PH26160A - Pharmaceutical compositions consisting of acylated phospholipids - Google Patents
Pharmaceutical compositions consisting of acylated phospholipids Download PDFInfo
- Publication number
- PH26160A PH26160A PH34151A PH34151A PH26160A PH 26160 A PH26160 A PH 26160A PH 34151 A PH34151 A PH 34151A PH 34151 A PH34151 A PH 34151A PH 26160 A PH26160 A PH 26160A
- Authority
- PH
- Philippines
- Prior art keywords
- cis
- octadecenoyl
- glycero
- phospholipid
- optionally
- Prior art date
Links
- 150000003904 phospholipids Chemical class 0.000 title claims abstract description 58
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 239000000203 mixture Substances 0.000 claims abstract description 34
- 150000002632 lipids Chemical class 0.000 claims abstract description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 16
- 239000003937 drug carrier Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 10
- 125000002252 acyl group Chemical group 0.000 claims abstract description 9
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims abstract description 7
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims abstract description 7
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims abstract description 7
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims abstract description 7
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 3
- 150000003905 phosphatidylinositols Chemical class 0.000 claims abstract description 3
- -1 1,2-ethylene Chemical group 0.000 claims description 40
- 239000000243 solution Substances 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 102000008070 Interferon-gamma Human genes 0.000 claims description 17
- 108010074328 Interferon-gamma Proteins 0.000 claims description 17
- 229940044627 gamma-interferon Drugs 0.000 claims description 17
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 15
- 239000011734 sodium Substances 0.000 claims description 15
- 229910052708 sodium Inorganic materials 0.000 claims description 14
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 229940034982 antineoplastic agent Drugs 0.000 claims description 11
- 239000002246 antineoplastic agent Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 10
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 8
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims description 8
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 7
- 125000001589 carboacyl group Chemical group 0.000 claims description 7
- 230000002519 immonomodulatory effect Effects 0.000 claims description 7
- 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 claims description 7
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 5
- 229960000684 cytarabine Drugs 0.000 claims description 5
- 229960001259 diclofenac Drugs 0.000 claims description 5
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 5
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 4
- 108010092160 Dactinomycin Proteins 0.000 claims description 4
- 102000000588 Interleukin-2 Human genes 0.000 claims description 4
- 108010002350 Interleukin-2 Proteins 0.000 claims description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 4
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 claims description 4
- 229960000640 dactinomycin Drugs 0.000 claims description 4
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 4
- 229960000975 daunorubicin Drugs 0.000 claims description 4
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 4
- 229960005420 etoposide Drugs 0.000 claims description 4
- 125000005639 glycero group Chemical group 0.000 claims description 4
- JLLYLQLDYORLBB-UHFFFAOYSA-N 5-bromo-n-methylthiophene-2-sulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(Br)S1 JLLYLQLDYORLBB-UHFFFAOYSA-N 0.000 claims description 3
- 229930192392 Mitomycin Natural products 0.000 claims description 3
- 229960003767 alanine Drugs 0.000 claims description 3
- 229960004857 mitomycin Drugs 0.000 claims description 3
- PIDSZXPFGCURGN-UHFFFAOYSA-N pirprofen Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CC=CC1 PIDSZXPFGCURGN-UHFFFAOYSA-N 0.000 claims description 3
- 229960000851 pirprofen Drugs 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 125000001095 phosphatidyl group Chemical group 0.000 claims description 2
- 102220187649 rs145044428 Human genes 0.000 claims description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims 1
- VWKQENHPWHYNDP-RSBZEYOASA-N (2r)-5-amino-2-[[(2s)-2-[2-[(2s,3r,4r,5s,6r)-3-amino-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxypropanoylamino]propanoyl]amino]-5-oxopentanoic acid Chemical compound NC(=O)CC[C@H](C(O)=O)NC(=O)[C@H](C)NC(=O)C(C)O[C@@H]1[C@@H](N)[C@@H](O)O[C@H](CO)[C@H]1O VWKQENHPWHYNDP-RSBZEYOASA-N 0.000 claims 1
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 claims 1
- 229930182847 D-glutamic acid Natural products 0.000 claims 1
- AEFLONBTGZFSGQ-VKHMYHEASA-N L-isoglutamine Chemical compound NC(=O)[C@@H](N)CCC(O)=O AEFLONBTGZFSGQ-VKHMYHEASA-N 0.000 claims 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims 1
- 125000001980 alanyl group Chemical group 0.000 claims 1
- 230000000118 anti-neoplastic effect Effects 0.000 claims 1
- 244000145841 kine Species 0.000 claims 1
- 108700008309 muramoyl-alanylisoglutamine Proteins 0.000 claims 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 claims 1
- 239000002502 liposome Substances 0.000 abstract description 61
- 230000000144 pharmacologic effect Effects 0.000 abstract description 10
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract description 4
- ZGSPNIOCEDOHGS-UHFFFAOYSA-L disodium [3-[2,3-di(octadeca-9,12-dienoyloxy)propoxy-oxidophosphoryl]oxy-2-hydroxypropyl] 2,3-di(octadeca-9,12-dienoyloxy)propyl phosphate Chemical compound [Na+].[Na+].CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COP([O-])(=O)OCC(O)COP([O-])(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC ZGSPNIOCEDOHGS-UHFFFAOYSA-L 0.000 abstract description 4
- 125000003342 alkenyl group Chemical group 0.000 abstract description 3
- 201000011510 cancer Diseases 0.000 abstract description 2
- 238000002512 chemotherapy Methods 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 150000008105 phosphatidylcholines Chemical class 0.000 abstract 1
- 229920006395 saturated elastomer Polymers 0.000 abstract 1
- 239000006185 dispersion Substances 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- 239000008346 aqueous phase Substances 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 239000000306 component Substances 0.000 description 14
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
- 239000008240 homogeneous mixture Substances 0.000 description 10
- 229940083542 sodium Drugs 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 210000002540 macrophage Anatomy 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 8
- 239000003242 anti bacterial agent Substances 0.000 description 8
- 229940088710 antibiotic agent Drugs 0.000 description 8
- 125000000016 octadecenoyl group Chemical group O=C([*])C([H])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 7
- 229910019142 PO4 Inorganic materials 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 125000004450 alkenylene group Chemical group 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 7
- 235000021317 phosphate Nutrition 0.000 description 7
- 239000010452 phosphate Substances 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 239000005977 Ethylene Substances 0.000 description 6
- 239000002260 anti-inflammatory agent Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 6
- 239000011261 inert gas Substances 0.000 description 6
- 238000007911 parenteral administration Methods 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 229940100198 alkylating agent Drugs 0.000 description 5
- 239000002168 alkylating agent Substances 0.000 description 5
- 229940121363 anti-inflammatory agent Drugs 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 5
- 239000002955 immunomodulating agent Substances 0.000 description 5
- 229940121354 immunomodulator Drugs 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 4
- 102000014150 Interferons Human genes 0.000 description 4
- 108010050904 Interferons Proteins 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000001741 anti-phlogistic effect Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229940079322 interferon Drugs 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- 108010028921 Lipopeptides Proteins 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 206010057249 Phagocytosis Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 3
- 229960001231 choline Drugs 0.000 description 3
- MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 230000008782 phagocytosis Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 2
- NKUHWWPUOXOIIR-CRCLSJGQSA-N (4r)-5-amino-4-[[(2s)-2-azaniumylpropanoyl]amino]-5-oxopentanoate Chemical compound C[C@H](N)C(=O)N[C@@H](C(N)=O)CCC(O)=O NKUHWWPUOXOIIR-CRCLSJGQSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
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- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
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- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
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- FUSNMLFNXJSCDI-UHFFFAOYSA-N tolnaftate Chemical compound C=1C=C2C=CC=CC2=CC=1OC(=S)N(C)C1=CC=CC(C)=C1 FUSNMLFNXJSCDI-UHFFFAOYSA-N 0.000 description 1
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- 230000032258 transport Effects 0.000 description 1
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- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
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- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000002476 tumorcidal effect Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
-
- 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
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The compositions consist of a) a phospholipid of the formula <IMAGE> in which m is two or three, R1 and R2 are, independently of one another, alkyl, alkenyl or acyl each with 10 to 20 C atoms, and X is a direct bond, C1-C4-alkylene, C2-C4-alkenylene or C1-C4-alkylene or C2-C4-alkenylene substituted by hydroxyl, or a pharmaceutically acceptable salt thereof, b) a phospholipid of the formula <IMAGE> in which R3 and R4 are the acyl group of a saturated or unsaturated carboxylic acid with 10 to 20 C atoms and 1 to 2 double bonds, c) a compound or a mixture of compounds with pharmacological properties and, where appropriate, d) a lipid from the group comprising phosphatidylcholines, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, cardiolipin and cholesterol and, where appropriate, a pharmaceutically acceptable carrier solution which is buffered to pH 7.0 to 7.8 and, where appropriate, pharmaceutically acceptable auxiliaries. The compositions can be used in the form of liposomes as administration systems, for example for cancer chemotherapy.
Description
Cola 26160
Sub ject matter of the present invention are phare= maceutical compositions containing acylated phospha- tidylethanolamine derivatives, phosphatidylethanole~ amine and compounds having pharmacological proper= ties. The present invention also relates to mixtures of the acylated phosphatidylethanolamine derivatives and phosphatidylethanolamine, a process for the pre- paration of the pharmaceutical compositions, and a method of use for the pharmaceutical compositions.
The pharmaceutical compositions according to the pre= sent invention are being administered in the form of liposomes.
Pharmaceutical administration systems based on lipo= somes have been described in the general review ia~ sued by G. Gregoriadis, Liposome Technology, Vol. II, : Incorporation of Drugs, Proteins and Genetic Material,
ERC Press 1984, Such systems have the advantage that biologically active material can be introduced into tissues by phagocytosis, especially into tissues of the reticulo~endothelial system. For example, a transe port mechanism is known how antibiotics are being in- troduced into infected tissues byphagocytosis thus ; causing the improved removal or destruction of the jnfecting microorganism. Endocytosis also is a help=
7c 26160 + ful mechanism in the combat of centres of inflame mation. Antirheumatic pharmaceuticals encapsulated in liposomes are preferably introduced into ine fected tissues as compared to "healthy" tissues.
