DE4127442A1 - Aq. dispersion of phospholipid(s) contg. fluorocarbon(s) - used as gas transporting media in diagnoses, and as an oxygen@ transporting substance e.g. a component of artificial blood - Google Patents
Aq. dispersion of phospholipid(s) contg. fluorocarbon(s) - used as gas transporting media in diagnoses, and as an oxygen@ transporting substance e.g. a component of artificial bloodInfo
- Publication number
- DE4127442A1 DE4127442A1 DE4127442A DE4127442A DE4127442A1 DE 4127442 A1 DE4127442 A1 DE 4127442A1 DE 4127442 A DE4127442 A DE 4127442A DE 4127442 A DE4127442 A DE 4127442A DE 4127442 A1 DE4127442 A1 DE 4127442A1
- Authority
- DE
- Germany
- Prior art keywords
- fluoro
- phospholipid
- oxygen
- transporting
- fluorocarbons
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000003904 phospholipids Chemical class 0.000 title claims abstract description 43
- 239000006185 dispersion Substances 0.000 title claims abstract description 21
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 8
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 title claims description 24
- 239000007789 gas Substances 0.000 title abstract description 5
- 239000000126 substance Substances 0.000 title abstract description 5
- 239000002473 artificial blood Substances 0.000 title abstract 2
- 239000002245 particle Substances 0.000 claims abstract description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000001301 oxygen Substances 0.000 claims abstract description 7
- 238000002604 ultrasonography Methods 0.000 claims abstract description 4
- 229940067631 phospholipid Drugs 0.000 claims description 40
- 239000003995 emulsifying agent Substances 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 16
- 229920000642 polymer Polymers 0.000 claims description 16
- -1 from 1 Chemical class 0.000 claims description 15
- 239000000787 lecithin Substances 0.000 claims description 11
- 235000010445 lecithin Nutrition 0.000 claims description 11
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 9
- GTNQBWBQOQZNCY-UHFFFAOYSA-N N-butyl-N-(fluoromethyl)butan-1-amine Chemical group FCN(CCCC)CCCC GTNQBWBQOQZNCY-UHFFFAOYSA-N 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 229950011087 perflunafene Drugs 0.000 claims description 7
- 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 claims description 7
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000008346 aqueous phase Substances 0.000 claims description 5
- CNCUKGDUDOASDV-UHFFFAOYSA-N 1-bromo-6-fluorohexane Chemical compound FCCCCCCBr CNCUKGDUDOASDV-UHFFFAOYSA-N 0.000 claims description 4
- RTFARVWMEFHIKS-UHFFFAOYSA-N 1-bromo-8-fluorooctane Chemical compound FCCCCCCCCBr RTFARVWMEFHIKS-UHFFFAOYSA-N 0.000 claims description 4
- PNCADGVKAQUIHO-UHFFFAOYSA-N 1-butyl-1-fluorocyclohexane Chemical compound CCCCC1(F)CCCCC1 PNCADGVKAQUIHO-UHFFFAOYSA-N 0.000 claims description 4
- JVNBJLUJOYZINW-UHFFFAOYSA-N 1-chloro-8-fluorooctane Chemical compound FCCCCCCCCCl JVNBJLUJOYZINW-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- BRKHZWFIIVVNTA-UHFFFAOYSA-N 4-cyclohexylmorpholine Chemical class C1CCCCC1N1CCOCC1 BRKHZWFIIVVNTA-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- ACQBVZAMLLRZGK-UHFFFAOYSA-N FCCCCC=CCCCCF Chemical compound FCCCCC=CCCCCF ACQBVZAMLLRZGK-UHFFFAOYSA-N 0.000 claims description 4
- LHAHSKRENHEOMW-UHFFFAOYSA-N FCCCCCCC=CCCCCCCF Chemical compound FCCCCCCC=CCCCCCCF LHAHSKRENHEOMW-UHFFFAOYSA-N 0.000 claims description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 4
- 229920001774 Perfluoroether Polymers 0.000 claims description 4
- 125000002723 alicyclic group Chemical group 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 238000000265 homogenisation Methods 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 229950004354 phosphorylcholine Drugs 0.000 claims description 4
- 125000003367 polycyclic group Chemical group 0.000 claims description 4
- 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 description 3
- UZFAMHCDHZHCEF-UHFFFAOYSA-N 3-fluoro-n,n-dipropylpropan-1-amine Chemical compound CCCN(CCC)CCCF UZFAMHCDHZHCEF-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
- JPDVBFJZKJAKKA-UHFFFAOYSA-N FC(CCCC1)N1C1CCCCC1 Chemical compound FC(CCCC1)N1C1CCCCC1 JPDVBFJZKJAKKA-UHFFFAOYSA-N 0.000 claims description 3
- UYDYAGYQKVHKNI-UHFFFAOYSA-N FC1N(CCOC2CCCCC2)CCOC1 Chemical compound FC1N(CCOC2CCCCC2)CCOC1 UYDYAGYQKVHKNI-UHFFFAOYSA-N 0.000 claims description 3
