung der Emulsion beträgt die mittlere Teil chengröße 150 nm und ist bei 25°C 30 Tage stabil.Another example of concentrated stable aqueous fluorocar bonemulsions is provided by SCHWEIGHART and KAYHART by Air Products and Chemicals in EP 282,949 (1988). The inventors achieve stable fluorocarbon emulsions greater than 60% w / v fluorocarbon by in addition to a phospholipid emulsifier 5 to 30% triglycerides long chain fatty acids can be used as co-surfactants. A be preferred composition consists of 75% perfluorodecalin, 1 up to 2% phospholipid and 20% fatty acid triglyceride. At a optimal composition of the emulsion is the middle part size 150 nm and is stable at 25 ° C for 30 days.
Der Erfindung liegt nun die Aufgabe zugrunde, eine wäßrige Disper sion Fluorcarbon enthaltender Phospholipidvesikel und ein Verfah ren zu ihrer Herstellung zu entwickeln, wobei die Fluorcarbone, die bisher mit Lipiden und Zusatzstoffen in Form klassischer Emul sionen als Emulsionspartikel stabilisiert wurde, nunmehr in käfig artige Phospholipidbilayerstrukturen (Vesikel) eingeschlossen sind.The invention is based on the object of an aqueous disperser sion fluorocarbon-containing phospholipid vesicle and a process to develop their production, whereby the fluorocarbons, the so far with lipids and additives in the form of classic emuls Sions was stabilized as an emulsion particle, now in a cage like phospholipid bilayer structures (vesicles) included are.
Es wurde erfindungsgemäß eine wäßrige Dispersion Fluorcarbon ent haltender Phospholipidvesikel gefunden, die dadurch gekennzeichnet ist, daß in der wäßrigen Dispersion die Phospholipidvesikel ein oder mehrere sauerstofftransportierende Fluorcarbone in einer Kon zentration zwischen 2 und 100% w/v käfigartig und mit lammellarer Schichtstruktur ausgebildet eingeschlossen enthalten und die wäß rige Dispersion diese Phospholipidvesikel mit einer einheitlichen Teilchengröße zwischen 200 und 400 nm enthält.According to the invention, an aqueous fluorocarbon dispersion was ent holding phospholipid vesicles found, which are characterized is that the phospholipid vesicles in the aqueous dispersion or more oxygen-transporting fluorocarbons in one con concentration between 2 and 100% w / v cage-like and with lambellar Layered structure included included and the aq rige dispersion these phospholipid vesicles with a uniform Contains particle size between 200 and 400 nm.
Die erfindungsgemäße Phospholipidvesikel sind die aus den natür lichen Phospholipiden hergestellten, wie aus Sojalecithine, Ei lecithine, oder die aus den synthetischen Phospholipiden herge stellten, wie aus 1,2-Dilauroyl-glycero-3-phosphorylcholin, 1,2- Distearoyl-glycero-3-phosphorylethanolamin, oder deren Derivate.The phospholipid vesicles according to the invention are those from the natural Lichen phospholipids, such as egg soy lecithins lecithins, or those derived from synthetic phospholipids made from 1,2-dilauroyl-glycero-3-phosphorylcholine, 1,2- Distearoyl-glycero-3-phosphorylethanolamine, or their derivatives.
Die erfindungsgemäßen sauerstofftransportierenden Fluorcarbone sind aus der Gruppe der geradkettigen und verzweigten Fluoralkane, der Mono- und Polycyclo-Fluoralkane, der aliphatischen tertiären Fluoramine, der cyclischen Fluoramine, der alicyclischen Fluor aminoether, der aliphatischen und polycyclischen Fluorether, der Bis-(Fluoralkyl)ethene, der Fluoralkylhalogenide oder aus Gemi schen von diesen ausgewählt. (Das Symbol F - bzw. Fluor - bedeutet nach J.A. Young, J. Chem. Doc. 14 (1974) 98 den perfluorierten Zustand der nachfolgend genannten chemischen Verbindung.)The oxygen-transporting fluorocarbons according to the invention are from the group of straight-chain and branched fluoroalkanes, the mono- and polycyclo-fluoroalkanes, the aliphatic tertiary Fluoramines, the cyclic fluoramines, the alicyclic fluorine aminoether, the aliphatic and polycyclic fluoroether, the Bis- (fluoroalkyl) ethenes, the fluoroalkyl halides or from Gemi selected by these. (The symbol F - or fluorine - means after J.A. Young, J. Chem. Doc. 14 (1974) 98 den perfluorinated Condition of the chemical compound mentioned below.)