Moreover, cytostatic agents, commonly known as "antie cancer drugs", when encapsulated in liposomes, can be introduced into specific ergans of the reticulo- endothelial system (liver apleen or marrow), Addi- tionally, due to filtration in the capillaries of the lung and subsequent transport by migrating mono- cytes, biologically active material, for example come pounds having immunomodulatory properties, can be concentrated in alveolar macrophages, This results in an improved action on metastatic lung tumours and in a simultaneous reduction of toxicity.
It has now surprisingly been found that the uptake . of liposomes and their endocytosis by macrophages, especially alveolar macrophages, is increased when= ever acylated phosphatidylethanolamine derivatives are incorporated in the shell structure of the lipo~ somes,
The present invention relates to pharmaceutical com- positions consisting of a) a phospholipid of the formula
7 [gr a (1) sn_ 1 cy 0 Ry 2 Rp0-CH 0 0 0 1 3 H 0 ”" 0 ” "
CH,- p= =(CH,) «NH=C-X=~C~OH
OH wherein m represents two or three, Ry and R, inde~ pendently of each other represent alkyl, alkenyl, or acyl each having from 10 to 20 carbon atoms, X ree presents the direct bond, C,=Cj=alkylene, Cy=Cy~ alkenylene, or C,-Cy=alkylene or C,-C,~alkenylene substituted by hydroxy or a pharmaceutically accept= able salt thereof, b) a phospholipid of the formula sn | 1 CH.,=0-R 2 3 2 * 3 R,,0-CH ° (11), ' . (+)
Cll =0-8=0-Cip=Clig=Ni o wherein Ry and Ry, represent the acyl group of a satu~ rated or an unsaturated carboxylic acid having from 10 to 20 carbon atoms and 1 - 2 double bonds, ¢) a compound or a mixture of compounds having phar- macological activity, and, optionally, d) a lipid selected from the group consis ting of phosphatidylcholine, phosphatidylserine, phoaphatidyle
‘ lr inositol, phosphatidylglycerol, cardiolipin and cholesterol and its derivatives, and, optionally, a pharmaceutically acceptable carrier solution buf- fered to pH 7.0 - 7.8, and, optionally, pharmaceutical- ly acceptable additives.
In the context of the description of the present in- vention, the general terms employed hereinbefore and hereinafter preferably have the following meanings:
The terms "lower" used in connection with definitions of organic radicals, for example lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl, etc., means that such organic radicals, unless expressly defined otherwise, contain up to 7, preferably up to U4, care bon atoms.
The nomenclature of the phospholipids of the formulae : I and II is in agreement with the recommendations of the IUPAC and 1UB Commission on Biochemical Nomen clature (CBN) according to the Eur. J. of Biochem, 79, 11-21 (1977) "Nomenclature of Lipids" (sn~nomen clature, stereospecific numberdng).
Unless indicated otherwise, generic names proposed by the World Health Organisation (WHO) (Recommended
International Non-proprietary Names) are used to dee
[0 26160 ‘fine the active ingredients, which names have been taken from the standard text book "Pharmazeuw tische Chemie" (E. Schroder, C. Rufer and R. Schmie=- chen, Thieme Verlag Stuttgart, 1982) and the Merck
Index (Tenth Edition).
In the synthetic phospholipid of the formula I (com= ponent a) m is preferably two.
Alkyl Ry and/or Ry is preferably straight-chained with an even number from 10 to 20 carbon atoms, for example n-decyl, n-dodecyl, n-tetradecyl, n~hexadecyl, n-octadecyl or n~-icosyl,.
Alkenyl R, and/or R, is preferably straight-chained : with an even number from 12 to 20 carbon atoms and a double bond, for example 9-cis~dodecenyl, 9-cis-te- tradecenyl, 9-cis~hexadecenyl, 6-cis-octa=decenyl, 6- . trans-octadecenyl, 9.cis=octadecenyl, Getrana~octa- decenyl or 9-cis-icosenyl.
Acyl Ry and/or R, is preferably straight-chained with an even number from 10-20 carbon atoms, for example
C,0=C,o=alkanoyl or Cy g=Cop-alkenoyle
Alkanoyl Ry and/or R, is preferably n-decanoyl, n= dodecanoyl, n-tetradecsnoyl, n-hexadecanoyl, n-octae ww 8 =
/,
Tif decanoyl and n-icosanoyl.
Alkenoyl Ry and/or R, is preferably 9-cis-dodecenoyl, 9-cis-tetradecenoyl, 9-cis~hexadecenoyl, 6-cis~octa- decenoyl, 6-trans-octadecenoyl, 9-cis=octadecenoyl, 9-trans-octadecenoyl, ll-cis=octadecenoyl and 9-cis=~ icosenoyl.
X defined as C,~Cy-alkylene is straight chained or branched Cy -Cy~alkylene, for example methylene, l,1~ ethylene, 1,1-, 1,2~ or l,3-propylene or, prefer- ably, l,2-ethylene.
X defined as C,-Cy~alkenylene is preferably straight chained alkenylene, for example vinylene, propylene, or 1,2- or 2,3=butylene,
X defined as C,=Cj-alkylene or €,=Cy-alkenylene subse tituted by hydroxy is preferably straight chained
Cy=Cy=alkylene substituted by 1 or, depending on the number of carbon atoms, up to 4 hydroxy groups, for example l=hydroxy-l,2-ethylene, 1l,2~dihydroxy=-l,2= ethylene, l= or 2-hydroxy-l,3-propylene or 1l,2=dihy- droxy~l,3-propylene.
A pharmaceutically acceptable salt of the phospholipid (I) is preferably formed by reaction with one or two equivalents of dilute aqueous alkalimetal hydroxide, for example sodium or potassium hydroxide and is,
Z(H 26160 preferably, the mono= or disodium salt.
Other pharmaceutically acceptable salts are formed by reaction with amines such as trimethyl, ethyl-, diethyl-. or triethylamine, piperidine, piperazine, 2-hydroxyethylpiperazine, cyclohexylamine, pyrrolie dine, or choline,
In the synthetic phospholipid (1) Ry and Ry prefer~ ably are straight chained alkenoyl with an even nume ber from 10 to 20 carbon atoms, for example 9-ciasw dodecenoyl, 9-cis=tetradecenoyl, 9-cis~hexadecenoyl, 6-cis-, 6-trans-, 9-cis, 9-trans-, or l1l-cis-octa= decenoyl, or 9-cis~icosenoyl, X is C,-C,~alkylene, for example l,2-ethylene or 1l,3-propylene, or C,=Cpy~ alkenylene, for example vinylene.
Most preferred are the sodium or disodium salts of : Ls N-/T,2-di-(9=cis-octadecenoyl)-en-glycero-3-phospho= ethanol/-N-hydroxysuccinylamine and He/T,2-die(9= cis-octadecenoyl)-sn~glycero=-3-phosphoethanol-N-hy= droxyglutarylamine.
In the phospholipid of the formula II (component b)) the acyl groups Ry and Ry, are preferably straight chained with an even number from 10 - 20 carbon atoms, for example Cy0~Cpp-alkanoyl or C1520" ale
“CU gy 26160 kenoyl, especially 9.cis-dodecenoyl, 9-cis-tetra= decenoyl, 9-cis-hexadecenoyl, 6-cis-, 6~trans-, 9- cig=, 9~trans- or 1l-cis=-octadecenoyl.
Most preferred is 1,2-di{9=cis-octadecenoyl)-sn~ glycero-3-phosphoethanolamine.
Compounds or mixtures of compounds having pharmaco- logical activity (component c)) are preferably drugs selected from the group consisting of antiphlogistice and/or antiinflammatory agents, antibiotics, antie ljeishmaniasis agents, antimycotics, antineoplastic agents, and compounds having immunomodulatory action.
Antiphlogistics and/or antiinflammatory agents are preferably glucocorticoids, for example cortisone, hydrocortisone, prednisone, prednisolone, fluocorto- lone, triamcinolone, methylprednisolone, prednylidene, paramethasone, dexamethasone, betamethasone, beclo=~ methasone, fluprednylidene, desoximethasone, fluo= cinolone, flumethasone, diflucortolone, eldcortolone, clobetazol, or fluorcortinebutylester, salts of substi tuted phenylacetic acids or 2-phenylpropionic acids, for example alclofenac, ibufenac, ibuprofen, clin=- danac, fenclorac, ketoprofen, fenoprofen, indoprofen, fenclofenac, diclofenac, flurbiprofen, pirprofen, naproxen, benoxaprofen, carprofen or cicloprofen;
ZG¢/ 0 analgesically active anthranilic acid derivatives, for example of the formula ~ COOH ~ if
SN (111)
NH
R | R 2 Tv ~~ ~ 1
TN
3 in which Rie R, and Rye independently of each other, represent hydrogen, methyl, chlorine or trifluoroe methyl, for example mefenamic acid, flufenamic acid, tolfenamic acid or meclofenamic acidi analgesically active anilino=substituted nicotinic acid derivaw tives, for example miflumic acid, chlonixin or flu- . 10 nixin; analgesically active heteroarylacetic acids or 2-heteroarylpropionic acids having a 2-indol=-3-yl or pyrrol-2=yl radical, for example indomethacin, oxmetacin, intrazol, acemetazin, cinmetacin, zome= pirac, tolmetin, colpirac or tiaprofenic acid, anale gesically active indenylacetic acids, for example sulindac, analgesically active heteroaryloxyacetic acids, for example benzadac,
Antibiotics are preferably tetracycline derivatives
Rl Jy) 26150 . “. of the formula:
Ry Ry, R Ra N(CH), » Ey | “on
Ll eT SA
CLL a.