- VZGNSQIEHPIHBA-UHFFFAOYSA-N n,n-dibutyl-4-fluorobutan-1-amine Chemical group CCCCN(CCCC)CCCCF VZGNSQIEHPIHBA-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 230000032258 transport Effects 0.000 claims description 3
- YHYBNVZCQIDLSQ-UHFFFAOYSA-N 1-fluorododecane Chemical compound CCCCCCCCCCCCF YHYBNVZCQIDLSQ-UHFFFAOYSA-N 0.000 claims description 2
- DHIVLKMGKIZOHF-UHFFFAOYSA-N 1-fluorooctane Chemical compound CCCCCCCCF DHIVLKMGKIZOHF-UHFFFAOYSA-N 0.000 claims description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 2
- LFJUYIZDMDUTPT-UHFFFAOYSA-N FC1N(CC2CCCCC2)CCOC1 Chemical compound FC1N(CC2CCCCC2)CCOC1 LFJUYIZDMDUTPT-UHFFFAOYSA-N 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 2
- 235000010469 Glycine max Nutrition 0.000 claims 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 2
- 244000068988 Glycine max Species 0.000 claims 1
- 229940042880 natural phospholipid Drugs 0.000 claims 1
- 239000003792 electrolyte Substances 0.000 abstract description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 abstract description 2
- 238000002512 chemotherapy Methods 0.000 abstract description 2
- 239000002872 contrast media Substances 0.000 abstract description 2
- 238000000338 in vitro Methods 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract description 2
- 238000001959 radiotherapy Methods 0.000 abstract description 2
- 230000035939 shock Effects 0.000 abstract description 2
- 206010061216 Infarction Diseases 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 abstract 1
- 230000000747 cardiac effect Effects 0.000 abstract 1
- 239000000969 carrier Substances 0.000 abstract 1
- 230000007574 infarction Effects 0.000 abstract 1
- 239000000839 emulsion Substances 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 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 3
- 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
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229940067606 lecithin Drugs 0.000 description 3
- 239000008347 soybean phospholipid Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 230000000694 effects Effects 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
- 230000007774 longterm Effects 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000012360 testing method 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
- 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 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
- VVMSRLPWMJZWBK-UHFFFAOYSA-N CC1CCCC2CCCCC12.[F] Chemical compound CC1CCCC2CCCCC12.[F] VVMSRLPWMJZWBK-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
- 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
- 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
- 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
- 230000009286 beneficial effect Effects 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
- 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
- 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
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000008344 egg yolk phospholipid Substances 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
- 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
- 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
- 239000012528 membrane 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
- 239000003960 organic solvent Substances 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
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 229920001993 poloxamer 188 Polymers 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
- 150000003839 salts Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000010998 test method 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
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-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
Abstract
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 transporting 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 suitable in the form of aqueous emulsions because of their chemical inertness and the gas solubility to ensure the transport of oxygen in biological systems. In the appropriate form, ie in a mixture with electrolytes, energy sources and oncotic substances, they can be used as blood substitutes and as special O 2 -transporting pharmaceutical preparations for the treatment of shock, heart attack and cerebral ischemia. Other applications include the support of radio and chemotherapy for malignant tumors and as a contrast medium in X-ray, magnetic resonance and ultrasound diagnostics.
