WO2007057005A1 - Lipopeptide compositions - Google Patents
Lipopeptide compositions Download PDFInfo
- Publication number
- WO2007057005A1 WO2007057005A1 PCT/DE2006/002064 DE2006002064W WO2007057005A1 WO 2007057005 A1 WO2007057005 A1 WO 2007057005A1 DE 2006002064 W DE2006002064 W DE 2006002064W WO 2007057005 A1 WO2007057005 A1 WO 2007057005A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amphomycin
- cyclodextrin
- derivatives
- lipopeptide
- weight
- Prior art date
Links
- 108010028921 Lipopeptides Proteins 0.000 title claims abstract description 84
- 239000000203 mixture Substances 0.000 title description 14
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 79
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 30
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- -1 carboxylphenyl Chemical group 0.000 claims description 65
- 239000011575 calcium Substances 0.000 claims description 48
- HVYFVLAUKMGKHL-USKUEUQVSA-N friulimicin Chemical class O=C1[C@H](C(C)C)NC(=O)[C@@H]([C@@H](C)N)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H]([C@H](C)C(O)=O)NC(=O)[C@H]2CCCCN2C(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)C\C=C/CCCCCCCC(C)C)[C@H](C)NC(=O)[C@@H]2CCCN21 HVYFVLAUKMGKHL-USKUEUQVSA-N 0.000 claims description 40
- HVYFVLAUKMGKHL-UHFFFAOYSA-N friulimicin B Chemical class O=C1C(C(C)C)NC(=O)C(C(C)N)NC(=O)CNC(=O)C(CC(O)=O)NC(=O)CNC(=O)C(CC(O)=O)NC(=O)C(C(C)C(O)=O)NC(=O)C2CCCCN2C(=O)C(NC(=O)C(CC(N)=O)NC(=O)CC=CCCCCCCCC(C)C)C(C)NC(=O)C2CCCN21 HVYFVLAUKMGKHL-UHFFFAOYSA-N 0.000 claims description 35
- 108010048810 friulimicin B Chemical class 0.000 claims description 35
- 229940097362 cyclodextrins Drugs 0.000 claims description 34
- 108010079465 amphomycin Proteins 0.000 claims description 32
- 230000003115 biocidal effect Effects 0.000 claims description 21
- XBNDESPXQUOOBQ-LSMLZNGOSA-N (2r,3s)-4-[[(2s)-1-[[2-[[(2s)-1-[[2-[[(2r,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-[(3s,9ar)-1,4-dioxo-3,6,7,8,9,9a-hexahydro-2h-pyrido[1,2-a]pyrazin-3-yl]ethyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-3-amino-1-oxobutan-2-yl]amino]-2-oxoethyl]am Chemical compound CCC(C)CCCCC\C=C\CC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)C(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H]([C@H](C)N)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)[C@H]1C(=O)N2CCCC[C@@H]2C(=O)N1 XBNDESPXQUOOBQ-LSMLZNGOSA-N 0.000 claims description 20
- 150000001413 amino acids Chemical class 0.000 claims description 16
- 239000001116 FEMA 4028 Substances 0.000 claims description 14
- 229960004853 betadex Drugs 0.000 claims description 14
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 13
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- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 12
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 12
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical class C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 claims description 12
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- 239000000654 additive Substances 0.000 claims description 8
- 229930188551 friulimicin Chemical class 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
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- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- ZDZVUYXFDHKIKT-BGTBYPPESA-N (2r,3s)-2-[[(2r)-2-[[2-[[(2r,3r)-2-[[(2s,4s)-6-amino-2-[[(2r)-4-amino-2-[[(2s)-4-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-4-amino-4-oxo-2-(tetradecanoylamino)butanoyl]amino]-3-methylbutanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoyl]amino]-4-oxobutanoyl]amino Chemical compound C([C@@H](NC(=O)[C@@H](C(C)C)NC(=O)[C@@H](CC(N)=O)NC(=O)CCCCCCCCCCCCC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](C[C@@H](O)CCN)C(=O)N[C@H]([C@@H](C)O)C(=O)NCC(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H]([C@@H](C)CC)C(O)=O)C1=CC=CC=C1 ZDZVUYXFDHKIKT-BGTBYPPESA-N 0.000 claims description 4
- AQZKCOXFXDOYRA-PVASSXKPSA-N (3S)-4-[[2-[[(2R,3S)-1-[[(2S)-1-[(2S)-2-[[(10aR)-3-methyl-1,5-dioxo-2,3,4,7,8,9,10,10a-octahydropyrido[1,2-a][1,4]diazepin-4-yl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-3-amino-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-3-[[2-[[(2S)-3-carboxy-2-[[(2S)-3-carboxy-2-[[(2S)-3-carboxy-2-[[(E)-10-methyldodec-3-enoyl]amino]propanoyl]-methylamino]propanoyl]amino]propanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical class CCC(C)CCCCC\C=C\CC(=O)N[C@@H](CC(O)=O)C(=O)N(C)[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H]([C@H](C)N)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1C(C)NC(=O)[C@H]2CCCCN2C1=O AQZKCOXFXDOYRA-PVASSXKPSA-N 0.000 claims description 4
- IESFUUMVTXJOQR-VESAVYSMSA-N 2-[(3s,6s,9s,12s,18r,21r,27s,30r,33s,34r)-6,30-bis(2-aminoethyl)-21-(2-amino-2-oxoethyl)-3-benzyl-9-[(2s)-butan-2-yl]-18-(carboxymethyl)-12-(1h-indol-3-ylmethyl)-34-methyl-33-(6-methyloctanoylamino)-2,5,8,11,14,17,20,23,26,29,32-undecaoxo-1-oxa-4,7,10,13, Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(N[C@H](CCN)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CC(N)=O)C(=O)N[C@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@H](C(=O)N[C@@H](CCN)C(=O)N1)[C@@H](C)CC)=O)NC(=O)CCCCC(C)CC)C1=CC=CC=C1 IESFUUMVTXJOQR-VESAVYSMSA-N 0.000 claims description 4
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- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- VZCCETWTMQHEPK-QNEBEIHSSA-N gamma-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O VZCCETWTMQHEPK-QNEBEIHSSA-N 0.000 description 1
- 235000020664 gamma-linolenic acid Nutrition 0.000 description 1
- 229960002733 gamolenic acid Drugs 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012913 medium supplement Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000021239 milk protein Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000004001 molecular interaction Effects 0.000 description 1
- 238000002663 nebulization Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000006916 nutrient agar Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920006393 polyether sulfone Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 244000000000 soil microbiome Species 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 108700038523 surfactin A Proteins 0.000 description 1
- PBEDWPIWZYHNPL-RHKAOURMSA-N surfactin A Chemical compound CC(C)CCCCCCC[C@@H]1CC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O1 PBEDWPIWZYHNPL-RHKAOURMSA-N 0.000 description 1
- 108010034149 surfactin synthetase Proteins 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000723 toxicological property Toxicity 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
Definitions
- the invention relates to novel pharmaceutical compositions containing lipopeptides, to the use of such compositions, to processes for their preparation and to their use as medicaments.
- Antibiotics from the class of lipopeptides that are characterized by being of a linear or cyclic peptide moiety, or a combination of both, with natural and / or unnatural, derivatized and / or non-derivatized amino acids to which a saturated or unsaturated acyl moiety is attached, optionally substituted by one or more phenyl or the like
- Cycloalkyl groups may be interrupted or connected to such groups or interrupted by one or more oxygen or nitrogen atoms, have proven in the past to be extremely effective against fungi and Gram-positive bacteria. For the majority of these compounds, however, toxic properties are also known.
- the compound daptomycin which is one of the class of A-21978C lipopeptides, damages skeletal muscle
- cyclodextrins in pharmaceutical compositions. Due to their circular structure, cyclodextrins have a hydrophilic outside and a hydrophobic inside pocket. By enveloping in particular hydrophobic regions of the molecules, cyclodextrins can achieve a "molecular encapsulation" or “masking" of active substances, which is used, for example, as a protective coating of sensitive molecules in cosmetic and pharmaceutical formulations. This allows improved solubilities of Substances, but also reduced toxicities, such as a reduction in the hemolytic properties of molecules (J. Pharmacobiodyn.
- the invention is therefore based on the technical problem of providing new pharmaceutical compositions with antibacterial, antiviral and / or antimycotic lipopeptides available whose compatibility is improved to the extent of preserving the physiological efficacy that even at very high concentrations, for example, in Infusions typically occur at short notice at the site of application, with only minor toxic side effects.
- the invention teaches a pharmaceutical composition
- a pharmaceutical composition comprising as active ingredient an antibacterial, antiviral, and / or antimycotic lipopeptide in a physiologically effective dose and a physiologically acceptable cyclodextrin or a cyclodextrin derivative.
- the invention is based on the surprising finding that, especially by using cyclodextrins or cyclodextrin derivatives, not only a reduction in the haemolytic properties of antibiotically acting lipopeptides is achieved, but rather that at the same time the antibiotic effect of the lipopeptides is retained while, for example, a masking with HSA leads to a reduced or completely suppressed antibiotic effect.
- the lipopeptide preferably has a structure according to formula I,
- X one of the amino acids Asn or Asp
- Y a straight-chain or branched, saturated or unsaturated aliphatic acyl radical having 6 to 22 carbon atoms, optionally interrupted by or linked to one or more phenyl or cycloalkyl groups or may be interrupted by one or more oxygen atoms.
- the amino acids of the peptide portion of the molecule can be derivatized (US2005 / 0153876 A1).
- X Asn, it is friulimicin or a friulimicin derivative.
- Y are in particular:
- (CH 3 ) 2 CH (CH 2 ) 7 CH CHCH 2 CO-, CH 3 (CH 2 ) 6 CO-, CH 3 (CH 2 ) 7 CO-, CH 3 (CH 2 ) 8 CO-, CH 3 (CH 2) 9 CO- 5 CH 3 (CH 2 KoCO-, CH 3 (CH 2) X1 CO-,
- the lipopeptide can be selected independently of the formula I from the group consisting of "amphomycin, amphomycin derivatives, friulimicin, friulimicin B, friulimicin derivatives, daptomycin, daptomycin derivatives, aspartocin, aspartocin derivatives, glumamycin, glumamycin derivatives, crystallomycin , Crystallomycin Derivatives, Zaomycin, Zaomycin Derivatives, Tsushimycin, Tsushimyin Derivatives, Laspartomycin, Laspartomycin Derivatives, Brevistin, Brevistin Derivatives, Cerexin B, Cerexin B Derivatives, Syringomycin and Its Derivatives, Antibiotic A-30912 and its Derivatives, Antibiotic A-54145 and its derivatives as well as Antibiotic A-21978C and its derivatives ".
- AMINOPHENYLPROPANOYL) 2 -AMPHOMYCIN, CH 3 - (CH 2) 9 -O-P-PH-C ( 0) - GLY-amphomycin, Ci 2 - (M-APA) -AMPHOMYCIN, C 5 - [ASP (OtBu)] AMPHOMYCIN, C 10 - (M-APA) -AMPHOMYCIN, CH 3 - (CH 2 ) 7 ) (CH 3 -
- Acetoxyacetyl, C 15 -AMPHOMYCIN-9- (1-adamantanylcarbonyl), C 15 -AMPHOMYCIN-9- (4-COTININECARBONYL), C 15 -AMPHOMYCIN-9- (4- FLUOROBENZOLYL), C 15 -AMPHOMYCIN-9- (S -ACETYLTHIOGLYCOYL), Ci 5 -AMPHOMYCIN-9- (4-BUTOXYBENZOYL), C 15 -AMPHOMYCIN-S- (6- OXOHEPTANOYL), C I5 -AMPHOMYCIN-9-OLEATE, C 15 -AMPHOMYCIN-9- (4- PENYLBENZOYL), C 15 -AMPHOMYCIN-9- (3-PHENOXYBENZOYL), C 15 - AMPHOMYCIN-9- (C ( O) - (CH 2 ) 2-PIPERIDINE, C 15
- AMPHOMYCIN, 1-ADAMANTANE O) -AMPHOMYCIN, (10-METHYL-ANDEC-2-ENOYL) -AMPHOMYCIN, (10-METHYL-DODEC-2-ENOYL) -AMPHOMYCIN, (12-METHYL-TETRADEC-2 ENOYL) -ASPARTOCIN, (10-METHYL-DODEC-2-ENOYL) -AMPHOMYCIN-9-GLY, (10-METHYL-DODEC-2-ENOYL) -AMPHOMYCIN-9-SAR, (10-METHYL-DODEC-2 ENOYL) -AMPHOMYCIN-9- (jß-ALA), (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN-9-GLY, (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN-9-SAR, ( 12-METHYL-TETRADEC-2
- R3 can also be bonded via a radical L, where Rl is OH or NH 2 , L being at least one amino acid, at least one substituted amino acid, -R'- (CO) -, -R'- (CO) - (NR ') -, or -O-Ph- (CO) -, wherein R' are each independently the same or different and a radical, as may be defined as R3 or R5, and / or wherein L - when R3 identical or different and independently of one another at least one amino acid, at least one substituted amino acid, - (CO) -, -R "- (CO) -, -SO 2 -, - (CS) -, - (PO) - , -O- (PO) -, -O- (CO) - R - O- (CO) (NR -) -, -NH- (CO) -, - NR'- (CO) -, -R ' I
- R3 may be glycine, ⁇ -alanine, GABA, 5-aminopentanoic acid, 6-aminohexanoic acid, gDAB, Orn, Dap, hLys, sarcosine, lysine, glycine-lysine, or sarcosine-lysine.
- Aminophenylacetic acid m-aminophenylacetic acid, L-BBTA, or any combination thereof.
- the pharmaceutical composition contains several different lipopeptides in each physiologically effective dose. Then it is a combination preparation or a broadband preparation.
- the lipopeptide may be free or as an alkali or alkaline earth salt, preferably as a sodium or calcium salt, in particular as a di-calcium salt (Ca 2 Cl 2 salt), or as an ammonium salt.
- an alkali or alkaline earth salt preferably as a sodium or calcium salt, in particular as a di-calcium salt (Ca 2 Cl 2 salt), or as an ammonium salt.
- the lipopeptide is preferably present in the pharmaceutical composition in a total amount (based on the amount of all lipopeptides used) of from 0.01 to 80% by weight, in particular from 0.05 to 50% by weight, preferably from 0.1 to 30% by weight added, the amount being based on the finished composition.
- Cyclodextrins are cyclic oligosaccharides composed of alpha-1,4 linked glucose units. Usually, six to eight glucose units (.alpha., .Beta. Or .gamma.-cyclodextrin) are linked together in a cyclodextrin molecule. In addition to the naturally occurring, unmodified cyclodextrins, there are a variety of chemically modified cyclodextrin derivatives that are physiologically compatible and can be used in the invention.
- the cyclodextrin or cyclodextrin derivative is preferably an ⁇ - or ⁇ -
- Cyclodextrin and may in particular have the general formula II,
- the glucopyranose units are ⁇ -D or ⁇ -L-glucose pyranose units.
- C 1 -C 8 -alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
- 1 to 3, preferably 1 to 2, of the radicals R 1, R 2 and R 3 can be different from H.
- R 1 is different from -H.
- 1, 2, 3, 4, 5, 6, or optionally 7 of the radicals Rl of a cyclodextrin molecule may be different from -H.
- R2 and R3 can then be -H.
- 1, 2, 3, 4, 5, 6, or optionally 7 of the radicals R3 of a cyclodextrin molecule may be different from -H.
- the cyclodextrin or cyclodextrin derivative may be selected from the group consisting of ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxy (C 1 -C 8 -alkyl) - ⁇ -cyclodextrin, hydroxy (C 1 -C 8 -alkyl) - ⁇ -cyclodextrin , (2-hydroxypropyl) - / 3-cyclodextrin, (2-hydroxypropyl) - ⁇ -cyclodextrin, sulpho- (C 1 -C 8 -alkyl) -ether- ⁇ -cyclodextrin, sulpho- (C 1 -C 8 -alkyl) -ether- ⁇ -cyclodextrin, Sulphobutyl ether- ⁇ -cyclodextrin, sulphobutyl ether- ⁇ -cyclodextrin. "In the case of the derivatives, in particular the radical on the oxygen
- the cyclodextrin or cyclodextrin derivative may be present in the pharmaceutical composition in an amount of 0.01 to 99% by weight, more preferably 0.05 to 80% by weight, preferably 0.1 to 50% by weight, based on the final composition be.
- the lipopeptide in the pharmaceutical composition with the cyclodextrin or cyclodextrin derivative in a lipopeptide / cyclodextrin molar ratio is from 100: 1 to 1: 500, preferably 10: 1 to 1:50, most preferably 2: 1 to 1:10, optionally with addition of additives and / or excipients in galenically customary amounts, mixed.
- the pharmaceutical composition will contain other additives and / or adjuvants, in particular galenic adjuvants, the selection of which depends on the selected dosage form.
- galenic preparation of the pharmaceutical composition according to the invention can be carried out in the usual way.
- counterions for ionic compounds are Ca ++ , CaCl + , Na + , K + , Li + or cyclohexylammonium, or Cl " , Br " , acetate, trifluoroacetate, propionate, lactate, oxalate, malonate, maleate, citrate, benzoate , Salicylate, etc. in question.
- Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection (iV, ip, im, sc) or nebulization (aerosols), dry powder inhalation preparations, transdermal systems, and sustained-release preparations prepared by conventional means such as excipients, disintegrants, binders, coating, swelling or lubricants, flavoring agents, Sweeteners and solubilizers, find use.
- adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile Water and mono- or polyhydric alcohols, such as glycerol, called.
- a pharmaceutical composition according to the invention can be prepared by mixing at least one substance combination used according to the invention in a defined dose with a pharmaceutically suitable and physiologically acceptable carrier and optionally further suitable active ingredients, additives or excipients with a defined dose and prepared to the desired administration form. Preference is given to solutions for injection in the customary preparation.
- Suitable diluents are polyglycols, ethanol, water and buffer solutions.
- Suitable buffer substances are, for example, N, N'-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, sodium bicarbonate or sodium carbonate, but it is also possible to work without a diluent.
- Physiologically acceptable salts be it the lipopeptide, be it the cyclodextrin or cyclodextrin derivative Salts with inorganic or organic acids, such as hydrochloric acid, sulfuric acid, acetic acid, citric acid, p-toluenesulfonic acid, or with inorganic or organic bases, such as NaOH, KOH, Mg (OH) 2 / diethanolamine, ethylenediarine, or with amino acids, such as arginine, lysine , Glutamic acid, etc. or with inorganic salts such as CaCl 2 , NaCl or their free ions such as Ca 2+ , Na + , Cl " , SO 4 2" or combinations thereof. They are manufactured according to standard methods.
- inorganic or organic acids such as hydrochloric acid, sulfuric acid, acetic acid, citric acid, p-toluenesulfonic acid, or with inorganic or organic bases, such as NaOH, KOH,
- a pharmaceutical composition according to the invention may contain: A) 0.01 to 80% by weight, in particular 0.05 to 50% by weight, preferably 0.1 to 30% by weight, lipopeptide, B) 0.01 to 99% by weight %, in particular 0.05 to 80% by weight, preferably 0.1 to 50% by weight of cyclodextrin or cyclodextrin derivative, C) 0.1 to 99.8% by weight, in particular 1 to 80% by weight, preferably 1 to 50% by weight of additives and / or auxiliaries and optionally diluents, wherein the components A) to C) always add up to 100% and wherein the lipopeptide in a physiologically effective dose with the cyclodextrin or cyclodextrin derivative in a molar ratio lipopeptide / cyclodextrin from 1: 500 to 10: 1, preferably 1: 100 to 10: 1, most preferably 1: 100 to 2: 1, optionally with the addition of additional and / or
- the invention further relates to the use of a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment and / or prophylaxis of viral, bacterial and / or parasitic infectious diseases and / or fungal diseases.
- a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment and / or prophylaxis of viral, bacterial and / or parasitic infectious diseases and / or fungal diseases. Examples of eligible diseases or
- Areas of application are: respiratory tract infections, skin and soft tissue infections, urinary tract infections, bile duct infections, sepsis, endocarditis, meningitis, surgical prophylaxis, wound infections or intra-abdominal infections.
- the medicament is prepared galenically for oral administration or for injection.
- the invention further relates to a method for the treatment of a bacterial, viral or parasitic infectious disease or a fungal disease, wherein a person suffering from the disease or threatens to fall ill, a physiologically effective dose of a medicament according to the invention is presented.
- the daily dose may be from 1 to 50,000 mg, preferably 50 to 30,000 mg, most preferably from 100 to 20,000 mg, of lipopeptide over a period of 1 to 60 days, preferably 1 to 30 days.
- Packaging units with a plurality of delivery units may be provided, each delivery unit being for administration within the above treatment plan is prepared.
- a delivery unit being for administration within the above treatment plan is prepared.
- HSA Human Serum Albumin
- Na 2 -Friulimicin B was dissolved in a concentration of 6400 mg / l in 0.9% NaCl solution with 20, 15, 10, 5, 1 or 0% HSA.
- 0.9% NaCl and the respective HSA concentrations further stock solutions of 3200, 1600, 800, 200 and 100 mg / l Na 2 -frululimicin were prepared for each of the listed HSA concentrations.
- 40 ⁇ l each of the friulimicin B / HSA mixture was mixed with 40 ⁇ l fresh human venous blood and then incubated at 37 ° C for 180 min.
- the measurement value of the standard with complete hemolysis was set as 100%.
- the measured values of the various reaction batches are set in relation to the value of this standard and expressed as a percentage.
- Table 1 shows the result of the hemolysis experiment with Na 2 friulimicin B and various HSA concentrations performed on human blood.
- the data on the concentration of HSA (in% w / v) and of Na 2 -friulimicin B (in mg / l, free acid) refer to the final concentrations in the reaction mixture.
- HSA suppresses with good efficiency Na 2 -friulimicin B-induced hemolysis from one concentration of about 2.5%.
- the subsequent determination of free serum hemoglobin content showed that after preincubation with 5% -10% HSA (w / v), final concentration in the reaction mixture, friulimicin B-induced hemolysis could be significantly minimized.
- This example demonstrates the effect of various modified or unmodified cyclodextrins on the lipopeptide-induced hemolytic effect. This serves Na 2 -Friulimicin B as an example molecule for the Antibiotics of lipopeptides.
- Na 2 -Friulimicin B was dissolved in a concentration of 3200 mg / l in 0.9% NaCl solution.
- 0.9% NaCl further stock solutions of 1600, 800, 200, 100 and 50 mg / 1 Na 2 -frululimicin were prepared.
- 20 .mu.l of these stock solutions each containing 20 .mu.l 0.9% NaCl or 2% solutions of (2-hydroxypropyl) - ⁇ -cyclodextrin (HP-y-CD), (2-hydroxypropyl) - / 3-cyclodextrin ( HP- / 3-CD) or ⁇ -cyclodextrin ( ⁇ -CD) mixed gently in 0.9% NaCl.
- the pre-incubation and experimental procedure for the determination of the hemolytic activity with fresh human venous blood was carried out according to example 1.
- Example 3 Minimization of Ca 2 Cl 2 -frulimicin B-induced hemolysis by the addition of modified / 3-cyclodextrins
- Ca 2 Cl 2 -friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and
- Ca 2 Cl 2 -frulimicin B was dissolved in concentrations of 100, 50, 40, 30, 20, 10 and 5 g / l in 20, 15, 12.5, 10, 7.5%
- Daptomycin was dissolved in a solution of 0% or 2.5% SBE- / 3-CD in 0.9% NaCl, 2.5 mM CaCl 2 .
- erythrocytes were isolated from fresh venal human blood collected in heparinized sample tubes. For this purpose, the erythrocytes were sedimented by centrifugation at 2500 RFC (5 min). The erythrocytes were washed three times with 0.9% NaCl and taken after the final centrifugation in a volume of 0.9% NaCl, which corresponds to the initial volume of the
- Blood sample corresponded. 40 .mu.l of the erythrocytes were mixed with 40 .mu.l of the reaction mixtures described above and incubated for 5 hours at 37 ° C with constant gentle shaking. The further experiment to determine the hemolytic activity was carried out according to Example 1. The results are shown in Table 5. Here, data on the concentrations of SBE- / 3-CD (in% w / v) and of daptomycin (in mg / l, free acid) refer to the final concentrations in the reaction mixture.
- SBE- / 3-CD also suppresses the cell lysis induced by a lipopeptide, here daptomycin, in an experiment with isolated erythrocytes.
- This experiment shows that SBE- / 3-CD can suppress toxic properties of very different lipopeptides.
- the hemolytic properties of daptomycin are due to an immediate interaction with the erythrocyte membrane. Similar mechanisms underlie the toxic effect on skeletal muscle described for daptomycin so that formulation of daptomycin or its derivatives with cyclodextrins also minimizes this toxic effect.
- Staphylococcus carnosus ATCC 51365 (DSM 20501) Staphylococcus aureus ATCC 29213 (DSM 2569) Staphylococcus aureus ATCC 33592 (DSM 11729) Staphylococcus epidermidis ATCC 12228 (DSM 1798)
- the amounts of cells used per spot were: S. carnosus ATCC 51365 5.5 ⁇ 10 3 CFU S. aureus ATCC 29213 7.6 ⁇ 10 3 CFU S. aureus ATCC 33592 2.2 X 10 4 CFU S. epidermidis ATCC 12228 1.1 X 10 4 CFU
- Example 7 Preparation of a Ca 2 Cl 2 -frulimicin B injection solution.
- Ca 2 Cl 2 -friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and suibutyl ether- ⁇ -cyclodextrin (SBE-jS-CD) as an example molecule for the cyclodextrins.
- Data on the content of Ca 2 Cl 2 -friulimicin B (in tng / 1) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture.
- the molar ratio in each case refers to the free acids of friulimicin B and SBE- / 3-CD.
- This example relates to the inhibition of haemolytic activity of various lipopeptides by cyclodextrins and shows the effect of a sulphoalkylethercyclodextrin on the cyclic peptide tyrocidine-induced hemolytic effect.
- Tyrocidine was dissolved in a concentration of 6400 mg / l in 0.9% NaCl solution.
- SBE- / 3-CD By dilution with a volume of 0.9% NaCl or 0.9% NaCl / 10% SBE- / 3-CD respectively stock solutions of 3200 mg / 1 Tyrocidin were prepared with or without 5% SBE-ß-CD.
- the pre-incubation and experimental procedure for the determination of the hemolytic activity with fresh venale human blood was carried out according to the example 1.