Erfindungsgemäß bevorzugte sauerstofftransportierende Fluorcarbone sind Fluor-Octan bis Fluor-Dodecan, Fluor-n-butyl-cyclohexan, Fluor-Decalin, Fluor-Methyldecalin, Fluor-Tripropylamin, Fluor- Dibutylmethylamin, Fluor-Tributylamin, Fluor-Cyclohexylmethyl morpholin, Fluor-Alkylsubstituierte Cyclohexylmorpholine, Fluor- Cyclohexylpiperidin und deren Fluor-Alkylderivate, Fluor-Cyclo hexyloxyethylmorpholin, Fluor-n-dihexylether, Fluor-2,5-dioxabi cyclo[4.4.0]decan, Fluor-4-methyloxymethyl-2,5-dioxabicyclo- [4.4.0]decan, Fluor-4-ethoxymethyl-2,5-dioxabicyclo[4.4.0]decan, Bis-(Fluorhexyl)ethen, Bis-(Fluorbutyl)ethen, Fluor-Octylchlorid, Fluor-Hexylbromid, Fluor-Octylbromid oder ein oder mehrere Gemi sche von diesen.Preferred oxygen-transporting fluorocarbons according to the invention are fluoro-octane to fluoro-dodecane, fluoro-n-butyl-cyclohexane, Fluorine-decalin, fluorine-methyldecalin, fluorine-tripropylamine, fluorine Dibutylmethylamine, fluoro-tributylamine, fluoro-cyclohexylmethyl morpholine, fluoro-alkyl substituted cyclohexylmorpholines, fluoro Cyclohexylpiperidine and their fluoro-alkyl derivatives, fluoro-cyclo hexyloxyethylmorpholine, fluoro-n-dihexyl ether, fluoro-2,5-dioxabi cyclo [4.4.0] decane, fluoro-4-methyloxymethyl-2,5-dioxabicyclo- [4.4.0] decane, fluoro-4-ethoxymethyl-2,5-dioxabicyclo [4.4.0] decane, Bis (fluorohexyl) ethene, bis (fluorobutyl) ethene, fluoro-octyl chloride, Fluoro-hexyl bromide, fluoro-octyl bromide or one or more mixtures of these.
Erfindungsgemäß besonders bevorzugte sauerstofftransportierende Fluorcarbone sind Fluor-Cyclohexylmethylmorpholin, Perfluor- Decalin oder Fluor-Dibutylmethylamin.According to the invention particularly preferred oxygen-transporting Fluorocarbons are fluorocyclohexylmethylmorpholine, perfluoro- Decalin or fluoro-dibutylmethylamine.
Weiterhin wurde erfindungsgemäß ein Verfahren zur Herstellung einer wäßrigen Dispersion Fluorcarbon enthaltender Phospholipid vesikel gefunden, das dadurch gekennzeichnet ist, daß man ein Phospholipid und ein oder mehrere sauerstofftransportierende Fluorcarbone in wäßriger Phase auf einen einheit lichen Teilchendurchmesser zwischen 200 und 400 nm homogenisiert, wobei man das Phos pholipid in einer Konzentration zwischen 2 und 12 Massenanteile in % und das oder die sauerstofftransportierenden Fluorcarbone in einer Konzentration von 2 bis 100% w/v einsetzt. Furthermore, a method for the production according to the invention an aqueous dispersion containing fluorocarbon phospholipid vesicle found, which is characterized in that one Phospholipid and one or more oxygen-transporting Fluorocarbons in the aqueous phase on one unit homogenized particle diameter between 200 and 400 nm, where the Phos pholipid in a concentration between 2 and 12 parts by mass in% and the or the oxygen-transporting fluorocarbons in a concentration of 2 to 100% w / v.
Die erfindungsgemäße Homogenisierung in wäßriger Phase kann man bevorzugt bei einem Druck zwischen 100 und 700 atm., insbesondere zwischen 300 und 500 atm. durchführen.The homogenization according to the invention in the aqueous phase can preferably at a pressure between 100 and 700 atm., in particular between 300 and 500 atm. carry out.