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 formation 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. YOKOYAMA (Green Gross Corp., Osaka) beansprucht mit US-Patent 39 62 439 (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. H. SLOVITER schützt mit US-P 43 97 870 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 44 97 829 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. Fluorcarbonemulsionen mit extrem hohen Fluorcarbongehalten von 30 bis 125% w/v in Form des F-Octylbromids werden von D. LONG jr. mit EP 3 07 087 (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. 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 Gross Corp., Osaka) claims US patent 39 62 439 (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 protects with US-P 43 97 870 a process for increasing 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 US-P 44 97 829 a process for the preparation of stable fluorocars bonemulsions, after which by ultrasonic exposure phospholipids in 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. Fluorocarbon emulsions with extremely high fluorocarbon contents of 30 up to 125% w / v in the form of F-octyl bromide are from D. LONG jr. With EP 3 07 087 (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 2 82 949 (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 2 82 949 (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 a co-surfactant. 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 80 und 400 nm enthält.According to the invention, an aqueous fluorocarbon dispersion was ent holding phospholipid vesicles found, which are characterized is that in the aqueous dispersion the phospholipid vesicles 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 80 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 made, such as from soy lecithins, egg lecithins, or those derived from synthetic phospholipids made, as 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, cyclic fluoramines, 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-Cyclohexylmethylmorpholin, Fluor-Alkylsubstituierte Cyclohexylmorpholine, Fluor-Cyclohexylpiperidin und deren Fluor-Alkylderivate, Fluor-Cyclohexyloxyethylmorpholin, Fluor-n-dihexylether, Fluor-2,5-dioxabicyclo[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 Gemische von diesen.Preferred oxygen-transporting fluorocarbons according to the invention are fluoro-octane to fluoro-dodecane, fluoro-n-butyl-cyclohexane, Fluoro-decalin, fluoro-methyldecalin, fluoro-tripropylamine, fluoro-dibutylmethylamine, Fluoro-tributylamine, fluoro-cyclohexylmethylmorpholine, Fluoro-alkyl substituted cyclohexylmorpholines, fluoro-cyclohexylpiperidine and their fluoroalkyl derivatives, fluoro-cyclohexyloxyethylmorpholine, Fluoro-n-dihexyl ether, fluoro-2,5-dioxabicyclo [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, perfluor 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 wahlweise unter Zusatz eines Ethylenoxid-Propylen oxid-Blockpolymeremulgators in wäßriger Phase auf einen einheit lichen Teilchendurchmesser zwischen 80 und 400 nm homogenisiert und die Phase der Fluorcarbon enthaltenden Phospholipidvesikel, nach dem Entfernen des Emulgators, isoliert, 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 einsetzen und den EO-PO- Blockpolymeremulgator in einer Konzentration zwischen 0,1 und 1,6 Massenanteile in %, insbesondere zwischen 0,5 und 0,9 Mas senanteile in %, zusetzen kann.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 optionally with the addition of an ethylene oxide propylene oxide block polymer emulsifier in aqueous phase on one unit homogenized particle diameter between 80 and 400 nm and the phase of the fluorocarbon-containing phospholipid vesicles, after removal of the emulsifier, isolated, 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 and use the EO-PO- Block polymer emulsifier in a concentration between 0.1 and 1.6% by mass, especially between 0.5 and 0.9 mas share in%.
Die erfindungsgemäße Homogenisierung in wäßriger Phase kann man bevorzugt bei einem Druck zwischen 100 und 700 atm., insbesondere zwischen 300 und 500 atm. oder mit Ultraschall einer Leistung zwischen 50 und 500 w/cm2 durchführen.The homogenization according to the invention in the aqueous phase can preferably be carried out at a pressure between 100 and 700 atm., In particular between 300 and 500 atm. or perform a power between 50 and 500 w / cm 2 with ultrasound.
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.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 their derivatives.
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 selected from 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 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.
Als EO-PO-Blockpolymeremulgator kann man wahlweise erfindungsgemäß einen solchen im Molmassenbereich größer 6000 Dalton mit einem Ethylenoxid-Anteil im Emulgatormolekül zwischen 15 und 30% oder ein Gemisch von diesen Verbindungen einsetzen.The EO-PO block polymer emulsifier can be used according to the invention one with a molecular weight greater than 6000 daltons Ethylene oxide content in the emulsifier molecule between 15 and 30% or use a mixture of these compounds.