- This example demonstrates the effect of ⁇ -cyclodextrins on the lipopeptide-induced hemolytic effect on the blood of various organisms.
- Ca 2 Cl 2 - Friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and sulfobutyl ether- ⁇ -cyclodextrin (SBE- / 3-CD) as examples of modified ⁇ -cyclodextrins.
- SBE- / 3-CD sulfobutyl ether- ⁇ -cyclodextrin
- Ca 2 Cl 2 -frulimicin B was dissolved in 0.9% NaCl solution with and without the addition of SBE- / 3-CD.
- SBE- / 3-CD was a molar ratio (SBE- / 3-CD: Friulimicin B) of 2.5: 1 before.
- the preincubation and experimental procedure for the determination of hemolytic activity with venal canine blood were carried out according to Example 1. The results are shown in Table 9.
- Data on the content of Ca 2 Cl 2 -frulimicin B (in mg / l) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture.
- the details of the molar ratio relate in each case to the free acids of friulimicin B and SBE- ⁇ -CD.
- SBE- / 3-CD in a molar ratio of 2.5: 1 SBE-ß-CD: Friulimicin B suppresses the Ca 2 Cl 2 -frulimicin B-induced lysis of erythrocytes in dog blood.
- This example demonstrates the effect of / 3-cyclodextrins on the lipopeptide-induced hemolytic effect on the blood of various organisms.
- Ca 2 Cl 2 - Friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and sulfobutyl ether-ß-cyclodextrin (SBE- / 3-CD) as an example of cyclodextrins.
- SBE- / 3-CD sulfobutyl ether-ß-cyclodextrin
- Ca 2 Cl 2 -frulimicin B was dissolved in 0.9% NaCl solution with and without the addition of SBE- / 3-CD. In the mixture with SBE- ⁇ -CD, a molar ratio (SBE / 3-CD: friulimicin B) of 5: 1 was present.
- the preincubation and experimental procedure for the determination of hemolytic activity with venal macaque blood were carried out according to Example 1.
- Data on the content of Ca 2 Cl 2 -frulimicin B (in mg / l) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture. The details of the molar ratio relate in each case to the free acids of friulimicin B and SBE- ⁇ -CD.
- the example shows that SBE- ⁇ -CD in a molar ratio of 5: 1 (SBE- / 3-CD: Friulimicin B) by Ca2Cl 2 -Friulimicin B suppresses induced lysis of erythrocytes in blood of macaques.
- This example demonstrates the effect of / 3-cyclodextrins on the antibiotic activity of lipopeptides in vivo.
- Ca 2 Cl 2 -friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and sulfobutyl ether
- SBE- ⁇ -CD ⁇ -cyclodextrin
- Ca 2 Cl 2 -frululimicin B was dissolved in 0.9% NaCl solution with and without addition of SBE- ⁇ -CD.
- SBE- / 3-CD was a molar ratio (SBE- / 3-CD: Friulimicin B) of 2.5: 1 before.
- the data for the Ca 2 Cl 2 -frulimicin B concentration (in mg / l) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture.
- the details of the molar ratio relate in each case to the free acids of friulimicin B and SBE- ⁇ -CD.
- Ca 2 Cl 2 -friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and sulfobutyl ether-J ⁇ -cyclodextrin (SBE-J ⁇ -CD) as examples of modified ⁇ -cyclodextrins.
- Ca 2 Cl 2 -frulimicin B was dissolved in 0.9% NaCl solution with and without the addition of SBE- / 3-CD.
- SBE-jß-CD was a molar ratio (SBE-jß-CD: Friulimicin B) of 2.5: 1 before.
- the data for the Ca 2 Cl 2 -frulimicin B concentration (in mg / l) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture.
- the details of the molar ratio relate in each case to the free acids of friulimicin B and SBE- ⁇ -CD.
- the Ca 2 Cl 2 -frulimicin B solutions with and without SBE- / 3-CD were administered once to female mice (CFW-I (Harlan Winkelmann, Germany)) (iv).
- the mortality rate of the animals within 24 hours was determined. It is shown in Table 11.
- the example shows that the acute toxicity of Ca 2 Cl 2 -friulimicin B is reduced by the presence of SBE- ⁇ -CD in a molar ratio of 2.5: 1 (SBE- / 3-CD: friulimicin B).
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Abstract
The invention relates to a pharmaceutical composition comprising as active ingredient a lipopeptide in physiologically effective dose, and a cyclodextrin or a cyclodextrin derivative.
Description
LIPOPEPTID ZUSAMMENSETZUNGEN LIPOPEPTIDE COMPOSITIONS
Gebiet der ErfindungField of the invention
Die Erfindung betrifft neue pharmazeutische Zusammensetzungen, die Lipopeptide enthalten, Verwendung solcher Zusammensetzungen, Verfahren zur deren Herstellung sowie deren Nutzung als Arzneimittel.The invention relates to novel pharmaceutical compositions containing lipopeptides, to the use of such compositions, to processes for their preparation and to their use as medicaments.
Hintergrund der Erfindung und Stand der TechnikBackground of the invention and prior art
Sekundärmetabolite, die durch lebende Organismen, insbesondere Mikroorganismen, produziert werden und die von ihnen abgeleiteten chemischen Varianten werden erfolgreich als Wirkstoffe in der Medizin verwendet. Besonders bei der Bekämpfung von Infektionskrankheiten hat sich der Einsatz von Sekundärmetaboliten bewährt. So wurde ein großer Anteil der heute verwendeten Antibiotika aus Bodenbakterien isoliert, den sogenannten Actinomyceten. Aufgrund der Entwicklung von Resistenzen gegen die jeweils eingesetzten Medikamente besteht ein permanenter Bedarf nach neuen antibiotischen Wirkstoffen mit neuartigen Wirkmechanismen. Trotz ihrer herausragenden antibiotischen und anderen pharmakologischen Eigenschaften scheitert bei vielen Sekundärmetaboliten eine Nutzung als Medikament letztendlich an den meist ebenfalls sehr ausgeprägten toxischen Eigenschaften für den Menschen.Secondary metabolites produced by living organisms, especially microorganisms, and the chemical variants derived from them are successfully used as active ingredients in medicine. Especially in the fight against infectious diseases, the use of secondary metabolites has been proven. Thus, a large proportion of the antibiotics used today was isolated from soil bacteria, the so-called Actinomycetes. Due to the development of resistance to the drugs used, there is a constant need for new antibiotic agents with novel mechanisms of action. Despite their outstanding antibiotic and other pharmacological properties, use as a drug in many secondary metabolites ultimately fails because of the usually very pronounced toxic properties for humans.
Antibiotika aus der Klasse der Lipopeptide, die dadurch charakterisiert sind, dass sie aus einem linearen oder
zyklischen Peptidanteil, oder eine Kombination von beidem, mit natürlichen und/oder unnatürlichen, derivatisierten und/oder nicht derivatisierten Aminosäuren mit denen ein gesättigter oder ungesättigter Acylrest verknüpft ist, der optional durch eine oder mehrere Phenyl- oderAntibiotics from the class of lipopeptides that are characterized by being of a linear or cyclic peptide moiety, or a combination of both, with natural and / or unnatural, derivatized and / or non-derivatized amino acids to which a saturated or unsaturated acyl moiety is attached, optionally substituted by one or more phenyl or the like
Cycloalkylgruppen unterbrochen oder mit solchen Gruppen verbunden oder durch einen oder mehrere Sauerstoff- oder Stickstoffatome unterbrochen sein kann, haben sich in der Vergangenheit als außerordentlich wirksam gegen Pilze und gram-positive Bakterien erwiesen. Für die Mehrzahl dieser Verbindungen sind jedoch auch toxische Eigenschaften bekannt .Cycloalkyl groups may be interrupted or connected to such groups or interrupted by one or more oxygen or nitrogen atoms, have proven in the past to be extremely effective against fungi and Gram-positive bacteria. For the majority of these compounds, however, toxic properties are also known.
Die zur Klasse der A-21978C Lipopeptide gezählte Verbindung Daptomycin schädigt beispielsweise den SkelettmuskelFor example, the compound daptomycin, which is one of the class of A-21978C lipopeptides, damages skeletal muscle
(Oleson et al. 2000 Antimicrobial agents and chemotherapy Vol. 44 No 11; 2948 - 2953) und eine Reihe weiterer Lipopeptide, beispielsweise Lychenysin (Grangemard I. et al., Applied Biochemistry and Biotechnology, Volume 90, Number 3, 2001, pp. 199-210(12)), Surfactin A (Hanka(Oleson et al., 2000 Antimicrobial Agents and Chemotherapy Vol. 44 No.11; 2948-2953) and a number of other lipopeptides, for example, lychenysine (Grangemard I. et al., Applied Biochemistry and Biotechnology, Volume 90, Number 3, 2001, pp. 436-935) 199-210 (12)), Surfactin A (Hanka
Symmank, Peter Franke, Wolfram Saenger and Frank Bernhard Modification of biologically active peptides: production of a novel lipohexapeptide after engineering of Bacillus subtilis surfactin synthetase) , FR131535 und Echinocandin (Fujie A, Iwamoto T, Sato B, Muramatsu H, Kasahara C, Furuta T, Hori Y, Hino M, Hashimoto S. Bioorg Med Chem Lett. 2001 Feb 12 ; 11 (3) : 399-402. FR131535, a novel water- soluble echinocandin-like lipopeptide: synthesis and biological properties. ) , Fengycin (J. of Antibiotics 29 (1986) 888-901.), Iturin A (Aranda FJ, Teruel JA, Ortiz A. Biochim Biophys Acta. 2005 JuI 15;1713 (1) : 51-6. Further aspects on the hemolytic activity of the antibiotic lipopeptide iturin A.), sowie Amphomycin- und Friulimicin-
ähnliche Lipopeptide (DE19807972) wirken hämolytisch.Symmank, Peter Franke, Wolfram Saenger and Frank Bernhard Modification of biologically active peptides: production of a novel lipohexapeptide after engineering of Bacillus subtilis surfactin synthetase), FR131535 and Echinocandin (Fujie A, Iwamoto T, Sato B, Muramatsu H, Kasahara C, Furuta T, Hori Y, Hino M, Hashimoto S. Bioorg Med Chem Lett 2001 Feb 12; 11 (3): 399-402 FR131535, a novel water-soluble echinocandin-like lipopeptide: synthesis and biological properties.), Fengycin ( J. of Antibiotics 29 (1986) 888-901.), Iturin A (Aranda FJ, Teruel JA, Ortiz A. Biochim Biophys Acta., 2005 Jul. 15; 1713 (1): 51-6.) Further aspects on the hemolytic activity of the antibiotic lipopeptide iturin A.), as well as amphomycin and friulimicin Similar lipopeptides (DE19807972) are haemolytic.
Ein wesentliches Problem für die Anwendung dieser Lipopeptide als Arzneimittel ist jedoch die Überwindung der toxikologischen Eigenschaften ohne Verschlechterung der antibiotischen Aktivität der Substanzen. Für die Anwendung dieser Substanzen als Medikament ist es daher notwendig, pharmazeutische Zusammensetzungen zu finden, die im Vergleich zur Reinsubstanz verbesserte pharmakologische Eigenschaften aufweisen. Es ist beispielsweise bekannt, dass die hämolytischen Eigenschaften einer Substanz oder eines Ions in der Anwesenheit von Serum Albumin reduziert werden, wobei dies durch die Interaktion mit dem Serum Albumin („Maskierungseffekt") bewirkt wird (Caffrey JM Jr, Smith HA, Schmitz JC, Merchant A, Frieden E. : Hemolysis of rabbit erythrocytes in the presence of copper ions . Inhibition by albumin and ceruloplasmin. Biol Trace Eiern Res. 1990 Apr;25 (1) : 11-9. ) . Dieser Maskierungseffekt mit Serum Albumin bewirkt jedoch häufig auch den Verlust der gewünschten Eigenschaften von Molekülen, so auch die antibiotische Aktivität von Lipopeptiden wie in Beispiel 1 dieser Erfindung dargestellt.A major problem for the application of these lipopeptides as drugs, however, is the overcoming of the toxicological properties without deterioration of the antibiotic activity of the substances. For the use of these substances as a medicament, it is therefore necessary to find pharmaceutical compositions which have improved pharmacological properties compared to the pure substance. It is known, for example, that the haemolytic properties of a substance or an ion are reduced in the presence of serum albumin, this being effected by the interaction with serum albumin ("masking effect") (Caffrey JM Jr, Smith HA, Schmitz JC, Merchant A, Peace E. Hemolysis of rabbit erythrocytes in the presence of copper ions Inhibition by albumin and ceruloplasmin Biol Trace eggs Res. 1990 Apr; 25 (1): 11-9.) However, this masking effect with serum albumin causes often also the loss of the desired properties of molecules, as well as the antibiotic activity of lipopeptides as shown in Example 1 of this invention.
Es ist bekannt, Cyclodextrine in pharmazeutischen Zusammensetzungen einzusetzen. Aufgrund ihrer zirkulären Struktur besitzen Cyclodextrine eine hydrophile Außenseite und eine hydrophobe Innentasche. Durch Umhüllung insbesondere von hydrophoben Bereichen der Moleküle, können Cyclodextrine eine "molekularen Verkapselung" bzw. "Maskierung" von Wirkstoffen erzielen, die beispielsweise als schützende Umhüllung empfindlicher Moleküle in kosmetischen und pharmazeutischen Formulierungen genutzt wird. Dadurch können verbesserte Löslichkeiten von
Substanzen aber auch verringerte Toxizitäten, wie beispielsweise eine Verringerung der hämolytischen Eigenschaften von Molekülen (J. Pharmacobiodyn. 1983 6(6): 408-14. Protective raechanism of beta-cyclodextrin for the hemolysis induced with phenothiazine neuroleptics in vitro. Irie T, Sunada M, Otagiri M, Uekama K.) erzielt werden.It is known to use cyclodextrins in pharmaceutical compositions. Due to their circular structure, cyclodextrins have a hydrophilic outside and a hydrophobic inside pocket. By enveloping in particular hydrophobic regions of the molecules, cyclodextrins can achieve a "molecular encapsulation" or "masking" of active substances, which is used, for example, as a protective coating of sensitive molecules in cosmetic and pharmaceutical formulations. This allows improved solubilities of Substances, but also reduced toxicities, such as a reduction in the hemolytic properties of molecules (J. Pharmacobiodyn. 1983 6 (6): 408-14.) Protective Raechanism of beta-cyclodextrin for the hemolysis induced with phenothiazine neuroleptics in vitro., Irie T, Sunada M, Otagiri M, Uekama K.).
Technisches Problem der ErfindungTechnical problem of the invention
Der Erfindung liegt daher das technische Problem zu Grunde, neue pharmazeutische Zusammensetzungen mit antibakteriell, antiviral und/oder antimycotisch wirkenden Lipopeptiden zur Verfügung zu stellen, deren Verträglichkeit bei Erhalt der physiologischen Wirksamkeit soweit verbessert ist, dass auch bei sehr hohen Konzentrationen, die zum Beispiel bei Infusionen typischerweise kurzfristig am Applikationsort entstehen, nur geringe toxische Nebenwirkungen auftreten.The invention is therefore based on the technical problem of providing new pharmaceutical compositions with antibacterial, antiviral and / or antimycotic lipopeptides available whose compatibility is improved to the extent of preserving the physiological efficacy that even at very high concentrations, for example, in Infusions typically occur at short notice at the site of application, with only minor toxic side effects.
Grundzüge der Erfindung und Ausführungsformen.Broad features of the invention and embodiments.
Zur Lösung dieses technischen Problems lehrt die Erfindung eine pharmazeutische Zusammensetzung enthaltend als Wirkstoff ein antibakteriell, antiviral, und/oder antimykotisch wirkendes Lipopeptid in physiologisch wirksamer Dosis sowie ein physiologisch verträgliches Cyclodextrin oder ein Cyclodextrin-Derivat .To solve this technical problem, the invention teaches a pharmaceutical composition comprising as active ingredient an antibacterial, antiviral, and / or antimycotic lipopeptide in a physiologically effective dose and a physiologically acceptable cyclodextrin or a cyclodextrin derivative.
Die Erfindung beruht auf der überraschenden Erkenntnis, dass speziell durch Einsatz von Cyclodextrinen bzw. Cyclodextrinderivaten nicht nur eine Reduktion der
hämolytischen Eigenschaften von antibiotisch wirkenden Lipopeptiden erreicht wird, sondern dass vielmehr auch gleichzeitig die antibiotische Wirkung der Lipopeptide erhalten bleibt, während dagegen beispielsweise eine Maskierung mit HSA zu einer reduzierten oder völlig unterdrückten antibiotischen Wirkung führt.The invention is based on the surprising finding that, especially by using cyclodextrins or cyclodextrin derivatives, not only a reduction in the haemolytic properties of antibiotically acting lipopeptides is achieved, but rather that at the same time the antibiotic effect of the lipopeptides is retained while, for example, a masking with HSA leads to a reduced or completely suppressed antibiotic effect.
Das Lipopeptid weist vorzugsweise eine Struktur gemäß Formel I auf,The lipopeptide preferably has a structure according to formula I,
Y-X-Dab-Pip-MeAsp-Asp-Gly-Asp-Gly-Dab-Val-ProY-X-Dab-Pip-MeAsp-Asp-Gly-Asp-Gly-Dab-Val-Pro
Formel IFormula I
auf, wobei X = eine der Aminosäuren Asn oder Asp ist, wobei Y = ein geradkettiger oder verzweigter, gesättigter oder ungesättigter aliphatischer Acylrest mit 6 bis 22 Kohlenstoffatomen ist, der optional durch eine oder mehrere Phenyl- oder Cycloalkylgruppen unterbrochen oder mit solchen Gruppen verbunden oder durch einen oder mehrere Sauerstoffatome unterbrochen sein kann. Die Aminosäuren des Peptidanteils des Moleküls können derivatisiert sein (US2005/0153876 Al) . Im Falle, dass X = Asn ist, handelt es sich um Friulimicin oder ein Friulimicin-Derivat . Im Falle, dass X = Asp ist, handelt es sich um Amphomycin oder ein Amphomycin-Derivat . Für Y kommen insbesondere in Frage:wherein X = one of the amino acids Asn or Asp, wherein Y = a straight-chain or branched, saturated or unsaturated aliphatic acyl radical having 6 to 22 carbon atoms, optionally interrupted by or linked to one or more phenyl or cycloalkyl groups or may be interrupted by one or more oxygen atoms. The amino acids of the peptide portion of the molecule can be derivatized (US2005 / 0153876 A1). When X = Asn, it is friulimicin or a friulimicin derivative. In the case where X = Asp, it is amphomycin or an amphomycin derivative. For Y are in particular:
(CH3 ) 2CH (CH2) 7CH=CHCH2CO- , CH3 (CH2) 6CO- , CH3 (CH2) 7CO- , CH3 (CH2) 8CO-, CH3 (CH2) 9CO-5 CH3(CH2KoCO-, CH3 (CH2) X1CO- ,(CH 3 ) 2 CH (CH 2 ) 7 CH = CHCH 2 CO-, CH 3 (CH 2 ) 6 CO-, CH 3 (CH 2 ) 7 CO-, CH 3 (CH 2 ) 8 CO-, CH 3 (CH 2) 9 CO- 5 CH 3 (CH 2 KoCO-, CH 3 (CH 2) X1 CO-,
CH3 (CH2J12CO-, CH3(CH2)I3CO-, CH3 (CH2) 14CO- , CH3 (CH2) 1SCO- , CH3CH(CH3) (CH2) 8CO-, CH3CH(CH3) (CH2) 9C0- , CH3CH (CH3) (CH2) 10CO-, CH3CH(CH3)(CH2)HCO-, CH3CH (CH3) (CH2) 12C0- , H2C=CH (CH2) 8C0- ,
H2C=CH (CH2)9CO-, CH3 (CH2) 7CH=CHCO- (trans) , CH3 (CH2) 8 CH= CHCO- (trans) , CH3 (CH2) I2CH=CHCO- (trans), CH3 (CH2) 3CH=CH (CH2) 7CO- (cis) , CH3(CH2)3CH=CH (CH2J7CO- (trans) ,CH 3 (CH 2 J 12 CO-, CH 3 (CH 2 ) I 3 CO-, CH 3 (CH 2 ) 14 CO-, CH 3 (CH 2 ) 1 S CO-, CH 3 CH (CH 3 ) (CH 2 ) 8 CO-, CH 3 CH (CH 3 ) (CH 2 ) 9 C0-, CH 3 CH (CH 3 ) (CH 2 ) 10 CO-, CH 3 CH (CH 3 ) (CH 2 ) H CO- , CH 3 CH (CH 3 ) (CH 2 ) 12 C0-, H 2 C = CH (CH 2 ) 8 C0-, H 2 C = CH (CH 2 ) 9 CO-, CH 3 (CH 2 ) 7 CH = CHCO- (trans), CH 3 (CH 2 ) 8 CH = CHCO- (trans), CH 3 (CH 2 ) 12 CH = CHCO- (trans), CH 3 (CH 2 ) 3 CH = CH (CH 2 ) 7 CO- (cis), CH 3 (CH 2 ) 3 CH = CH (CH 2 J 7 CO- (trans),
CH3 (CH2)3CH=CH (CH2) 8CO- (trans) , CH3 (CH2) 5CH=CH(CH2) 7CO- (eis), CH3 (CH2)5CH=CH (CH2J7CO- (trans),CH 3 (CH 2 ) 3 CH = CH (CH 2 ) 8 CO- (trans), CH 3 (CH 2 ) 5 CH = CH (CH 2 ) 7 CO- (ice), CH 3 (CH 2 ) 5 CH = CH (CH 2 J 7 CO- (trans),
CH3 (CH2) 5CH=CH (CH2) 8CO- (eis) , CH3 (CH2) 10CH=CH (CH2) 4C0- (eis) ,CH 3 (CH 2 ) 5 CH = CH (CH 2 ) 8 CO- (ice), CH 3 (CH 2 ) 10 CH = CH (CH 2 ) 4 C0- (ice),
CH3 (CH2) 10CH=CH (CH2J4CO- (trans) , CH3 (CH2) 7CH=CH (CH2) 7C0- (cis) , CH3 (CH2J7CH=CH (CHa)7CO- (trans),CH 3 (CH 2 ) 10 CH = CH (CH 2 J 4 CO- (trans), CH 3 (CH 2 ) 7 CH = CH (CH 2 ) 7 C0- (cis), CH 3 (CH 2 J 7 CH = CH (CHa) 7 CO- (trans),
CH3 (CH2) 5CH=CH (CH2) 9C0- (trans) , CH3 (CH2) 3 (CH2CH=CH) 2(CH2) 7C0- (eis) , CH3 (CH2) 3 (CH2CH=CH) 2 (CH2) aCO- (trans) ,CH 3 (CH 2) 5 CH = CH (CH 2) 9 C0- (trans), CH 3 (CH 2) 3 (CH 2 CH = CH) 2 (CH 2) 7 C0- (ice), CH 3 ( CH 2 ) 3 (CH 2 CH = CH) 2 (CH 2 ) a CO- (trans),
CH3 (CH2) 3 (CH2CH=CH) 2(CH2) 9C0- (eis) , CH3 (CH2CH=CH) 3 (CH2) 7C0- (cis) , CH3 (CH2) 3 (CH2CH=CH) 3 (CHa)4CO- (eis),CH 3 (CH 2) 3 (CH 2 CH = CH) 2 (CH 2) 9 C0- (ice), CH 3 (CH 2 CH = CH) 3 (CH 2) 7 C0- (cis), CH 3 ( CH 2 ) 3 (CH 2 CH = CH) 3 (CHa) 4 CO- (ice),
CH3(CH2CH=CH)4(CHa)4CO- (eis) , CH3 (CH2) 3 (CH2CH=CH) 4 (CH2) 3C0- (cis) , CH3 (CH2CH=CH) s (CH2)2CO- (eis) , H2C=CH (CH3) 8C0- , CH3 (CH2) 3CH=CH (CH2) 7C0-, CH3 (CH2) 7CH=CH (CH2) 7C0- ,CH 3 (CH 2 CH = CH) 4 (CHa) 4 CO- (ice), CH 3 (CH 2) 3 (CH 2 CH = CH) 4 (CH 2) 3 C0 (cis), CH 3 (CH 2 CH = CH) s (CH 2 ) 2 CO- (ice), H 2 C = CH (CH 3 ) 8 C0-, CH 3 (CH 2 ) 3 CH = CH (CH 2 ) 7 C0-, CH 3 (CH 2 ) 7 CH = CH (CH 2 ) 7 C0-,
CH3 (CH2) 4CH=CH-CH=CH- (CH2) 8C0- ,CH 3 (CH 2 ) 4 CH = CH-CH = CH- (CH 2 ) 8 C0-,
(CHs)2C=CHCH2 [CH2C (CH3) =CHCH2]2CO, Phe-Phe-CH2CO- , Phe-(CHs) 2 C =CHCH 2 [CH 2 C (CH 3 ) CHCHCH 2 ] 2 CO, Phe-Phe-CH 2 CO-, Phe-
(CH2) 9CO-, Phe-O- (CH2) I0CO-, CH3 (CH2) 7-Phe-CO- , Phe-Phe-CO-,(CH 2 ) 9 CO, Phe-O- (CH 2 ) 10 CO, CH 3 (CH 2 ) 7 -Phe-CO-, Phe-Phe-CO-,
CH3 (CH2) 6-Phe-CO-, CH3 (CH2) 6-O-Phe-CO- , CH3 (CH2) 7-O-Phe-CO- , Phe- (CH2) 2-Phe-CO-, CH3CH2-PtLe- (CH2) 2-Phe-CO~ , Phe-Phe-CH 3 (CH 2 ) 6 -Phe-CO-, CH 3 (CH 2 ) 6 -O-Phe-CO-, CH 3 (CH 2 ) 7 -O-Phe-CO-, Phe- (CH 2 ) 2 -Phe-CO-, CH 3 CH 2 -PtLe- (CH 2 ) 2 -Phe-CO -, Phe-Phe-
(CH2) 2-Phe-CO-, Phe- (CH2) 2-Phe- (CH2) 2-Phe-CO-, CH3 (CH2) 3-Phe- (CH2) 2-Phe-CO- , CH3 (CH2) 5-O-Phe- (CH2) 2-Phe-CO- , (CH3) 2CH (CH2) 6CH=CHCH2CO- (eis) , (CH3) 2 CH (CH2) 6 CH= CHCH2 CO- ( trans ), (CH3) 2CH (CH2) 7CH=CHCH2CO- (eis) , (CH3)2CH (CHa)7CH=CHCH2CO- (trans) ,(CH 2 ) 2 -Phe-CO, Phe (CH 2 ) 2 -Phe- (CH 2 ) 2 -Phe-CO-, CH 3 (CH 2 ) 3 -Phe- (CH 2 ) 2 -Phe- CO, CH 3 (CH 2 ) 5 -O-Phe- (CH 2 ) 2 -Phe-CO-, (CH 3 ) 2 CH (CH 2 ) 6 CH = CHCH 2 CO- (ice), (CH 3 ) 2 CH (CH 2 ) 6 CH = CHCH 2 CO- (trans), (CH 3 ) 2 CH (CH 2 ) 7 CH = CHCH 2 CO- (ice), (CH 3 ) 2 CH (CHa) 7 CH = CHCH 2 CO- (trans),
CH3CH2(CHCH3) (CH2) 5CH=CHCH2CO- (eis) ,CH 3 CH 2 (CHCH 3 ) (CH 2 ) 5 CH = CHCH 2 CO- (ice),
CH3CH2(CHCH3) (CH2) 5CH=CHCH2CO- (trans),CH 3 CH 2 (CHCH 3 ) (CH 2 ) 5 CH = CHCH 2 CO- (trans),
CH3CH2 ( CHCH3 ) ( CH2 ) 7CH=CHCH2CO- ( eis ) ,CH 3 CH 2 (CHCH 3 ) (CH 2 ) 7 CH = CHCH 2 CO- (ice),
CH3CH2(CHCH3) (CH2) 7CH=CHCH2CO- (trans) , CH3CH2(CHCH3) (CH2) 7CH=CHCH2CO- (eis) , CH3 (CH2) 8 CH= CHCO- (eis) ,CH 3 CH 2 (CHCH 3) (CH 2) 7 CH = CHCH 2 CO- (trans), CH 3 CH 2 (CHCH 3) (CH 2) 7 CH = CHCH 2 CO- (ice), CH 3 (CH 2 ) 8 CH = CHCO- (ice),
CH3 (CH2) 8CH=CHCO- (trans) , CH3 (CH2) 9 CH= CHCO- (eis) ,CH 3 (CH 2 ) 8 CH = CHCO- (trans), CH 3 (CH 2 ) 9 CH = CHCO- (ice),
CH3 (CH2) 8CH=CHCO- (trans) , CH3(CH2J7CH=CHCO- (eis) ,CH 3 (CH 2 ) 8 CH = CHCO- (trans), CH 3 (CH 2 J 7 CH = CHCO- (ice)
CH3(CH2J7CH=CHCO- (trans) , wobei Phe für einen nicht
substituierten oder mit Cl-8 Alkyl einfach oder 2 bis 4- fach substituierten Benzolring und wobei -Phe- für ortho, metha, oder para der Bindungen steht.CH 3 (CH 2 J 7 CH = CHCO- (trans), where Phe is not for one substituted or with Cl-8 alkyl single or 2 to 4 times substituted benzene ring and wherein -Phe- is ortho, metha, or para of the bonds.