Die für das Herstellungsverfahren erfindungsgemäßen Phospholipide sind natürlich hergestellte, wie die Sojalecithine, die Eilecithi ne, oder die synthetisch hergestellten, wie 1,2-Dilauroyl-glycero- 3-phosphorylcholin, 1,2-Distearoyl-glycero-3-phosphorylethanol amin, oder deren Derivate, wobei insbesondere der Phosphatidylcholingehalt hoch ist, wie z. B. im Sojalecithin bis zu 35% oder im Eilecithin bis 75%. Bei den synthetisch hergestellten Phospholipiden ist die Möglichkeit des Einsatzes von reinen 1,2-acyl-glycero-phosphoryl-cholinen gegeben.The phospholipids according to the invention for the production process are naturally produced, like the soy lecithins, the egg lecithi ne, or the synthetically produced, such as 1,2-dilauroyl-glycero- 3-phosphorylcholine, 1,2-distearoyl-glycero-3-phosphorylethanol amine or its derivatives, the phosphatidylcholine content being particularly high, such as B. in soy lecithin up to 35% or in egg lecithin up to 75%. This is possible with the synthetically produced phospholipids the use of pure 1,2-acyl-glycerophosphoryl-cholines given.
Für das Herstellungsverfahren kann man erfindungsgemäß als sauer stofftransportierende Fluorcarbone die aus der Gruppe der gerad kettigen und verzweigten Fluoralkane, der Mono- und Polycyclo- Fluoralkane, der aliphatischen tertiären Fluoramine, der cycli schen Fluoramine, der alicyclischen Fluoraminoether, der aliphati schen und polycyclischen Fluorether, der Bis-(Fluoralkyl)-ethene, der Fluoralkylhalogenide oder aus Gemischen von diesen ausgewählt einsetzen.According to the invention, the manufacturing process can be considered acidic substance-transporting fluorocarbons from the group of straight chain and branched fluoroalkanes, the mono- and polycyclo- Fluoroalkanes, the aliphatic tertiary fluoramines, the cycli between fluoramines, alicyclic fluoraminoethers, aliphati and polycyclic fluoroethers, the bis (fluoroalkyl) ethenes, the fluoroalkyl halides or mixtures thereof deploy.
Als erfindungsgemäß bevorzugt für das Herstellungsverfahren lassen sich als sauerstofftransportierende Fluorcarbone Fluor-Octan bis Fluor-Dodecan, Fluor-n-butylcyclohexan, Fluor-Decalin, Fluor- Methyldecalin, Fluor-Tripropylamin, Fluor-Dibutylmethylamin, Fluor-Tributylamin, Fluor-Cyclohexylmethylmorpholin, Fluor- Alkylsubstituierte Cyclohexylmorpholine, Fluor-Cyclohexyl piperidin und deren Fluor-Alkylderivate, Fluor-Cyclohexyloxy ethylmorpholin, Fluor-2,5-dioxabicyclo[4.4.0]decan, Fluor-4- methoxymethyl-2,5-dioxabicyclo[4.4.0]decan, Bis-(Fluorhexyl)-ethen, Bis-(Fluorbutyl)-ethen, Fluor-Octylchlorid, Fluor-Hexyl bromid, Fluor-Octylbromid oder ein oder mehrere Gemische von diesen einsetzen. As preferred according to the invention for the manufacturing process itself as the oxygen-transporting fluorocarbons fluoro-octane Fluorododecane, fluoro-n-butylcyclohexane, fluoro-decalin, fluorine Methyldecalin, fluoro-tripropylamine, fluoro-dibutylmethylamine, Fluor tributylamine, fluorocyclohexylmethylmorpholine, fluorine Alkyl substituted cyclohexylmorpholines, fluoro-cyclohexyl piperidine and its fluoro-alkyl derivatives, fluoro-cyclohexyloxy ethylmorpholine, fluoro-2,5-dioxabicyclo [4.4.0] decane, fluoro-4- methoxymethyl-2,5-dioxabicyclo [4.4.0] decane, bis (fluorohexyl) ethene, Bis (fluorobutyl) ethene, fluoro-octyl chloride, fluoro-hexyl bromide, fluoro-octyl bromide or one or more mixtures of use this.
Erfindungsgemäß besonders bevorzugte sauerstofftransportierende Fluorcarbone sind Fluor-Cyclohexylmethylmorpholin, Perfluor-Deca lin oder Fluor-Dibutylmethylamin.According to the invention particularly preferred oxygen-transporting Fluorocarbons are fluorocyclohexylmethylmorpholine, perfluoro-deca lin or fluoro-dibutylmethylamine.