SO . CAN ne oo
T oY Y ; [[ contin on 1
OH 0 OH 0 in which Ry represents hydrogen or pyrrolidin-l-yl- methyl, R, represents hydrogen or hydroxy, Ry re- presents hydrogen, hydroxy or methyl, Ry, represents hydrogen or methyl, and Rg represents hydrogen, chlo- rine or dimethylamino, for example chlorotetracycline, oxytetracycline, tetracycline, dimethylchlorbstra~ cycline, metacycline, doxycycline, minocycline or rolitetracycline, aminoglycosides, for example kana- mycin, amikacin, gentamicin Cyo Cal Cc, or Cop? siso-~ micin, netilmicin, spectinomycin, streptomycin, to~ ’ bremycin, neomycin B, dibecacin, or kanendomycin, makrolides, for example maridomycin or erythromycin, lincomycins, for example clindamycin or lincomycin, penicillanic acid and cephalosporanic acid deriva~ tives having antibiotic activity with 6p- or 7p-acyl- amino groups, which are present in fermentatively, semi-synthetically or eynthetically obtainable leap ORIGINAL D — .
La) 0 » ' 26160 6p-acylaminopenicillanic acid or 7p-acylaminoce- phalosporanic acid derivatives or in 7p-acylamino= cephalosporanic acid derivatives modified in the 3= position, for example penicillanic acid derivatives that have becone known under the names penicillin
G or V, phenethicillin, propicillin, nafcillin, oxa~ cillin, cloxacillin, dicloxacillin, flucloxacillin, cyclacillin, epicillin, mecillinam, methicillin, azlocillin, sulbenicilling ticarcillin, mezlocillin, piperacillin, carindacillin, azidocillin or ciclazile lin, or cephalosporin derivatives that have become known under the names cefaclor, cefuroxime, cefazlur, cephacetrile, cefazolin, cephalexin, cefadroxil, cephaloglycin, cefoxitin, cophaloridine, cephsulodin, cefotinm, ceftazidine, cefonicid, cefotaxime, cefe menoxime, ceftizoxime, cephalothin, cepharadine, cefamandol, cephnnone, cephapirin, cefroxadin, cefa- trizine, cefazedone, ceftrixon or ceforanid, other pelactam antibodies of the clavam; penem or carba- penem type, for example moxalactam, clavulanic acid, nocardicine A, sulbactam, aztreonam or thienamycine, or other antibiotics of the bicomycin, novidbiocin, chlor- or thiamphenicol, rifampicin=-, fosfomycine=, colistin~ or vancomycin type.
Antileishmaniasis agents preferably are antimony - 14 - : -~
BAD ORI=™'
\ ‘ 26160 compounds, for example potassium antimonyl tartrate, stibophen, sodium atibocaptate, or sodium stiboglucon= ate.
Antimycotice are, for example, thiocarbonic acid de- rivatives, for example dibenzthione, tolnaftate, or tolcidate, imidazole derivatives, for example clo- trimazole, miconazole, econazole, jconazole, or keto- conazole, or polyene derivatives such as nystatine, natamycine, or amphotericine Be
Antineoplastic agents preferably are alkylating agents having the bis=(2-chloroethyl)-amine group such as chlormethine, chlorambucile, melphalan, uramuse tine, mannomustine, extramustinephosphat, mechlor- ethaminoxide, cyclophosphamide, ifosfamide, or tri- fosfamide, alkylating agents having a substituted : aziridine group, for example tetramine, thiotepa, triaziquone, or mitomycine, alkylating agents of the methanesul fonic enter type such as busulfane, alkylat~ ing Nealkyl=N-nitrosourea derivatives, for example carmustine, lomustine, aemustine, or streptozotocine, alkylating agents of the mitobronitole, dacarbazine, or procarbazins type, complexing agents such as cig= platin, antimetabolites of the folic acid type, for example methotrexate, purine derivatives such as mercaptopurine, thioguanine, azathioprine, tiami=- - 15 ~- \ga0 ORIGIN! A
Ally 26160 prine, vidarabine, or puromycine, pyrimidine derie= vatives, for example fluorouracil, floxuridine, tegafur, cytarabine, jdoxuridine, flucytosine, an- tibiotics such as dactinomycin, daunorubicin, doxo- rubicin, mithramycin, bleomycin A, or B, or etopo- side, or vinca alcaloids, optionally in combination with chlormethamine, prednisolone, prednisone, or pro- carbazine.
Compounds or mixtures of compounds having immunomodu- latory actian are, for example, muramylpeptides of the formula
R30
Jl
Pi 5
R,~CH N NHCOCH3
COR, wherein R, represents the L-Ala=D-isoGln=-L-Ala=2-(1,2- 41palmi toyl-an-glycero-3-hydroxyphosphoryloxy) ethyl amide, L-Ala=D-01u=(C yp g=LmAla-2-(1,2-dipalnitoyl- sn-glycero-3-hydroxyphosphoryloxy)ethylamides L=Ala- p-is0Gln=-OH, L-Ala-D-0ln-Ni,O-n-butylesters Le-Ala~
D-isoGln-Le=(atearoyl)-Lys, L-Val-D=Gln=NH,-gq-n-methyl= ester, L-Ala-D-isoGln-L-Ala-1,2-dipalmitoyl-sn-gly= - 16 ~ (= Ce —
BAD CRIGINAL -~ aay 1 26160 cerineester or the L=Ala«D-iseGln-lL=Ala~choles= terineester group, R, represents hydrogen, methyl or n-propyl, Rs represents hydrogen, n~astearoyl, 10=(2,3~dimethoxy~1,4edioxo~5-methyl)=~2,5-cyclo~ hexadienoyl, 2-behenoyloxy=2-methyl-propanoyl or ne octanoyl, and R, represents hydrogen or n-octanoyl, as well as the 2-palmitoylthio derivative thereof, lipopeptides such as n=lauroyleL-Ala-D-isoGln~{(m-DAF«~
Gly) =NH,, n-lauroyl=LeAla=D-isotln=(L=DAP-0ly)=NH,, n-lauroyl-L-Ala=D=i50Gln-(L-Lys=D-Ala)=NH,, n-octanoyle
L=Ala-D-is0Gln=(L=lys=D=Ala)=NH, or palmitoyl-Cys=(2R) 2¢3-dilauroyloxy=propyl)=Ala=D=Glu-(Gly~taurine=Na)=
NH, or are lymphokines which are produced by lympho=~ cytes, monocytes or macrophages after stimulation by antigenes or mitogenes,
Lymphokines are especially gamma interferon, especial ly natural or recombinant human gamma interferon, es=- pecially human gamma-interferon obtainable according to the European Patent Applications 63,482 (10-27-82); 77,670 (4-27=83); 83,777 (7-20=83); 88,540 (9-14-83); 89,676 (9-28-83); 95,350 (11-30-83); 99,084 (1-25-84); 110,044 (6-13-84); 112,967 (7-11=84); and the Inter= national (PCT) Applications (w0) 83/04,053 (11-24-83) or WO 84/02,129 (6-7-84).
Preferred is human gamma-interferon of the following amino acid sequences: “17 = Co — rec a
BAD ORIGINAL 9 \
aay : 26160
H N=Cys-Tyr-Cys-Gln-Asp=Pro-Tyr-Val-Gln-Glu=Ala=Glu-
Asn-LeusLys=Lys=Tyr-Phe=isn-Ala-Gly-His-Ser-Asp=Val=
Ala-Asp-Asn~Gly-Thr-Leu=Phe-Leu-Gly-Ile-Leu~Lys-Asn-
Trp=Lys-Glu-Glu-Ser-Asp-Arg-lys-Ile-Met-Oln-Ser-Gln-
Ile-Val-Ser-pPhe~Tyr=-Pho=Lys~lL,eu~Phe-Lys=Asn~Phe«Ly "=
Asp-Asp-Gln=~Ser-Ile-Gln-Lys~-Ser-Val=Glu-Thr=Ile~- .
Lys-0lu-Asp-Met-Asn-Val~Lys-Phe~Phe-Asn-Ser-Asn-Lys-
Lys=Lys~-Arg-Asp-Asp~Phe-Glu-Lys-Leu-ThreAsn~Tyr-Ser-
Val-Thr-Asp-Leu~Asn-Val-Gln~Arg-Lys-Ala-Ile-His-Glu= l0 Leu=Ile~-Gln-Val-Met-Ala-Glu-Leu=Ser-pPro-Ala=-Ala-Lys=-
Thr=Glu~Lys-Arg-Lys-Arg-Ser-Gln-Met~Leu-Phe-Gln=Gly-
Arg-Arg-Ala-Ser=Gln~OH, according to the Luropean Patent Application 121,157 (10-10-87) and
H,N-Cys-Tyr-Cys-Gln-Asp=Pro=Tyr-Val-Lys-Glu-Ala=
Glu-Asn-Leu-Lys-Lys=Thr-Phe-Asn-Ala=-0ly-His-Ser- . Asp-Val-Ala=-Asp-Asn-0ly-Thr-Leu-Phe-Leu-Gly~Ile-
Leu-Lys~Asn=Trp=-Lys-Glu-Glu-Ser-Asp-Arg-Lys-Ile=-
Met-Gln-Ser-Gln-Ile-Val-Ser-Phe~Tyr-Phe-Lys-Leu~
Phe-Lys-Asn=Phe-Lys=Asp=Asp~Gln-Ser-Ile-Gln-Lys=-
Ser-Val-Glu-Thr=Ile~Lys=Glu~Asp=Net-Asn~Val~Lys=
Phe-~Phe-Asn-Ser-Asn=Lys-Lys-Lys=Arg~Asp=-Asp=FPhe«=
Glu-Lys=Leu=Thr-Asn-Tyr-Ser-Val-Thr-Asp=LeusAsne
Val-Gln-Arg-Lys~Ala-Ile-His-Glu-Leu-Ile-Gln=Vale . 25 Met-Ala=Ulu-Leu~Ser-Pro~-Ala-Ala~Lys-Thr-Gly-Lys~
Arg-Lys=-Arg-Ser-Gln-Met-Leu~Phe-Arg-Gly-Arg-Arg=
7 {s ny : + 26160
Ala-Ser-Gln-OH, TT according to the British Patent Specification 2,107,718, human interleukine 2 obtainable, for example, from the culture filtrates of cell cultures of leukemia or lym=- phoma cslls after activation or stimulation with human
T-cell mitogenes and by purification with reverse phase
HPLC, culture filtrates that contain mixtures of come pounds known as migration inhibition factor (MIF), leus kocytes migration inhibition factor, macrophages, acti vating factor (MAF), colony stimulating factor, as well as interleukine 1 and 2 and gamma interfoner and which are obtained from cultures of human T-lymphocytes from the spleen or from peripheral blood after stimulation by antigenes or mitogenes, or example human T-cell leukemia~ lymphoma virus (HTLV I or II), phytohaemagglutinine, or concanavaline, especially those culture filtrates or isolates that contain a high percentnge of macrophage activating factor (MAF).