Zur Herstellung solcher Lipopeptide wird im Einzelnen beispielsweise auf die Literaturstellen DE 198 07 972 Al, EP 0 629 636 Al, EP 0 688 789 Al und US 2005/0153876 Al verwiesen.For the preparation of such lipopeptides, reference is made in detail, for example, to the publications DE 198 07 972 A1, EP 0 629 636 A1, EP 0 688 789 A1 and US 2005/0153876 A1.
Das Lipopeptid kann unabhängig von der Formel I ausgewählt sein aus der Gruppe bestehend aus "Amphomycin, Amphomycin- Derivate, Friulimicin, Friulimicin B, Friulimicin-Derivate, Daptomycin, Daptomycin-Derivate, Aspartocin, Aspartocin- Derivate, Glumamycin, Glumamycin-Derivate, Crystallomycin, Crystallomycin-Derivate, Zaomycin, Zaomycin-Derivate, Tsushimycin, Tsushimyin-Derivate, Laspartomycin, Laspartomycin-Derivate, Brevistin, Brevistin-Derivate, Cerexin B, Cerexin B-Derivate, Syringomycin und seine Derivate, Antibiotic A-30912 und seine Derivate, Antibiotic A-54145 und seine Derivate sowie Antibiotic A-21978C und seine Derivate" .The lipopeptide can be selected independently of the formula I from the group consisting of "amphomycin, amphomycin derivatives, friulimicin, friulimicin B, friulimicin derivatives, daptomycin, daptomycin derivatives, aspartocin, aspartocin derivatives, glumamycin, glumamycin derivatives, crystallomycin , Crystallomycin Derivatives, Zaomycin, Zaomycin Derivatives, Tsushimycin, Tsushimyin Derivatives, Laspartomycin, Laspartomycin Derivatives, Brevistin, Brevistin Derivatives, Cerexin B, Cerexin B Derivatives, Syringomycin and Its Derivatives, Antibiotic A-30912 and its Derivatives, Antibiotic A-54145 and its derivatives as well as Antibiotic A-21978C and its derivatives ".
Das Lipopeptid kann des Weiteren unabhängig von der Formel I ausgewählt sein aus der Gruppe bestehend aus ,,Ci5- AMPHOMYCIN, CI5-AMPHOMYCIN-9-GLY, CI5-AMPHOMYCIN-9-GLY-LYS, CI5-AMPHOMYCIN-9-LEU, Ci0-AMPHOMYCIN, Cn-AMPHOMYCIN, Ci2- AMPHOMYCIN, CI3-AMPHOMYCIN, C14-AMPHOMYCIN, C16-AMPHOMYCIN, CI7-AMPHOMYCIN, C28-AMPHOMYCIN, OLEOYL-AMPHOMYCIN, CH3- (CH2) n-O-P-PH-C(=O) -AMPHOMYCIN, CH3- (CH2) I5-O-P-PH-C (=0) - AMPHOMYCIN, HO- (CH2) 15-C (=0) - AMPHOMYCIN, CH3- (CH2) 9-O-P-PH- C (=0) -AMPHOMYCIN, CH3- (CH2) 7-O-P-PH-C (=0) -AMPHOMYCIN, CH3- (CH2)II-NH-SUCCINYL-AMPHOMYCIN, CI2-P-HYDRAZINOBENZOIC ACID- AMPHOMYCIN, CI5-AMPHOMYCIN-9-GABA, C14-AMPHOMYCIN-9-GLY, CI5-
AMPHOMYCIN- 9 -SAR, C15-AMPHOMYCIN- 9 -AHX, C15 -AMPHOMYCIN- 9- INA, C15 -AMPHOMYCIN- 9- (P-NO2-PHE) , C15-AMPHOMYCIN- 9 -GLY- PHE, C15 -AMPHOMYCIN- 9 -GLU, C15 -AMPHOMYCIN- 9- (P-F-PHE) , C15- AMPHOMYCIN- 9 - (ß- CHA) , C15 -AMPHOMYCIN- 9 -HPHE, C15-AMPHOMYCIN- 9 -GLY- GLY- GLY, C15-AMPHOMYCIN- 9 -C (=0) - (CH2) io-NH2, C15 - AMPHOMYCIN- 9- (/3-CYANO-ALA) , C15 -AMPHOMYCIN- 9 -ILE, C15- AMPHOMYCIN- 9 -GLY-VAL, C15 -AMPHOMYCIN- 9 -ASN, C15-AMPHOMYCIN- 9 -TYR, C15-AMPHOMYCIN- 9 -TRP, C15 -AMPHOMYCIN- 9 -PHG, C15- AMPHOMYCIN- 9 -GLY- GLY, C15 -AMPHOMYCIN- 9 -GLN, C15-AMPHOMYCIN- 9-THR, C15 -AMPHOMYCIN- 9 -PRO-GLY, C15 -AMPHOMYCIN- 9 -GLY- LEU, C15-AMPHOMYCIN- 9 -TYR (ET) , C15 -AMPHOMYCIN- 9 -GLY- SUC, C15- AMPHOMYCIN-9-GLY-AC, C13 -AMPHOMYCIN- 9 -GABA, C14-AMPHOMYCIN- 9-GLY-LYS, C15 -AMPHOMYCIN- 9 -TYR (ME) , C13 -AMPHOMYCIN- 9 -GLY, C13-AMPHOMYCIN -9-(/3-ALA) , C13-AMPHOMYCIN -9-SAR, C13- AMPHOMYCIN -9 -AHX, C12-AMPHOMYCIN -9-GABA, C12-AMPHOMYCIN - 9-GLY, C14-AMPHOMYCIN- 9- (ß-ALA) , C14 -AMPHOMYCIN- 9 -SAR, C14- AMPHOMYCIN- 9 -AHX, C14 -AMPHOMYCIN- 9 -GABA, C13 -AMPHOMYCIN- 9- ALA, C13 -AMPHOMYCIN- 9- (D-ALA) , C13 -AMPHOMYCIN- 9- (D-PRO) , C15- AMPHOMYCIN-9- (D-ALA) , C15 -AMPHOMYCIN- 9- (D-PRO) , C15- AMPHOMYCIN- 9 -GLY-GABA, C15-AMPHOMYCIN- 9-GLY- (D-ALA) , C15- AMPHOMYCIN- 9- (/3-ALA) -AHX, C15 -AMPHOMYCIN- 9 -GABA-VAL, C15- AMPHOMYCIN- 9 -GABA-AHX, C12 -AMPHOMYCIN- 9- (/3-ALA) , C12- AMPHOMYCIN- 9 -SAR, C16 -AMPHOMYCIN- 9 -SAR, C10 -AMPHOMYCIN- 9- (/3- ALA) , Cio-AMPHOMYCIN-9-SAR, C17 -AMPHOMYCIN- 9 -SAR, C16- AMPHOMYCIN- 9- (/3-ALA) , C17-AMPHOMYCIN- 9- (/3-ALA) , C15-The lipopeptide may further be selected independently of the formula I from the group consisting of Ci ,, 5 - amphomycin, C I5 -AMPHOMYCIN-9-GLY, C I5 -AMPHOMYCIN-9-GLY-LYS, C-9 I5 -AMPHOMYCIN -LEU, Ci 0 -AMPHOMYCIN, Cn-AMPHOMYCIN, Ci 2 - AMPHOMYCIN, C I3 -AMPHOMYCIN, C 14 -AMPHOMYCIN, C 16 -AMPHOMYCIN, C 17 -AMPHOMYCIN, C 28 -AMPHOMYCIN, OLEOYL-AMPHOMYCIN, CH 3 - ( CH 2 ) nOP-PH-C (= O) -AMPHOMYCIN, CH 3 - (CH 2 ) 15 -OP-PH-C (= O) - AMPHOMYCIN, HO- (CH 2 ) 15 -C (= O) - AMPHOMYCIN, CH 3 - (CH 2 ) 9 -OP-PH-C (= O) -AMPHOMYCIN, CH 3 - (CH 2 ) 7 -OP-PH-C (= O) -AMPHOMYCIN, CH 3 - (CH 2 ) II -NH-succinyl-amphomycin, C I2 -P HYDRAZINOBENZOIC ACID amphomycin, C I5 -AMPHOMYCIN-9-GABA, C 14 -AMPHOMYCIN-9-GLY, C I5 - AMPHOMYCIN-9-SAR, C 15 -AMPHOMYCIN-9-AHX, C 15 -AMPHOMYCIN-9-INA, C 15 -AMPHOMYCIN-9- (P-NO 2 -PHE), C 15 -AMPHOMYCIN-9-GLY-PHE , C 15 -AMPHOMYCIN-9-GLU, C 15 -AMPHOMYCIN-9- (PF-PHE), C 15 - AMPHOMYCIN-9 - (β-CHA), C 15 -AMPHOMYCIN-9 -HPHE, C 15 -AMPHOMYCIN- 9 -GLY-GLY-GLY, C 15 -AMPHOMYCIN-9 -C (= O) - (CH 2 ) 10 -NH 2 , C 15 - AMPHOMYCIN-9- (/ 3-CYANO-ALA), C 15 -AMPHOMYCIN - 9 -ILE, C 15 - AMPHOMYCIN-9 -GLY-VAL, C 15 -AMPHOMYCIN-9-ASN, C 15 -AMPHOMYCIN-9-TYR, C 15 -AMPHOMYCIN-9-TRP, C 15 -AMPHOMYCIN-9 - PHG, C 15 - AMPHOMYCIN-9-GLY-GLY, C 15 -AMPHOMYCIN-9-GLN, C 15 -AMPHOMYCIN-9-THR, C 15 -AMPHOMYCIN-9-PRO-GLY, C 15 -AMPHOMYCIN-9-GLY - LEU, C 15 -AMPHOMYCIN-9-TYR (ET), C 15 -AMPHOMYCIN-9 -GLY-SUC, C 15 - AMPHOMYCIN-9-GLY-AC, C 13 -AMPHOMYCIN-9 -GABA, C 14 -AMPHOMYCIN - 9-GLY-LYS, C 15 -AMPHOMYCIN-9-TYR (ME), C 13 -AMPHOMYCIN-9 -GLY, C 13 -AMPHOMYCIN-9 - (/ 3-ALA), C 13 -AMPHOMYCIN-9-SAR , C 13 - AMPHOMYCIN-9 -AHX, C 12 -AMPHOMYCIN-9-GABA , C 12 -AMPHOMYCIN-9-GLY, C 14 -AMPHOMYCIN-9- (β-ALA), C 14 -AMPHOMYCIN-9-SAR, C 14 -AMPHOMYCIN-9-AHX, C 14 -AMPHOMYCIN-9 GABA, C 13 -AMPHOMYCIN- 9- ALA, C13 -AMPHOMYCIN- 9- (D-ALA), C 13 -AMPHOMYCIN- 9- (D-PRO), C 15 - amphomycin-9- (D-ALA), C 15 -AMPHOMYCIN-9- (D-PRO), C 15 -AMPHOMYCIN-9-GLY-GABA, C 15 -AMPHOMYCIN-9-GLY- (D-ALA), C 15 - AMPHOMYCIN-9- (/ 3-ALA) -AHX, C 15 -AMPHOMYCIN-9 -GABA-VAL, C 15 -AMPHOMYCIN-9 -GABA-AHX, C 12 -AMPHOMYCIN-9- (/ 3-ALA), C 12 -AMPHOMYCIN-9 -SAR, C 16 -AMPHOMYCIN-9-SAR, C 10 -AMPHOMYCIN-9- (/ 3-ALA), Cio-AMPHOMYCIN-9-SAR, C 17 -AMPHOMYCIN-9-SAR, C 16 - AMPHOMYCIN-9- (/ 3-ALA ), C 17 -AMPHOMYCIN-9- (/ 3-ALA), C 15 -
AMPHOMYCIN-9-GLY-C6, C15-AMPHOMYCIN- 9 -ALA, CH3- (CH2) 15 -NH- C(=0) -AMPHOMYCIN- 9 -GLY, CH3- (CH2) 15-SO2-AMPHOMYCIN-9-GLY, C2- PABA-AMPHOMYCIN, C12- (P-APA) -AMPHOMYCIN- 9-GLY, C12-PABA- AMPHOMYCIN- 9-GLY, CH3- (CH2) u-0-P-PH-C (=0) -AMPHOMYCIN- 9 -GLY, C12- (P-TRANS-CINNAMYL) -AMPHOMYCIN- 9 -GLY, CH3- (CH2) Ü-O-P-PH- C) -GLY-AMPHOMYCIN- 9-GLY, C14-PABA-GLY-AMPHOMYCIN- 9-GLY, CH3- (CH2) 11-NH-C(=O) -AMPHOMYCIN- 9 -GLY, C15 -AMPHOMYCIN- 9 -AHX -GLY, C15 -AMPHOMYCIN- 9 -GABA- GABA, C15 -AMPHOMYCIN- 9 -HPRO, C15-
AMPHOMYCIN-9- (D-PIP) , CH3- (CH2) 11-NH-C (=0) -AMPHOMYCIN-9- (/?- ALA), CH3- (CH2) I1-NH-C(SO) -AMPHOMYCIN-9-SAR, CH3- (CH2) I5-SO2- GLY-AMPHOMYCIN, CH3- (CH2) 9-SO2-PHE-AMPHOMYCIN, CH3- (CH2) 9- SO2-GLY-AMPHOMYCIN-9-LYS, CH3- (CH2) 9-SO2-GLY-AMPHOMYCIN-9- GLY, Ci2-GLY-AMPHOMYCIN, C8- (P-APA) -AMPHOMYCIN, Ci4-GLY-AMPHOMYCIN-9-GLY-C 6 , C 15 -AMPHOMYCIN-9-ALA, CH 3 - (CH 2 ) 15 -NH-C (= O) -AMPHOMYCIN-9-GLY, CH 3 - (CH 2 ) 15 - SO 2 -AMPHOMYCIN-9-GLY, C 2 - PABA-AMPHOMYCIN, C 12 - (P-APA) -AMPHOMYCIN-9-GLY, C 12 -PABA-AMPHOMYCIN-9-GLY, CH 3 - (CH 2 ) u -0-P-PH-C (= O) -AMPHOMYCIN-9-GLY, C 12 - (P-TRANS-CINNAMYL) -AMPHOMYCIN-9 -GLY, CH 3 - (CH 2 ) O -OP-PH- C ) -GLY-AMPHOMYCIN-9-GLY, C 14 -PABA-GLY-AMPHOMYCIN-9-GLY, CH 3 - (CH 2 ) 11 -NH-C (= O) -AMPHOMYCIN-9-GLY, C 15 -AMPHOMYCIN - 9 -AHX -GLY, C 15 -AMPHOMYCIN-9 -GABA-GABA, C 15 -AMPHOMYCIN-9-H-PRORO, C 15 - Amphomycin-9- (D-PIP), CH 3 - (CH 2) 11-NH-C (= 0) -AMPHOMYCIN-9- (/? - ALA), CH 3 - (CH 2) -NH-C I1 (SO) -AMPHOMYCIN-9-SAR, CH 3 - (CH 2 ) I 5 -SO 2 - GLY-AMPHOMYCIN, CH 3 - (CH 2 ) 9 -SO 2 -PH-AMPHOMYCIN, CH 3 - (CH 2 ) 9 - SO 2 -Gly-amphomycin-9-LYS, CH 3 - (CH 2) 9 SO 2 -Gly-amphomycin-9- GLY, C 2 -Gly-amphomycin, C 8 - (P-APA) -AMPHOMYCIN , Ci 4 -GLY-
AMPHOMYCIN, CI6-GLY-AMPHOMYCIN, C18-GLY-AMPHOMYCIN, CI2- (P- AMINOPHENYLPROPANOYL) -AMPHOMYCIN, C12- (P-Amphomycin, C I6 -Gly-amphomycin, C 18 -Gly-amphomycin, C I2 - (P- AMINOPHENYLPROPANOYL) -AMPHOMYCIN, C 12 - (P-
AMINOPHENYLPROPANOYL) 2-AMPHOMYCIN, CH3- (CH2) 9-O-P-PH-C (=0) - GLY-AMPHOMYCIN, Ci2- (M-APA) -AMPHOMYCIN, Ci5- [ASP- (OTBU) ] - AMPHOMYCIN, C10-(M-APA)-AMPHOMYCIN, CH3- (CH2) 7) (CH3-AMINOPHENYLPROPANOYL) 2 -AMPHOMYCIN, CH 3 - (CH 2) 9 -O-P-PH-C (= 0) - GLY-amphomycin, Ci 2 - (M-APA) -AMPHOMYCIN, C 5 - [ASP (OtBu)] AMPHOMYCIN, C 10 - (M-APA) -AMPHOMYCIN, CH 3 - (CH 2 ) 7 ) (CH 3 -
(CH2) 5) CH-C (=0) -GLY-AMPHOMYCIN, C15-PHG-AMPHOMYCIN, C15- (D- PHE) -AMPHOMYCIN, PH-O- (CH2) X1-GLY-AMPHOMYCIN, Ci0- (L-BBTA) - AMPHOMYCIN, Ci2- (P-APA) -AMPHOMYCIN, Ci2- (P-AMINO-TRANS- CINNAMYL) -AMPHOMYCIN, CH3- (CH2) n-O-P-PH-C (=0) -GLY- AMPHOMYCIN, CH3- (CH2) 9- (P-APA) -AMPHOMYCIN, Ci2-PABA-GLY-(CH 2) 5) CH-C (= 0) -Gly-amphomycin, C 15 -PHG-amphomycin, C 15 - (D-Phe) -AMPHOMYCIN, PH-O- (CH 2) X1 -Gly-amphomycin, Ci 0 - (L-BBTA) - amphomycin, Ci 2 - (P-APA) -AMPHOMYCIN, C i2 - (P-amino-trans-cinnamyl) -AMPHOMYCIN, CH 3 - (CH 2) nOP-PH-C ( = 0) -GLY-AMPHOMYCIN, CH 3 - (CH 2 ) 9 - (P-APA) -AMPHOMYCIN, Ci 2 -PABA-GLY-
AMPHOMYCIN, CI5-AMPHOMYCIN-9- (D-ORN) , C14-AMPHOMYCIN-9-GLY- LYS, C14-AMPHOMYCIN-9-LYS, C14-AMPHOMYCIN-9-ORN, C13- AMPHOMYCIN-9-GLY-LYS, C15-AMPHOMYCIN-9-LYS, C15-AMPHOMYCIN- 9-ORN, C15-AMPHOMYCIN-9-GDAB, C15-AMPHOMYCIN- 9-DAP, C13- AMPHOMYCIN-9-LYS, C13-AMPHOMYCIN-9-ORN, C13-AMPHOMYCIN-9- GDAB, C13-AMPHOMYCIN-9-DAP, C12-AMPHOMYCIN-9-LYS, C12- AMPHOMYCIN^9-GDAB, C14-AMPHOMYCIN-9-GDAB, C14-AMPHOMYCIN-9- DAP, C16-AMPHOMYCIN-9-GLY-LYS, C17-AMPHOMYCIN-9-GLY-LYS, C12- AMPHOMYCIN-9-GLY-LYS, C15-AMPHOMYCIN-9-SAR-ORN, C15- AMPHOMYCIN-9-SAR-GDAB, C15-AMPHOMYCIN-9-SAR-DAP, C15- AMPHOMYCIN-9- (jS-ALA) , Ci5-AMPHOMYCIN-9- (/3-ALA) -ORN, jß- ISOMER OF Ci5-AMPHOMYCIN-9- (/3-ALA) , ANHYDRO ISOMER OF C15- AMPHOMYCIN-9- (/3-ALA) , C15-AMPHOMYCIN-9- (D-PRO) - (D-LYS) , C15- AMPHOMYCIN-9-GLY- (D-LYS) , C15-AMPHOMYCIN-9-GLY-ORN, C15- AMPHOMYCIN-9-GLY-GDAB, C15-AMPHOMYCIN-9- (/3-ALA) -LYS, C15- AMPHOMYCIN-9-GABA-LYS, Ci5-AMPH0MYCIN-9-GLY-DAP, Ci5- AMPHOMYCIN-9-GLY-HLYS, Ci5-AMPHOMYCIN-9-GABA-GDAB, Ci5- AMPHOMYCIN-9-PRO, C15-AMPHOMYCIN-9-AIB, Ci5-AMPHOMYCIN-9-
MECYS, C15-AMPHOMYCIN-9-NVL, C15-AMPHOMYCIN-9-ABU, C15- AMPHOMYCIN-9-CIT, C15-AMPHOMYCIN-9- (ME)2ARG, C15-AMPHOMYCIN- 9-HYP, C15-AMPHOMYCIN-9- (P-APA) , C15-AMPHOMYCIN-9-VAL, C15- AMPHOMYCIN-9- (ME)3LYS, C15-AMPHOMYCIN-9-NLE, C15-AMPHOMYCIN- 9-LYS, C15-AMPHOMYCIN-9- (/3-ALA) - (5-AVA) , C15-AMPHOMYCIN-9- (/3-ALA)-VAL, /?-ISOMER OF C15-AMPHOMYCIN-9- (/3-ALA) -VAL, C15- AMPHOMYCIN-9- (5-AVA) - (/3-ALA) , Cis-AMPHOMYCIN-9-GLY-LYS-GLY, C15-AMPHOMYCIN-9-GLY-LYS-LYS , QL5-AMPHOMYCIN-9-GLY-GLY-LYS, Ci5-AMPHOMYCIN-9-LYS-GLY, C15-AMPHOMYCIN-9-LYS-LYS, C15- AMPHOMYCIN-9-LYS-LYS-LYS, C15-AMPHOMYCIN-9-GLY- (D-LEU) , C15- AMPHOMYCIN-9-GLY-AHX, C15-AMPHOMYCIN-9-SAR-AHX, C15- AMPHOMYCIN-9-SAR-LYS, C15-AMPHOMYCIN-9-DAP- (/3-N- (/3-ALA) ) , C15-AMPHOMYCIN-9-C6, C15-AMPHOMYCIN- 9-PLA, C15-AMPHOMYCIN-9- PCA, C15-AMPHOMYCIN-9- (CARBAMOYL-LEU) , C15-AMPHOMYCIN-9-C8, C15-AMPHOMYCIN-9-CHEXYL, C15-AMPHOMYCIN- 9-C4, C15-AMPHOMYCIN- 9- (2-NORBORNANEACETYL) , C15-AMPHOMYCIN- 9- (N-BENZOYL-TYR- PABA) , C15-AMPHOMYCIN-9- ( (S) - (+) -5-OXO-2-TET-AMPHOMYCIN, C 15 -AMPHOMYCIN-9- (D-ORN), C 14 -AMPHOMYCIN-9-GLY-LYS, C 14 -AMPHOMYCIN-9-LYS, C 14 -AMPHOMYCIN-9-ORN, C 13 - AMPHOMYCIN-9 -GLY-LYS, C 15 -AMPHOMYCIN-9-LYS, C 15 -AMPHOMYCIN-9-ORN, C 15 -AMPHOMYCIN-9-GDAB, C 15 -AMPHOMYCIN-9-DAP, C 13 - AMPHOMYCIN-9-LYS, C 13 -AMPHOMYCIN-9-ORN, C 13 -AMPHOMYCIN-9-GDAB, C 13 -AMPHOMYCIN-9-DAP, C 12 -AMPHOMYCIN-9-LYS, C 12 - AMPHOMYCIN ^ 9-GDAB, C 14 -AMPHOMYCIN- 9-GDAB, C 14 -AMPHOMYCIN-9-DAP, C 16 -AMPHOMYCIN-9-GLY-LYS, C 17 -AMPHOMYCIN-9-GLY-LYS, C 12 - AMPHOMYCIN-9-GLY-LYS, C 15 -AMPHOMYCIN -9-SAR-ORN, C 15 -AMPHOMYCIN-9-SAR-GDAB, C 15 -AMPHOMYCIN-9-SAR-DAP, C 15 - AMPHOMYCIN-9- (jS-ALA), C i 5 -AMPHOMYCIN-9- / 3-ALA) -ORN, jS- ISOMER OF Ci 5 -AMPHOMYCIN-9- (/ 3-ALA), ANHYDRO ISOMER OF C 15 - AMPHOMYCIN-9- (/ 3-ALA), C 15 -AMPHOMYCIN-9- (D-PRO) - (D-LYS), C 15 - AMPHOMYCIN-9-GLY- (D-LYS), C 15 -AMPHOMYCIN-9-GLY-ORN, C 15 - AMPHOMYCIN-9-GLY-GDAB, C 15 -AMPHOMYCIN-9- (/ 3-ALA) -Lys, C 15 - amphomycin-9-GABA-LYS, Ci -AMPH0MYCIN 5-9-G LY-DAP, C 5 - amphomycin-9-GLY-HLYS, Ci -AMPHOMYCIN 5-9-GABA GDAB, C 5 - amphomycin-9-PRO, C 15 -AMPHOMYCIN-9-AIB, Ci-5 -AMPHOMYCIN 9 - MECYS, C 15 -AMPHOMYCIN-9-NVL, C 15 -AMPHOMYCIN-9-ABU, C 15 - AMPHOMYCIN-9-CIT, C 15 -AMPHOMYCIN-9- (ME) 2 ARG, C 15 -AMPHOMYCIN-9-HYP , C 15 -AMPHOMYCIN-9- (P-APA), C 15 -AMPHOMYCIN-9-VAL, C 15 - AMPHOMYCIN-9- (ME) 3 LYS, C 15 -AMPHOMYCIN-9-NLE, C 15 -AMPHOMYCIN- 9-LYS, C 15 -AMPHOMYCIN-9- (/ 3-ALA) - (5-AVA), C 15 -AMPHOMYCIN-9- (/ 3-ALA) -VAL, / - ISOMER OF C 15 -AMPHOMYCIN- 9- (/ 3-ALA) -VAL, C 15 -AMPHOMYCIN-9- (5-AVA) - (/ 3-ALA), Cis-AMPHOMYCIN-9-GLY-LYS-GLY, C 15 -AMPHOMYCIN-9- GLY-LYS-LYS, QL 5 -AMPHOMYCIN-9-GLY-GLY-LYS, C 5 -AMPHOMYCIN-9-LYS-GLY, C 15 -AMPHOMYCIN-9-LYS-LYS, C 15 - AMPHOMYCIN-9-LYS LYS-LYS, C 15 -AMPHOMYCIN-9-GLY- (D-LEU), C 15 -AMPHOMYCIN-9-GLY-AHX, C 15 -AMPHOMYCIN-9-SAR-AHX, C 15 - AMPHOMYCIN-9-SAR LYS, C 15 -AMPHOMYCIN-9-DAP- (/ 3-N- (/ 3-ALA)), C 15 -AMPHOMYCIN-9-C 6 , C 15 -AMPHOMYCIN-9-PLA, C 15 -AMPHOMYCIN-9 - PCA, C 15 -AMPHOMYCIN-9- (CARBAMOYL-LEU), C 15 -AMPHOMYCIN-9-C 8 , C 15 -AMPHOMYCIN-9-CHEXYL, C 15 -AMPHOMYCIN-9-C 4 , C 15 -AMPHOMYCIN- 9- (2 -NORBORNANEACETYL), C 15 -AMPHOMYCIN-9- (N-BENZOYL-TYR-PABA), C 15 -AMPHOMYCIN-9- ((S) - (+) -5-OXO-2-TET)
RAHYDROFURANCARBONYL) , C15-AMPHOMYCIN-9-PHENYLPROPYNYL, C15- AMPHOMYCIN-9- (CARBAMOYL-/3-ALA) , C15-AMPHOMYCIN-9-ACRYL, C15- AMPHOMYCIN-9- (1-NAPTHYLACETYL) , C15-AMPHOMYCIN-9- (4-RAHYDROFURANCARBONYL), C 15 -AMPHOMYCIN-9-PHENYLPROPYNYL, C 15 - AMPHOMYCIN-9- (CARBAMOYL- / 3-ALA), C 15 -AMPHOMYCIN-9-ACRYL, C 15 - AMPHOMYCIN-9- (1-NAPTHYL ACETYL), C 15 -AMPHOMYCIN-9- (4-
PHENOXYBENZOYL) , C15-AMPHOMYCIN-9- (2-NAPTHYLACETYL) , C15- AMPHOMYCIN-9- (2 -FURYL) , C15-AMPHOMYCIN-9-CROTONYL, C15- AMPHOMYCIN-9- (3 , 4- (METHYLENEDIOXY) PHENYLACETYL) , C15- AMPHOMYCIN- 9-C10, C15-AMPHOMYCIN-9- (γ-OXO-5-ACENAPTHENE- BUTANYL) , C15-AMPHOMYCIN- 9-HYDROCINNAMYL, C15-AMPHOMYCIN-9- (Ot-KETOBUTYL) , C15-AMPHOMYCIN-9-GERANYL, C15-AMPHOMYCIN-9- (O-ANISYL) , C15-AMPHOMYCIN-9-PHENYLECATYL, C15-AMPHOMYCIN-9- (2-BUTYNYL) , C15-AMPHOMYCIN-9- (3 , 5-BIS (CF3) PHENYLACETYL) , C15-AMPHOMYCIN- 9- (3 , 4-METHYLENEDIOXY-CINNAMYL) , C15- AMPHOMYCIN-9- (TRANS-CINNAMYL) , C15-AMPHOMYCIN-9-PHENOXYBENZOYL), C 15 -AMPHOMYCIN-9- (2-NAPTHYL ACETYL), C 15 - AMPHOMYCIN-9- (2-FURYL), C 15 -AMPHOMYCIN-9-CROTONYL, C 15 - AMPHOMYCIN-9- (3, 4- (METHYLENEDIOXY) PHENYLACETYL), C 15 - AMPHOMYCIN-9-C 10 , C 15 -AMPHOMYCIN-9- (γ-OXO-5-ACENAPTHENE-BUTANYL), C 15 -AMPHOMYCIN-9-HYDROCINNAMYL, C 15 -AMPHOMYCIN-9 - (Ot-KETOBUTYL), C 15 -AMPHOMYCIN-9-GERANYL, C 15 -AMPHOMYCIN-9- (O-ANISYL), C 15 -AMPHOMYCIN-9-PHENYLECATYL, C 15 -AMPHOMYCIN-9- (2-BUTYNYL) , C 15 -AMPHOMYCIN-9- (3,5-BIS (CF 3 ) PHENYL ACETYL), C 15 -AMPHOMYCIN-9- (3, 4-METHYLENEDIOXY-CINNAMYL), C 15 - AMPHOMYCIN-9- (TRANS-CINNAMYL) , C 15 -AMPHOMYCIN-9-
