DE102005056194A1 - New lipopeptide compositions - Google Patents

Abstract

The invention relates to a pharmaceutical composition containing as active ingredient a lipopeptide in a physiologically effective dose and a cyclodextrin or a cyclodextrin derivative.

Description

Territory of invention

The The invention relates to novel pharmaceutical compositions containing lipopeptides contain, use of such compositions, processes for their Production and use thereof as a medicine.

Background of the invention and state of the art

Secondary metabolites, produced by living organisms, especially microorganisms and the chemical variants derived from them successfully used as active ingredients in medicine. Especially at the fight Infectious diseases has become the use of secondary metabolites proven. It became a big one Proportion of antibiotics used today isolated from soil bacteria, the so-called Actinomycetes. Due to the development of resistance There is a permanent one against the drugs used Need for new antibiotic agents with novel mechanisms of action. Despite her outstanding antibiotic and other pharmacological Properties fail in many secondary metabolites use as Drug ultimately to the most also very pronounced toxic Properties for the people.

antibiotics from the class of lipopeptides characterized by that they consist of a linear or cyclic peptide fraction, or a Combination of both, with natural and / or unnatural, derivatized and / or underivatized amino acids with which a saturated or unsaturated Linked acyl residue which is optionally substituted by one or more phenyl or cycloalkyl groups interrupted or connected to such groups or by one or several oxygen or nitrogen atoms can be interrupted, have proven to be exceptionally effective in the past Fungi and gram-positive bacteria proved. For the majority of these compounds However, toxic properties are also known.

For 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) and a number of other lipopeptides, such as Lychenysin (Grangemard I. et al. , Applied Biochemistry and Biotechnology, Volume 90, Number 3, 2001, pp. 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), FR 131535 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. a novel watersoluble echinocandin-like lipopeptides: 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-like lipopeptides ( DE 19807972 ) are haemolytic.

One significant problem for However, the application of these lipopeptides as drugs is the overcoming the toxicological properties without deterioration of the antibiotic activity the substances. For the application of these substances as a drug it is therefore necessary to find pharmaceutical compositions compared to Pure substance have improved pharmacological properties. For example, it is known that the hemolytic properties of a Substance or an ion reduced in the presence of serum albumin This is caused by the interaction with the 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 Elem Res. 1990 Apr; 25 (1):. 11-9). However, this masking effect with serum albumin also often causes the loss of the desired Properties of molecules, as well as the antibiotic activity of lipopeptides as in Example 1 of this invention.

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. As a result, improved solubilities of substances but also reduced toxicities, such as a Reduction of Hemolytic Properties of Molecules (J. Pharmacobiodyn. 1983 6 (6): 408-14. Protective mechanism of beta-cyclodextrin for the hemolysis induced with phenothiazine neuroleptics in vitro., Irie T, Sunada M, Otagiri M, Uekama K.) be achieved.

technical Problem of the invention

Of the The invention is therefore based on the technical problem, new pharmaceutical Compositions with antibacterial, antiviral and / or antimycotic acting lipopeptides available to provide their compatibility as far as the physiological effectiveness is improved, that even at very high concentrations, for example, during infusions typically occur at short notice at the application site, only small toxic side effects occur.

Broad features of the invention and embodiments.

to solution This technical problem teaches the invention a pharmaceutical Composition containing as active ingredient an antibacterial, antiviral, and / or antifungal lipopeptide in physiologically effective Dose as well as a physiologically acceptable cyclodextrin or a Cyclodextrin derivative.

The Invention is based on the surprising Recognizing that specifically through the use of cyclodextrins or Cyclodextrin derivatives not only a reduction of hemolytic Properties of antibiotically acting lipopeptides is achieved, but rather that at the same time the antibiotic effect the lipopeptides are retained while, for example, a masking with HSA to a reduced or completely suppressed antibiotic Effect leads.

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 A1). 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:

The lipopeptide preferably has a structure according to formula I, formula I.

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:

For the preparation of such lipopeptides, for example, reference is made to the literature DE 198 07 972 A1 . EP 0 629 636 A1 . EP 0 688 789 A1 and US2005 / 0153876 A1.