Preferred are N-acetylmuramyl=L-alanyl-D-isoglutaminyle-
L-alanine-2-(1,2-dipalmitoyl-sn-glycero-3~hydroxyphos~ phoryloxy)-ethylamide, sodium-N-acetyl~D-muramyle-Le alanyl-D-isoglutamine of the formula V, optionally in combination with purified, natural or recombinant human gamma interferon.
Lipids (compdnent d) selected from the group consiste ing of phosphatidylcholine, phosphatidyleerine, phos=~ phatidylinositol, phosphatidylglycerol and cardio~ lipin, are synthetic phospholipids or are mixtures of phospholipids having various acyl groups of dife
7H 26160 ferent molecular weight and structure, for example soy bean or chicken egg phosphatidylcholine or phos- phatidylchinoline from bovine brain, bovine liver or porcine liver, phosphatidylserine from bovine brain, phosphatidylinositol from soybean or from yeast, phosphatidylglycerol from egg yolk, or cardiolipin from bovine heart,
Derivatives of cholesterol are for example, chodestane, coprostene, ergosterol or stigmasterol,
The pharmaceutical compositions according to the pree sent invention, when applied in the form of liposomes, are characterized by their excellent phagocytosis.
For example, phagocytosis of multilamellar liposomes consisting of a 3:7 molar mixture of sodium=N-/T,2« di-(9=cis-octadecenoyl)-sn-glycero-3=phosphosthanol/~
N=-hydroxysuccinylamine (1) and dioleoylphosphatidyl= ’ ethanolamine (II) or sodiumeNe/1,2-di-(9=cis=octa= decenoyl)-sn-glycero-3-phosphoethanol/-N-hydroxygluta- rylamine (I) and dioleoylphosphatidylethanolamine (11) by mouse peritoneal macrophages is higher than phae gocytosis of multilamellar liposomes conaisting exe cluaively of phosphatidylethanolamine or of a 3:7 molar mixture of phospltidylserine and phosphatidyl= choline. This can be demonstrated in-vitro by incuba- tion of mouse peritoneal macrophages with multilamellar . 20 = LAQORIGINAL Py
2 ell : ‘ 26160 liposomes containing race amounts of 125, as a lipo- some marker. At regular intervals the cultures are washed and the amount of cell-associated radiation is determined. Moreover, liposomes consisting of phospholipids of formula I and II in a molar ration of 3:7 containing immunomodulators such as MDP and gamma interferon show higher activation of macrophages to the tumoricidal state at low doses than liposomes consisting of phophatidyl choline and phosphatidyl serine containing the same amount of MDP and gamma- interferon. This can also be shown in vitro by plat- ing peritoneal mouse macrophages in culture wells and activating the macrophages with multilamellar lipeo=- somes consisting of sodium-N-/T,2-di-(9~cia-octadece= noyl)-sn-glycero=-3-phosphoethanol/-N-hydroxysuccinyle amine (I) and dioleoylphosphatidylethanolamine (II) in a molar 3:7 ratio containing MDP dnd gamma inter ’ feron and with multilamellar liposomes consisting of phosphatidylcholine and phosphatidylserine in the same molar ratio containing MDP and gamma interferen.
The liposome preparations are used at a concentrae tion of 100 mmol of total phospholipid per well and contains 6 units redembinant immune gamma interfemen and 0.2 g MDP. After washing the wells 10" [12517 iododeoxyuridine « labeled BL6 melanoma cells are added. Cytoxity is determined after 72 hours of cocultivation by measuring the radioactivity asso ciated with the adherent viable target cells after washing the cultures three times with Hank's ba= lanced salt solution. Percent cytotoxicity can be calculated with respect to the counts per minute in control cultures containing unactivated macrophages and target cells.
The pharmaceutical compositions according to the pre pent invention, when applied in the form of lipe= somes, are also characterized by their excellent re- lease properties at low pH=values. The release pro- perties of liposomes consisting of disodium~Ne/T,2-diw (9=cis-octadecenoyl)-sn-glycero-3-phosphoethanol/-N= hydroxysuccinylamine and 1,2-di-(9=-cis-octadecenoyl)= sn-glycero-3-phosphoethanolamine in a molar ratio of . 3 : 7 are analyzed according to the fluorescence method to measure the leakage from liposomes at low pH-values as described by kllens et al. Biochemistry 1984, 23, 1532-1538. To investigate the pH dependence of leakage, liposomes are injected into buffer solu=- tions ranging from pH 4.0 to 7.4 and the percentage of the entrapped 8-aminonaphthalene~1,3,6-trisulfonic acid (ANTS) and p=xylylene-bisepyridinium dibromide (DPX) which replace the encapsuled pharmaceutica in i ar1g() this assay, is determined, Complete encapsulation of the water soluble fluorophore ANTS complexed with the "quencher" DPX extinguishes most of the ANTS fluorescence. Leakage of ANTS from the liposomes could be followed by the increase in fluorescence due to the relief of DPX "quenching's
It has now been found that there is essentially no leakage above pl 6.0. However, when the pH is de= creased, there is a concomitant enhancement in the amount of ANTS/DPX release from the liposomes with half maximal release occurring at approximately PH 4,5 and complete release at about 4.0.
It is known that pathologic tissues have an ambient pH that is considerably lower than that of normal tissues.
For example of primary tumors, metastasis, inflamma- . tion, and infection have reduced local pH-environments.
The liposomes of the present jnvention, therefore, would deliver their content, for example antiinflammatory drugs or {mmunoaodulators specifically to the site of inflammation, the primary tumor or metastasis and re- lease these drugs in the acidic environment of these pathologic tissues, For example, liposomes consist ing of a 3:7 molar mixture of disodium-N-/T,2-di-(9~- {a-octadecenoyl)-an-glycero-3-phoaphosthanol/-Hi-hy= droxysuccinylamine (I) and dioleoylphosphatidylethanol=
7alhp 26160 amine release more of their content, for example an effective dose of recombinant human gamma interferon, at low pH values, e.g. pH 4, than at higher or neu~ tral pH values. This can be shown in-vitro in buf- fer solutions of pH 7.4 and pH # by determining at regular time intervals the radiation of marked 125.
Interferon released from the lipids. For example, at a pH-value of about 4 more than 25% of enclosed gamma-interferon are released from liposomes after 180 minutes.
Therefore, the pharmaceutical compositions according to the present invention, when applied in the form of liposomes, are excellent administration systema for drug delivery to the reduced local pH environment of pathologic tissues. Therefore, they are especially useful in the cancer chemotherapy for combating meta- . static tumor cells.
Aqueous liposome dispersions wherein the phospholipids of the formulae I and II are the encapsulating material and compounds or a mixture of compounds having pharmae= cologic activity are encapsulated, optionally after cone centration or isolation of the liposomes, for example in the (ultra) centrifuge, are suitable for therapeutic pur=- poses for parenteral (bukkal, lingual, sub=lingual, 1.v.,
Yl 1 or1a() iece, topical, s.c., i.m. or nasal) administra= tion.
For parenteral administration (topical) the liposomes containing aqueous dispersion can be mixed with cus- tomary thickeners, for example hydroxypropylmethyl- cellulose, suitable preservatives, antioxidants and perfumes, and can be used in the form of a lotion or a gel for application to the skin or mucous mem- branes.
For parenteral administration, the aqueous dispersion of the enriched liposomes can be suspended in a suite able carrier liquid, for example sterile, calcium free, isotonic sodium chloride or glucose solution, optionally buffered to pH 7.2 = Tobe
The dosage of the active ingredient to be adminis- tered is generally the highest snd lowest dose amount as prescribed, for example in the Deutsches Arzneimite telbuch (DAB) [German Pharmacopoieia/ for the specific active ingredient for the particular form of adminise tration, the age of the patient and the health of the patient. Aqueous liposome dispersions also have ghe advantage, however, that active ingredients adminis. tered in smaller doses may, nevertheless, pass to the receptors and produce a therapeutic effect, or, on
2 (rly 26160 administration of higher doeges, undesirable side effects may be avoided,
The preferred dosage amount for the liposome encape sulated immunomodulators of the muramylpeptide or lipopeptide type is about 0.001 up to 10 mg/kg body weight per dose. For human gamma interferon or mixe tures containing MAF the preferred dosage amount is about 0.01 ml liposome dispersion per kilo body weight containing 100 ~ 1000 units of gamma interferon or MAF.
If muramylpeptides are administered in combination with gamma interferon, it is estimated that the highest dose to be applied to & human of about 70 kg weight is about 10 mg of liposomes per kilo body weight contain- ing 3 microgram of the muramylpeptide and 1500 units of gamma interferon. The highest and the lowest dose of the encapsulated material, the concentration of the i phospholipids in the aqueous phase as well as the con= centration of the encapsulated compounds can be varied according to results to be established experimentally in clinical trials.
The present invention preferably relates to pharma= ceutical compositions consisting of a) a phospholipid of the formula I,wherein m repre= sents two, Ry and R, are defined as above, X re= presents C,=Cy~alkylene, C,-Cy~nlkenylene or Cy=
2p » A )
Cy-alkylene substituted by hydroxy or a pharmaceu- tically acceptable salt thereof, b) a phospholipid of the formula II, wherein Ry and
Ry independently of each other represent straight chained C,0~Cyp-alkanoyl or C10=Cap=alkenoyl, c) a compound or a combination of compounds having pharmacological activity, and, optionally, a pharma- ceutically acceptable carrier solution buffered to pH 7e2=7ehts
More preferably, the present invention relates to pharmaceutical compositions consisting of a) a phospholipid of the formula I, wherein m repre=- sents two, Ry and R, are defined as above, X repree sents C,=Cj-alkylene or C,-Cj=~alkenylene, or a phar= maceutically acceptable salt thereof, : b) a phospholipid of the formula 1I, wherein Ry and
Ry independently of each other represent straight chained C,o=Cq=alkanoyl or Ci0=Copmalkenoyl, ¢) a compound or a combination of compounds selected from the group consisting of antiphlogistica and/or antiinflammatory agents, antibiotics, antileishmaniasis agents, antineoplastic agents and immunomodulators and, optionally, a pharmaceutically acceptable car= rier solution buffered to pH 7.2 = 7.4.