ACETOXYACETYL, C15-AMPHOMYCIN-9- (1-ADAMANTANYLCARBONYL) , C15-AMPHOMYCIN-9- (4-COTININECARBONYL) , C15-AMPHOMYCIN-9- (4- FLUOROBENZOLYL) , C15-AMPHOMYCIN-9- (S-ACETYLTHIOGLYCOYL) ,
Ci5-AMPHOMYCIN-9- (4-BUTOXYBENZOYL) , C15-AMPHOMYCIN-S- (6- OXOHEPTANOYL), CI5-AMPHOMYCIN-9-OLEATE, C15-AMPHOMYCIN-9- (4- PENYLBENZOYL), C15-AMPHOMYCIN-9- (3-PHENOXYBENZOYL) , C15- AMPHOMYCIN-9- (C (=0) - (CH2) 2-PIPERIDINE, C15-AMPHOMYCIN-9- (N, N1 -DIMETHYL-GABA) , C15-AMPHOMYCIN-S- (N-ETHYL-GLY) , C15- " AMPHOMYCIN- 9-SAR- (N,N-DIMETHYL-GLY) , C15-AMPHOMYCIN-S- (N- BENZYL-GLY), C15-AMPHOMYCIN-S- (N, N-DIETHYL-/3-ALA) , C10- AMPHOMYCIN- 9-C10 , C15-AMPHOMYCIN-9- (N-METHYL-GABA) , CH3- (CH2) i5-NH-C(=0) -AMPHOMYCIN, C15-AMPHOMYCIN-S-PGLU, CH3- (CH2) n-NH-C (=0) -AMPHOMYCIN, CH3- (CH2) 7-NH-C(=O) -AMPHOMYCIN, CH3- (CH2) i3-NH-C (=0) -AMPHOMYCIN, CH3- (CH2) X1-NH-C (=0) - AMPHOMYCIN, C15-AMPHOMYCIN-C (=0) -NH-N-BUTYL, C15-AMPHOMYCIN- C (=0) -NH-CYCLOHEXYL, C15-AMPHOMYCIN-C (=0) -NH-FURFURYL, C15- AMPHOMYCIN-C (=0) -NH-2-FLUOROBENZYL, C15-AMPHOMYCIN-C (=0) - NH-M-CF3-PHENYL, C15-AMPHOMYCIN-C (=0) -NH-P-CF3-PHENYL, C15- AMPHOMYCIN-C (=0) -NH-3 -FLUOROPHENYL, C15-AMPHOMYCIN- (D-SER) , C15-AMPHOMYCIN-(D-TYR), C15-AMPHOMYCIN-(D-TRP), C13- AMPHOMYCIN-9-GLU, C15-AMPHOMYCIN-9- (4-HYDROXYBENZYL) , C15- AMPHOMYCIN-9-N, N-DI- (P-HYDROXYBENZYL) , C15-AMPHOMYCIN-9- (N7N-DIMETHYLGLYCINE), CH3- (CH2J9-SO2-GLY-AMPHOMYCIN, CH3- (CH2) 15-SO2-PHE-AMPHOMYCIN, CH3- (CH2) 13-NH-C (=0) -AMPHOMYCIN- 9-GLY-LYS, CH3- (CH2) 13-NH-C(=O) -AMPHOMYCIN-9- (/3-ALA) , CH3- (CH2) I3-NH-C (=0) -AMPHOMYCIN-9-GLY, C12-PABA-AMPHOMYCIN-9- (ß- ALA) , C16- (P-APA) -AMPHOMYCIN, C8-PABA-AMPHOMYCIN, C10-PABA- AMPHOMYCIN, C11-PABA-AMPHOMYCIN, C13-PABA-AMPHOMYCIN, CH3-Acetoxyacetyl, C 15 -AMPHOMYCIN-9- (1-adamantanylcarbonyl), C 15 -AMPHOMYCIN-9- (4-COTININECARBONYL), C 15 -AMPHOMYCIN-9- (4- FLUOROBENZOLYL), C 15 -AMPHOMYCIN-9- (S -ACETYLTHIOGLYCOYL), Ci 5 -AMPHOMYCIN-9- (4-BUTOXYBENZOYL), C 15 -AMPHOMYCIN-S- (6- OXOHEPTANOYL), C I5 -AMPHOMYCIN-9-OLEATE, C 15 -AMPHOMYCIN-9- (4- PENYLBENZOYL), C 15 -AMPHOMYCIN-9- (3-PHENOXYBENZOYL), C 15 - AMPHOMYCIN-9- (C (= O) - (CH 2 ) 2-PIPERIDINE, C 15 -AMPHOMYCIN-9- (N, N 1 -DIMETHYL-GABA) , C 15 -AMPHOMYCIN-S- (N-ETHYL-GLY), C 15 - " AMPHOMYCIN-9-SAR- (N, N-DIMETHYL-GLY), C 15 -AMPHOMYCIN-S- (N-BENZYL-GLY) , C 15 -AMPHOMYCIN-S- (N, N-DIETHYL- / 3-ALA), C 10 -AMPHOMYCIN-9-C 10 , C 15 -AMPHOMYCIN-9- (N-METHYL-GABA), CH 3 - ( CH 2 ) i 5 -NH-C (= O) -AMPHOMYCIN, C 15 -AMPHOMYCIN-S-PGLU, CH 3 - (CH 2 ) n -NH-C (= O) -AMPHOMYCIN, CH 3 - (CH 2 ) 7 -NH-C (= O) -AMPHOMYCIN, CH 3 - (CH 2) i 3 -NH-C (= 0) -AMPHOMYCIN, CH 3 - (CH 2) X1 is -NH-C (= 0) - AMPHOMYCIN, C 15 -AMPHOMYCIN-C (= O) -NH-N-BUTYL, C 15 -AMPHOMYCINC (= O) -NH-CYCLOHEXYL, C 15 -AMPHOMYCIN-C (= O) -NH-FURFURYL, C 15 - AMPHOMYCIN-C (= O) -NH-2-FLUOROBENZYL, C 15 -AMPHOMYCIN-C (= O) - NH-M-CF 3 -PHENYL, C 15 -AMPHOMYCIN-C (= O) -NH-P -CF 3 -PHENYL, C 15 - amphomycin-C (= 0) -NH-3 -FLUOROPHENYL, C 15 -AMPHOMYCIN- (D-Ser), C 15 -AMPHOMYCIN- (D-Tyr), C 15 -AMPHOMYCIN- (D-TRP), C 13 - AMPHOMYCINE-9-GLU, C 15 -AMPHOMYCIN-9- (4-HYDROXYBENZYL), C 15 - AMPHOMYCIN-9-N, N-DI- (P-HYDROXYBENZYL), C 15 -AMPHOMYCIN-9- (N 7 N-DIMETHYLGLYCINES), CH 3 - (CH 2 J 9 -SO 2 -GLY-AMPHOMYCIN, CH 3 - (CH 2 ) 15 -SO 2 -PH-AMPHOMYCIN, CH 3 - (CH 2 ) 13 -NH-C (= 0) -AMPHOMYCIN- 9-GLY-LYS, CH 3 - (CH 2) 13 -NH-C (= O) -AMPHOMYCIN-9- (/ 3-ALA), CH 3 - (CH 2) I 3 -NH-C (= O) -AMPHOMYCIN-9-GLY, C 12 -PABA-AMPHOMYCIN-9- (β-ALA), C 16 - (P-APA) -AMPHOMYCIN, C 8 -PABA-AMPHOMYCIN, C 10 -PABA-AMPHOMYCIN, C 11 -PABA-AMPHOMYCIN, C 13 -PABA-AMPHOMYCIN, CH 3 -
(CH2) 10-NH-C(=O) - (/3-ALA) -AMPHOMYCIN, CH3- (CH2) 15-NH-C (=0) - (P- PHENYLACETYL) -AMPHOMYCIN, CH3- (CH2) 7-NH-C (=0) - (P- PHENYLACETYL) -AMPHOMYCIN, CH3- (CH2)13-NH-C(=O)-(P- PHENYLACETYL) -AMPHOMYCIN, CH3- (CH2) lo-NH-C (=0) - (P- PHENYLACETYL) -AMPHOMYCIN, CH3- (CH2) 13-NH-C (=0) - (GABA) - AMPHOMYCIN, CH3- (CH2) 13-NH-C (=0) - (M-PHENYLACETYL) - AMPHOMYCIN, C10- (M-AMINOBENZOYL) -AMPHOMYCIN, C11- (M- AMINOBENZOYL) -AMPHOMYCIN, CH3- (CH2) 13-NH-C (=0) - (/3-ALA) -
AMPHOMYCIN, C12-(M-AMINOBENZOYL)-AMPHOMYCIN, CI3-(M- AMINOBENZOYL)-AMPHOMYCIN, BORONATE-PINACOL-ESTER-RESIN, 41- OCTYL-BIPHENYL-4 -CARBOXYL-AMPHOMYCIN, Ci3- (P-APA) - AMPHOMYCIN, Ci4- (P-APA) -AMPHOMYCIN, CH3- (CH2) 15-NH-C (=0) - (M- PHENYLACETYD-AMPHOMYCIN, CI4- (M-APA) -AMPHOMYCIN, Ci3-(P-(CH 2 ) 10 -NH-C (= O) - (/ 3-ALA) -AMPHOMYCIN, CH 3 - (CH 2 ) 15 -NH-C (= O) - (P-PHENYLACETYL) -AMPHOMYCIN, CH 3 - (CH 2 ) 7 -NH-C (= O) - (P-PHENYLACETYL) -AMPHOMYCIN, CH 3 - (CH 2 ) 13 -NH-C (= O) - (P-PHENYLACETYL) -AMPHOMYCIN, CH 3 - (CH 2 ) lo -NH-C (= O) - (P-PHENYLACETYL) -AMPHOMYCIN, CH 3 - (CH 2 ) 13 -NH-C (= O) - (GABA) - AMPHOMYCIN, CH 3 - ( CH 2 ) 13 -NH-C (= O) - (M-PHENYLACETYL) - AMPHOMYCIN, C 10 - (M-AMINOBENZOYL) -AMPHOMYCIN, C 11 - (M-AMINOBENZOYL) -AMPHOMYCIN, CH 3 - (CH 2 ) 13 -NH-C (= 0) - (/ 3-ALA) - Amphomycin, C 12 - (M-aminobenzoyl) -AMPHOMYCIN, C I3 - (M-aminobenzoyl) -AMPHOMYCIN, boronate-pinacol ESTER RESIN, 4 1 - octyl-biphenyl-4-carboxyl amphomycin, C 3 - (P -APA) - AMPHOMYCIN, Ci 4 - (P-APA) -AMPHOMYCIN, CH 3 - (CH 2 ) 15 -NH-C (= O) - (M-PHENYLACETYD-AMPHOMYCIN, C I4 - (M-APA) - AMPHOMYCIN, Ci 3 - (P-
APA) -AMPHOMYCIN, CH3- (CH2) I0-NH-C (=0) -GABA-AMPHOMYCIN, N, N' - DI-C8- (M, M-DIAMINOBENZOYL) -AMPHOMYCIN, CH3- (CH2) 7-NH-C(=O) -APA) -AMPHOMYCIN, CH 3 - (CH 2 ) 10 -NH-C (= O) -GABA-AMPHOMYCIN, N, N '- DI-C 8 - (M, M-DIAMINOBENZOYL) -AMPHOMYCIN, CH 3 - ( CH 2 ) 7 -NH-C (= O) -
(M-PHENYLACETYL) -AMPHOMYCIN, CH3- (CH2) I3-NH-C (=0) -GLY- AMPHOMYCIN, 1-DODECYL-lH- (1,2,3) -TRIAZOLE-4-CARBOXYLIC ACID, 1-DODECYL-IH- (1,2, 3) -TRIAZOLE-4 -CARBOXYL-AMPHOMYCIN, Ci5- (M-APA) -AMPHOMYCIN, Ci3- (ASP- (OME) ) -AMPHOMYCIN, C15-(P- APA)-AMPHOMYCIN, Ci5- (ASP- (OME) )) -AMPHOMYCIN, C11- (ASP-(M-PHENYLACETYL) -AMPHOMYCIN, CH 3 - (CH 2 ) 13 -NH-C (= O) -GLY-AMPHOMYCIN, 1-DODECYL-1H- (1,2,3) -TRIAZOLE-4-CARBOXYLIC ACID, 1-DODECYL-IH- (1,2,3) -TRIAZOLE-4-CARBOXYL-AMPHOMYCIN, Ci 5 - (M-APA) -AMPHOMYCIN, Ci 3 - (ASP- (OME)) -AMPHOMYCIN, C 15 - ( P-APA) -AMPHOMYCIN, Ci 5 - (ASP- (OME)) -AMPHOMYCIN, C 11 - (ASP-
(OTBU) ) -AMPHOMYCIN, C13- (ASP- (OTBU) ) -AMPHOMYCIN, C11- (ASP-(OTBU)) -AMPHOMYCIN, C 13 - (ASP- (OTBU)) -AMPHOMYCIN, C 11 - (ASP-
(OME) ) -AMPHOMYCIN, C15- (ASP- (OME) ) -AMPHOMYCIN, C15- AMPHOMYCIN- 9-C (=0) -NH- (0-CF3-PHENYL) , N, N1 -DI-C6- (M, M- DIAMINOBENZOYL) -AMPHOMYCIN, N, N1 -DI-Ci2- (M, M- DIAMINOBENZOYL) -AMPHOMYCIN, CH3- (CH2) 7-NH-C (=0) - (jß-ALA) - AMPHOMYCIN, (4-PHENYLBENZOYL) -AMPHOMYCIN, (2 -(OME)) -AMPHOMYCIN, C 15 - (ASP- (OME)) -AMPHOMYCIN, C 15 - AMPHOMYCIN-9-C (= O) -NH- (O-CF 3 -PHENYL), N, N 1 -DI -C 6 - (M, M diaminobenzoyl) -AMPHOMYCIN, N, N 1 -DI-Ci 2 - (M, M diaminobenzoyl) -AMPHOMYCIN, CH 3 - (CH 2) 7 -NH-C (= 0) - (jß-ALA) - AMPHOMYCIN, (4-PHENYL-BENZOYL) -AMPHOMYCIN, (2 -
(PHENYLMETHYL) -BENZOYL-AMPHOMYCIN, N, N-DIETHYL-PABA- AMPHOMYCIN, (3,4,5-TRIMETHOXYBENZOYL) -AMPHOMYCIN, (4- TBUTYLBENZOYL) -AMPHOMYCIN, (3- (PHENOXY) -BENZOYL) - AMPHOMYCIN, Ci5-AMPHOMYCIN-9- (D-DAP) , ß-ISOMER OF CH3-(PHENYLMETHYL) -BENZOYL-AMPHOMYCIN, N, N-DIETHYL-PABA-AMPHOMYCIN, (3,4,5-TRIMETHOXYBENZOYL) -AMPHOMYCIN, (4-TBUTYLBENZOYL) -AMPHOMYCIN, (3- (PHENOXY) -BENZOYL) -AMPHOMYCIN, Ci 5 -AMPHOMYCIN-9- (D-DAP), β-ISOMER OF CH 3 -
(CH2) I3-NH-C (=0) -AMPHOMYCIN, /3-ISOMER OF CH3- (CH2) 10-NH- C (=0) - (GABA) -AMPHOMYCIN, LYS-GLY-AMPHOMYCIN-9-Ci5/ LYS-GLY- AMPHOMYCIN-9-Ci3, (11-(PHENOXY)UNDECANOYL)-AMPHOMYCIN, N- Ci2- ( (IS, 4S) -4-AMINOCYCLOHEXYLCARBOXYLIC ACID) , Ci-2- (CH2) I3 -NH-C (= 0) -AMPHOMYCIN, / 3-ISOMER OF CH 3 - (CH 2) 10 -NH-C (= 0) - (GABA) -AMPHOMYCIN, LYS-GLY-AMPHOMYCIN- 9-5 Ci / LYS-GLY-amphomycin-9-C 3, (11- (phenoxy) undecanoyl) -AMPHOMYCIN, N- Ci 2 - ((IS, 4S) -4-AMINOCYCLOHEXYLCARBOXYLIC ACID), Ci 2 -
( (IS, 4S) -4 -AMINOCYCLOHEXYLCARBOXYL) -AMPHOMYCIN, (2 - DODECANOYLAMINO-THIAZOL-4-YL) -ACETIC ACID, (2- DODECANOYLAMINO-THIAZOL-4 -YL) ACETYL-AMPHOMYCIN, 8- DODECYLOXY-QUINOLINE-2-CARBOXYLIC ACID, (8-DODECYLOXY- QUINOLINE-2-CARBONYL) -AMPHOMYCIN, /3-ISOMER OF (8- DODECYLOXY-QUINOLINE-2-CARBONYL) -AMPHOMYCIN, Ci5- AMPHOMYCIN-9-PHE, Ci5-AMPHOMYCIN-9-C15 # C15-AMPHOMYCIN-9- ( [2-
(2-METHOXY-ETHOXY)-ETHOXY]-ACETYL), Cio-SAR-AMPHOMYCIN, C14- SAR-AMPHOMYCIN, C8-SAR-AMPHOMYCIN, C15-AMPHOMYCIN-9-CI2, Ci5- AMPHOMYCIN-9- (11-PHENOXYUNDE-CANOYL) , C15-AMPHOMYCIN-9- (3- FURAN-2-YL-ACRYLOYL) , C15-AMPHOMYCIN-9- (3- (BENZENESULFONYDPROPIONOYL), CI5-AMPHOMYCIN-9- (4- (PYREN-2- YL)BUTYROYL) , CI5-AMPHOMYCIN-9-SUC, CI5-AMPHOMYCIN-9-PRO- LYS, BOC-AMPHOMYCIN, AMPHOMYCIN-9- (/3-ALA) , AMPHOMYCIN-9- SAR, GLY-AMPHOMYCIN-9-FMOC, C6-GLY-AMPHOMYCIN- 9-FMOC, C8- GLY-AMPHOMYCIN-9-FMOC, C10-GLY-AMPHOMYCIN-9-FMOC, C8-(M- APA) -AMPHOMYCIN, CH3- (CH2) I0-NH-C (=0) - (M-PHENYLACETYL) -((IS, 4S) -4 -AMINOCYCLOHEXYLCARBOXYL) -AMPHOMYCIN, (2-DODECANOYLAMINO-THIAZOLE-4-YL) ACETIC ACID, (2-DODECANOYLAMINO-THIAZOL-4-YL) ACETYL-AMPHOMYCIN, 8-DODECYLOXY-QUINOLINE- 2-CARBOXYLIC ACID, (8-DODECYLOXYQUINOLINE-2-CARBONYL) -AMPHOMYCIN, / 3-ISOMER OF (8-DODECYLOXY-QUINOLINE-2-CARBONYL) -AMAMPHOMYCIN, CIP 5 - AMPHOMYCIN-9-PHE, CIC 5 - AMPHOMYCIN-9-C 15 # C 15 -AMPHOMYCIN-9- (2- (2-methoxyethoxy) ethoxy] acetyl), Cio-SAR-amphomycin, C 14 - SAR amphomycin, C 8 -SAr-amphomycin, C 15-C-9 -AMPHOMYCIN I2, C 5 - amphomycin 9 - (11-PHENOXYUNDE-CANOYL), C 15 -AMPHOMYCIN-9- (3-FURAN-2-YL-ACRYLOYL), C 15 -AMPHOMYCIN-9- (3- (BENZENESULFONYDPROPIONOYL), C I5 -AMPHOMYCIN-9- 4- (PYREN-2-YL) BUTYROYL), C 15 -AMPHOMYCIN-9-SUC, C 15 -AMPHOMYCIN-9-PRO-LYS, BOC-AMPHOMYCIN, AMPHOMYCIN-9- (/ 3-ALA), AMPHOMYCIN-9 - SAR, GLY-AMPHOMYCIN-9-FMOC, C 6 -GLY-AMPHOMYCIN-9-FMOC, C 8 - GLY-AMPHOMYCIN-9-FMOC, C 10 -GLY-AMPHOMYCIN-9-FMOC, C 8 - (M- APA) -AMPHOMYCIN, CH 3 - (CH 2) I0 -NH-C (= 0) - (M-phenylacetyl) -
AMPHOMYCIN, 1-ADAMANTANE- (=0) -AMPHOMYCIN, (10-METHYL-UNDEC- 2-ENOYL) -AMPHOMYCIN, (10-METHYL-DODEC-2-ENOYL) -AMPHOMYCIN, (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN, (10-METHYL-DODEC- 2-ENOYL) -AMPHOMYCIN-9-GLY, (10-METHYL-DODEC-2-ENOYL) - AMPHOMYCIN-9-SAR, (10-METHYL-DODEC-2-ENOYL) -AMPHOMYCIN-9- (jß-ALA) , (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN- 9-GLY, (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN-9-SAR, (12-METHYL- TETRADEC-2-ENOYL) -ASPARTOCIN-9- (/S-ALA) , (12- ACETYLAMINODODECANOYD-AMPHOMYCIN, und (12-AMINODODECOYL) - AMPHOMYCIN". Zur Struktur, deren Terminologie und derAMPHOMYCIN, 1-ADAMANTANE (= O) -AMPHOMYCIN, (10-METHYL-ANDEC-2-ENOYL) -AMPHOMYCIN, (10-METHYL-DODEC-2-ENOYL) -AMPHOMYCIN, (12-METHYL-TETRADEC-2 ENOYL) -ASPARTOCIN, (10-METHYL-DODEC-2-ENOYL) -AMPHOMYCIN-9-GLY, (10-METHYL-DODEC-2-ENOYL) - AMPHOMYCIN-9-SAR, (10-METHYL-DODEC-2 ENOYL) -AMPHOMYCIN-9- (jß-ALA), (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN-9-GLY, (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN-9-SAR, ( 12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN-9- ( / S-ALA), (12-ACETYLAMINODODECANOYD-AMPHOMYCIN, and (12-AMINODODECOYL) -AMPHOMYCIN. "The structure, terminology, and art
Synthese solcher Lipopeptide wird auf die Literaturstelle US 2005/0153876 Al, „Compositions of Lipopeptide Antibiotic Derivatives and Methods of use thereof" der Migenix Inc., Kanada, verwiesen. Hierbei handelt es sich um Lipopeptide, welche unter die Formel Ia fallen,
For the synthesis of such lipopeptides, reference is made to US 2005/0153876 A1, "Compositions of Lipopeptide Antibiotic Derivatives and Methods of Use" of Migenix Inc., Canada, which are lipopeptides which fall under the formula Ia,
Formel IaFormula Ia
wobei in Formel Ia R3 auch über einen Rest L gebunden sein kann, wobei Rl OH oder NH2 ist, wobei L zumindest eine Aminosäure, zumindest eine substituierte Aminosäure, -R'- (CO)-, -R'- (CO) - (NR') - , oder -O-Ph- (CO) - ist, wobei R' jeweils unabhängig voneinander gleich oder verschieden und ein Rest, wie als R3 oder R5 definiert sein kann, und/oder wobei L - bei Bindung von R3 über einen Rest L gleich oder verschieden und unabhängig voneinander zumindest eine Aminosäure, zumindest eine substituierte Aminosäure, -(CO)-, -R"- (CO)-, -SO2-, -(CS)-, -(PO)-, -0-(PO)-, -0-(CO)- R--0- (CO) (NR-)-, -NH-(CO)-, - NR'- (CO)-, -R'- (CO)-, -R-- (CO) - (NR') -, oder -O-Ph- (CO) - ist, wobei R' jeweils unabhängig voneinander gleich oder
verschieden und ein Rest, wie als R3 oder R5 definiert sein kann, wobei L bei Dab9 vorzugsweise -(CO)- ist, wobei R2 -OR5, -SR5, NR5R5, -(CO) -R5, - (CO) -0-R5, -(CO)- NHR4 , - (CO) -NR4R4 , - (CS) -NHR4 , - (CS) -NR4R4 , - (CNR4) -NHR4 oder -(CNR4) -NR4R4, R5- (CO) , SO2R5 , -(SO)-RS, -(PO)(ORS) 2, -(PO) (ORS), COOH, SO3H, -PO3H, -F, -Cl, -Br, -I, oder Trihalomethyl ist, wobei R3 -H, -0R5, -SR5, -NR5R5, -CN, -NO2, -N3, -(CO)-RS, -(CO)-O-RS, -(C0)-NR5R5, -(CS)-NR5R5, - (CNR5) -NR5R5 , -(CO)- H, -RS-(CO), -S02R5, -(PO)(ORS)2/ - (PO) (0R5) , -CO2H, -SO3H, -PO3H, -F, -Cl, -Br, -I, Trihalomethyl, Cl-C25-Alkyl, substituiertes Cl-C25-Alkyl, Cl-C25-Heteroalkyl, substituiertes Cl-C25-Heteroalkyl/ C5-C10-Aryl, C5-C15- Arylaryl, substituiertes C5-C15-Arylaryl, C5-C15-Biaryl, substituiertes C5-C15-Biaryl, 5-10-gliedriges Heteroaryl, substituiertes 5-10-gliedriges Heteroaryl, C6-C26 Arylalkyl, substituiertes C6-C26-Arylalkyl, 6-26-gliedriges Heteroarylalkyl , substituiertes 6-26-gliedriges Heteroarylalkyl , zumindest eine Aminosäure, oder zumindest eine substituierte Aminosäure ist, wobei R4 unabhängig voneinander gleich oder verschieden Cl- C10-Alkyl, Cl7-C26-Arylalkyl, 17-26-gliedriges Heteroarylalkyl, geradkettiges oder verzweigtes, gesättigtes oder einfach oder mehrfach ungesättigtes C7- C25-Alkyl, optional Hydroxy-substituiert, primäres oder sekundäres Amin, zumindest eine Aminosäure oder zumindest eine substituierte Aminosäure ist, wobei R5 unabhängig voneinander gleich oder verschieden Cl- C10-Alkyl, C5-C10-Aryl, 5-10-gliedriges Heteroaryl, C6-C26- Arylalkyl, 6-26-gliedriges Heteroarylalykl, geradkettiges oder verzweigtes, gesättigtes oder einfach oder mehrfach ungesättigtes C5-C25-Alkyl, optional Hydroxy-substituiert, primäres oder sekundäres Amin, zumindest eine Aminosäure