Die Bedingungen für das Herstellungsverfahren wurden erfindungs gemäß so gewählt, daß der Einschluß der Fluorcarbone in den Käfig der Bilayerstrukturen erfolgt und unilamellare bzw. multilamel lare, auf die Teilchengröße bezogene, einheitliche Vesikel ge bildet werden.The conditions for the manufacturing process were fiction accordingly chosen so that the inclusion of the fluorocarbons in the cage of the bilayer structures and unilamellar or multilamel lare, based on particle size, uniform vesicles be formed.
Während bekanntermaßen durch Emulgatormoleküle in der Adsorptions schicht von 0/W-Systemen stabilisierte Emulsionspartikel thermody namisch instabil sind, stellen lipidstabilisierte Partikel mit Bi layerstrukturen thermodynamisch stabile Systeme dar.While known to emulsifier molecules in the adsorption layer of emulsion particles stabilized by 0 / W systems thermody are namically unstable, lipid-stabilized particles with Bi layer structures represent thermodynamically stable systems.
Untersuchungen an den entsprechenden Systemen haben ergeben, daß die resultierenden fluorcarbongefüllten Vesikel in ihrer Stabili tät unabhängig von der Zeit sind. Eine Lagerung bei Raumtemperatur ist möglich ohne das üblicherweise auftretende Teilchenwachstum, und eine thermische Belastung bei 90°C ist ohne negative Auswir kungen durchführbar.Studies on the corresponding systems have shown that the resulting fluorocarbon-filled vesicles in their stability are independent of time. Storage at room temperature is possible without the usual particle growth, and a thermal load at 90 ° C has no negative effects feasible.
Im Gegensatz zu den vorherrschenden konventionellen Fluorcarbon emulsionen sind die entsprechenden Vesikelstrukturen unabhängig von der Art des verwendeten Fluorcarbons und der vesikulierten Menge. Auf diesem Wege lassen sich unproblematisch hochkonzen trierte z. B. 100%ige w/v Lipidvesikel erzeugen. Vorteilhaft dabei ist die entgegen der Erwartung nur geringfügig ansteigende Visko sität.In contrast to the prevailing conventional fluorocarbon emulsions, the corresponding vesicle structures are independent on the type of fluorocarbon used and the vesiculated Quantity. In this way, you can easily concentrate stepped z. B. Generate 100% w / v lipid vesicles. Advantageous is the visco that only slightly increases contrary to expectations sity.
Die Ausbildung der Vesikelstruktur bei den spezifischen Verfah rensbedingungen ist durch eine Anzahl von Untersuchungsmethoden (³¹P-NMR, Gelchromatographie, PCS, Stabilitätsuntersuchungen) verifiziert worden.The formation of the vesicle structure in the specific process conditions is determined by a number of examination methods (31 P NMR, gel chromatography, PCS, stability studies) been verified.
Im Gegensatz zu wäßrigen Vesikeln weisen fluorcarbongefüllte Vesikel eine Polaritätsumkehr auf, d. h. die Fettsäurereste des Phospholipidmoleküls sind zum unpolaren Fluorcarbonkern der Vesikel ausgerichtet, die damit als inverse Vesikel anzusehen ist. Ungeachtet dessen, erfolgt der Aufbau der lamellaren Schichten, die bis zur Ausbildung flüssig-kristalliner Strukturen führen kann.In contrast to aqueous vesicles, fluorocarbon filled Vesicle reverses polarity, i. H. the fatty acid residues of the Phospholipid molecules are the non-polar fluorocarbon nucleus Aligned vesicles, which is therefore to be regarded as an inverse vesicle. Regardless, the lamellar layers build up, which lead to the formation of liquid-crystalline structures can.
Die extreme Stabilität der Aggregate resultiert aus der Ausbildung multilamellarer Schichtstrukturen, der Orientierung negativer Oberflächenladungen und der Wasseraufnahme (Quellvermögen) der lamellaren Strukturen. Die für Emulsionssysteme entscheidende De pression der Grenzflächenspannung durch einen Emulgator ist für das vorliegende Phospholipidsystem nicht relevant.The extreme stability of the units results from the training multilamellar layer structures, the orientation of negative ones Surface charges and water absorption (swelling capacity) of the lamellar structures. The decisive De for emulsion systems pression of the interfacial tension by an emulsifier is for the present phospholipid system is not relevant.