The present invention specifically relates to phar= maceutical compositions consisting of a) a phospholipid of the formula I, wherein m re- presents two, Ry and R, inde pendently of each other represent straight chained alkanoyl or alkenoyl with an even number from 10 to 20 carbon atoms, X repre- sents C,~Cy alkylene, for example 1,2-ethylene or 1,3-propylene, or C,-C,-alkenylene, for example, vinylene, or a pharmaceutically acceptable salt thereof, b) a phospholipid of the formula II, wherein Ry and
Ry, represent straight chained Cy o=Coo-alkenoyl with an even number from 10 to 20 carbon atoms, ¢) & compound or a combinatkton of compounds selected from the group consisting of antiphlogistics and/or . antiinflammatory agents, antibiotics, antineoplastic agents and immunomodulators and, optionally, & phare= maceutically acceptable carrier solution buffered to pH 7.2=Telte
The invention more specifically relates to pharma~ ceutical compositions consisting of a) a phospholipid of the formula I, wherein m repre- sents two, Ry and R, independently of each other res w 28 =
‘ 26160 present 9=cis~dodecenoyl, 9~cis~tetradecenoyl, 9- cis-hexadecenoyl, 6~cis-, 6-transe=, 9-cise=, 9« trans-, or ll-cis-octadecenoyl, or 9-cis-icosenoyl,
X represents C,~Cy=alkylene, for example 1,2~ ethylene or 1l,3-propylens, or C,-Cj~alkenylene, for example vinylene, or a pharmaceutically acceptable salt thereof, b) a phospholipid of the formula II, wherein Ry and
R, independently of each other represent 9ecis-do=- decenoyl, 9=cis~tetradecenoyl, 9-cis-hexadecenoyl, 6-cig~, 6-trans-, 9-cis-, 9=-trans-, or ll=-cis-octa= decenoyl, or 9-cis-icosenoyl, ¢) a compound or a combination of compounds selected from the group consisting of antiphlogistics and/or antiinflammatory agents, antibiotics, antineoplastic agents and immunomodulators, and, optionally, a pharmaceutically acceptable carrier solution buffered to pH 7.2-7.h4,
Especially, the present invention relates to phar= maceutical compositions consisting of a) sodium or disodium=N~-/I,2-di=(9=cis-octadecenoyl)= sn-glycero-3-phosphoethanol/-N-hydroxysuccinylamine or sodium or disodium-N-/I,2-di=(9=cis-octadecenoyl)= sn-glycero-3-phosphoethanol/=N-hydroxyglutarylamine,
tl 261 b) 1,2-di-(9=-cis-octadecenoyl)-sn-glycero-3~phospho- ethanolamine, ¢) a compound or a combination of compounds of the group consisting of diclofenac, pkrprofen, mitomycin, cytarabine, dactinomycin, daunorubicin, doxorubicine etoposide, Neacetylmuramyl-Lealanyl-D~isoglutaminyl-
L-alanine=2-(1,2=dipalmitoyl-sn-glycero-3-hydroxy- phosphoryloxy)=~ethylamide, sodium=N-acetyl=D-muramyle=
L-alanyl=-D-isoglutamine, sodium-N-acetyldesmethyls muramyl-L=alanyl-D-isoglutamine, purified, natural or recombinant human gamma interferon, interleukine 2, and compounds obtained from cultures of human T-lymphocytes from the spleen or from peripheral blood after stimula=- tion by antigenes or mitogenes and which are charac~ terized by a high percentage of macrophage activating factor (MAF), and, optionally, a pharmaceutically acceptable carrier solution buffered to pH 7e2 = Tole
Most preferred are pharmaceutical compositions cone sisting of a) sodium or disodium-N=/T,2-di-(9-cis-octadecenoyl)= sn-glycero-3-phospho-ethanol/-N-hydroxysuccinylamine or sodium or disodium-N=/T,2-di-(9-cis-octadecenoyl)- an-glycero-3-phosphoethanol/-N-hydroxyglutarylamine, b) 1,2-di=(9-cis-octadecenoyl)-sn-glycero-3-phospho- ethanolamine,
2-0 leq) 1 26160 ¢) a compound or a combination of compounds consist- ing of N-acetylmuramyl-L-alanyl-D-isoglutaminyl-Le alanine-2-(1,2-dipalmitoyl~sn-hydroxyphosphoryloxy)= ethylemide, sodium-N-acetyl-D-muramyl-L-alanyl-D-iso= glutamine, sodium-N-acetyldesmethylmuramyl-Lealanyle
D-glutamine, and purified, natural or recombinant human gamma interferon, and, optionally, a pharmaceutically acceptable carrier solution buffered to pH 7.2=7.k4.
The invention also relates to mixtures of synthetic phospholipids of the formulae I and II and, optionally, a lipid selected from the group consisting of phos- phatidylcholine, phosphatidylserine, phosphatidylino=~ sitol, phosphatidylglycerol, cardiolipin, and, ope tionally, cholesterol and its derivatives, especially mixtures wherein the ratio of the phospholipid (I) to the phospholipid (II) is from ahout 10 to 90 to about . 50 to 50 mole per cent. The ratio of 30 to 70 mole per cent is especially preferred. The mixtures are use ful for preparing liposomes in an aqueous phase containing the component c) «= compounds or a combination of com- pounds having pharmacological activity.
The invention also relates to a process for the pre- paration of the pharmaceutical compositions mentioned above or of the mixture mentioned above, characterized
Zl in that a) =a homogeneous mixture consisting of phospholipids of the formulae I and II, a lipophilic compound or mixture of compounds having pharmacological activity and, optionally, a lipid mentioned above from natural sources is prepared and, optionally, the homogeneous mixture thus obtained is dispersed in an aqueous phase or, b) a homogeneous mixture consisting of phospholipids of the formulae 1 and II and, optionally, a lipid mene tioned above from natural sources is prepared and, op- tionally, the homogeneous mixture thus obtained is dis= persed in an aqueous phase containing a hydrophilic com= pound or mixture of compounds having pharmacological activity and, if necessary, the aqueous dispersion thus obtained is buffered to pH 7.0 « 7.8 and, if desired, . non-encapsulated lipids and/or compounds having phar= macological activity are separated from the aqueous phase/or the liposomes thus obtained are concentrated or separated off from the aqueous phase,
The homogeneous mixture is prepared by formation of a film or of a lyophilisate,
The film is prepared according to method a) by dissolve
TU ly t 26160 ing the phospholipids (I) and (II) and the lipophilic compound or mixture of compounds and, optionally, a lipid mentioned above from natural sources or accorde ing to method b) by dissolving the phospholipids (I) and (II) and, optionally, a lipid mentioned above from natural sources in an organic solvent and stripe ring the solvent,
Suitable solvents are, for example, unsubstituted or substituted, for example, halogenated, aliphatic or cycloaliphatic hydrocarbons, for example n-hexane, cyclohexane, methylenechloride, or chloroform, alco- hols, for example methanol or ethanol, lower alkane= carboxylic acid esters or amides, for example acetic acid ethylester or dimethylformamide, or ethers, for example diethylether, tetrahydrofurane or dioxane, or mixtures of these solvents, The organic solvent is . subsequently stripped by applying a vacuum, preferably a high vacuum, or by blowing off with an inert gas, for example nitrogen.
The lyophilisate is formed according to method a) by dissolving the phospholipids (I) and (I1) and the li= pophilic compounds or mixture of compounds or accord=- ing to method b) by dissolving the phospholipids (I) and (II) in an organic solvent according to the method an, 26160 as described in the U.5. Patent Specification No. 4,311,712. Suitable solvents are in the solid form together with the phospholipids (I) and (11) at the temperature of the lyophilisation process and are having a melting point of more than 0°C., for example glacial acetic acid, benzene or dioxane, especially tert-butanol,
A homogeneous mixture may also be prepared by spraye drying a solution of the phospholipids (1) and (II) and of the encapsulating material in an organic solvent having a low boiling point such as chloroform. A pow= der is obtained by this method.
The ratio of the phospholipid component (1) to the phospholipid component (11) in the homogeneous mixture is approximately 10 v. 90 up to 50 v. 50 mole per cent.
Preferred is the ratio 30 ve. 70 mole per cent, The approximate ratio of the molar amounts of the encape~ sulated material (gamma=interferon) divided by the total amount of the phospholipids (I) and (II) is about 0.0001 to O.1 v. 1.0, preferably 0.005 to 0.01 v. Ole
The dispersion is carried out by mechanical agitation (shaking, stirring, Vortex mixer) the aqueous phase to which according to method a) the homogenous mixture ily, 26160 3 sa" of the phospholipids (I) and (II) and the lipophilic compounda or the lipophilic mixture of compounds have ing pharmacological activity have been added, Accord~ ing to method b) the aqueous phase containing the hy=- drophilic compounds or mixture of compounda having pharmacological properties is added to the homogeneous mixture of the phoapholipide (I) and (II).
A mixture of small, large, unilamellar or multilamel=- lar liposomes is formed spontaneously at a high rate without supplying external energy. Approximately O,1 to UO per cent per weight, preferably 2 to 20 per cent per weight, of the homogeneous mixture relative to the total weight of the aqueous dispersion can be dise persed in the aqueous phase, Such dispersions can further be diluted to about 1 micromole lipid per ml.
Such liposome dispersions have entrapped approximate- ly 2.5 microliters of the aqueous phase per micromole of the lipid.
Acidic or basic aqueous dispersions are buffered to approximately pH 7.0 - 7.8, preferably 7.2 = 7.lk.
Preferably, the dispersion is carried out in an aqueous phase having a pH from 7.2 to 7.h.