oder zumindest eine substituierte Aminosäure, oder jede Kombination hiervon ist. R3 kann im Falle einer Aminosäure Glycin, ß-Alanin, GABA, 5-Aminopentansäure, 6- Aminohexansäure, gDAB, Orn, Dap, hLys, Sarcosin, Lysin, Glycin-Lysin, oder Sarcosin-Lysin sein. L kann insbesondere Glycin, Sarcosin, Phenylglycin, Phenylalanin, o- Methylasparticacid, o—t-butyl-Asparticacid, p- Aminophenylacetyl, (p-Aminophenylpropanoyl)n mit n=l oder 2, m-Aminophenylacetyl , (m-Aminophenylpropanoyl)n mit n=l oder 2, o-Aminophenylacetyl, (o-Aminophenylpropanoyl)n mit n=l oder 2, GABA, p-Aminobenzoesäure (PABA, m- Aminobenzoesäure, o-Aminobenzoesäure, p- Hydrazinobenzoesäure, m-Hydrazinobenzoesäure, o- Hydrazinobenzoesäure, p-Amino-trans-cinnamyl, m-Amino- trans-cinnamyl, o-Amino-trans-cinnamyl, p-where in formula Ia R3 can also be bonded via a radical L, where Rl is OH or NH 2 , L being at least one amino acid, at least one substituted amino acid, -R'- (CO) -, -R'- (CO) - (NR ') -, or -O-Ph- (CO) -, wherein R' are each independently the same or different and a radical, as may be defined as R3 or R5, and / or wherein L - when R3 identical or different and independently of one another at least one amino acid, at least one substituted amino acid, - (CO) -, -R "- (CO) -, -SO 2 -, - (CS) -, - (PO) - , -O- (PO) -, -O- (CO) - R - O- (CO) (NR -) -, -NH- (CO) -, - NR'- (CO) -, -R ' Is - (CO) -, -R-- (CO) - (NR ') -, or -O-Ph- (CO) -, wherein R' are each independently equal to or different and a radical as may be defined as R3 or R5, wherein L in Dab9 is preferably - (CO) -, where R2 is -OR5, -SR5, NR5R5, - (CO) -R5, - (CO) -O- R5, - (CO) - NHR4, - (CO) -NR4R4, - (CS) -NHR4, - (CS) -NR4R4, - (CNR4) -NHR4 or - (CNR4) -NR4R4, R5- (CO), SO 2 R 5, - (SO) -RS, - (PO) (ORS) 2, - (PO) (ORS), COOH, SO 3 H, -PO 3 H, -F, -Cl, -Br, -I or trihalomethyl, wherein R3 is -H, -0R5, -SR5, -NR5R5, -CN, -NO 2, -N 3, - (CO) RS, - (CO) -O-RS, - (C0) -NR5R5, - (CS) -NR5R5, - (CNR5) -NR5R5, - (CO) - H, -RS- (CO), -S0 2 R 5, - (PO) (ORS) 2 / - (PO) ( 0R5), -CO 2 H, -SO 3 H, -PO 3 H, -F, -Cl, -Br, -I, trihalomethyl, C 1 -C 25 -alkyl, substituted C 1 -C 25 -alkyl, C 1 -C 25 -heteroalkyl , substituted C1-C25 heteroalkyl / C5-C10 aryl, C5-C15 aryl aryl, substituted C5-C15 aryl aryl, C5-C15 biaryl, substituted C5-C15 biaryl, 5-10 membered heteroaryl, substituted 5- 10-membered heteroaryl, C6-C26 arylalkyl, substituted C6-C26 arylalkyl, 6-26-membered heteroarylalkyl, substituted 6- Is 26-membered heteroarylalkyl, at least one amino acid, or at least one substituted amino acid, wherein R4 are independently identical or different C1-C10-alkyl, Cl7-C26-arylalkyl, 17-26-membered heteroarylalkyl, straight-chain or branched, saturated or mono- or polyunsaturated C7-C25-alkyl, optionally hydroxy-substituted, primary or secondary amine, at least one amino acid or at least one substituted amino acid, wherein R5 independently and identically or differently C1-C10-alkyl, C5-C10-aryl, 5-10 heteroaryl, C6-C26 arylalkyl, 6-26 membered heteroaryl, straight or branched, saturated or mono- or polyunsaturated C5-C25 alkyl, optionally hydroxy-substituted, primary or secondary amine, at least one amino acid or at least one substituted amino acid, or any combination thereof. In the case of an amino acid, R3 may be glycine, β-alanine, GABA, 5-aminopentanoic acid, 6-aminohexanoic acid, gDAB, Orn, Dap, hLys, sarcosine, lysine, glycine-lysine, or sarcosine-lysine. In particular, L can be glycine, sarcosine, phenylglycine, phenylalanine, o-methylasparticacid, o-t-butyl-asparticacid, p-aminophenylacetyl, (p-aminophenylpropanoyl) n with n = 1 or 2, m-aminophenylacetyl, (m-aminophenylpropanoyl) n with n = 1 or 2, o-aminophenylacetyl, (o-aminophenylpropanoyl) n with n = 1 or 2, GABA, p-aminobenzoic acid (PABA, m-aminobenzoic acid, o-aminobenzoic acid, p-hydrazinobenzoic acid, m-hydrazinobenzoic acid, Hydrazinobenzoic acid, p-amino-trans-cinnamyl, m-amino-trans-cinnamyl, o-amino-trans-cinnamyl, p-
Aminophenylessigsäure, m-Aminophenylessigsäure, L-BBTA, oder jede Kombination hiervon sein.Aminophenylacetic acid, m-aminophenylacetic acid, L-BBTA, or any combination thereof.
Es ist möglich, dass die pharmazeutische Zusammensetzung mehrere verschiedene Lipopeptide in jeweils physiologisch wirksamer Dosis enthält. Dann handelt es sich um ein Kombinationspräparat bzw. ein Breitbandpräparat.It is possible that the pharmaceutical composition contains several different lipopeptides in each physiologically effective dose. Then it is a combination preparation or a broadband preparation.
Im Einzelnen kann das Lipopeptid frei oder als Alkali- oder Erdalkalisalz, vorzugsweise als Na- oder Calcium-Salz, insbesondere als Di-Calcium-Salz (Ca2Cl2-Salz) , oder als Ammoniumsalz vorliegen.Specifically, the lipopeptide may be free or as an alkali or alkaline earth salt, preferably as a sodium or calcium salt, in particular as a di-calcium salt (Ca 2 Cl 2 salt), or as an ammonium salt.
Das Lipopeptid ist in der pharmazeutischen Zusammensetzung vorzugsweise in einer Gesamtmenge (bezogen auf die Menge aller eingesetzter Lipopeptide) von 0,01 bis 80 Gewichts-%, insbesondere von 0,05 bis 50 Gewichts-%, vorzugsweise von
0,1 bis 30 Gewichts-%, zugegeben, wobei die Mengenangabe auf die fertige Zusammensetzung bezogen ist .The lipopeptide is preferably present in the pharmaceutical composition in a total amount (based on the amount of all lipopeptides used) of from 0.01 to 80% by weight, in particular from 0.05 to 50% by weight, preferably from 0.1 to 30% by weight added, the amount being based on the finished composition.
Grundsätzlich sind alle physiologisch verträglichen Cyclodextrine und Cyclodextrinderivate einsetzbar.In principle, all physiologically acceptable cyclodextrins and cyclodextrin derivatives can be used.
Cyclodextrine sind zyklische Oligosaccharide, die aus alpha -1,4 verknüpften Glucosebausteinen zusammengesetzt sind. Üblicherweise sind sechs bis acht Glucosebausteine (α>-, ß- , bzw. γ-Cyclodextrin) in einem Cyclodextrinmolekül miteinander verbunden. Neben den natürlich vorkommenden, unmodifizierten Cyclodextrinen, gibt es eine Vielzahl chemisch modifizierter Cyclodextrin-Derivate, die physiologisch verträglich sind und im Rahmen der Erfindung eingesetzt werden können. Das Cyclodextrin oder Cyclodextrin-Derivat ist vorzugsweise ein α- oder ß-Cyclodextrins are cyclic oligosaccharides composed of alpha-1,4 linked glucose units. Usually, six to eight glucose units (.alpha., .Beta. Or .gamma.-cyclodextrin) are linked together in a cyclodextrin molecule. In addition to the naturally occurring, unmodified cyclodextrins, there are a variety of chemically modified cyclodextrin derivatives that are physiologically compatible and can be used in the invention. The cyclodextrin or cyclodextrin derivative is preferably an α- or β-
Cyclodextrin und kann insbesondere die allgemeine Formel II aufweisen,Cyclodextrin and may in particular have the general formula II,
Formel II
wobei Rl, R2, und R3 gleich oder verschieden und ein beliebiger physiologisch verträglicher Rest sein kann, vorzugsweise -H, Cl-C8-Alkyl, -SO2OH, -PO(OH)2, oder -CO-R4 mit R4 = Cl-C8-Alkyl ist, wobei das Cl-C8-Alkyl einfach oder mehrfach an gleichen oder an verschiedenen C-Atomen mit -OH, -COOH, -CONHR5, -NHCOR6, -SO2OH, -PO(OH)2, oder Tetrazol-5-yl mit R5 = -H oder Cl-C4-Alkyl und R6 = carboxylphenyl sein kann, wobei n = 6, 7 oder 8, wobei Rl, R2 und R3 in verschiedenen Glucopyranoseeinheiten randomisiert sein können, wobei ein Sauerstoffatom oder mehrere Sauerstoffatome der Glucopyranoseeinheiten, insbesondere das Sauerstoffatom an C6, durch Schwefelatome ersetzt sein können, einschließlich physiologisch verträglicher Salze solcher Cyclodextrine. Vorzugsweise handelt es sich bei den Glucopyranoseeinheiten um α-D- oder α-L-Glucosepyranoseeinheiten. Cl-C8-Alkyl umfasst insbesondere Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl und Tertiär-Butyl . Im Mittel können 1 bis 3, vorzugsweise 1 bis 2 der Reste Rl, R2 und R3 verschieden von H sein. Vorzugsweise ist insbesondere Rl verschieden von -H. Dabei können 1, 2, 3, 4, 5, 6, oder ggf. 7 der Reste Rl eines Cyclodextrinmoleküls verschieden von -H sein. R2 und R3 können dann -H sein. Zusätzlich können aber auch 1, 2, 3, 4, 5, 6, oder ggf. 7 der Reste R3 eines Cyclodextrinmoleküls verschieden von -H sein.Formula II wherein R 1, R 2 and R 3 may be the same or different and may be any physiologically acceptable radical, preferably -H, C 1 -C 8 -alkyl, -SO 2 OH, -PO (OH) 2 , or -CO-R 4 where R 4 = Cl C 8 -alkyl, wherein the C 1 -C 8 -alkyl may be mono- or polysubstituted by identical or different C atoms with -OH, -COOH, -CONHR 5, -NHCOR 6, -SO 2 OH, -PO (OH) 2 , or Tetrazol-5-yl with R5 = -H or C1-C4 alkyl and R6 = carboxylphenyl, where n = 6, 7 or 8, wherein Rl, R2 and R3 may be randomized in different Glucopyranoseeinheiten, wherein one or more oxygen atom Oxygen atoms of Glucopyranoseeinheiten, in particular the oxygen atom at C6, may be replaced by sulfur atoms, including physiologically acceptable salts of such cyclodextrins. Preferably, the glucopyranose units are α-D or α-L-glucose pyranose units. In particular, C 1 -C 8 -alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. On average, 1 to 3, preferably 1 to 2, of the radicals R 1, R 2 and R 3 can be different from H. Preferably, in particular, R 1 is different from -H. In this case, 1, 2, 3, 4, 5, 6, or optionally 7 of the radicals Rl of a cyclodextrin molecule may be different from -H. R2 and R3 can then be -H. In addition, however, 1, 2, 3, 4, 5, 6, or optionally 7 of the radicals R3 of a cyclodextrin molecule may be different from -H.
Im Einzelnen kann das Cyclodextrin oder Cyclodextrinderivat ausgewählt sein aus der Gruppe bestehend aus "α- Cyclodextrin, ß-Cyclodextrin, Hydroxy- (Cl-C8-alkyl) -α- Cyclodextrin, Hydroxy- (Cl-C8-alkyl) -ß-Cyclodextrin, (2- Hydroxypropyl) -/3-Cyclodextrin, (2-Hydroxypropyl) -α- Cyclodextrin, Sulpho- (Cl-C8-alkyl) -ether-α-cyclodextrin, Sulpho- (Cl-C8-alkyl) -ether-ß -cyclodextrin,
Sulphobutylether-α-cyclodextrin, Sulphobutylether-ß- cyclodextrin" . Bei den Derivaten ist insbesondere der Rest am Sauerstoffatom des C6 Atomes verschieden von -H.Specifically, the cyclodextrin or cyclodextrin derivative may be selected from the group consisting of α-cyclodextrin, β-cyclodextrin, hydroxy (C 1 -C 8 -alkyl) -α-cyclodextrin, hydroxy (C 1 -C 8 -alkyl) -β-cyclodextrin , (2-hydroxypropyl) - / 3-cyclodextrin, (2-hydroxypropyl) -α-cyclodextrin, sulpho- (C 1 -C 8 -alkyl) -ether-α-cyclodextrin, sulpho- (C 1 -C 8 -alkyl) -ether- β-cyclodextrin, Sulphobutyl ether-α-cyclodextrin, sulphobutyl ether-β-cyclodextrin. "In the case of the derivatives, in particular the radical on the oxygen atom of the C6 atom is different from -H.
Das Cyclodextrin oder Cyclodextrinderivat kann in der pharmazeutische Zusammensetzung in einer Menge von 0,01 bis 99 Gewichts-%, insbesondere von 0,05 bis 80 Gewichts-%, vorzugsweise 0,1 bis 50 Gewichts-%, bezogen auf die fertige Zusammensetzung, zugegen sein.The cyclodextrin or cyclodextrin derivative may be present in the pharmaceutical composition in an amount of 0.01 to 99% by weight, more preferably 0.05 to 80% by weight, preferably 0.1 to 50% by weight, based on the final composition be.
Vorzugsweise ist das Lipopeptid in der pharmazeutischen Zusammensetzung mit dem Cyclodextrin oder Cyclodextrinderivat in einem molaren Verhältnis Lipopeptid/Cyclodextrin von 100:1 bis 1:500, vorzugsweise 10:1 bis 1:50, höchstvorzugsweise 2:1 bis 1:10, optional unter Zugabe von Zusatz- und/oder Hilfsstoffen in galenisch üblichen Zusatzmengen, gemischt.Preferably, the lipopeptide in the pharmaceutical composition with the cyclodextrin or cyclodextrin derivative in a lipopeptide / cyclodextrin molar ratio is from 100: 1 to 1: 500, preferably 10: 1 to 1:50, most preferably 2: 1 to 1:10, optionally with addition of additives and / or excipients in galenically customary amounts, mixed.
In aller Regel wird die pharmazeutische Zusammensetzung weitere Zusatz- und/oder Hilfsstoffe, insbesondere galenische Hilfsstoffe, enthalten, deren Auswahl von der gewählten Darreichungsform abhängt. Die galenische Herrichtung der erfindungsgemäßen pharmazeutischen Zusammensetzung kann dabei in fachüblicher Weise erfolgen. Als Gegenionen für ionische Verbindungen kommen beispielsweise Ca++, CaCl+, Na+, K+, Li+ oder Cyclohexylammonium, bzw. Cl", Br", Acetat, Trifluoracetat, Propionat, Laktat, Oxalat, Malonat, Maleinat, Citrat, Benzoat, Salicylat usw. in Frage. Geeignete feste oder flüssige galenische Zubereitungsformen sind beispielsweise Granulate, Pulver, Dragees, Tabletten, (Mikro-) Kapseln, Suppositorien, Sirupe, Säfte, Suspensionen, Emulsionen, Tropfen oder Lösungen zur Injektion (i.V., i.p., i.m.,
s. c.) oder Vernebelung (Aerosole), Zubereitungsformen zur Trockenpulverinhalation, transdermale Systeme, sowie Präparate mit protrahierter Wirkstoff-Freigabe, bei deren Herstellung übliche Hilfsmittel wie Trägerstoffe, Spreng-, Binde-, Überzugs-, Quellungs-, Gleit- oder Schmiermittel, Geschmacksstoffe, Süßungsmittel und Lösungsvermittler, Verwendung finden. Als Hilfsstoffe seien beispielsweise Magnesiumcarbonat, Titandioxid, Lactose, Mannit und andere Zucker, Talcum, Milcheiweiß, Gelatine, Stärke, Zellulose und ihre Derivate, tierische und pflanzliche Öle wie Lebertran, Sonnenblumen-, Erdnuss- oder Sesamöl, Polyethylenglycole und Lösungsmittel, wie etwa steriles Wasser und ein- oder mehrwertige Alkohole, beispielsweise Glycerin, genannt. Eine erfindungsgemäße pharmazeutische Zusammensetzung ist dadurch herstellbar, dass mindestens ein erfindungsgemäß verwendete Substanzkombination in definierter Dosis mit einem pharmazeutisch geeigneten und physiologisch verträglichen Träger und ggf. weiteren geeigneten Wirk-, Zusatz- oder Hilfsstoffen mit definierter Dosis gemischt und zu der gewünschten Darreichungsform hergerichtet ist. Bevorzugt sind Lösungen zur Injektion in der fachüblichen Herrichtung.As a rule, the pharmaceutical composition will contain other additives and / or adjuvants, in particular galenic adjuvants, the selection of which depends on the selected dosage form. The galenic preparation of the pharmaceutical composition according to the invention can be carried out in the usual way. Examples of counterions for ionic compounds are Ca ++ , CaCl + , Na + , K + , Li + or cyclohexylammonium, or Cl " , Br " , acetate, trifluoroacetate, propionate, lactate, oxalate, malonate, maleate, citrate, benzoate , Salicylate, etc. in question. Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection (iV, ip, im, sc) or nebulization (aerosols), dry powder inhalation preparations, transdermal systems, and sustained-release preparations prepared by conventional means such as excipients, disintegrants, binders, coating, swelling or lubricants, flavoring agents, Sweeteners and solubilizers, find use. Examples of adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile Water and mono- or polyhydric alcohols, such as glycerol, called. A pharmaceutical composition according to the invention can be prepared by mixing at least one substance combination used according to the invention in a defined dose with a pharmaceutically suitable and physiologically acceptable carrier and optionally further suitable active ingredients, additives or excipients with a defined dose and prepared to the desired administration form. Preference is given to solutions for injection in the customary preparation.
Als Verdünnungsmittel kommen Polyglykole, Ethanol, Wasser und Pufferlösungen in Frage. Geeignete Puffersubstanzen sind beispielsweise N,N"-Dibenzylethylendiamin, Diethanolamin, Ethylendiamin, N-Methylglucamin, N- Benzylphenethylamin, Diethylamin, Phosphat, Natriumbicarbonat , oder Natriumcarbonat . Es kann aber auch ohne Verdünnungsmittel gearbeitet werden.Suitable diluents are polyglycols, ethanol, water and buffer solutions. Suitable buffer substances are, for example, N, N'-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, sodium bicarbonate or sodium carbonate, but it is also possible to work without a diluent.