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 uniform, vesicles based on particle size be formed.
Während bekanntermaßen durch Emulgatormoleküle in der Adsorptions schicht von O/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 O / 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 Amount. In this way, you can concentrate without any problems stepped z. B. Generate 100% w / v lipid vesicles. Advantageous here 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 under the specific process conditions has been verified by a number of test methods ( 31 P-NMR, gel chromatography, PCS, stability tests).
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 results in multi lamellar vesicles with electronically detectable 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.
Der bei der Vesikulierung wahlweise zur Anwendung kommende EO-PO- Blockpolymeremulgator hat nicht die Aufgabe, die Fluorcarbon tropfen im klassischen Sinne zu stabilisieren, sondern in den Prozeß der Käfigbildung einzugreifen.The EO-PO- that is optionally used for vesiculation Block polymer emulsifier does not have the task of fluorocarbon to stabilize drops in the classic sense, but in the Intervene process of cage formation.
Nach Vorstellung von P. Fromherz (Chem. Phys. Letters 94 (1983) 259) reduziert das Blockpolymer die Grenzflächenspannung an den Kanten des aus Bilayerschichten wachsenden sphärischen Aggregats und beschleunigt aus energetischen Gründen den Abschluß der Vesi kelbildung bei einheitlichen Teilchengrößen.According to P. Fromherz (Chem. Phys. Letters 94 (1983) 259) the block polymer reduces the interfacial tension at the Edges of the spherical aggregate growing from bilayer layers and accelerates the completion of Vesi for energetic reasons cone formation with uniform particle sizes.
Eine systematische Untersuchung der Bildung und Stabilität von Vesikeln mit Mischungen von Phospholipiden und Blockpolymeremul gatoren zwischen 0 und 100% hat maximale Stabilisierung für Ge mische mit 90 bis 95% Phospholipid und 5 bis 10% EO-PO-Block polymer ergeben. Das Tensid kann bei Bedarf beispielsweise durch Dialyse gegen Wasser unter Beibehaltung der vorteilhaften Eigen schaften des Systems abgetrennt werden.A systematic study of the formation and stability of Vesicles with mixtures of phospholipids and block polymer emul gators between 0 and 100% has maximum stabilization for Ge mix with 90 to 95% phospholipid and 5 to 10% EO-PO block polymer result. The surfactant can, for example, if necessary Dialysis against water while maintaining the beneficial properties system.
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 2 80 130, 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 41 01 446.4, 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 2 80 130, 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 41 01 446.4, 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) unter Zu satz von 1,2 g eines EO-PO-Blockpolymeremulgators (Molmasse 8500, EO-Gehalt 20%) 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. 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.160 g of highly pure F-cyclohexylmethylmorpholine (bp. 174 ° C, critical solubility temperature in n-hexane 38.5 ° C, LD 50 <47.5 g / kg ip in the mouse) were treated with 160 ml of a 7.4% soy lecithin -Dis persion (commercial product, free of lysolecithin) with addition of 1.2 g of an EO-PO block polymer emulsifier (molecular weight 8500, EO content 20%) in a high pressure homogenizer with cooling and argon purge at 500 bar. With automatic registration of the vesicle diameter, the process was continued up to mean particle diameters of 220 nm. 200 ml of an 80% vesicle dispersion were obtained, the structure of which was characterized by 31 P and 19 F NMR studies. The vesicle phase was sterilized by autoclaving at 121 ° C. for 20 minutes. The oxygen solubility was 35 ml O 2/100 ml. Iv toxicity studies in the rat were negative.