Method a) is preferred in the event that lipnphilic water insoluble compounds are encapsulated in lipoe somes, for example lipophilic muramyltripeptides.
Method b) is preferred in the event that hydrophilic water insoluble compounds are encapsulated in lipo= somes, for example cytarabine or cytostatic compounds such as triflosfamide.
The preparation of the pharmaceutical compositions according to the present invention in the form of lipo- somes can also be carried out by other methods known in the art for preparing liposomes, for example by sonication with ultrasonic waves, by infusion methods or reversed phase evaporation.
The dispersion step is performed at temperatures bee low 60°, preferably at room temperature, In case of a potential thermal sensitivity of the encapsulated . material, the dispersion is carried out under cooling and , optionally, under inert gas atmosphere, for exam=~ ple nitrogen or argon atmosphere.
The liposomes obtained can be made storage stable in the aqueous phase up to several weeks or months after addition of stabilizers, for example mannite or lactose.
The size of the liposomes formed depends, inter alia, on the structure of the active ingredient and the
Tl lun ] ' 26160 lipid component, the mixing ratio of the components and the concentration of these components in the aqueous dispersion. Thus, for example, by increase ing or reducing the concentration of the lipid compo- nents aqueous phases having a high content of small or large liposomes are produced.
The separation of small liposomes from large liposomes is effected by means of conventional separation methods, for example sedimentation of the large liposomes in an ultracentrifuge, by gel filtration or extrusion through straight-pored filters. For example, on centrifuging, for example from 5 to 60 minutes in a rotational field giving rise to an inertial force equivalent to a gravis tational field of 5000-40 000 x g, large liposomes are deposited at the bottom of the vessel, whilst small liposomes remain dispersed and can be decanted off. . After repeated centrifugation, complete separation of ‘ large liposomes from small liposomes is achieved,
Preferably, liposomes are separated from the aqueous phase in the event that according to method b) the aqueous phsse contains non-encapsulated water insoluble compounds or pharmaceuticals. Especially, water 80« juble antineoplastic agents, for example alkylating agents such as cyclofosfamide, should be separated off any 26160 by filtration, ultrafiltration, dialysis or by cen- trifugation in order to prevent eventual side effects caused by non-encapsulated compounds. The liposome fraction can be admixed with a carrier solution buf= fered to pH 7.2 = 7.4, for example isotoniq sterile sodium chloride solution buffered to pH 7.2 = 7.he
Liposomes in the aqueous phase having a diameter greater than 6.0 x 1078 m, for example large multila=- mellar liposomes, can be separated off by gel filtra= tion, for example with Sepharose or Sephacryl as care riers.
By extrusion through straight-pored filters, for exam=- ple membrane filters of the acrodisct®, Nucleopore' ®) or polycarbonate type having a pore diameter of approximately 1.0 x 1078 - 1.0 x 1078 m at a pressure of approximately from 0.1 to 1.5 bar and a filtration rate of approximately 20 ml/h, a particularly uniform size distribution of the liposomes is obtained.
The formation of liposomes and their content in the aqueous phase can be detected in a manner known per ge by using various physical analytical methods, for example by microscopy of freeze-fracture samples and thin sections in an electron microscope, by X=ray re= i.
L 0) 0 1 26160 prog NY fraction, by dynamic light scattering, by mass detere mination of the filtrate in an analytical ultracen- trifuge and, especially, by spectroscopy, fer exame ple in the nuolear magnetic resonance spectrux x, 136 and 3%),
Synthetic phospholipids of tha formula I are known.
Their preparation as intermediates has boen described in tho European Patent Application No. 56992.
The phospholipids of the formula II are all known.
Some of them are commercially available (Avantd, Fluka,
Serva, Signa).
The pharmaceuticals mentioned above, especially the antiphlogistic, antirheumatic, antileishmaniasis agents, antimyocoticr, antibiotics or antineoplastic agents are all known see, for example, MERCK Index,
Tenth Edition.
The preperation of muramylpeptides of the formula V has been desoribed in the British Patent Bpecifioa- tion 1,570,625, and in the European Patent Applicae tions 25,495 (3-25-81f and 21,367 (1-7-81). Immunce modulators of the lipopeptide type are also knowm, see European Patent Application 114,787 and European
Patent Specification 330,
The preparation of purified, natural or recombinant, -39- on ORIGINAL 2
Zul 26160 ganna interferon has been described 4n the European patent Application 63,482 (10-27-82) 77,670 (h=27-83)18 83,540 (7-13=83)1 89,676 (9-28-83)% 95,350 (11-30-8303 99,08% (1-25-8l)3 110,0kl (6-13-84)3 112,976 (7-11-8%)3 121,157 (10-10-84) in the British Patent ppecification 2,107,718 as vell as in the International (PCT) Appli~ cations (WO) 83/04053 (11-24-83) or VO 8402129 (6-7-84)¢
The preparation of purified interleukine 2 is dese oribed in the European patent Application 106,179 (4-29-84) and in the US Patent gpecification ih 448,879.
The buffer solutions of pH 7,0 to 7,8 preferably sre sterile phosphate puffer solutions vased on the dihy- } arogenphosphate/nydrogenphosphate equilibrium (xfy- ; pO, /Na HPO)» The preperation of these duffer solue 19 tions ia described in standard oanuals, for example . vHuger's Handbuch der Pharmaseutischen Praxis’, springer verlag, Vole 1, PE. 357-359. Especially sterile, jeotonic caloiunefree puffer selution of pR
IY (Dulbecco) OF Hank's Balanced galt Solution (Mahe ploproducts, walkersville MD USA) is used.
The following examples are j11ustrating the invention without 1imiting the ecope thereof. Temperatures are given in degrees Celaiun.
Example 1! a) Ina round flask 84,70 mg (0,098 mmol) swe oan »
Co BAD ORIGINAL om —
TOI e160
Se ! disodiumeN=/T,2-di=(9=cis=octadecenoyl)=~sn=glycero- 3-phoaphoethanol/=-N«hydroxysuccinylamine and 168.10 mge (0.226 mmol) 1,2-di=(9=-cis-octadecenoyl)~sn= glycero-3-phosphoethanolamine are dissolved in a sufficient amount of tert-butanol until both lipids are dissolved. The solution is filtered under sterile conditions over rorodisct® filter (2.0 x 1077 m) and is bottled in a sterile vial, This vial is frozen at =45°, A vacuum is applied to the frozen vial and the solvent is removed until room temperature has been reached. The vial is sealed under inert gas atmos- phere, for example argon atmosphere.
To this vial containing a lyophilisate of the lipid components mentioned above, 2.5 ml. of a sterile, phosphate buffered (pH 7.2 = 7.4), calcium free so- dium chloride solution (Dulbecco) containing doxorubi- : cin in a concentration of 4 g/l are added with a sterile syringe. The vial is then shaken for ten minutes on a standardized laboratory shaker (Vortex, speed 6) and is placed in a centrifuge. After centri fugation in a gravitational field of about 40,000 x ge. for about 60 minutes, the supernatant is decanted,
The liposome dispersion is resuspended in 2.5 ml. 0.85% sterile, phosphate buffered (pH 7.2 = 7.4) mo=
Tig 26160 dium chloride solution (Dulbecco). The centrifuga= tion and resuspension are repeated until the super- natant is free of doxorubicin. The liposome disper= sion obtained is suitable for parenteral administra- tion. b) Preparation of sodium-N=/T,2-di=(9-cis-octadecenoyl)= 200.6 mg (270 micromol) 1,2-di=(9-cis-octadecenoyl)= sn-glycero-3-phosphoethanolamine are dried under nitrogen and placed under high vacuum for two hours.
The dry lipid is dissolved in 10 ml. of freshly disé tilled pyridine containing S54 mg. (540 micromol) sucw cinic acid anhydride. The reaction mixture is stirred for two hours under nitrogen atmosphere at 55°, The excess pyridine is removed by evaporization under re= duced pressure and the excess succinic acid anhydride ) is hydrolyzed by suspending the residue in a mixture of chloroform=methanod=0.58% aqueous sodium chloride solution (1:2:0.8 v/v). The product is extracted by partitioning after addition of one volume chloroform and one volume 0.58% aqueous sodium chloride solution,
The lower phase is washed three times with a mixture of chloroform=methanol=0.58% aqueous sodium chloride solution (3:48:47 v/v). The solvent is removed by
) “2160 rotary evaporation and the residue is resuspended in chloroform. Rf (Merck silicagel 60 plates): 0.375 (chloroform, methanol, water-65/25/4); UV: 254.6 nm (broad); m.p. 154°C.
Example 2: In a manner analogous to Example 1 aqueous liposome dispersions are prepared containing 84.70 mg (0.098 mmol) disodiun-N/1,2-di-(9-cis-octadecenoyl)= sn-glycero-3-phosphoethanol/~N=hydroxy-succinylamine and 168.10 mg (0.226 mmol) 1,2-di-(9=cis-octadecenoyl)= an-glycero-3~phosphoethanolamine and 0.1 mg up to 10 mg N-acetyl-L-muramyl«L~alanyl-D-isoglutamine-sodium salt or 0,1 mg up to 10 mg N-acetyldesmethylmuramyle
L-alanyl-D-isoglutamine-sodium salt or 1000 to 100,000 units of recombinont human immune gamma-interferon ob- tainable according to LP«A-121,157 (Kyowa Hakko Kogyo
Co.) or a combination of 1000 to 1000,000 units of i this recombinant human immune gamma~interferon with 50-200 microgram sodjum-N-acetyl-Demuramyl-L-alanyl=-
Deisoglutamine or sodium-N-acetyldesmethylmuramyl.
L-alanyl=D=igsoglutamine.