Physiologisch verträgliche Salze, sei es des Lipopeptids, sei es des Cyclodextrins oder Cyclodextrinderivats, sind
Salze mit anorganischen oder organischen Säuren, wie Salzsäure, Schwefelsäure, Essigsäure, Citronensäure, p- Toluolsulfonsäure, oder mit anorganischen oder organischen Basen, wie NaOH, KOH, Mg(OH)2/ Diethanolamin, Ethylendiarain, oder mit Aminosäuren, wie Arginin, Lysin, Glutaminsäure usw. oder mit anorganischen Salzen, wie CaCl2, NaCl oder deren freie Ionen, wie Ca2+, Na+, Cl", SO4 2" oder Kombinationen hieraus . Sie werden nach Standardmethoden hergestellt.Physiologically acceptable salts, be it the lipopeptide, be it the cyclodextrin or cyclodextrin derivative Salts with inorganic or organic acids, such as hydrochloric acid, sulfuric acid, acetic acid, citric acid, p-toluenesulfonic acid, or with inorganic or organic bases, such as NaOH, KOH, Mg (OH) 2 / diethanolamine, ethylenediarine, or with amino acids, such as arginine, lysine , Glutamic acid, etc. or with inorganic salts such as CaCl 2 , NaCl or their free ions such as Ca 2+ , Na + , Cl " , SO 4 2" or combinations thereof. They are manufactured according to standard methods.
Im Einzelnen kann eine erfindungsgemäße pharmazeutische Zusammensetzung enthalten: A) 0,01 bis 80 Gewichts-%, insbesondere 0,05 bis 50 Gewichts-%, vorzugsweise 0,1 bis 30 Gewichts-%, Lipopeptid, B) 0,01 bis 99 Gewichts-%, insbesondere 0,05 bis 80 Gewichts-%, vorzugsweise 0,1 bis 50 Gewichts-% Cyclodextrin bzw. Cyclodextrinderivat, C) 0,1 bis 99,8 Gewichts-%, insbesondere 1 bis 80 Gewichts-%, vorzugsweise 1 bis 50 Gewichts-% Zusatz- und/oder Hilfsstoffe sowie optional Verdünnungsmittel, wobei sich die Komponenten A) bis C) stets zu 100% addieren und wobei das Lipopeptid in einer physiologisch wirksamen Dosis mit dem Cyclodextrin oder Cyclodextrinderivat in einem molaren Verhältnis Lipopeptid/Cyclodextrin von 1:500 bis 10:1, vorzugsweise 1:100 bis 10:1, höchstvorzugsweise 1:100 bis 2:1, optional unter Zugabe von Zusatz- und/oderIn detail, a pharmaceutical composition according to the invention may contain: A) 0.01 to 80% by weight, in particular 0.05 to 50% by weight, preferably 0.1 to 30% by weight, lipopeptide, B) 0.01 to 99% by weight %, in particular 0.05 to 80% by weight, preferably 0.1 to 50% by weight of cyclodextrin or cyclodextrin derivative, C) 0.1 to 99.8% by weight, in particular 1 to 80% by weight, preferably 1 to 50% by weight of additives and / or auxiliaries and optionally diluents, wherein the components A) to C) always add up to 100% and wherein the lipopeptide in a physiologically effective dose with the cyclodextrin or cyclodextrin derivative in a molar ratio lipopeptide / cyclodextrin from 1: 500 to 10: 1, preferably 1: 100 to 10: 1, most preferably 1: 100 to 2: 1, optionally with the addition of additional and / or
Hilfsstoffen in galenisch üblichen Zusatzmengen, gemischt wird.Excipients in galenically customary amounts, is mixed.
Sofern vorstehend und nachstehend Angaben zu Gew.-%, molaren Verhältnissen und/oder Dosen gemacht sind, beziehen sich die angegebenen Werte stets auf die sogenannte freie Säure des Lipopeptids, sofern es in Salzform eingesetzt wird. Gegenionen von Salzformen sind also nicht mit
berechnet, sondern durch, das atomare Gewicht von Wasserstoff ersetzt. Gegenionen sind vielmehr als Zusatz- oder Hilfsstoffe eingesetzt.If the above and below information on wt .-%, molar ratios and / or doses are made, the values given always refer to the so-called free acid of the lipopeptide, if it is used in salt form. Counterions of salt forms are therefore not with calculated, but by replacing the atomic weight of hydrogen. Instead, counterions are used as additives or auxiliaries.
Die Erfindung betrifft des Weiteren die Verwendung einer erfindungsgemäßen pharmazeutischen Zusammensetzung zur Herstellung eines Arzneimittels zur Behandlung und/oder Prophylaxe von viralen, bakteriellen und/oder parasitären Infektionskrankheiten und/oder von Pilzerkrankungen. Beispiele für in Frage kommende Erkrankungen oderThe invention further relates to the use of a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment and / or prophylaxis of viral, bacterial and / or parasitic infectious diseases and / or fungal diseases. Examples of eligible diseases or
Anwendungsgebiete sind: Atemwegsinfektionen, Haut- und Weichteilinfektionen, HarnwegsInfektionen, Gallenwegsinfektionen, Sepsis, Endokarditis, Meningitis, OP-Prophylaxe, Wundinfektionen oder intraabdominale Infektionen.Areas of application are: respiratory tract infections, skin and soft tissue infections, urinary tract infections, bile duct infections, sepsis, endocarditis, meningitis, surgical prophylaxis, wound infections or intra-abdominal infections.
Bevorzugt ist es, wenn das Arzneimittel zur oralen Gabe oder zur Injektion galenisch hergerichtet ist.It is preferred if the medicament is prepared galenically for oral administration or for injection.
Die Erfindung betrifft des Weiteren ein Verfahren zur Behandlung einer bakteriellen, viralen oder parasitären Infektionskrankheit oder einer Pilzerkrankung, wobei einer Person, die an der Krankheit erkrankt ist oder droht hieran zu erkranken, eine physiologisch wirksame Dosis eines erfindungsgemäßen Arzneimittels dargereicht wird. Dabei kann die Tagesdosis von 1 bis 50000 mg, vorzugsweise 50 bis 30000 mg, höchstvorzugsweise von 100 bis 20000 mg, Lipopeptid über einen Zeitraum von 1 bis 60 Tage, vorzugsweise 1 bis 30 Tage, betragen.The invention further relates to a method for the treatment of a bacterial, viral or parasitic infectious disease or a fungal disease, wherein a person suffering from the disease or threatens to fall ill, a physiologically effective dose of a medicament according to the invention is presented. The daily dose may be from 1 to 50,000 mg, preferably 50 to 30,000 mg, most preferably from 100 to 20,000 mg, of lipopeptide over a period of 1 to 60 days, preferably 1 to 30 days.
Es können Verpackungseinheiten mit einer Mehrzahl von Gabeeinheiten vorgesehen sein, wobei jede Gabeeinheit zur Gabe innerhalb des vorstehenden Behandlungsplans
hergerichtet ist. Beispielsweise kann einePackaging units with a plurality of delivery units may be provided, each delivery unit being for administration within the above treatment plan is prepared. For example, a
Verpackungseinheit nl=5 bis n2=500 Gabeeinheiten enthalten, wobei jede Gabeeinheit ml=l/5 bis m2=l Tagesdosis an Lipopeptid enthält . Die Verpackungseinheit ist dann für einen Behandlungsplan eingerichtet, welcher 1 bis 5 Gaben pro Tag über eine Dauer von ol bis o2 Tagen vorsieht, wobei sich o dann berechnet als ol=nl*m2 und o2=n2*ml, bzw. bei vorgegebenem o und m sich n berechnet als n = o/m.Packing unit nl = 5 to n2 = 500 units containing each administration unit ml = l / 5 to m2 = 1 daily dose of lipopeptide. The packaging unit is then set up for a treatment plan which provides 1 to 5 doses per day for a period of from ol to o2 days, where o is then calculated as ol = nl * m2 and o2 = n2 * ml, respectively m is calculated as n = o / m.
Im Folgenden wird die Erfindung durch Vergleichsbeispiele und nicht limitierende erfindungsgemäße Beispiele näher erläutert .The invention is explained in more detail below by comparative examples and non-limiting examples according to the invention.
Beispiel 1: Minimierung der Friulimicin B-induziertenExample 1: Minimization of friulimicin B-induced
Hämolyse durch Humanes Serum Albumin (HSA) ; VergleichsbeispielHemolysis by Human Serum Albumin (HSA); Comparative example
Na2-Friulimicin B wurde in einer Konzentration von 6400 mg/1 in 0,9 % NaCl-Lösung mit 20, 15, 10, 5, 1 oder 0% HSA gelöst. Durch Verdünnung mit 0,9% NaCl und den jeweiligen HSA-Konzentrationen wurden weitere Stammlösungen von 3200, 1600, 800, 200 und 100 mg/1 Na2-Friulimicin für jede der aufgelisteten HSA-Konzentrationen hergestellt. Nach Vorinkubation für 2 Stunden bei Raumtemperatur wurden jeweils 40 μl der Friulimicin B/HSA Mischung mit 40 μl frischem venalen menschlichen Blut gemischt und anschließend bei 37° C für 180 min inkubiert. Als Negativkontrolle wurden Mischungen von Vollblut mit den unterschiedlichen HSA-Konzentrationen in 0,9% NaCl angesetzt, als Standard für die Kompletthydrolyse wurde eine Mischung von 40 μl frischem venalen menschlichen Blut mit 40 μl Wasser eingesetzt. Anschließend wurde der Grad
der durch die Inkubation induzierten Hämolyse wie folgt bestimmt: Die Proben wurden vorsichtig entweder mit Wasser (Standard) oder mit 1 ml 0,9% NaCl gemischt. Nach Zentrifugation der Proben bei 2500 RFC (5 min) wurde die Absorption des Überstandes im Spektralphotometer bei 540 nm bestimmt. Vor der Messung der Proben wurde das Spektralphotometers mit der jeweiligen oben beschriebenen Negativkontrolle kalibriert. Für die Bestimmung des Grads der Hämolyse der verschiedenen Reaktionsansätze wurde der Messwert des Standards mit kompletter Hämolyse als 100 % gesetzt. Die Messwerte der verschiedenen Reaktionsansätze werden ins Verhältnis zum Wert dieses Standards gesetzt und in Prozent angegeben. Tabelle 1 zeigt das Ergebnis des Hämolyseversuchs mit Na2-Friulimicin B und verschiedenen HSA-Konzentrationen durchgeführt mit menschlichem Blut.Na 2 -Friulimicin B was dissolved in a concentration of 6400 mg / l in 0.9% NaCl solution with 20, 15, 10, 5, 1 or 0% HSA. By dilution with 0.9% NaCl and the respective HSA concentrations, further stock solutions of 3200, 1600, 800, 200 and 100 mg / l Na 2 -frululimicin were prepared for each of the listed HSA concentrations. After preincubation for 2 hours at room temperature, 40 μl each of the friulimicin B / HSA mixture was mixed with 40 μl fresh human venous blood and then incubated at 37 ° C for 180 min. As a negative control mixtures of whole blood with different HSA concentrations in 0.9% NaCl were used, as a standard for the complete hydrolysis, a mixture of 40 ul fresh human venous blood was used with 40 ul of water. Subsequently, the degree the incubation-induced hemolysis was determined as follows: The samples were mixed gently with either water (standard) or with 1 ml of 0.9% NaCl. After centrifugation of the samples at 2500 RFC (5 min), the supernatant absorbance in the spectrophotometer was determined to be 540 nm. Before measuring the samples, the spectrophotometer was calibrated with the respective negative control described above. For the determination of the degree of hemolysis of the different reaction batches, the measurement value of the standard with complete hemolysis was set as 100%. The measured values of the various reaction batches are set in relation to the value of this standard and expressed as a percentage. Table 1 shows the result of the hemolysis experiment with Na 2 friulimicin B and various HSA concentrations performed on human blood.
Hierbei beziehen sich die Angaben der Konzentration des HSA (in % w/v) sowie des Na2-Friulimicin B (in mg/1, freie Säure) auf die Endkonzentrationen im Reaktionsansatz.Here, the data on the concentration of HSA (in% w / v) and of Na 2 -friulimicin B (in mg / l, free acid) refer to the final concentrations in the reaction mixture.
Tabelle 1Table 1
Hämolytische Aktivität in- Abhängigkeit von der Na2-Friulimicin B-Konzentration (mg/1) in Anwesenheit von verschiedenen HSA-Konzentrationen in vitro (Angabe in %)Hemolytic activity dependent on the Na 2 -frirulimicin B concentration (mg / l) in the presence of various HSA concentrations in vitro (expressed in%)
Friulimicinkonzentration in mg/1 0 0 100 200 800 1600 3200Friulimicin concentration in mg / 1 0 0 100 200 800 1600 3200
Ansatz mit 0% HSA 0 4, 6 5, ,2 6,5 11,8 13,6 Ansatz mit 2,5% 0 0, 7 2 2,7 3, .2 3, ,9 HSAMixture with 0% HSA 0 4, 6 5,, 2 6,5 11,8 13,6 Approach with 2,5% 0 0, 7 2 2,7 3, .2 3,, 9 HSA
Ansatz mit 5% HSA 0 0, 1 1 1,9 1, .1 1, ,7 Ansatz mit 7,5% 0 0 O1 ,4 1,6 1, .5 1, ,3 HSABatch with 5% HSA 0 0, 1 1 1,9 1, .1 1,, 7 Batch with 7.5% 0 0 O 1 , 4 1.6 1, .5 1,, 3 HSA
Ansatz mit 10% HSA 0 0 0,3 0,5 0,8 0,3Batch with 10% HSA 0 0 0.3 0.5 0.8 0.3
HSA unterdrückt mit guter Effizienz die durch Na2- Friulimicin B-induzierte Hämolyse ab einer Konzentration
von etwa 2,5%. Die sich anschließende Bestimmung des Gehalts an freiem Hämoglobin im Serum zeigte, dass nach Vorinkubation mit 5% - 10% HSA (w/v) , finale Konzentration im Reaktionsansatz) die Friulimicin B-induzierte Hämolyse signifikant minimiert werden konnte.HSA suppresses with good efficiency Na 2 -friulimicin B-induced hemolysis from one concentration of about 2.5%. The subsequent determination of free serum hemoglobin content showed that after preincubation with 5% -10% HSA (w / v), final concentration in the reaction mixture, friulimicin B-induced hemolysis could be significantly minimized.
Die Bestimmung der antibiotischen Aktivität von derartigen Na2-Friulimicin B/HSA Zusammensetzungen in vitro mit Staphylococcus aureus und Enterococcus faecalis gemessen entsprechend den folgenden erfindungsgemäßen Beispielen, zeigte jedoch, wie in Tabelle 2 dargestellt, ebenfalls eine starke Reduktion der antibiotischen Aktivität.However, the determination of the antibiotic activity of such Na 2 -friulimicin B / HSA compositions in vitro with Staphylococcus aureus and Enterococcus faecalis, measured according to the following examples of the invention, also showed, as shown in Table 2, a strong reduction in antibiotic activity.
Tabelle 2 Bestimmung der minimalen Hemmhofkonzentration (MHK) von Na2-Friulimicin in Anwesenheit von HSATable 2 Determination of minimum inhibitory concentration (MIC) of Na 2 -frululimicin in the presence of HSA
MHK- WertMIC value
Mediumszusatz [μg/ml]Medium supplement [μg / ml]
S. aureus ATCC 29213 0% HSA 2S. aureus ATCC 29213 0% HSA 2
S. aureus ATCC 29213 L4% HSA 8S. aureus ATCC 29213 L 4% HSA 8
E. faecalis ATCC 29212 0% HSA 4E. faecalis ATCC 29212 0% HSA 4
E. faecalis ATCC 29212 4% HSA >64E. faecalis ATCC 29212 4% HSA> 64
Beispiel 2: Minimaerung der durch Na2-Friulimicin B- induzierten Hämolyse durch den Zusatz von Cyc1odextrinenExample 2: Minimaerung of Na 2 -Friulimicin B-induced hemolysis by the addition of Cyclodextrinen
Dieses Beispiel zeigt die Wirkung verschiedener modifizierter oder unmodifizierter Cyclodextrine auf den durch Lipopeptide-induzierten hämolytischen Effekt. Hierbei dient Na2-Friulimicin B als Beispielmolekül für die
Antibiotika der Lipopeptide.This example demonstrates the effect of various modified or unmodified cyclodextrins on the lipopeptide-induced hemolytic effect. This serves Na 2 -Friulimicin B as an example molecule for the Antibiotics of lipopeptides.
Na2-Friulimicin B wurde in einer Konzentration von 3200 mg/1 in 0,9 % NaCl-Lösung gelöst. Durch Verdünnung mit 0,9% NaCl wurden weitere Stammlösungen von 1600, 800, 200, 100 und 50 mg/1 Na2-Friulimicin hergestellt. Je 20 μl dieser Stammlösungen wurden jeweils mit 20 μl 0,9%igem NaCl oder 2%igen Lösungen von (2-Hydroxypropyl) -γ-Cyclodextrin(HP-γ- CD) , (2-Hydroxypropyl) -/3-Cyclodextrin (HP-/3-CD) oder α- Cyclodextrin (α-CD) in 0,9% NaCl vorsichtig gemischt. Die Vorinkubation und Versuchsdurchführung zur Bestimmung der hämolytischen Aktivität mit frischem venalen menschlichen Blut wurde entsprechend dem Beispiel 1 durchgeführt . Experimente bei einer Endkonzentration von 0,5 % (w/v) der unterschiedlichen Cyclodextrine und den angegebenenNa 2 -Friulimicin B was dissolved in a concentration of 3200 mg / l in 0.9% NaCl solution. By dilution with 0.9% NaCl further stock solutions of 1600, 800, 200, 100 and 50 mg / 1 Na 2 -frululimicin were prepared. 20 .mu.l of these stock solutions each containing 20 .mu.l 0.9% NaCl or 2% solutions of (2-hydroxypropyl) -γ-cyclodextrin (HP-y-CD), (2-hydroxypropyl) - / 3-cyclodextrin ( HP- / 3-CD) or α-cyclodextrin (α-CD) mixed gently in 0.9% NaCl. The pre-incubation and experimental procedure for the determination of the hemolytic activity with fresh human venous blood was carried out according to example 1. Experiments at a final concentration of 0.5% (w / v) of the different cyclodextrins and the indicated
Endkonzentrationen des Na2-Friulimicin B (in mg/1, freie Säure) erbrachten die in Tabelle 3 dargestellten Ergebnisse.Final concentrations of Na 2 -friulimicin B (in mg / l, free acid) gave the results shown in Table 3.
Tabelle 3Table 3
Hämolytische Aktivität in Abhängigkeit von der Na2-Hemolytic activity as a function of Na 2 -
Friulimicin-Konzentration in Anwesenheit verschiedenerFriulimicin concentration in the presence of various
Cyclodextrine in vitro (Angabe in %)Cyclodextrins in vitro (expressed in%)
Die Bestimmung des Gehalts an freiem Hämoglobin im Serum
zeigte, dass nach Vorinkubation mit 0,5 % HP-γ-CD keine signifikante Reduktion der Na2-Friulimicin B-induzierten Hämolyse feststellbar war. γ-Cyclodextrine haben aufgrund ihres Zuckergrundgerüsts im Vergleich zu α- und ß- Cyclodextrinen ein größeres Hohlraumvolumen in ihrer hydrophoben Bindetasche. Überraschenderweise konnte jedoch nach Vorinkubation mit 0,5 % HP-/3-CD und α-CD eine signifikante Reduktion der di-Natrium-Friulimicin B- induzierten Hämolyse nachgewiesen werden.Determination of the content of free hemoglobin in serum showed that after preincubation with 0.5% HP-γ-CD no significant reduction of Na 2 -friulimicin B-induced hemolysis was observed. Due to their sugar backbone, γ-cyclodextrins have a larger void volume in their hydrophobic binding pocket compared to α- and β-cyclodextrins. Surprisingly, however, a significant reduction in di-sodium-friulimicin B-induced hemolysis was detected after preincubation with 0.5% HP- / 3-CD and α-CD.
Beispiel 3: Minimierung der Ca2Cl2-Friulimicin B- induzierten Hämolyse durch den Zusatz von modifizierten /3-CyclodextrinenExample 3: Minimization of Ca 2 Cl 2 -frulimicin B-induced hemolysis by the addition of modified / 3-cyclodextrins
Dieses Beispiel zeigt die Wirkung von ß-Cyclodextrinen auf den durch Lipopeptide-induzierten hämolytischen Effekt inThis example demonstrates the effect of β-cyclodextrins on the lipopeptide-induced hemolytic effect in
Anwesenheit von hohen Konzentrationen des Lipopeptids .Presence of high concentrations of the lipopeptide.
Hierbei dient Ca2Cl2-Friulimicin B als Beispielmolekül für die Antibiotika aus der Klasse der Lipopeptide undHere, Ca 2 Cl 2 -friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and
Sulfobutylether-ß-Cyclodextrin (SBE-ß-CD) sowie HP-/3-CD alsSulfobutyl ether-β-cyclodextrin (SBE-β-CD) and HP- / 3-CD as
Beispiele für modifizierte /?-Cyclodextrine.Examples of modified /? - cyclodextrins.
Ca2Cl2-Friulimicin B wurde in einer Konzentration von 100, 50, 40, 30, 20, 10 und 5 g/l in 20, 15, 12,5, 10, 7,5%Ca 2 Cl 2 -frulimicin B was dissolved in concentrations of 100, 50, 40, 30, 20, 10 and 5 g / l in 20, 15, 12.5, 10, 7.5%
SBE-ß-CD in 0,9 % NaCl-Lösung beziehungsweise 12,5% HP-ß-CD in 0,9 % NaCl-Lösung gelöst. Die Vorinkubation und Versuchsdurchführung zur Bestimmung der hämolytischen Aktivität mit frischem venalen menschlichen Blut wurden entsprechend dem Beispiel 1 durchgeführt. Abweichend erfolgte die Inkubation der finalen Reaktionsansätze mit Blut für 60 min bei 37° C. Die Ergebnisse sind in Tabelle 4 dargestellt. Angaben des Ca2Cl2-Friulimicin B (in mg/1,
freie Säure) und der Cyclodextrine beziehen sich auf die Endkonzentrationen im Reaktionsansatz.SBE-β-CD dissolved in 0.9% NaCl solution or 12.5% HP-β-CD in 0.9% NaCl solution. The pre-incubation and experimental procedure for the determination of the hemolytic activity with fresh human venous blood were carried out according to Example 1. Notwithstanding, the incubation of the final reaction mixtures with blood for 60 min at 37 ° C. The results are shown in Table 4. Details of Ca 2 Cl 2 -frulimicin B (in mg / l, free acid) and the cyclodextrins are based on the final concentrations in the reaction mixture.
Tabelle 4Table 4
Hämolytische Aktivität in Abhängigkeit von der Ca2Cl2-Hemolytic activity as a function of Ca 2 Cl 2 -
Friulimicin-Konzentration in Anwesenheit verschiedenerFriulimicin concentration in the presence of various
Cyclodextrine in vitro (Angabe in %)Cyclodextrins in vitro (expressed in%)
Überraschenderweise konnte festgestellt werden, daß HP-/3- CD, insbesondere aber auch SBE-/3-CD selbst bei sehr hohen Konzentrationen des hämolytisch sehr aktiven Ca2Cl2-Salzes von Friulimicin B die durch den Wirkstoff induzierte Hämolyse unterdrücken. Diese Ergebnisse zeigen, dass selbst bei extremen Wirkstoffkonzentrationen, die nur für kurze Zeit unmittelbar an Injektions- oder Infusionsstellen auftreten, nach Vorinkubation mit modifizierten ß- Cyclodextrinen die hämolytische Wirkung von Ca2Cl2- Friulimicin B über einen Zeitraum von einer Stunde signifikant unterdrückt werden kann.Surprisingly, it was found that HP- / 3-CD, but in particular also SBE / 3-CD, even at very high concentrations of the haemolytically very active Ca 2 Cl 2 salt of friulimicin B, suppress the hemolysis induced by the active ingredient. These results show that even with extreme drug concentrations that occur only for a short time directly at injection or infusion sites, after preincubation with modified ß-cyclodextrins, the hemolytic effect of Ca 2 Cl 2 - friulimicin B over a period of one hour are significantly suppressed can.
Beispiel 4: Minimierung der Daptomycin-induzierten Hämolyse durch den Zusatz von modifizierten ß-Example 4 Minimization of Daptomycin-Induced Hemolysis by the Addition of Modified β-
Cyclodextrinen
Dieses Beispiel zeigt die Wirkung einescyclodextrins This example shows the effect of a
Sulphoalkylethercyclodextrins auf den durch das Lipopeptid Daptomycin bei isolierten Erythrozyten in der Anwesenheit von CaCl2 induzierten hämolytischen Effekt.Sulphoalkylethercyclodextrins on the induced by the lipopeptide daptomycin in isolated erythrocytes in the presence of CaCl 2 hemolytic effect.
Daptomycin wurde in einer Lösung von 0% oder 2,5% SBE-/3-CD in 0,9 % NaCl, 2 , 5 mM CaCl2 gelöst. Zur Durchführung der Hämolyseversuche wurden Erythrozyten aus frischem venalen menschlichen Blut, das in heparinisierten Probenröhrchen aufgefangen wurde, isoliert. Hierzu wurden die Erythrozyten durch Zentrifugation bei 2500 RFC (5 min) sedimentiert . Die Erythrozyten wurden dreimal mit 0,9% NaCl gewaschen und nach der abschließenden Zentrifugation in einem Volumen 0,9% NaCl aufgenommen, das dem Ausgangsvolumen derDaptomycin was dissolved in a solution of 0% or 2.5% SBE- / 3-CD in 0.9% NaCl, 2.5 mM CaCl 2 . To perform the hemolysis experiments, erythrocytes were isolated from fresh venal human blood collected in heparinized sample tubes. For this purpose, the erythrocytes were sedimented by centrifugation at 2500 RFC (5 min). The erythrocytes were washed three times with 0.9% NaCl and taken after the final centrifugation in a volume of 0.9% NaCl, which corresponds to the initial volume of the
Blutprobe entsprach. 40 μl der Erythrozyten wurden mit 40 μl der vorstehend beschriebenen Reaktionsansätze versetzt und 5 Stunden bei 37° C unter stetem vorsichtigem Schütteln inkubiert . Die weitere Versuchsdurchführung zur Bestimmung der hämolytischen Aktivität wurde entsprechend dem Beispiel 1 durchgeführt. Die Ergebnisse sind in Tabelle 5 dargestellt. Hierbei beziehen sich Angaben der Konzentrationen von SBE-/3-CD (in % w/v) sowie des Daptomycin (in mg/1, freie Säure) auf die Endkonzentrationen im Reaktionsansatz.Blood sample corresponded. 40 .mu.l of the erythrocytes were mixed with 40 .mu.l of the reaction mixtures described above and incubated for 5 hours at 37 ° C with constant gentle shaking. The further experiment to determine the hemolytic activity was carried out according to Example 1. The results are shown in Table 5. Here, data on the concentrations of SBE- / 3-CD (in% w / v) and of daptomycin (in mg / l, free acid) refer to the final concentrations in the reaction mixture.