Entsprechend dem Konzentrationsverhältnis von Fluorcarbon und zur Vesikulierung eingesetztem Phospholipid werden unilamellare ge füllte Phospholipidvesikel mit Vesikeldurchmessern von bis zu 100 nm erhalten. Ein Überschuß an Phospholipid in Bezug auf den theoretisch zu berechnenden unilamellaren Zustand ergibt multi lamellare Vesikel mit elektronenmikroskopisch nachweisbaren kon zentrischen Bilayern. Deren Teilchengrößen können bis auf Werte von über 400 nm ansteigen. Die Vereinheitlichung der Vesikel durchmesser im Herstellungsprozeß ist von eminenter Bedeutung, da eine breite Teilchengrößenverteilung nachteilig für die biomedizi nische Anwendung ist. Bekanntermaßen werden Partikel größer 400 nm zunehmend toxisch und durch sukzessive Phagozytierung im RES dem Blutkreislauf entzogen. According to the concentration ratio of fluorocarbon and Vesiculation used phospholipid are unilamellar ge filled phospholipid vesicles with vesicle diameters up to Get 100 nm. An excess of phospholipid in relation to the theoretically calculated unilamellar state gives multi lamellar vesicles with con centric bilayers. Their particle sizes can be down to values rise above 400 nm. The unification of the vesicles diameter in the manufacturing process is of paramount importance because a broad particle size distribution detrimental to the biomedical African application is. As is known, particles larger than 400 nm increasingly toxic and due to successive phagocytosis in the RES Blood circulation withdrawn.
Die Vorbereitung eines natürlichen Phospholipds kann beispiels
weise wie folgt erfolgen:
Kommerzielles Sojalecithin der Zusammensetzung von ca. 30% Phos
phatidylcholin, ca. 30% Phosphatidylethanolamin und ca. 30%
Phosphatidylinositol wird in einem organischen Lösungsmittel
(Chloroform, Chloroform/Methanol) gelöst. Das Lösungsmittel wird
am Rotationsverdampfer im Vakuum entfernt und das Phospholipidge
misch an der Kolbenwandung als Film abgeschieden. Durch Zugabe von
destilliertem Wasser wird das Lecithin unter Liposomenbildung mit
einer definierten Konzentration aufgenommen.A natural phospholipd can be prepared as follows, for example:
Commercial soy lecithin with the composition of approx. 30% phosphatidylcholine, approx. 30% phosphatidylethanolamine and approx. 30% phosphatidylinositol is dissolved in an organic solvent (chloroform, chloroform / methanol). The solvent is removed on a rotary evaporator in vacuo and the phospholipidge is mixed as a film on the flask wall. By adding distilled water, the lecithin is taken up with liposome formation at a defined concentration.
Die sauerstofftransportierenden Fluorcarbone werden nach bekannten und industriell eingeführen Verfahren hergestellt. Dabei werden die perfluorierten aliphatischen und cyclischen tertiären Amine bevorzugt durch elektrochemische Fluorierung der KW-Analoga in flüssigem Fluorwasserstoff (Simons-Prozeß) erzeugt (z. B. per fluorierte N-cyclohexylmethyl-Derivate sekundärer Amine; Groß, Rüdiger, Jonethal, DD-PS 280.130, 1988). Dagegen werden fluorierte Ether und Alkane bzw. Cycloalkane vorzugsweise durch Fluorierung mit Cobalt(III)fluorid in der Gasphase hergestellt (u. a. per fluorierte polycycloaliphatische Ether, DE-Patentanmeldung AZ - P 4101446.4, 1991). Ein weiteres Verfahren von Bedeutung ist die chemische Synthese ausgehend von perfluorierten Verbindungen wie Perfluoralkyljodiden. Auf diesem Wege ist der Zugang zu Verbindun gen des Typs der Bis(F-Alkyl)ethene möglich.The oxygen-transporting fluorocarbons are known and industrially introduced processes. In doing so the perfluorinated aliphatic and cyclic tertiary amines preferably by electrochemical fluorination of the KW analogues in liquid hydrogen fluoride (Simons process) generated (e.g. by fluorinated N-cyclohexylmethyl derivatives of secondary amines; Big, Rudiger, Jonethal, DD-PS 280.130, 1988). In contrast, fluorinated Ethers and alkanes or cycloalkanes preferably by fluorination made with cobalt (III) fluoride in the gas phase (including per fluorinated polycycloaliphatic ethers, DE patent application AZ - P 4101446.4, 1991). Another method of importance is that chemical synthesis based on perfluorinated compounds such as Perfluoroalkyl iodides. In this way there is access to connection gene of the type of bis (F-alkyl) ethenes possible.