Example 3: a) In a round flask 84,70 mg (0,098 mmol) disodium-N-/T,2-di=(9-cis-octadecenoyl)-sn-glycero~3- phosphoethanol/-N=-hydroxyauccinylamine and 168.10 mg (0.226 mmol) 1,2-di=(9-cis=-octadecenoyl)-sneglycero= - 43 a ae / {4 0 26160 3-phosphoethanolamine are dissolved in a sufficient amount of tert-butanol until both lipids are dis- solveds The solution is filtered under sterile cone ditions over porodisc‘®) filter (2.0 x 10°" m) and is bottled in a sterile vial. This vial is rotated at 1750 rpm (rotations per minute) and the solvent is : removed in a stream of purified, filtered (at the pressure of 1 bar) dry nitrogen. The vial is eva= cuated in a high vacuum of 6.0 x 10™2 mbar and is stable under argon inert gas atmosphere,
To this vial containing a thin film of the lipid com= ponents mentioned above, 2.5 ml. of a sterile, phos- phate buffered (pH 7.2-7.4), calcium free sodium chloride solution (pulbecco) containing diclofenac in a concentration of 2 g/1 are added with a sterile syringe. The vial is then shaken for ten minutes on ’ a standardized laboratory shaker (Vortex, speed 6) and is placed in a centrifuge. After centrifugation in a gravitational field of about 40,000 x ge for about 60 minutes the supernatant is decanted. The liposome dispersion is resuspended in 2.5 ml. 0.85% sterile, phosphate buffered (pH 7.2 = 7.4) sodium chloride solution (Dulbecco) and is suitable for parenteral administration. - bly -
Example 4: In a round flask O.1l mg N-acetylmuramyl
L-alanyl=D-isoglutaminyl-L~alanine-2-(1,2-dipalmi= toyl-sn-glycero=3-hydroxyphosphoryloxy)-ethylamide (preparation according to European Patent Specifie cation 25,495), 84,70 mg (0.098 mmol) disodium-N- /T,2-di~(9-cis-octadecenoyl)~sn-glycero=3-phospho= ethanol/~Nehydroxysuccinylamine and 168.10 mg (0.226 mMol) 1,2-di~=(9-cis-octadecenoyl)-sn-glycero~3~phos= phoethanolamine are dissolved in a sufficient amount of sterile tert-butanol until all components are dis~ solved. The solution is filtered under sterile eed ditions over Acrodisc‘® filter (2.0 x 1077 m) and is bottled in a sterile vial. The vial is rotated at 1750 rpm and the solvent is blown of ff in a stream of purified, filtered (at the pressure of 1 bar) dry nitrogen. The vial is evacuated in a high vacuum of 6.0 x 1072 mbar and is sealed under argon inert gas atmosphere.
To this vial containing a thin film of the components mentioned above 10 ml. of a sterile, phosphate buf fered (pH 7.2 - 7.4), calcium free sodium chloride solution (Dulbecco) are added with a sterile syringe.
The vial is then shaken for 10 minutes on a standardized laboratory shaker (Vortex, speed 6). The liposomes dispersion obtained is storage stable at 4° and is
7 1G 26160 suitable for parenteral administration,
Example 5: In a round flask 0.1 mg Neacetylmuramyl-
LealanyleD-isoglutaminyleLealanine-2-(1,2-dipalmi= toyl-sn-glycero-3-hydroxyphosphoryloxy)=-ethylamide (preparation according to European Patent Specification 25,495), 84.70 mg (0.098 mmol) disodium=Ne/T,2-di=(9= cis-octadecenoyl)-sn~glycero-3-phosphoethanol/-N-hy~ droxysuccinylamine and 168.10 mg (0.226 mmol) 1,2-di~ (9=-cis=octadecenoyl)=sn-glycero=3-phosphoethanolamine are dissolved in a sufficient amount of sterile tert butanol until all components are dissolved. The so« lution is filtered under stiler conditions over acrodise® filter (2.0 x 107 m) and is bottled in a sterile vial. This vial is frozen at -45°, A vacuum is applied to the frozen vial and the solvent is re- moved until room temperature has been reached. The . vial is sealed under argon inert gas atmosphere,
To this vial containing a lyophilisate of the compo- nents mentioned above 10 ml. of a sterile, phosphate buffered (pH 7.2 = 7.4), calcium free sodium chloride solution (Dulbecco) are added with a sterile syringe.
The vial is then shaken for 10 minutes on a stan-~ dardized laboratory shaker (Vortex, apeed 6). The liposome dispersion obtained is storage stable at 4°
20 J 26160 and is suitable for parenteral administration,
Example 6: In a manner analogous to Examples 4 or S liposome dispersions are prepared containing 0.1 mg. to 10 mg N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L= alanine-2-(1,2-dipalmitoyl-sn-glycero-3-hydroxyphose phoryloxy)=-ethylamide, 84,70 mg (0.098 mmol) disodium~
N=/T,2-di=(9-cis~octadecenoyl)-sn=glycero-3=~phosphow ethanol/-N-hydroxy-succinylamine and 168,10 mg (0.226 mmol) 1,2-die(9-cis~octadecenoyl)-sn-glycero=3-phos= phoethanolamine,
Example 7: In a manner analogous to Example 1 lipo~ some dispersions are prepared containing 86.3 mg (0.098 mmol) disodium-N-/T,2-di=(9~cis-octadecenoyl)~sn-gly= cero=3-phosphoethanol/-N«hydroxyglutarylamine and 168.1 mg (0,026 mmol) 1l,2-di=(9~cis~octadecenoyl)=-sn-glycero=- 3-phosphoethanolamine and 0.1 mg up to 10 mg Neacetyl-
Lemuramyl=L-alanyl-D-isoglutamine~sodium salt or 0,1 mg up to 10 mg N~acetyl-desmethylmuramyl-Lealanyle=De= isoglutamine sodium salt,
Claims (1)
- WHAT IS CLAIMED 1S:1. A pharmaceutical composition consisting of a) a phospholipid of the formula an 1 CH,=0=R 2 = 272 (1. 3 R,0-CH 0 0 ©H.«0~P=O0=(CH,) -NH C-X~C=OH CHy=0-F 2'n OH wherein m represents two, Ry and R, represent acyl each having from 10 to 20 carbon atoms, X represents C,~Cj-alkylene, or a pharmaceutically acceptable salt thereof, b) a phospholipid of the formula sn 1 CH,~0-R —z v2 (11), 3 R), 0-CH -4 . © i CH y=0~P=0~CH; =CH NM 0 wherein Ry and Ry, represent the acyl group of a satue rated or an unsaturated carboxylic acid having from 10 to 20 carbon atoms and 1 = 2 double bonds, ¢) a compound or a mixture of compounds having im- munomodulatory action or antineoplastic properties, and, optionally,ayn ' 26160 d) a lipid from natural sources selected from the group consisting of phosphatidylcholine, phosphatidyl=~ serine, phosphatidylinositol, phosphatidylglycerol, cardio= lipin and cholesterol and its derivatives, and, op=~ tionally, a pharmaceutically acceptable carrier solu tion buffered to pH 7.0 = 7.8, and, optionally, pharma- ceutically acceptable additives. 2e A pharmaceutical composition according to Claim 1 consisting of a) a phospholipid of the formula I, wherein m repre= sents two, Ry and R, are defined as in Claim 1, X re=- presents C,=Cj~alkylene, or a pharmaceutically accept~ able salt thereof, b) a phospholipid of the formula II, wherein Ry and Ry, independently of each other represent straight chained C10"C20 ~alkanoyl or C10=Cro=alkenoylo ¢) a compound or a combination of compounds having immunomodulatory action or antineoplastic agents, and. optionally, a pharmaceutically acceptable carrier lution buffered to pH 7.2=7.4, ‘ “, Se A pharmaceutical composition according te Claim 1 consisting of a) a phospholipid of the formula I, wherein m repre=-_ Or ® <P, > 2%; - %s %, > Yo % on - 49 9 3—_ . ‘> * BAD ORIGINAL 9 ¢ZG sents two, Ry and R, independently of each other re- present straight chained alkanoyl or alkenoyl with an even number from 10 to 20 carbon atoms, X repre~ sents C,-Cy=alkylene, or a pharmaceutically accepts bo) able salt thereof, b) a phospholipid of the formula II, wherein Ry and Ry, represent straight chained Cy o-Cpp=alkenoyl with an even number from 10 to 20 carbon atoms, ¢) a compound or a combination of compounds having {immunomodulatory action or antineoplastic agents and, optionally, a pharmaceutically acceptable carrier so= lution buffered to pH 7.2-7.k. 4, A pharmaceutical composition according to Claim 1, consisting of a) = phospholipid of the formula I, wherein m repre- sents two, Ry and R, independently of each other re= present 9-cis-octadecenoyl, X represents 1,2-ethylene or l,3-propylene, or a pharmaceutically acceptable salt thereof, b) a phospholipid of the formula II, wherein R, and Ry, represent 9-cis-octadecenoyl, ¢) ' a compound or a combination of compounds having immunomodulatory action or antineoplastic agents and, eo 50 »optionally, a pharmaceutically acceptable carrier solution buffered to pH 7.2-7.h. Se A pharmaceutical composition according to Claim 1, consisting of a) sodium~N-/1,2-di-(9=cis-octadecenoyl)=-en=glycero= 3-phosphoethanol/-N-hydroxysuccinylamine or sodiume N-/1,2-di-(9-cis-octadecenoyl)~-sn=glycero-3-phospho=~ ethanol/-N-hydroxyglutarylamine, b) 1,2-di~(9-cis-octadecenoyl)=-sn=glycero-3-phoepho= ethanolamine, d) a compound or a combination of compounds having immunomodulatory action or antineoplastic agents and, optionally, a pharmaceutically acceptable carrier so~- lution buffered to pH 7.2-7.h.6. A pharmaceutical composition according to Claim 1, consisting