Tabelle 5Table 5
Hämolytische Aktivität in Abhängigkeit von der Daptomycin- Konzentration in Anwesenheit von SBE-/3-CD in vitro (Angabe in %)
Hemolytic activity as a function of daptomycin concentration in the presence of SBE / 3 CD in vitro (expressed in%)
SBE-/3-CD unterdrückt auch im Versuch mit isolierten Erythrozyten die durch ein Lipopeptid, hier Daptomycin, induzierte Zelllyse. Dieses Experiment zeigt, dass SBE-/3-CD toxische Eigenschaften sehr unterschiedlicher Lipopeptide unterdrücken kann. Die hämolytischen Eigenschaften des Daptomycin sind auf eine unmittelbare Interaktion mit der Erythrozytenmembran zurückzuführen. Ähnliche Mechanismen liegen der für Daptomycin beschriebenen toxische Wirkung auf den Skelettmuskel zugrunde, so dass eine Formulierung von Daptomycin oder seinen Derivaten mit Cyclodextrinen auch diesen toxischen Effekt minimiert.SBE- / 3-CD also suppresses the cell lysis induced by a lipopeptide, here daptomycin, in an experiment with isolated erythrocytes. This experiment shows that SBE- / 3-CD can suppress toxic properties of very different lipopeptides. The hemolytic properties of daptomycin are due to an immediate interaction with the erythrocyte membrane. Similar mechanisms underlie the toxic effect on skeletal muscle described for daptomycin so that formulation of daptomycin or its derivatives with cyclodextrins also minimizes this toxic effect.
Beispiel 5 : Auswirkungen des Zusatzes von Cyclodextrinen auf die antibiotische Aktivität von Ca2Cl2- Friulimicin B.Example 5 Effects of Addition of Cyclodextrins on the Antibiotic Activity of Ca 2 Cl 2 - Friulimicin B.
Die Auswirkungen von Cyclodextrinen auf die antibiotische Aktivität von Ca2ci2-Friulimicin B wurden durch in vitro Experimente zur Wachstumsinhibition von gram-positiven Bakterien untersucht . Hierbei wurde die minimale Hemmkonzentration zur Wachstumsinhibierung durch Kultivierung der Bakterien auf Nähragar (Agardilution) nach den CLSI (früher NCCLS) Richtlinien bestimmt (NationalThe effects of cyclodextrins on the antibiotic activity of Ca 2 ci 2 -frirulimicin B were investigated by in vitro experiments on the growth inhibition of gram-positive bacteria. Here, the minimum inhibitory concentration for growth inhibition was determined by culturing the bacteria on nutrient agar (agar digestion) according to the CLSI (formerly NCCLS) guidelines (National
Committee for Clinical Laboratory Standards. 2003. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved Standard — 6th ed. Document M7-A6. Clinical and Laboratory Standards
Institute, Wayne, PA, USA) . Dabei wurden verschiedene molare Mischungsverhältnisse des Lipopeptids Ca2Cl2- Friulimicin B mit SBE-/3-CD in Ca-Ionen adjustiertem Müller- Hinton Medium getestet. Die für die Kultivierungsmethoden getesteten gram-positiven Stämme waren:Committee for Clinical Laboratory Standards. 2003. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved Standard - 6 th ed. Document M7-A6. Clinical and Laboratory Standards Institute, Wayne, PA, USA). Various molar mixing ratios of the lipopeptide Ca 2 Cl 2 -friulimicin B with SBE / 3-CD in Ca-ion-adjusted Müller-Hinton medium were tested. The gram-positive strains tested for the cultivation methods were:
Staphylococcus carnosus ATCC 51365 (DSM 20501) Staphylocσccus aureus ATCC 29213 (DSM 2569) Staphylococcus aureus ATCC 33592 (DSM 11729) Staphylococcus epidermidis ATCC 12228 (DSM 1798)Staphylococcus carnosus ATCC 51365 (DSM 20501) Staphylococcus aureus ATCC 29213 (DSM 2569) Staphylococcus aureus ATCC 33592 (DSM 11729) Staphylococcus epidermidis ATCC 12228 (DSM 1798)
Die eingesetzten Zellmengen pro Spot (Sollwert: 5 * 103 - 5 * 104 CFU) lagen bei: S. carnosus ATCC 51365 5,5 X 103 CFU S. aureus ATCC 29213 7,6 X 103 CFU S. aureus ATCC 33592 2,2 X 104 CFU S. epidermidis ATCC 12228 1,1 X 104 CFUThe amounts of cells used per spot (target value: 5 × 10 3 - 5 × 10 4 CFU) were: S. carnosus ATCC 51365 5.5 × 10 3 CFU S. aureus ATCC 29213 7.6 × 10 3 CFU S. aureus ATCC 33592 2.2 X 10 4 CFU S. epidermidis ATCC 12228 1.1 X 10 4 CFU
Tabelle 6Table 6
Antibiotische Aktivität (MHK in /ig/ml) von Ca2Cl2- Friulimicin B in Abhängigkeit von der SBE-ß-CO-Menge (angegeben ist das molare Mengenverhältnis) in vitroAntibiotic activity (MIC in / ig / ml) of Ca 2 Cl 2 - friulimicin B as a function of the amount of SBE-β-CO (the molar ratio is indicated) in vitro
Überraschenderweise beeinflusst das Cyclodextrin in diesen Experimenten die antibiotische Aktivität von Ca2Cl2- Friulimicin B nicht negativ obwohl durch die molekulare Interaktion der Cyclodextrine mit Friulimicin bei den gleichen molaren Verhältnissen die hämolytische Eigenschaft des Lipopeptids fast komplett unterdrückt werden kann.
Beispiel 6: Inhibierung der hämolytischen Aktivität verschiedener Lipopeptide durch CyclodextrineSurprisingly, the cyclodextrin in these experiments does not adversely affect the antibiotic activity of Ca 2 Cl 2 - friulimicin B although the molecular interaction of the cyclodextrins with friulimicin at the same molar ratios almost completely suppresses the hemolytic property of the lipopeptide. Example 6: Inhibition of hemolytic activity of various lipopeptides by cyclodextrins
Dieses Beispiel zeigt die Wirkung einesThis example shows the effect of a
Sulphoalkylethercyclodextrins auf den durch verschiedene Lipopeptide induzierten hämolytischen Effekt. Die Lipopeptide wurden in einer Konzentration von 6400 mg/1 in 0,9 % NaCl-Lösung gelöst. Durch Verdünnung mit einem Volumen 0,9% NaCl oder 0,9% NaCl/10% SBE-/3-CD wurden jeweils Stammlösungen von 3200 mg/1 Lipopeptid (freie Säure) mit oder ohne 5% SBE-/3-CD hergestellt. Die Vorinkubation und Versuchsdurchführung zur Bestimmung der hämolytischen Aktivität mit frischem venalen menschlichen Blut wurde entsprechend dem Beispiel 1 durchgeführt und erbrachten die in Tabelle 7 dargestellten Ergebnisse. Dargestellt ist die prozentuale Inhibition der Lipopeptid- induzierten Hämolyse durch die Anwesenheit von 2,5% SBE-/3- CD bei einer Lipopeptid-Konzentration von 1600 mg/1. Bei den getesteten Lipopeptiden handelt es sich um Friulimicin- Derivate und Amphomycin-Derivate, deren Acylrest verändert wurde. Alle Lipopeptide weisen eine Struktur gemäß Formel ISulphoalkylethercyclodextrins on the induced by various lipopeptides hemolytic effect. The lipopeptides were dissolved at a concentration of 6400 mg / l in 0.9% NaCl solution. By dilution with a volume of 0.9% NaCl or 0.9% NaCl / 10% SBE- / 3-CD, stock solutions of 3200 mg / l lipopeptide (free acid) with or without 5% SBE- / 3-CD were prepared , The preincubation and experimental procedure for the determination of the hemolytic activity with fresh human venous blood was carried out according to Example 1 and gave the results shown in Table 7. Shown is the percent inhibition of lipopeptide-induced hemolysis due to the presence of 2.5% SBE / 3 CD at a lipopeptide concentration of 1600 mg / l. The lipopeptides tested are friulimicin derivatives and amphomycin derivatives whose acyl moiety has been altered. All lipopeptides have a structure according to formula I.
Y-X-Dab-Pip-MeAsp-Asp-Gly-Asp-Gly-Dab-Val-ProY-X-Dab-Pip-MeAsp-Asp-Gly-Asp-Gly-Dab-Val-Pro
Formel IFormula I
auf, wobei die untersuchten Lipopeptide folgendermaßen charakterisiert sind:
X Ywith the lipopeptides investigated being characterized as follows: XY
Amphoraycin Asp 10-Methyldodec-3en-säureAmphoraycin Asp 10-methyldodec-3enoic acid
Friulimicin B Asn 12-methyltridec-3-en-säureFriulimicin B Asn 12-methyltridec-3-enoic acid
CBS000201 Asn 12-MethyltridecansäureCBS000201 Asn 12-methyltridecanoic acid
CBSÖ00205 Asn 15-Phenyl-n-pentadecaiicarbonsäureCBSÖ00205 Asn 15-phenyl-n-pentadecaiicarboxylic acid
CBS000203 Asn StearinsäureCBS000203 Asn stearic acid
CBS000204 Asn γ- LinolensäureCBS000204 Asn γ-linolenic acid
CBS000217 Asn 4- [2- (4-Phenethyl-phenyl) -ethyl] - benzoesäureCBS000217 Asn 4- [2- (4-phenethylphenyl) ethyl] benzoic acid
und Y durch Amidierung mit dem extrazirkuläre Asn oder Asp des Peptids verknüpft wurde. Zur Herstellung solcher Lipopeptide wird im Einzelnen beispielsweise auf die Literaturstelle EP 0 688 789 Al verwiesen.and Y was linked by amidation to the extracircular Asn or Asp of the peptide. For the preparation of such lipopeptides, reference is made in detail, for example, to the document EP 0 688 789 A1.
Tabelle 7Table 7
Inhibition der hämolytischen Aktivität verschiedenerInhibition of hemolytic activity of various
Lipopeptide bei einer Konzentration von 1600 mg/1 inLipopeptides at a concentration of 1600 mg / 1 in
Anwesenheit von 2,5 % SBE-ß-CDPresence of 2.5% SBE-ß-CD
Diese Ergebnisse zeigen, daß Cyclodextrine im Wesentlichen unabhängig vom Acyl- und Peptidylrest eines Lipopeptids in der Lage sind, die Hämolyse zu reduzieren.
Beispiel 7: Herstellung einer Ca2Cl2-Friulimicin B Injektionslösung.These results indicate that cyclodextrins, substantially independent of the acyl and peptidyl moieties of a lipopeptide, are capable of reducing hemolysis. Example 7: Preparation of a Ca 2 Cl 2 -frulimicin B injection solution.
100 mg Ca2Cl2-Friulimicin B und 770 mg SBE-ß-CD werden in steriler 0,9% NaCl-Lösung gelöst, durch eine Polyethersulfon-Membran (0,2 μm, non-pyrogenic) filtriert und lyophilisiert. Das gesamte Lyophilisat wird in 10 ml Wasser für Injektionslösungen gelöst, in eine sterile Ampulle gefüllt. Anschließend wird die Ampulle mit einem Septum verschlossen.100 mg Ca 2 Cl 2 -frulimicin B and 770 mg SBE-β-CD are dissolved in sterile 0.9% NaCl solution, filtered through a polyethersulfone membrane (0.2 μm, non-pyrogenic) and lyophilized. The entire lyophilizate is dissolved in 10 ml of water for injection solutions, filled into a sterile ampoule. The ampoule is then closed with a septum.
Beispiel 8: Minimierung der Ca2Cl2-Friulimicin B- induzierten Hämolyse durch den Zusatz unterschiedlicher Konzentrationen von SuIfobutylether-ß-Cyclodextrin (SBE-ß-CD)Example 8 Minimization of Ca 2 Cl 2 -Friulimicin B-Induced Hemolysis by the Addition of Different Concentrations of Su-Fiobutyl Ether-β-Cyclodextrin (SBE-β-CD)
Dieses Beispiel zeigt die Wirkung unterschiedlicher Verhältnisse von Cyclodextrinen zu Lipopeptide auf den durch die Lipopeptide induzierten hämolytischen Effekt. Hierbei dient Ca2Cl2-Friulimicin B als Beispielmolekül für die Antibiotika aus der Klasse der Lipopeptide und SuIfobutylether-ß-Cyclodextrin (SBE-jS-CD) als Beispielmolekül für die Cyclodextrine.This example demonstrates the effect of different ratios of cyclodextrins to lipopeptides on the lipopeptide-induced hemolytic effect. Here, Ca 2 Cl 2 -friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and suibutyl ether-β-cyclodextrin (SBE-jS-CD) as an example molecule for the cyclodextrins.
Ca2Cl2-Friulimicin B wurde in einer Konzentration von 2500 mg/1 in 0,9 % NaCl-Lösung gelöst. Unterschiedlichen Ansätzen dieser 0,9 % NaCl-Lösungen wurden verschiedene SBE-ß-CD Konzentrationen zugesetzt, so daß folgende molare Verhältnisse (SBE-ß-CD : Friulimicin B) vorlagen: 0:1; 1:10; 1:5; 1:1; 2,5:1; 5:1; 10:1.
Die Vorinkubation und Versuchsdurchführung zur Bestimmung der hämolytischen Aktivität mit frischem venalen menschlichem Blut wurden entsprechend dem Beispiel 1 durchgeführt. In Tabelle 8 ist dargestellt, welcher Anteil der durch 2500 mg/1 Ca2Cl2-Friulimicin B in Abwesenheit von SBE-/3-CD induzierten Hämolyse durch den Zusatz von SBE-/3-CD in den angegebenen molaren Verhältnissen reduziert wird.Ca 2 Cl 2 -frulimicin B was dissolved in a concentration of 2500 mg / l in 0.9% NaCl solution. Different approaches of these 0.9% NaCl solutions, various SBE-ß-CD concentrations were added so that the following molar ratios (SBE-ß-CD: Friulimicin B) were: 0: 1; 1:10; 1: 5; 1: 1; 2.5: 1; 5: 1; 10: 1st The pre-incubation and experimental procedure for the determination of the hemolytic activity with fresh human venous blood were carried out according to example 1. Table 8 shows the proportion of hemolysis induced by 2500 mg / l Ca 2 Cl 2 -frulimicin B in the absence of SBE- / 3-CD reduced by the addition of SBE- / 3-CD in the indicated molar ratios.
Angaben des Gehalts an Ca2Cl2-Friulimicin B (in tng/1) beziehen sich auf die Endkonzentrationen der freien Säure des Friulimicin B im Reaktionsansatz. Die Angaben des molaren Verhältnisses beziehen sich jeweils auf die freien Säuren von Friulimicin B und SBE-/3-CD.Data on the content of Ca 2 Cl 2 -friulimicin B (in tng / 1) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture. The molar ratio in each case refers to the free acids of friulimicin B and SBE- / 3-CD.
Tabelle 8Table 8
Reduktion der durch 2500 mg/1 Ca2Cl2-Friulimicin B induzierten Hämolyse durch SBE-/3-CD in vitro (Angabe in %)Reduction of hemolysis induced by 2500 mg / l Ca 2 Cl 2 -frulimicin B by SBE- / 3-CD in vitro (data in%)
Molares Verhältnis SBE-/S-CD : Friulimicin B Reduktion der induzierten HämolyseMolar ratio SBE / S-CD: friulimicin B reduction of induced hemolysis
0 : 1 0 %0: 1 0%
1 : 10 11 %1: 10 11%
1 : 5 28 %1: 5 28%
1 : 1 80 %1: 1 80%
2,1 5 : 1 96 %2.1 5: 1 96%
5 : 1 98 %5: 1 98%
10 : 1 100 %10: 1 100%
Überraschenderweise konnte festgestellt werden, daß SBE-jß- CD schon in substöchiometrischen Konzentrationen die durch Ca2Cl2-Friulimicin B-induzierte Hämolyse selbst bei einer Friulimicin B-Konzentration von 2500 mg/1 während einer Inkubationsdauer von 3 Stunden unterdrückt.
Beispiel 9 : Auswirkung von Cyclodextrinen auf die haemolytische Aktivität eines zyklischen PeptidsSurprisingly, it was found that even in substoichiometric concentrations, SBE-jβ-CD suppresses Ca 2 Cl 2 -frulimicin B-induced hemolysis even at a friulimicin B concentration of 2500 mg / l during a 3-hour incubation period. Example 9: Effect of Cyclodextrins on the Hemolytic Activity of a Cyclic Peptide
Dieses Beispiel betrifft die Inhibierung der haemolytisehen Aktivität verschiedener Lipopeptide durch Cyclodextrine und zeigt die Wirkung eines Sulphoalkylethercyclodextrins auf den durch das zyklische Peptid Tyrocidin induzierten hämolytischen Effekt. Tyrocidin wurde in einer Konzentration von 6400 mg/1 in 0,9 % NaCl-Lösung gelöst. Durch Verdünnung mit einem Volumen 0,9% NaCl oder 0,9% NaCl/10% SBE-/3-CD wurden jeweils Stammlösungen von 3200 mg/1 Tyrocidin mit oder ohne 5% SBE-ß-CD hergestellt. Die Vorinkubation und Versuchsdurchführung zur Bestimmung der hämolytischen Aktivität mit frischem venalen menschlichem Blut wurde entsprechend dem Beispiel 1 durchgeführt. Die Auswertung dieses Versuchs zeigte, daß die durch 1600 mg/1 Tyrocidin induzierte Hämolyse in Anwesenheit von 2,5% SBE- ß-CD um 178% verstärkt wird. Der Zusatz von Cyclodextrinen unterdrückt also nicht für jede hämolytisch wirkende Substanz die Lyse der Erythrozyten.This example relates to the inhibition of haemolytic activity of various lipopeptides by cyclodextrins and shows the effect of a sulphoalkylethercyclodextrin on the cyclic peptide tyrocidine-induced hemolytic effect. Tyrocidine was dissolved in a concentration of 6400 mg / l in 0.9% NaCl solution. By dilution with a volume of 0.9% NaCl or 0.9% NaCl / 10% SBE- / 3-CD respectively stock solutions of 3200 mg / 1 Tyrocidin were prepared with or without 5% SBE-ß-CD. The pre-incubation and experimental procedure for the determination of the hemolytic activity with fresh venale human blood was carried out according to the example 1. The evaluation of this experiment showed that the hemolysis induced by 1600 mg / 1 tyrocidine was increased by 178% in the presence of 2.5% SBE-β-CD. The addition of cyclodextrins therefore does not suppress the lysis of the erythrocytes for every haemolytic substance.
Beispiel 10: Minimierung der Ca2Cl2-Friulimicin B- induzierten Hämolyse mit Hundeblut durchExample 10 Minimization of Ca 2 Cl 2 -Friulimicin B-Induced Hemolysis with Dog Blood
Sulfobutylether-/3-Cyclodextrin (SBE-ß-CD)Sulfobutyl ether / 3-cyclodextrin (SBE-β-CD)
Dieses Beispiel zeigt die Wirkung von ß-Cyclodextrinen auf den durch Lipopeptide-induzierten hämolytischen Effekt mit dem Blut verschiedener Organismen. Hierbei dient Ca2Cl2- Friulimicin B als Beispielmolekül für die Antibiotika aus der Klasse der Lipopeptide und Sulfobutylether-ß- Cyclodextrin (SBE-/3-CD) als Beispiele für modifizierte ß- Cyclodextrine. Die Experimente wurden mit Hundeblut
durchgeführt .This example demonstrates the effect of β-cyclodextrins on the lipopeptide-induced hemolytic effect on the blood of various organisms. Here, Ca 2 Cl 2 - Friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and sulfobutyl ether-β-cyclodextrin (SBE- / 3-CD) as examples of modified β-cyclodextrins. The experiments were done with dog blood carried out .
Ca2Cl2-Friulimicin B wurde in 0,9 % NaCl-Lösung mit und ohne Zusatz von SBE-/3-CD gelöst. Im Ansatz mit SBE-/3-CD lag ein molares Verhältnisse (SBE-/3-CD : Friulimicin B) von 2,5 : 1 vor. Die Vorinkubation und Versuchsdurchführung zur Bestimmung der hämolytischen Aktivität mit venalem Hundblut wurden entsprechend dem Beispiel 1 durchgeführt . Die Ergebnisse sind in Tabelle 9 dargestellt. Angaben des Gehalts an Ca2Cl2-Friulimicin B (in mg/1) beziehen sich auf die Endkonzentrationen der freien Säure des Friulimicin B im Reaktionsansatz. Die Angaben des molaren Verhältnisses beziehen sich jeweils auf die freien Säuren von Friulimicin B und SBE-ß-CD.Ca 2 Cl 2 -frulimicin B was dissolved in 0.9% NaCl solution with and without the addition of SBE- / 3-CD. In the approach with SBE- / 3-CD was a molar ratio (SBE- / 3-CD: Friulimicin B) of 2.5: 1 before. The preincubation and experimental procedure for the determination of hemolytic activity with venal canine blood were carried out according to Example 1. The results are shown in Table 9. Data on the content of Ca 2 Cl 2 -frulimicin B (in mg / l) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture. The details of the molar ratio relate in each case to the free acids of friulimicin B and SBE-β-CD.
Tabelle 9Table 9
Reduktion der durch Ca2Cl2-Friulimicin B induzierten Hämolyse durch SBE-ß-CD in vitro mit Blut von Hund (Angabe in %)Reduction of Ca 2 Cl 2 -frulimicin B-induced hemolysis by SBE-β-CD in vitro with blood of the dog (in%)
Das Beispiel zeigt, daß SBE-/3-CD in einem molaren Verhältnis von 2,5 : 1 (SBE-ß-CD : Friulimicin B) die durch Ca2Cl2-Friulimicin B induzierte Lyse von Erythrozyten in Hundeblut unterdrückt .The example shows that SBE- / 3-CD in a molar ratio of 2.5: 1 (SBE-ß-CD: Friulimicin B) suppresses the Ca 2 Cl 2 -frulimicin B-induced lysis of erythrocytes in dog blood.
Beispiel 11: Minimierung der Ca2Cl2-Friulimicin B- induzierten Hämolyse mit Blut von Makakken (Macaca fascicularis) durch Sulfobutylether-/3-
Cyclodextrin (SBE-ß-CD)Example 11 Minimization of Ca 2 Cl 2 -Friulimicin B-Induced Hemolysis with Macaque Macaca (Macaca fascicularis) by Sulfobutyl Ether- / 3 Cyclodextrin (SBE-ß-CD)
Dieses Beispiel zeigt die Wirkung von /3-Cyclodextrinen auf den durch Lipopeptide induzierten hämolytischen Effekt mit dem Blut verschiedener Organismen. Hierbei dient Ca2Cl2- Friulimicin B als Beispielmolekül für die Antibiotika aus der Klasse der Lipopeptide und Sulfobutylether-ß- Cyclodextrin (SBE-/3-CD) als Beispiel für Cyclodextrine. Die Experimente wurden mit dem Blut von Makakken durchgeführt .This example demonstrates the effect of / 3-cyclodextrins on the lipopeptide-induced hemolytic effect on the blood of various organisms. Here, Ca 2 Cl 2 - Friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and sulfobutyl ether-ß-cyclodextrin (SBE- / 3-CD) as an example of cyclodextrins. The experiments were performed with the blood of Makakken.
Ca2Cl2-Friulimicin B wurde in 0,9 % NaCl-Lösung mit und ohne Zusatz von SBE-/3-CD gelöst. Im Ansatz mit SBE-ß-CD lag ein molares Verhältnisse (SBE-/3-CD : Friulimicin B) von 5 : 1 vor. Die Vorinkubation und Versuchsdurchführung zur Bestimmung der hämolytischen Aktivität mit venalem Makakkenblut wurden entsprechend dem Beispiel 1 durchgeführt. Angaben des Gehalts an Ca2Cl2-Friulimicin B (in mg/1) beziehen sich auf die Endkonzentrationen der freien Säure des Friulimicin B im Reaktionsansatz . Die Angaben des molaren Verhältnisses beziehen sich jeweils auf die freien Säuren von Friulimicin B und SBE-ß-CD.Ca 2 Cl 2 -frulimicin B was dissolved in 0.9% NaCl solution with and without the addition of SBE- / 3-CD. In the mixture with SBE-β-CD, a molar ratio (SBE / 3-CD: friulimicin B) of 5: 1 was present. The preincubation and experimental procedure for the determination of hemolytic activity with venal macaque blood were carried out according to Example 1. Data on the content of Ca 2 Cl 2 -frulimicin B (in mg / l) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture. The details of the molar ratio relate in each case to the free acids of friulimicin B and SBE-β-CD.
Tabelle 10Table 10
Reduktion der durch Ca2Cl2-Friulimicin B induzierten Hämolyse durch SBE-ß-CD in vitro mit Blut von MakakkenReduction of Ca 2 Cl 2 -frulimicin B-induced hemolysis by SBE-β-CD in vitro with blood of macaque
(Angabe in %)(In%)
Das Beispiel zeigt, daß SBE-ß-CD in einem molaren Verhältnis von 5 : 1 (SBE-/3-CD : Friulimicin B) die durch
Ca2Cl2-Friulimicin B induzierten Lyse von Erythrozyten in Blut von Makakken unterdrückt .The example shows that SBE-β-CD in a molar ratio of 5: 1 (SBE- / 3-CD: Friulimicin B) by Ca2Cl 2 -Friulimicin B suppresses induced lysis of erythrocytes in blood of macaques.
Beispiel 12 : Beeinflussung der antibiotischen Aktivität vonExample 12: Influence on the antibiotic activity of
Lipopeptiden durch Cyclodextrine in vivoLipopeptides by cyclodextrins in vivo
Dieses Beispiel zeigt die Wirkung von /3-Cyclodextrinen auf die antibiotische Aktivität von Lipopeptiden in vivo. Hierbei dient Ca2Cl2-Friulimicin B als Beispielmolekül für die Antibiotika aus der Klasse der Lipopeptide und Sulfobutylether-|ß-Cyclodextrin (SBE-ß-CD) als Beispiele für modifizierte ß-Cyclodextrine. Dargestellt sind Ergebnisse einer Studie mit einem intranasalem Lungeninfektionsmodell in der Maus .This example demonstrates the effect of / 3-cyclodextrins on the antibiotic activity of lipopeptides in vivo. Here, Ca 2 Cl 2 -friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and sulfobutyl ether | β-cyclodextrin (SBE-β-CD) as examples of modified β-cyclodextrins. The results of a study with an intranasal lung infection model in the mouse are shown.