Die Erfindung wird durch folgende Ausführungsbeispiele noch näher erläutert, wobei die Erfindung nicht auf diese Beispiele beschränkt ist.The invention is illustrated by the following exemplary embodiments explained, the invention is not limited to these examples is.
160 g hochreines F-Cyclohexylmethylmorpholin (Sdp. 174°C, kri tische Löslichkeitstemperatur in n-Hexan 38,5°C, LD₅₀ <47,5 g/kg i.p. in der Maus) wurden mit 160 ml einer 7,4% Sojalecithin-Dis persion (kommerzielles Produkt, frei von Lysolecithin) in einem Hochdruckhomogenisator unter Kühlung und Argonspülung bei 500 bar homogenisiert. Bei automatischer Re gistrierung der Vesikeldurchmesser wurde der Prozeß bis zu mitt leren Teilchendurchmessern von 220 nm fortgeführt.160 g of highly pure F-cyclohexylmethylmorpholine (bp. 174 ° C, kri table solubility temperature in n-hexane 38.5 ° C, LD₅₀ <47.5 g / kg i.p. in the mouse) were treated with 160 ml of a 7.4% soy lecithin dis persion (commercial product, free of lysolecithin) in a high pressure homogenizer with cooling and Homogenized argon purge at 500 bar. With automatic re registration of the vesicle diameter the process was up to medium continued particle diameters of 220 nm.
Es wurden 200 ml einer 80% Vesikeldispersion erhalten, deren Struktur durch ³¹P- und ¹⁹F-NMR-Untersuchungen charakterisiert wurde. Die Sterilisierung der Vesikel-Phase erfolgte durch Auto klavierung bei 121°C für 20 Minuten. Die Sauerstofflöslichkeit betrug 35 ml O₂/100 ml. Toxizitätsuntersuchungen i.v. in der Ratte waren negativ.200 ml of an 80% vesicle dispersion were obtained, the Structure characterized by 31 P and 31 F NMR studies has been. The vesicle phase was sterilized by auto piano at 121 ° C for 20 minutes. The oxygen solubility was 35 ml O₂ / 100 ml. Toxicity studies i.v. in the rat were negative.
Die Komplettierung zum biokompatiblen Blutersatzmittel erfolgte mit einem Adjuvantienpaket von 20 Vol-% (Elektrolyte, Glucose, Albumin).The completion to the biocompatible blood substitute took place with an adjuvant package of 20 vol% (electrolytes, glucose, Albumin).
60 g Perfluordecalin wurden mit 58 ml einer 8,6% wäßrigen Ei- Lecithin-Dispersion unter Eiskühlung und N₂-Atmosphäre in Intervallen homogenisiert. Es wurde eine stabile 60% w/v PFD-Vesikeldispersion mit einem mittleren Teilchendurchmesser von 200 nm und einer Viskosität von 11 cP erhalten. Die Vesikelstruktur wurde durch Linienform und Linienbreite (201,6 Hz) des ³¹P-NMR-Signals bestätigt. Eine weitere Charakterisierung erfolgte durch Gelfiltration der wäßrigen Vesikeldispersion an einer Shodex OH pak B-Säule mit RI-Detektion (negativer Peak). Die Vesikeldispersion ist bei Raumtemperatur langzeitstabil. Alterungsversuche bei 90°C über 4 Stunden ergaben ein nur uner hebliches Teilchenwachstum und keine Zerstörung der Vesikel struktur.60 g of perfluorodecalin were mixed with 58 ml of an 8.6% aqueous egg Lecithin dispersion under ice cooling and N₂ atmosphere homogenized at intervals. It became a stable 60% w / v PFD vesicle dispersion with an average particle diameter of 200 nm and a viscosity of 11 cP obtained. The vesicle structure was determined by line shape and line width (201.6 Hz) of the 31 P NMR signal confirmed. Another characterization was carried out by gel filtration of the aqueous vesicle dispersion a Shodex OH pak B column with RI detection (negative peak). The vesicle dispersion is long-term stable at room temperature. Attempts at aging at 90 ° C for 4 hours gave only a very bad result substantial particle growth and no destruction of the vesicles structure.