of a) sodium-N-/T,2-di=(9=cis-octadecenoyl)~sn=glycero= 3-phosphoethanol/-N-hydroxysuccinylamine or sodium=Ne« [Iy2-di=(9-cis-octadecenoyl)~-nn-glycero=3-phospho= ethanol/-N-hydroxyglutarylamine, b) 1,2-die(9=-cis-octadecenoyl)=-sn-glycero-3-phospho= ethanolamine, ¢) a compound or a combination of compounds selectedOil 26160 from the group consisting of diclofenac, pirprofen, mitomycin, cytarabine, dactinomycin, daunorubicin, doxorubicine, etoposide, N-scetylmuramyl-L-alanyl-D- isoglutaminyl-L-alanine-2~-(1,2-dipalmitoyl-sn-glycero= 3-hydroxyphosphoryloxy)=-ethylamide, N-acetylmuramyle L=alanyl=D-glutamic acid=-(C / —alanine-2-(1,2-dipalmi- toyl-sn-glycero=~3-hydroxyphosphoryloxy)~-ethylamide~ disodium salt, N-acetyl-D-muramyl-L-alanyl-D-isoglu= tamine-sodium salt, N-acetyldesmethyl-muramyl-L-alanyle p-isoplutamine-sodium salt, N-acetylmuramyl=L-alanyle D-glutamine-cp-n-butylester, NL (N-acetylmuramyl-L-alanyl= D-isoglutaminyl)~N’ ~stearoyl=L-lysine, 6-O=stearoyle Neacetylmuramyl-L-alanine=-D-isoglutamine and lymphoe kines, and, optionally, a pharmaceutically acceptable carrier solution buffered to pH 7.2 =~ Pelte Te A pharmaceutical composition according to Claim ’ 1, consisting of a) sodiun-N=/T,2-di-(9-cis-octadecenoyl)-sn=glycero= 3-phosphoethanol/-N-hydroxysuccinylamine or sodiume N-/T,2-d1=(9-cis-octadecenoyl)-sn-glycero-3-phospho= ethanol/-N-hydroxyglutarylamine. b) 1,2-di-(9-cis-octadecenoyl)-sn-glycero-3-phospho= ethanolamine, ¢) a compound or a combination of compounds selected) 26160 from the group consisting of diclofenac, pirprofen, mitomycin, cytarabine, dactinomycin, daunorubicin, doxorubicine, etoposide, N-acetylmuramyl-L-alanyle D-isoglutaminyl-Lealanine-2-(1,2-dipalmitoyl-en=gly~ cero-3-hydroxyphosphoryloxy)-ethylamide, sodium=N=- acetyl-D=muramoyl-L-alanyl-D-isoglutamine, sodium=Ne acetyldesmethylmuramyl-L-alanyleD-isoglutamine, puri= fied, natural or recombinant human gamma interferon or interleukine 2, and, optionally, a pharmaceutically acceptable carrier solution buffered to pH 7e2=7.h,8. A pharmaceutical composition according to Claim 1, consisting of a) sodium-N-/T,2-di-(9-cis-octadecenoyl)-en-glycero= 3-phosphoethanol/-N-hydroxysuccinylamine or sodiume Ne/1,2-di=(9-~cis-octadecenoyl)-sn-glycero-3-phos- phoethanol/-N-hydroxyglutarylamine, b) 1,2-di-(9-cis-octadecenoyl)-sn-glycero-3-phospho- ethanolamine, ¢) a compound or a combination of compounds consist= ing of Neacetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine= 2-(1,2-dipalmitoyl-sn=hydroxyphosphoryloxy)=ethylamide, sodium~N-acetyl-D-muramyl-L-alanyl-D~isoglutamine, B0= dium-N-acetyldesmethylmuremyl=Lealanyl-D-isoglutamine, and purified, natural or recombinant human gamma inter-7 U/l 26160 feron and, optionally, a pharmaceutically acoept= able carrier solution buffered to pH 7e2=Tolte9. A pharmaceutical composition according to Claim 1, wherein the ratio of the phospholipid com= ponent (I) to the phospholipid component (11) is approximately 10 = 90 to approximately 50 = 50 mole per cent.10. A pharmaceutical composition according to Claim 10, wherein the ratio of the phospholipid com= ponent (I) to the phospholipid component (11) is approximately 30 - 70 mole per cent.11. A mixture suitable for the preparation of a pharmaceutical composition according to Claim 1 con=~ taining a) a phospholipid of the formula I, } b) a phospholipid of the formula II, and, optionally, a lipid from natural sources selected from the group consisting of phosphatidylcholine, phosphatidylserine, phosphatidylinoaitol, phosphatidylglycerol, cardio= lipin and, optionally, cholesterol and its derivae tives. ALAN JAY SCHROIT RAJIV NAYAR Inventors - 5h -
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US76662585A | 1985-08-19 | 1985-08-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
PH26160A true PH26160A (en) | 1992-03-18 |
Family
ID=25077017
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PH34151A PH26160A (en) | 1985-08-19 | 1986-07-18 | Pharmaceutical compositions consisting of acylated phospholipids |
Country Status (18)
Country | Link |
---|---|
EP (1) | EP0213523B1 (en) |
JP (1) | JPS6296431A (en) |
KR (1) | KR870001838A (en) |
AT (1) | ATE59002T1 (en) |
AU (1) | AU591162B2 (en) |
CA (1) | CA1273575A (en) |
DD (1) | DD248736A5 (en) |
DE (1) | DE3676133D1 (en) |
DK (1) | DK165314C (en) |
ES (1) | ES2001099A6 (en) |
FI (1) | FI863311A (en) |
GR (1) | GR862144B (en) |
HU (1) | HU206045B (en) |
NO (1) | NO171886C (en) |
NZ (1) | NZ217239A (en) |
PH (1) | PH26160A (en) |
PT (1) | PT83204B (en) |
ZA (1) | ZA866200B (en) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0256989A1 (en) * | 1986-08-18 | 1988-02-24 | Board Of Regents, The University Of Texas System | Pharmaceutical administration systems containing chemotactic peptides |
DK86988A (en) * | 1987-02-25 | 1988-08-26 | Takeda Chemical Industries Ltd | LIPOSOM PREPARATION AND APPLICATION THEREOF |
WO1991014423A1 (en) * | 1990-03-20 | 1991-10-03 | Otsuka Pharmaceutical Co., Ltd. | Liposome preparation |
NZ267310A (en) * | 1993-05-21 | 1996-09-25 | Liposome Co Inc | Liposome compositions with reduced adverse physiological reactions |
ATE198419T1 (en) * | 1994-10-14 | 2001-01-15 | Liposome Co Inc | ETHERLIPID LIPOSOMES AND THEIR THERAPEUTIC USE |
US6589503B1 (en) | 1998-06-20 | 2003-07-08 | Washington University | Membrane-permeant peptide complexes for medical imaging, diagnostics, and pharmaceutical therapy |
US8038984B2 (en) | 1998-06-20 | 2011-10-18 | Washington University | Membrane-permeant peptide complexes for treatment of sepsis |
US7306784B2 (en) | 1998-06-20 | 2007-12-11 | Washington University | Membrane-permeant peptide complexes for medical imaging, diagnostics, and pharmaceutical therapy |
WO2006026184A2 (en) | 2004-08-20 | 2006-03-09 | Washington University | Blood brain barrier permeation peptides |
JP2006248978A (en) * | 2005-03-10 | 2006-09-21 | Mebiopharm Co Ltd | New liposome preparation |
EP3676296A1 (en) | 2017-08-30 | 2020-07-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Anti-mesothelin radiolabelled single domain antibodies suitable for the imaging and treatment of cancers |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3218027A1 (en) * | 1982-05-13 | 1983-11-17 | A. Nattermann & Cie GmbH, 5000 Köln | PHOSPHOLIPID SOLUTIONS |
-
1986
- 1986-07-18 PH PH34151A patent/PH26160A/en unknown
- 1986-08-14 PT PT83204A patent/PT83204B/en not_active IP Right Cessation
- 1986-08-15 CA CA000516015A patent/CA1273575A/en not_active Expired - Fee Related
- 1986-08-15 FI FI863311A patent/FI863311A/en not_active Application Discontinuation
- 1986-08-18 JP JP61191795A patent/JPS6296431A/en active Pending
- 1986-08-18 AU AU61556/86A patent/AU591162B2/en not_active Ceased
- 1986-08-18 NZ NZ217239A patent/NZ217239A/en unknown
- 1986-08-18 HU HU863618A patent/HU206045B/en not_active IP Right Cessation
- 1986-08-18 DE DE8686111368T patent/DE3676133D1/en not_active Expired - Fee Related
- 1986-08-18 KR KR1019860006783A patent/KR870001838A/en not_active Application Discontinuation
- 1986-08-18 ZA ZA866200A patent/ZA866200B/en unknown
- 1986-08-18 NO NO863315A patent/NO171886C/en unknown
- 1986-08-18 DD DD86293707A patent/DD248736A5/en not_active IP Right Cessation
- 1986-08-18 GR GR862144A patent/GR862144B/en unknown
- 1986-08-18 ES ES8601163A patent/ES2001099A6/en not_active Expired
- 1986-08-18 DK DK392786A patent/DK165314C/en not_active IP Right Cessation
- 1986-08-18 EP EP86111368A patent/EP0213523B1/en not_active Expired - Lifetime
- 1986-08-18 AT AT86111368T patent/ATE59002T1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
HUT41634A (en) | 1987-05-28 |
GR862144B (en) | 1986-12-23 |
KR870001838A (en) | 1987-03-28 |
CA1273575A (en) | 1990-09-04 |
NO863315L (en) | 1987-02-20 |
DD248736A5 (en) | 1987-08-19 |
PT83204A (en) | 1986-09-01 |
EP0213523B1 (en) | 1990-12-12 |
FI863311A0 (en) | 1986-08-15 |
FI863311A (en) | 1987-02-20 |
PT83204B (en) | 1989-03-30 |
DK165314C (en) | 1993-03-29 |
DE3676133D1 (en) | 1991-01-24 |
NO863315D0 (en) | 1986-08-18 |
ATE59002T1 (en) | 1990-12-15 |
NO171886C (en) | 1993-05-19 |
NZ217239A (en) | 1989-09-27 |
DK392786A (en) | 1987-02-20 |
DK392786D0 (en) | 1986-08-18 |
EP0213523A3 (en) | 1987-10-14 |
ES2001099A6 (en) | 1988-04-16 |
ZA866200B (en) | 1987-03-25 |
JPS6296431A (en) | 1987-05-02 |
EP0213523A2 (en) | 1987-03-11 |
HU206045B (en) | 1992-08-28 |
AU591162B2 (en) | 1989-11-30 |
DK165314B (en) | 1992-11-09 |
AU6155686A (en) | 1987-02-26 |
NO171886B (en) | 1993-02-08 |
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