Ca2Cl2-Friulimicin B wurde in 0,9 % NaCl-Lösung mit und ohne Zusatz von SBE-ß-CD gelöst. Im Ansatz mit SBE-/3-CD lag ein molares Verhältnisse (SBE-/3-CD : Friulimicin B) von 2,5 : 1 vor. Die Angaben zur Ca2Cl2-Friulimicin B Konzentration (in mg/1) beziehen sich auf die Endkonzentrationen der freien Säure des Friulimicin B im Reaktionsansatz . Die Angaben des molaren Verhältnisses beziehen sich jeweils auf die freien Säuren von Friulimicin B und SBE-ß-CD.Ca 2 Cl 2 -frululimicin B was dissolved in 0.9% NaCl solution with and without addition of SBE-β-CD. In the approach with SBE- / 3-CD was a molar ratio (SBE- / 3-CD: Friulimicin B) of 2.5: 1 before. The data for the Ca 2 Cl 2 -frulimicin B concentration (in mg / l) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture. The details of the molar ratio relate in each case to the free acids of friulimicin B and SBE-β-CD.
Weibliche Mäuse (CFW-I (Harlan Winkelmann, Deutschland)) wurden intranasal mit Streptococcus pneumoniae L3TV (l*106 CfU/Maus) infiziert. 1 und 4 Stunden nach der Infizierung wurden den Tieren eine Gesamtdosis von 20 mg Ca2Cl2- Friulimicin B / kg mit und ohne SBE-/3-CD (5%) subkutan verabreicht . 24 Stunden nach Infektion wurde eine Keimzahlbestimmung in der Lunge durch Ausplattierung eines Gewebeaufschlusses auf Agarplatten in einer dem Fachmann
vertrauten Weise durchgeführt. Die Auswertung dieser Studie zeigte, daß überraschenderweise SBE-/3-CD die antibiotische Wirkung von Ca2Cl2-Friulimicin B verstärkt (Mann Whitney- Test p=0, 0159) .Female mice (CFW-I (Harlan Winkelmann, Germany)) were infected intranasally with Streptococcus pneumoniae L3TV (1 × 10 6 CFU / mouse). At 1 and 4 hours after infection, animals were given a total dose of 20 mg Ca 2 Cl 2 - friulimicin B / kg with and without SBE- / 3-CD (5%) subcutaneously. 24 hours after infection, a germ count in the lung was determined by plating a tissue digest on agar plates in a person skilled in the art familiar way. The evaluation of this study showed that, surprisingly, SBE- / 3-CD enhances the antibiotic action of Ca 2 Cl 2 -frululimicin B (Mann Whitney test p = 0, 0159).
Beispiel 13 : Beeinflussung der akuten Toxizität vonExample 13: Influence of Acute Toxicity of
Lipopeptiden durch Cyclodextrine in vivoLipopeptides by cyclodextrins in vivo
Dieses Beispiel zeigt die Wirkung von /3-Cyclodextrinen auf die durch hohe Konzentrationen von Lipopeptiden hervorgerufenen akuttoxischen Effekte in Mäusen. Hierbei dient Ca2Cl2-Friulimicin B als Beispielmolekül für die Antibiotika aus der Klasse der Lipopeptide und Sulfobutylether-jß-Cyclodextrin (SBE-jß-CD) als Beispiele für modifizierte ß-Cyclodextrine.This example demonstrates the effect of / 3-cyclodextrins on the acute toxicity effects in mice caused by high concentrations of lipopeptides. Here, Ca 2 Cl 2 -friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and sulfobutyl ether-Jβ-cyclodextrin (SBE-Jβ-CD) as examples of modified β-cyclodextrins.
Ca2Cl2-Friulimicin B wurde in 0,9 % NaCl-Lösung mit und ohne Zusatz von SBE-/3-CD gelöst. Im Ansatz mit SBE-jß-CD lag ein molares Verhältnisse (SBE-jß-CD : Friulimicin B) von 2,5 : 1 vor. Die Angaben zur Ca2Cl2-Friulimicin B Konzentration (in mg/1) beziehen sich auf die Endkonzentrationen der freien Säure des Friulimicin B im Reaktionsansatz. Die Angaben des molaren Verhältnisses beziehen sich jeweils auf die freien Säuren von Friulimicin B und SBE-ß-CD.Ca 2 Cl 2 -frulimicin B was dissolved in 0.9% NaCl solution with and without the addition of SBE- / 3-CD. In the mixture with SBE-jß-CD was a molar ratio (SBE-jß-CD: Friulimicin B) of 2.5: 1 before. The data for the Ca 2 Cl 2 -frulimicin B concentration (in mg / l) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture. The details of the molar ratio relate in each case to the free acids of friulimicin B and SBE-β-CD.
Die Ca2Cl2-Friulimicin B-Lösungen mit und ohne SBE-/3-CD wurden weiblichen Mäusen (CFW-I (Harlan Winkelmann, Deutschland) ) einmalig verabreicht (iv) . Die Sterblichkeitsrate der Tiere innerhalb von 24 Stunden wurde bestimmt. Sie ist in Tabelle 11 dargestellt.The Ca 2 Cl 2 -frulimicin B solutions with and without SBE- / 3-CD were administered once to female mice (CFW-I (Harlan Winkelmann, Germany)) (iv). The mortality rate of the animals within 24 hours was determined. It is shown in Table 11.
Tabelle 11 Sterblichkeitsrate von Mäusen nach einmaliger iv
Verabreichung von Ca2Cl2-Friulimicin B mit und ohne SBE-/3-Table 11 Mortality rate of mice after single iv Administration of Ca 2 Cl 2 -frululimicin B with and without SBE- / 3
CD (Angabe in %)CD (in%)
Das Beispiel zeigt, daß die akute Toxizität von Ca2Cl2- Friulimicin B durch die Anwesenheit von SBE-ß-CD in einem molaren Verhältnis von 2,5 : 1 (SBE-/3-CD : Friulimicin B) reduziert wird.
The example shows that the acute toxicity of Ca 2 Cl 2 -friulimicin B is reduced by the presence of SBE-β-CD in a molar ratio of 2.5: 1 (SBE- / 3-CD: friulimicin B).
Claims
1. Pharmazeutische Zusammensetzung enthaltend als1. Pharmaceutical composition containing as
Wirkstoff ein Lipopeptid in physiologisch wirksamer Dosis sowie ein Cyclodextrin oder ein Cyclodextrin- Derivat .Active ingredient a lipopeptide in a physiologically effective dose and a cyclodextrin or a cyclodextrin derivative.
2. Pharmazeutische Zusammensetzung nach Anspruch 1, wobei das Lipopeptid eine Struktur gemäß Formel I2. A pharmaceutical composition according to claim 1, wherein the lipopeptide has a structure according to formula I.
Y-X-Dab-Pip-MeAsp-Asp-Gly-Asp-Gly-Dab-Val-ProY-X-Dab-Pip-MeAsp-Asp-Gly-Asp-Gly-Dab-Val-Pro
Formel I aufweist,Having formula I,
wobei X = eine der Aminosäuren Asn oder Asp ist, wobei Y = geradkettiger oder verzweigter, gesättigter oder ungesättigter aliphatischer Acylrest mit 6 bis 22 Kohlenstoffatomen ist, der optional durch eine oder mehrere Phenyl- oder Cycloalkylgruppen unterbrochen oder mit solchen Gruppen verbunden oder durch einen oder mehrere Sauerstoffatome unterbrochen sein kann, oder ein physiologisch verträgliches Salz einer solchen Verbindung.wherein X = one of the amino acids Asn or Asp, wherein Y = straight-chain or branched, saturated or unsaturated aliphatic acyl radical having 6 to 22 carbon atoms, optionally interrupted by or linked to one or more phenyl or cycloalkyl groups or by one or more multiple oxygen atoms may be interrupted, or a physiologically acceptable salt of such a compound.
3. Pharmazeutische Zusammensetzung nach Anspruch 1 oder 2, wobei das Lipopeptid ausgewählt ist aus der Gruppe bestehend aus "Amphomycin und Amphomycin-Derivate. The pharmaceutical composition according to claim 1 or 2, wherein the lipopeptide is selected from the group consisting of "amphomycin and amphomycin derivatives.
4. Pharmazeutische Zusammensetzung nach einem der4. Pharmaceutical composition according to one of
Ansprüche 1 bis 3, wobei das Lipopeptid ausgewählt ist aus der Gruppe bestehend aus "Amphomycin, Amphomycin- Derivate, Friulimicin, Friulimicin B, Friulimicin- Derivate, Daptomycin, Daptomycin-Derivate, Aspartocin, Aspartocin-Derivate, Glumamycin, Glumamycin-Derivate, Crystallomycin, Crystallomycin-Derivate, Zaomycin, Zaomycin-Derivate, Tsushimycin, Tsushimyin-Derivate, Laspartomycin, Laspartomycin-Derivate, Brevistin, Brevistin-Derivate, Cerexin B, Cerexin B-Derivate, Syringomycin und seine Derivate, Antibiotic A-30912 und seine Derivate, Antibiotic A-54145 und seine Derivate sowie Antibiotic A-21978C und seine Derivate".Claims 1 to 3, wherein the lipopeptide is selected from the group consisting of "amphomycin, amphomycin derivatives, friulimicin, friulimicin B, friulimicin derivatives, daptomycin, daptomycin derivatives, aspartocin, aspartocin derivatives, glumamycin, glumamycin derivatives, crystallomycin , Crystallomycin Derivatives, Zaomycin, Zaomycin Derivatives, Tsushimycin, Tsushimyin Derivatives, Laspartomycin, Laspartomycin Derivatives, Brevistin, Brevistin Derivatives, Cerexin B, Cerexin B Derivatives, Syringomycin and Its Derivatives, Antibiotic A-30912 and its Derivatives, Antibiotic A-54145 and its derivatives as well as Antibiotic A-21978C and its derivatives ".
5. Pharmazeutische Zusammensetzung nach einem der5. Pharmaceutical composition according to one of
Ansprüche 1 bis 4, enthaltend mehrere verschiedene Lipopeptide in jeweils physiologisch wirksamer Dosis.Claims 1 to 4, containing several different lipopeptides in each physiologically effective dose.
6. Pharmazeutische Zusammensetzung nach einem der6. Pharmaceutical composition according to one of
Ansprüche 1 bis 5, wobei das Lipopeptid als Alkali- oder Erdalkalisalz, vorzugsweise als Na- oder Calcium- SaIz, insbesondere als Di-Calcium-Salz (Ca2Cl2-SaIz) , oder als Ammoniumsalz vorliegt, oder wobei das Lipopeptid neutral ist, oder wobei das Lipopeptid als kationischer Anteil eines Salzes vorliegt, wobei in der letzten Alternative als Gegenion vozugsweise ein Ion aus der Gruppe bestehend aus „Hydrochlorid, SuIfonat, Nitrat, Phosphat, Succinat, Maleat, Citrat, Tartrat, Lactat, Gluconat undSulfonat" eingesetzt sein kann. Claims 1 to 5, wherein the lipopeptide is present as alkali or alkaline earth salt, preferably as Na or calcium SaIz, in particular as a di-calcium salt (Ca 2 Cl 2 -SaIz), or as an ammonium salt, or wherein the lipopeptide is neutral , or wherein the lipopeptide is present as a cationic portion of a salt, wherein in the latter alternative as Gegenion vozugsweise an ion selected from the group consisting of "hydrochloride, sulfonate, nitrate, phosphate, succinate, maleate, citrate, tartrate, lactate, gluconate and sulfonate" can be.
7. Pharmazeutische Zusammensetzung nach einem der7. Pharmaceutical composition according to one of
Ansprüche 1 bis 6, enthaltend das Lipopeptid in einer Gesamtmenge von 0,001 bis 20 Gewichts-%, insbesondere von 0,05 bis 20 Gewichts-%, vorzugsweise von 0,1 bis 5 Gewichts-% .Claims 1 to 6, containing the lipopeptide in a total amount of 0.001 to 20% by weight, in particular from 0.05 to 20% by weight, preferably from 0.1 to 5% by weight.
8. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 bis 7, wobei das Cyclodextrin oder Cyclodextrin-Derivat ein α- oder ß-Cyclodextrin ist und vorzugsweise die allgemeine Formel II aufweist8. Pharmaceutical composition according to one of claims 1 to 7, wherein the cyclodextrin or cyclodextrin derivative is an α- or ß-cyclodextrin and preferably has the general formula II
Formel IIFormula II
wobei Rl, R2, und R3 gleich oder verschieden und ein beliebiger physiologisch verträglicher Rest sein kann, vorzugsweise -H, Cl-C8-Alkyl, -SO2OH, -PO(OH)2, oder - CO-R4 mit R4 = Cl-C8-Alkyl ist, wobei das Cl-C8-Alkyl einfach oder mehrfach an gleichen oder an verschiedenen C-Atomen mit -OH, -COOH, -CONHR5, -NHCOR6, -SO2OH, - PO(OH)2, oder Tetrazol-5-yl mit R5 = -H oder Cl-C4- Alkyl und R6 = carboxylphenyl sein kann, wobei n = 6 oder 7 , wobei Rl, R2 und R3 in verschiedenen Glucopyranoseeinheiten randomisiert sein können, wobei ein Sauerstoffatom oder mehrere Sauerstoffatome der Glucopyranoseeinheiten, insbesondere das Sauerstoffatom an C6, durch Schwefelatome ersetzt sein können, einschließlich physiologisch verträglicher Salze solcher Cyclodextrine.wherein R 1, R 2 and R 3 may be the same or different and may be any physiologically acceptable radical, preferably -H, C 1 -C 8 -alkyl, -SO 2 OH, -PO (OH) 2 , or -CO-R 4 where R 4 = Cl C8 alkyl, wherein the C1-C8 alkyl one or more times on the same or on different carbon atoms with -OH, -COOH, -CONHR5, -NHCOR6, -SO 2 OH, - PO (OH) 2, or tetrazol-5-yl where R5 = -H or Cl- C4 alkyl and R6 = carboxylphenyl, where n = 6 or 7, wherein Rl, R2 and R3 may be randomized in different Glucopyranoseeinheiten, wherein one or more oxygen atoms of the glucopyranose units, in particular the oxygen atom at C6, may be replaced by sulfur atoms including physiologically acceptable salts of such cyclodextrins.
9. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 bis 8, wobei das Cyclodextrin oder Cyclodextrinderivat ausgewählt ist aus der Gruppe bestehend aus "α-Cyclodextrin, ß-Cyclodextrin, Hydroxy- (Cl-C8-alkyl) -α-Cyclodextrin, Hydroxy- (Cl-C8~alkyl) -ß- Cyclodextrin, (2-Hydroxypropyl) -ß-Cyclodextrin, (2- Hydroxypropyl) -α-Cyclodextrin, Sulpho- (Cl-C8-alkyl) - ether-α-cyclodextrin, Sulpho- (Cl-C8-alkyl) -ether-ß - cyclodextrin, Sulphobutylether-α-cyclodextrin, Sulphobutylether-ß-cyclodextrin" .9. A pharmaceutical composition according to any one of claims 1 to 8, wherein the cyclodextrin or cyclodextrin derivative is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, hydroxy- (C 1 -C 8 -alkyl) -α-cyclodextrin, hydroxy- C 1 -C 8 -alkyl) -β-cyclodextrin, (2-hydroxypropyl) -β-cyclodextrin, (2-hydroxypropyl) -α-cyclodextrin, sulpho (C 1 -C 8 -alkyl) ether-α-cyclodextrin, sulpho ( C 1 -C 8 -alkyl) ether-β-cyclodextrin, sulphobutyl ether-α-cyclodextrin, sulphobutyl ether-β-cyclodextrin ".
10. Pharmazeutische Zusammensetzung nach einem der10. Pharmaceutical composition according to one of
Ansprüche 1 bis 9, enthaltend das Cyclodextrin oder Cyclodextrinderivat in einer Menge von 0,001 bis 50 Gewichts-%, insbesondere von 0,01 bis 30 Gewichts-%, vorzugsweise 0,1 bis 20 Gewichts-%. Claims 1 to 9, containing the cyclodextrin or cyclodextrin derivative in an amount of 0.001 to 50% by weight, in particular from 0.01 to 30% by weight, preferably 0.1 to 20% by weight.
11. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 bis 9, enthaltend weitere Zusatz- und/oder HilfStoffe, insbesondere galenische Hilfsstoffe.11. Pharmaceutical composition according to one of claims 1 to 9, containing further additives and / or auxiliaries, in particular galenic adjuvants.
12. Pharmazeutische Zusammensetzung nach Anspruch 11 enthaltend12. A pharmaceutical composition according to claim 11 containing
A) 0,001 bis 20 Gewichts-%, insbesondere 0,05 bis 20 Gewichts-%, vorzugsweise 0,1 bis 5 Gewichts-%,A) 0.001 to 20% by weight, in particular 0.05 to 20% by weight, preferably 0.1 to 5% by weight,
Lipopeptid,lipopeptide
B) 0,001 bis 79,9 Gewichts-%, insbesondere 0,01 bis 30 Gewichts-%, vorzugsweise 0,1 bis 20 Gewichts-% Cyclodextrin bzw. Cyclodextrinderivat, C) 0,1 bis 99,998 Gewichts-%, insbesondere 50 bis 99,98 Gewichts-%, vorzugsweise 95 bis 99,98 Gewichts-% Zusatz- und/oder Hilfsstoffe sowie optional Verdünnungsmittel , wobei sich die Komponenten A) bis C) stets zu 100% addieren.B) 0.001 to 79.9% by weight, in particular 0.01 to 30% by weight, preferably 0.1 to 20% by weight of cyclodextrin or cyclodextrin derivative, C) 0.1 to 99.998% by weight, in particular 50 to 99 , 98% by weight, preferably 95 to 99.98% by weight of additives and / or auxiliaries and optionally diluents, the components A) to C) always adding up to 100%.
13. Verwendung einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 1 bis 12 zur Herstellung eines Arzneimittels zur Behandlung und/oder Prophylaxe von viralen und/oder bakteriellen und/oder parasitären Infektionskrankheiten und/oder von Pilzerkrankungen.13. Use of a pharmaceutical composition according to any one of claims 1 to 12 for the manufacture of a medicament for the treatment and / or prophylaxis of viral and / or bacterial and / or parasitic infectious diseases and / or fungal diseases.
14. Verwendung nach Anspruch 13 , wobei das Arzneimittel galenisch zur oralen Gabe oder zur Injektion hergerichtet ist durch Mischung mit galenischen HiIs- und Trägerstoffen. 14. Use according to claim 13, wherein the medicament is prepared galenically for oral administration or for injection by mixing with galenical HiIs- and carriers.
15. Verfahren zur Behandlung einer bakteriellen, viralen oder parasitären Infektionskrankheit und/oder einer Pilzerkrankung, wobei einer Person, die an der15. A method for treating a bacterial, viral or parasitic infectious disease and / or a fungal disease, wherein a person, at the
Krankheit erkrankt ist oder droht hieran zu erkranken, eine physiologisch wirksame Dosis eines Arzneimittels nach einem der Ansprüche 1 bis 12 dargereicht wird.Disease is or is about to fall ill, a physiologically effective dose of a drug according to any one of claims 1 to 12 is presented.
16. Verfahren nach Anspruch 15, wobei der Person eine Tagesdosis von 1 bis 50000 mg, vorzugsweise 50 bis 30000 mg, höchstvorzugsweise von 100 bis 20000 mg, Lipopeptid über einen Zeitraum von 1 bis 60 Tage, vorzugsweise 1 bis 30 Tage, dargereicht wird.16. The method of claim 15, wherein the person is a daily dose of 1 to 50,000 mg, preferably 50 to 30,000 mg, most preferably from 100 to 20,000 mg, lipopeptide over a period of 1 to 60 days, preferably 1 to 30 days, is given.
17. Verpackungseinheit mit einer Mehrzahl von17. Packaging unit with a plurality of
Gabeeinheiten, wobei jede Gabeeinheit zur Gabe innerhalb eines Behandlungsplans nach einem der Ansprüche 15 oder 16 hergerichtet ist.Delivery units, wherein each delivery unit is prepared for administration within a treatment plan according to one of claims 15 or 16.
18. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung nach einem der Ansprüche 1 bis 12, wobei das Lipopeptid in einer physiologisch wirksamen Dosis mit dem Cyclodextrin oder Cyclodextrinderivat in einem molaren Verhältnis Lipopeptid/Cyclodextrin von 100:1 bis 1:500, vorzugsweise 10:1 bis 1:50, höchstvorzugsweise 2:1 bis 1:10, optional unter Zugabe von Zusatz- und/oder Hilfsstoffen in galenisch üblichen Zusatzmengen, gemischt wird. 18. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 12, wherein the lipopeptide in a physiologically effective dose with the cyclodextrin or cyclodextrin derivative in a molar ratio lipopeptide / cyclodextrin of 100: 1 to 1: 500, preferably 10: 1 to 1:50, most preferably 2: 1 to 1:10, optionally with the addition of additives and / or excipients in galenically customary amounts added mixed.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MX2008006476A MX2008006476A (en) | 2005-11-21 | 2006-11-20 | Lipopeptide compositions. |
| CA002630497A CA2630497A1 (en) | 2005-11-21 | 2006-11-20 | Lipopeptide compositions |
| AU2006314942A AU2006314942A1 (en) | 2005-11-21 | 2006-11-20 | Lipopeptide compositions |
| EP06805527A EP1951311A1 (en) | 2005-11-21 | 2006-11-20 | Lipopeptide compositions |
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|---|---|---|---|
| DE102005056194A DE102005056194A1 (en) | 2005-11-21 | 2005-11-21 | New lipopeptide compositions |
| DE102005056194.2 | 2005-11-21 |
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| EP (1) | EP1951311A1 (en) |
| CN (1) | CN101370524A (en) |
| AU (1) | AU2006314942A1 (en) |
| CA (1) | CA2630497A1 (en) |
| DE (1) | DE102005056194A1 (en) |
| MX (1) | MX2008006476A (en) |
| WO (1) | WO2007057005A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150218221A1 (en) * | 2012-09-24 | 2015-08-06 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Method for producing a cyclic peptide |
| WO2020229369A1 (en) * | 2019-05-10 | 2020-11-19 | Xellia Pharmaceuticals Aps | Daptomycin aqueous formulations |
| WO2024250929A1 (en) * | 2023-06-07 | 2024-12-12 | 中国医学科学院医药生物技术研究所 | Group of cyclic alkaline lipopeptide compounds, and preparation method therefor and use thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19807972A1 (en) * | 1998-02-25 | 1999-08-26 | Hoechst Marion Roussel De Gmbh | Lipopeptide antibiotic calcium salts, process for their preparation and use |
| WO2001082971A2 (en) * | 2000-05-02 | 2001-11-08 | Theravance, Inc. | Cyclodextrin containing glycopeptide antibiotic compositions |
| WO2001097851A2 (en) * | 2000-06-21 | 2001-12-27 | Cubist Pharmaceuticals, Inc. | Compositions and methods to improve the oral absorption of antimicrobial agents |
| WO2002032459A2 (en) * | 2000-10-17 | 2002-04-25 | Massachusetts Institute Of Technology | Method of increasing the efficacy of antibiotics by complexing with cyclodextrins |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4411025A1 (en) * | 1994-03-30 | 1995-10-05 | Hoechst Ag | New lipopeptide A1437 derivs. with modified acyl gp. |
| US7527807B2 (en) * | 2000-06-21 | 2009-05-05 | Cubist Pharmaceuticals, Inc. | Compositions and methods for increasing the oral absorption of antimicrobials |
-
2005
- 2005-11-21 DE DE102005056194A patent/DE102005056194A1/en not_active Ceased
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2006
- 2006-11-20 CN CNA2006800511655A patent/CN101370524A/en active Pending
- 2006-11-20 MX MX2008006476A patent/MX2008006476A/en not_active Application Discontinuation
- 2006-11-20 CA CA002630497A patent/CA2630497A1/en not_active Abandoned
- 2006-11-20 EP EP06805527A patent/EP1951311A1/en not_active Withdrawn
- 2006-11-20 WO PCT/DE2006/002064 patent/WO2007057005A1/en active Application Filing
- 2006-11-20 AU AU2006314942A patent/AU2006314942A1/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19807972A1 (en) * | 1998-02-25 | 1999-08-26 | Hoechst Marion Roussel De Gmbh | Lipopeptide antibiotic calcium salts, process for their preparation and use |
| WO2001082971A2 (en) * | 2000-05-02 | 2001-11-08 | Theravance, Inc. | Cyclodextrin containing glycopeptide antibiotic compositions |
| WO2001097851A2 (en) * | 2000-06-21 | 2001-12-27 | Cubist Pharmaceuticals, Inc. | Compositions and methods to improve the oral absorption of antimicrobial agents |
| WO2002032459A2 (en) * | 2000-10-17 | 2002-04-25 | Massachusetts Institute Of Technology | Method of increasing the efficacy of antibiotics by complexing with cyclodextrins |
Non-Patent Citations (2)
| Title |
|---|
| IRIE T ET AL: "PROTECTIVE MECHANISM OF BETA-CYCLODEXTRIN FOR THE HEMOLYSIS INDUCEDWITH PHENOTIAZINE NEUROLEPTICS IN VITRO", JOURNAL OF PHARMACOBIO-DYNAMICS, TOKYO, JP, vol. 6, no. 6, 1983, pages 408 - 414, XP000911177, ISSN: 0386-846X * |
| UEKAMA K ET AL: "CYCLODEXTRIN DRUG CARRIER SYSTEMS", CHEMICAL REVIEWS, ACS,WASHINGTON, DC, US, vol. 98, no. 5, July 1998 (1998-07-01), pages 2045 - 2076, XP000771829, ISSN: 0009-2665 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101370524A (en) | 2009-02-18 |
| EP1951311A1 (en) | 2008-08-06 |
| MX2008006476A (en) | 2008-09-26 |
| DE102005056194A1 (en) | 2007-07-12 |
| CA2630497A1 (en) | 2007-05-24 |
| AU2006314942A1 (en) | 2007-05-24 |
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