12,5 g F-Dibutylmethylamin (Sdp. 133°C, kritische Löslichkeits temperatur in n-Hexan 46°C, LD₅₀ <55 g/kg) wurden mit 43 ml einer wäßrigen 5% Sojalecithin-Dispersion unter Kühlung und Inertgas homogenisiert. Der mittlere Teilchendurchmesser betrug 200 nm. Nach Komplettierung zum Blutersatzmittel wurde mit einer 20% Dispersion ein partieller Blutaustausch an Ratten vorgenommen. Mittels ¹⁹F-NMR-tomographischer Untersuchungen am lebenden Tier sowie an isolierten Organen (Leber, Niere, Herz) wurde die F-DBMA Akkumulation bzw. Exkretion in zeitlicher Abhängigkeit verfolgt.12.5 g F-dibutylmethylamine (bp 133 ° C, critical solubility temperature in n-hexane (46 ° C, LD₅₀ <55 g / kg) were treated with 43 ml of a aqueous 5% soy lecithin dispersion with cooling and inert gas homogenized. The average particle diameter was 200 nm. After completing the blood substitute, a 20% Dispersion made a partial blood exchange in rats. Using ¹⁹F-NMR tomographic examinations on living animals and on isolated organs (liver, kidney, heart) the F-DBMA Accumulation or excretion tracked as a function of time.
Claims (7)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4127442A DE4127442C2 (en) | 1991-08-17 | 1991-08-17 | Aqueous dispersion of fluorocarbon-containing phospholipid vesicles and a process for their preparation |
| CH2560/92A CH684628A5 (en) | 1991-08-17 | 1992-08-17 | Aqueous dispersion of fluorocarbon-containing phospholipid vesicles and a method for their preparation. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4127442A DE4127442C2 (en) | 1991-08-17 | 1991-08-17 | Aqueous dispersion of fluorocarbon-containing phospholipid vesicles and a process for their preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE4127442A1 DE4127442A1 (en) | 1993-02-18 |
| DE4127442C2 true DE4127442C2 (en) | 1996-08-22 |
Family
ID=6438634
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE4127442A Expired - Fee Related DE4127442C2 (en) | 1991-08-17 | 1991-08-17 | Aqueous dispersion of fluorocarbon-containing phospholipid vesicles and a process for their preparation |
Country Status (2)
| Country | Link |
|---|---|
| CH (1) | CH684628A5 (en) |
| DE (1) | DE4127442C2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5876696A (en) | 1993-01-25 | 1999-03-02 | Sonus Pharmaceuticals, Inc. | Composition comprising a fluorine containing surfactant and perfluoropentane for ultrasound |
| US8012457B2 (en) | 2004-06-04 | 2011-09-06 | Acusphere, Inc. | Ultrasound contrast agent dosage formulation |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6989141B2 (en) | 1990-05-18 | 2006-01-24 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
| US5578292A (en) | 1991-11-20 | 1996-11-26 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
| IN172208B (en) | 1990-04-02 | 1993-05-01 | Sint Sa | |
| USRE39146E1 (en) | 1990-04-02 | 2006-06-27 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
| US7083778B2 (en) | 1991-05-03 | 2006-08-01 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
| US5445813A (en) * | 1992-11-02 | 1995-08-29 | Bracco International B.V. | Stable microbubble suspensions as enhancement agents for ultrasound echography |
| US6613306B1 (en) | 1990-04-02 | 2003-09-02 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
| US5409688A (en) * | 1991-09-17 | 1995-04-25 | Sonus Pharmaceuticals, Inc. | Gaseous ultrasound contrast media |
| MX9205298A (en) | 1991-09-17 | 1993-05-01 | Steven Carl Quay | GASEOUS ULTRASOUND CONTRASTING MEDIA AND METHOD FOR SELECTING GASES TO BE USED AS ULTRASOUND CONTRASTING MEDIA |
| DE69230885T3 (en) * | 1991-09-17 | 2008-01-24 | Ge Healthcare As | GASOUS ULTRASONIC CONTRASTING AGENTS |