Die Komplettierung zum biokompatiblen Blutersatzmittel erfolgte mit einem Adjuvantienpaket von 20 Vol-% (Elektrolyte, Glucose, Albumin).The completion of 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 und 0,5 g Pluronic F 68 unter Eiskühlung und N2-Atmosphäre 15 Minuten mit einem Ultraschalldesintegrator (180 W/cm2) in Intervallen beschallt. Es wurde eine stabile 60% w/v PFD-Vesikeldispersion mit einem mittleren Teilchendurchmesser von 140 nm und einer Viskosität von 11 cP erhalten. Das Tensid wurde durch Dialyse über eine semipermeable Membran abgetrennt. 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 sonicated with 58 ml of an 8.6% aqueous egg lecithin dispersion and 0.5 g of Pluronic F 68 under ice cooling and N 2 atmosphere for 15 minutes with an ultrasonic disintegrator (180 W / cm 2 ) at intervals. A stable 60% w / v PFD vesicle dispersion with an average particle diameter of 140 nm and a viscosity of 11 cP was obtained. The surfactant was removed by dialysis over a semipermeable membrane. The vesicle structure was confirmed by the line shape and line width (201.6 Hz) of the 31 P-NMR signal. A further characterization was carried out by gel filtration of the aqueous vesicle dispersion on a Shodex OH pak B column with RI detection (negative peak). The vesicle dispersion is long-term stable at room temperature. Aging tests at 90 ° C for 4 hours showed only insignificant particle growth and no destruction of the vesicle 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 US-homogenisiert. Der mittlere Teilchendurchmesser betrug 110 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 of F-dibutylmethylamine (bp. 133 ° C., critical solubility temperature in n-hexane 46 ° C., LD 50 <55 g / kg) were mixed with 43 ml of an aqueous 5% soy lecithin dispersion with cooling and inert gas US Pat. homogenized. The mean particle diameter was 110 nm. After completion of the blood substitute, a partial blood exchange was carried out on rats using a 20% dispersion. The F-DBMA accumulation or excretion was monitored as a function of time using 19 F-NMR tomographic examinations on living animals and on isolated organs (liver, kidney, heart).
Claims (16)
Priority Applications (2)
| 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 |
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| Publication Number | Publication Date |
|---|---|
| DE4127442A1 true DE4127442A1 (en) | 1993-02-18 |
| DE4127442C2 DE4127442C2 (en) | 1996-08-22 |
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| 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)
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| CH (1) | CH684628A5 (en) |
| DE (1) | DE4127442C2 (en) |
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| DE4221256A1 (en) * | 1992-06-26 | 1994-01-05 | Lancaster Group Ag | Galenic composition for topical use |
| DE4221268A1 (en) * | 1992-06-26 | 1994-01-05 | Lancaster Group Ag | Use of a dermatological to support the oxygen transport in the skin |
| WO1994000097A1 (en) * | 1992-06-26 | 1994-01-06 | Lancaster Group Ag | Topical application composition |
| WO1994000098A1 (en) * | 1992-06-26 | 1994-01-06 | Lancaster Group Ag | Cosmetic containing phospholipids and fluorocarbon compounds |
| WO1994009829A1 (en) * | 1992-11-02 | 1994-05-11 | Bracco International B.V. | Stable microbubble suspensions as enhancement agents for ultrasound echography |
| WO1994016739A1 (en) * | 1993-01-25 | 1994-08-04 | Sonus Pharmaceuticals, Inc. | Phase shift colloids as ultrasound contrast agents |
| WO1995005144A1 (en) * | 1993-08-13 | 1995-02-23 | Lancaster Group Ag | Functional oxygenated composition containing phospholipids and fluorocarbon |
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| WO2005016309A1 (en) * | 2003-08-11 | 2005-02-24 | Rovi Gmbh & Co. Kosmetische Rohstoffe Kg | Cosmetic composition promoting oxygen transport into the skin |
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| US8012457B2 (en) | 2004-06-04 | 2011-09-06 | Acusphere, Inc. | Ultrasound contrast agent dosage formulation |
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| US4497829A (en) * | 1982-07-27 | 1985-02-05 | The University Of Pennsylvania | Process for preparing perfluorochemical emulsion artificial blood |
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- 1991-08-17 DE DE4127442A patent/DE4127442C2/en not_active Expired - Fee Related
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- 1992-08-17 CH CH2560/92A patent/CH684628A5/en not_active IP Right Cessation
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| 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 |
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Also Published As
| Publication number | Publication date |
|---|---|
| DE4127442C2 (en) | 1996-08-22 |
| CH684628A5 (en) | 1994-11-15 |
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