| US6723303B1 (en) | 1991-09-17 | 2004-04-20 | Amersham Health, As | Ultrasound contrast agents including protein stabilized microspheres of perfluoropropane, perfluorobutane or perfluoropentane |
| IL104084A (en) | 1992-01-24 | 1996-09-12 | Bracco Int Bv | Long-lasting aqueous suspensions of pressure-resistant gas-filled microvesicles their preparation and contrast agents consisting of them |
| US5641509A (en) * | 1992-06-26 | 1997-06-24 | Lancaster Group Ag | Preparation for topical use |
| DE4221269C1 (en) * | 1992-06-26 | 1993-12-09 | Lancaster Group Ag | Preparation for topical use |
| DE4221256C2 (en) * | 1992-06-26 | 1997-07-10 | Lancaster Group Ag | Galenic composition for topical use |
| DE4221268C2 (en) * | 1992-06-26 | 1997-06-12 | Lancaster Group Ag | Use of a dermatological to support the oxygen transport in the skin |
| DE4221255C2 (en) * | 1992-06-26 | 1994-09-15 | Lancaster Group Ag | Cosmetolipid-containing cosmetic |
| US5558855A (en) * | 1993-01-25 | 1996-09-24 | Sonus Pharmaceuticals | Phase shift colloids as ultrasound contrast agents |
| IL108416A (en) | 1993-01-25 | 1998-10-30 | Sonus Pharma Inc | Phase shift colloids as ultrasound contrast agents |
| US5885564A (en) * | 1993-08-13 | 1999-03-23 | Lancaster Group Gmbh | Functional oxygenated composition containing phospholipids and fluorocarbon |
| DE4327679A1 (en) * | 1993-08-13 | 1995-02-16 | Lancaster Group Ag | Functional oxygenated preparation |
| CN1068229C (en) | 1993-12-15 | 2001-07-11 | 勃勒柯研究有限公司 | Gas mixtures useful as ultrasound contrast media |
| DE19715478A1 (en) * | 1997-04-10 | 1998-10-15 | Lancaster Group Gmbh | Cosmetic and dermatological agent based on hard magnetic particles |
| DE10336841A1 (en) * | 2003-08-11 | 2005-03-17 | Rovi Gmbh & Co. Kosmetische Rohstoffe Kg | Cosmetic composition for promoting oxygen transport into the skin |
| RU2259819C1 (en) * | 2004-03-01 | 2005-09-10 | Кузнецова Ирина Николаевна | Emulsion of perfluoroorganic compounds of medicinal indication and method for its obtaining |
| CN100574809C (en) * | 2005-01-10 | 2009-12-30 | 重庆海扶(Hifu)技术有限公司 | A kind of high-strength focusing ultrasonic therapy fluorocarbon emulsion analog assistant and application thereof |
| DE102007015598A1 (en) * | 2007-03-29 | 2008-10-02 | Heinrich-Heine-Universität Düsseldorf | Use of fluorochemical compounds for diagnostic purposes using imaging techniques |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4497829A (en) * | 1982-07-27 | 1985-02-05 | The University Of Pennsylvania | Process for preparing perfluorochemical emulsion artificial blood |
-
1991
- 1991-08-17 DE DE4127442A patent/DE4127442C2/en not_active Expired - Fee Related
-
1992
- 1992-08-17 CH CH2560/92A patent/CH684628A5/en not_active IP Right Cessation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5876696A (en) | 1993-01-25 | 1999-03-02 | Sonus Pharmaceuticals, Inc. | Composition comprising a fluorine containing surfactant and perfluoropentane for ultrasound |
| US8012457B2 (en) | 2004-06-04 | 2011-09-06 | Acusphere, Inc. | Ultrasound contrast agent dosage formulation |
| US8586005B2 (en) | 2004-06-04 | 2013-11-19 | Acusphere, Inc. | Ultrasound contrast agent dosage formulation |
Also Published As
| Publication number | Publication date |
|---|---|
| CH684628A5 (en) | 1994-11-15 |
| DE4127442A1 (en) | 1993-02-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8110 | Request for examination paragraph 44 | ||
| 8127 | New person/name/address of the applicant |
Owner name: GROSS, UDO, DR., 13057 BERLIN, DE RUEDIGER, STEPHA |
|
| D2 | Grant after examination | ||
| 8363 | Opposition against the patent | ||
| 8339 | Ceased/non-payment of the annual fee |