The Lipopeptide can be independent selected from 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 ".

wobei in Formel Ia R3 auch über einen Rest L gebunden sein kann,
wobei R1 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)-, -O-(PO)-, -O-(CO)-R'-O-(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)-O-R5, -(CO)-NHR4, -(CO)-NR4R4, -(CS)-NHR4, -(CS)-NR4R4, -(CNR4)-NHR4 oder -(CNR4)-NR4R4, R5-(CO), SO₂R5, -(SO)-R5, -(PO)(OR5)2, -(PO)(OR5), COOH, SO₃H, -PO₃H, -F, -Cl, -Br, -I, oder Trihalomethyl ist,
wobei R3 -H, -OR5, -SR5, -NR5R5, -CN, -NO₂, -N₃, -(CO)-R5, -(CO)-O-R5, -(CO)-NR5R5, -(CS)-NR5R5, -(CNR5)-NR5R5, -(CO)-H, -R5-(CO), -SO₂R5, -(PO)(OR5)₂, -(PO)(OR5), -CO₂H, -SO₃H, -PO₃H, -F, -Cl, -Br, -I, Trihalomethyl, Cl-C25-Alkyl, substituiertes C1-C25-Alkyl, C1-C25-Heteroalkyl, substituiertes C1-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 C7-C10-Alkyl, C17-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 C1-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, β-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 = 1 oder 2, m-Aminophenylacetyl, (m-Aminophenylpropanoyl)_n mit n = 1 oder 2, o-Aminophenylacetyl, (o-Aminophenylpropanoyl)_n mit n = 1 oder 2, GABA, p-Aminobenzoesäure (PABA, m-Aminobenzoesäure, o-Aminobenzoesäure, p-Hydrazinobenzoesäure, m-Hydrazinobenzoesäure, o-Hydrazinobenzoesäure, p-Amino-trans-cinnamyl, m-Aminotrans-cinnamyl, o-Amino-trans-cinnamyl, p-Aminophenylessigsäure, m-Aminophenylessigsäure, L-BBTA, oder jede Kombination hiervon sein.The lipopeptide may furthermore be selected independently of the formula I from the group consisting of "C ₁₅ -AMPHOMYCIN, C ₁₅ -AMPHOMYCIN-9-GLY, C ₁₅ -AMPHOMYCIN-9-GLY-LYS, C ₁₅ -AMPHOMYCIN-9- LEU, C ₁₀ -AMPHOMYCIN, C ₁₁ -AMPHOMYCIN, C ₁₂ -AMPHOMYCIN, C ₁₃ -AMPHOMYCIN, C ₁₄ -AMPHOMYCIN, C ₁₆ -AMPHOMYCIN, C ₁₇ -AMPHOMYCIN, C ₁₈ -AMPHOMYCIN, OLEOYL-AMPHOMYCIN, CH ₃ - ( CH _{2) 11} -O-P-PH-C (= O) -AMPHOMYCIN, CH ₃ - (CH _{2) 15} -O-P-PH-C (= O) -AMPHOMYCIN, HO- (CH _{2) 15} -C (= O ) -AMPHOMYCIN, CH ₃ - (CH _{2) 9} -O-P-PH-C (= O) -AMPHOMYCIN, CH ₃ - (CH _{2) 7} -O-P-PH-C (= O) -AMPHOMYCIN, CH ₃ - ( CH ₂ ) ₁₁ -NH-SUCCINYL-AMPHOMYCIN, C ₁₂ -P-HYDRAZINOBENZOIC ACID-AMPHOMYCIN, C ₁₅ -AMPHOMYCIN-9-GABA, C ₁₄ -AMPHOMYCIN-9-GLY, C ₁₅ -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- (β-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- (β-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, C ₁₃ -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 -RMPHOMYCIN-9-GLY- (D-ALA), C ₁₅ -AMPHOMYCIN-9- (β-ALA) -AHX, C ₁₅ -AMPHOMYCIN -9-GA BA-VAL, C ₁₅ -AMPHOMYCIN-9-GABA-AHX, C ₁₂ -AMPHOMYCIN-9- (β-ALA), C ₁₂ -AMPHOMYCIN-9-SAR, C ₁₆ -AMPHOMYCIN-9-SRR, C ₁₀ -AMPHOMYCIN -9- (β-ALA), C ₁₀ -AMPHOMYCIN-9-SAR, C ₁₇ -AMPHOMYCIN-9-SAR, C ₁₆ -AMPHOMYCIN-9- (β-ALA), C ₁₇ -RMPHOMYCIN-9- (β- ALA), C ₁₅ -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 ) ₁₁ -OP-PH-C (= O) -AMPHOMYCIN-9-GLY, C ₁₂ - (P-TRANS-CINNAMYL) -AMPHOMYCIN-9-GLY, CH ₃ - (CH ₂ ) ₁₁ -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-HPRO, C ₁₅ -AMPHOMYCIN-9- (D-PIP), CH ₃ - (CH ₂ ) ₁₁ -NH-C (= O) -AMPHOMYCIN-9- (β-ALA), CH ₃ - (CH _{2) 11} -NH-C (= O) -AMPHOMYCIN-9-SAR, CH ₃ - (CH ₂ ) ₁₅ -SO ₂ -GLY-AMPHOMYCTN, CH ₃ - (CH ₂ ) ₉ -SO ₂ -PH-AMPHOMYCIN, CH ₃ - (CH ₂ ) ₉ -SO ₂ -GL Y amphomycin-9-LYS, CH ₃ - (CH _{2) 9} SO ₂ -Gly-amphomycin-9- GLY, C ₁₂ -Gly-amphomycin, C ₈ - (P-APA) -AMPHOMYCIN, C ₁₄ -Gly -AMPHOMYCIN, C ₁₆ -GLY-AMPHOMYCIN, C ₁₈ -GLY-AMPHOMYCIN, C ₁₂ - (P-AMINOPHENYLPROPANOYL) -AMPHOMYCIN, C ₁₂ - (P-AMINOPHENYLPROPANOYL) ₂ -AMPHOMYCIN, CH ₃ - (CH ₂ ) ₉ -OP -PH-C (= O) -GLY-AMPHOMYCIN, C ₁₂ - (M-APA) -AMPHOMYCIN, C ₁₅ - [ASP- (OTBU)] - AMPHOMYCIN, C ₁₀ - (M-APA) -AMPHOMYCIN, CH ₃ - (CH ₂ ) ₇ ) (CH ₃ - (CH ₂ ) ₅ ) CH-C (= O) -GLY-AMPHOMYCIN, C ₁₅ -PHG-AMPHOMYCIN, C ₁₅ - (D-PHE) -AMPHOMYCIN, PH-O - (CH ₂ ) ₁₁ -GLY-AMPHOMYCIN, C ₁₀ - (L-BBTA) -AMPHOMYCIN, C ₁₂ - (P-APA) -AMPHOMYCIN, C ₁₂ - (P-AMINO-TRANS-CINNAMYL) -AMPHOMYCIN, CH ₃ (CH ₂ ) ₁₁ -OP-PH-C (OO) -GLY-AMPHOMYCIN, CH ₃ - (CH ₂ ) ₉ - (P-APA) -AMPHOMYCIN, C ₁₂ -PABA-GLY-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 -AMPHOMYCTN-9-LYS, C ₁₃ -AMPHOMYCIN-9-ORN, C ₁₃ -AMPHOMYCIN-9-GDAB, C ₁₃ -AMPHOMYCIN-9-DAP, C ₁₂ -AMPHOMYCIN-9-LYS, C ₁₂ -AMPHOMYCTN-9-GDRB, 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- (β-ALA), C ₁₅ -AMPHOMYCIN-9- (β-) ALA) -ORN, β-ISOMER OF C ₁₅ -AMPHOMYCIN-9- (β-ALA), ANHYD RO ISOMER C ₁₅ -AMPHOMYCIN-9- (β-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- (β-ALA) -LYS, C ₁₅ -AMPHOMYCIN-9-GABA-LYS, C ₁₅ - AMPHOMYCIN-9-GLY-DAP, C ₁₅ -AMPHOMYCIN-9-GLY-HLYS, C ₁₅ -AMPHOMYCIN-9-GABA-GDAB, C ₁₅ -AMPHOMYCIN-9-PRO, C ₁₅ -AMPHOMYCIN-9-AIB, C ₁₅ -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- (β-ALA) - (5-AVA), C ₁₅ -AMPHOMYCIN-9- (β-ALA) -VAL, β-ISOMER OF C ₁₅ - AMPHOMYCIN-9- (β-ALA) VAL, C ₁₅ -AMPHOMYCIN-9- (5-AVA) - (β-ALA), C ₁₅ -AMPHOMYCIN-9-GLY-LYS-GLY, C ₁₅ -AMPHOMYCIN-9 -GLY-LYS-LYS, C ₁₅ -AMPHOMYCIN-9-GLY-GLY-LYS, C ₁₅ -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- (β-N- (β-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 - AMPHOMXCIN-9- (N-BENZOYL-TYR-PABA), C ₁₅ -AMPHOMYCIN-9 - ((S) - (+) - 5-OXO-2-TET-RAHYDROFURANCAR BONYL), C ₁₅ -AMPHOMYCIN-9-PHENYLPROPYNYL, C ₁₅ -AMPHOMYCIN-9- (CARBAMOYL-β-ALA), C ₁₅ -AMPHOMYCIN-9-ACRYL, C ₁₅ -AMPHOMYCIN-9- (1-NAPTHYL ACETYL), C ₁₅ -AMPHOMYCIN-9- (4-PHENOXYBENZOYL), C ₁₅ -AMPHOMYCIN-9- (2-NAPTHYL ACETYL), C ₁₅ -AMPHOMYCTN-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 -RMPHOMYCIN-9- (α -KETOBUTYL), C ₁₅ -AMPHOMYCIN-9-GERANYL, C ₁₅ -AMPHOMYCIN-9- (O-ANIS YL), 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, C ₁₅ -AMPHOMYCIN-9- (1-ADAMANTANYLCARBONYL), C ₁₅ - AMPHOMYCIN-9- (4-CININECARBONYL), C ₁₅ -AMPHOMYCIN-9- (4-FLUOROBENZOLYL), C ₁₅ -AMPHOMYCIN-9- (S-ACETYLTHIOGLYCOYL), C ₁₅ -AMPHOMYCIN-9- (4-BUTOXYBENZOYL), C _15- AMPHOMYCIN-9- (6-OXOHEPTANOYL), C ₁₅ -AMPHOMYCIN-9-OLEATE, C ₁₅ -AMPHOMYCIN-9- (4-PENYLBENZOYL), C ₁₅ -AMPHOMYCIN-9- (3-PHENOXYBENZOYL), C ₁₅ - AMPHOMYCIN-9- (C (= O) - (CH ₂ ) ₂ -PTPERIDINES, C ₁₅ -AMPHOMYCIN-9- (N, N'-DIMETHYL-GABA), C ₁₅ -AMPHOMYCIN-9- (N-ETHYL-GLY ) C ₁₅ -AMPHOMYCIN-9-SAR- (N, N-DIMETHYL-GLY), C ₁₅ -AMPHOMYCIN-9- (N-BENZYL-GLY), C ₁₅ -AMPHOMYCIN-9- (N, N-DIETHYL-) β-ALA), C ₁₀ -AMPHOMYCIN-9-C ₁₀ , C ₁₅ -AMPHOMYCIN-9- (N-METHYL-GABA), CH ₃ - (CH ₂ ) ₁₅ -NH-C (= O) -AMPHOMYCIN, C ₁₅ -AMPHOMYCIN-9-pGlu, CH ₃ - (CH _{2) 11} -NH-C (= O) -AMPHOMYCIN, CH ₃ - ( CH ₂ ) ₇ -NH-C (OO) -AMPHOMYCIN, CH ₃ - (CH ₂ ) ₁₃ -NH-C (OO) -AMPHOMYCIN, CH ₃ - (CH ₂ ) ₁₁ -NH-C (= O) -AMPHOMYCIN, C ₁₅ -AMPHOMYCIN-C (= O) -NH-N-BUTYL, C ₁₅ -AMPHOMYCIN-C (= 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 (= O) -NH-3-FLUOROPHENYL, C ₁₅ -AMPHOMYCIN (D-SER), C ₁₅ -AMPHOMYCIN (D-TYR), C ₁₅ -AMPHOMYCIN - (D-TRP), C ₁₃ -AMPHOMYCIN-9-GLU, C ₁₅ -AMPHOMYCIN-9- (4-HYDROXYBENZYL), C ₁₅ -AMPHOMYCIN-9-N, N-DI- (P-HYDROXYBENZYL), C ₁₅ -AMPHOMYCIN-9- (N, N-DIMETHYLGLYCINE), CH ₃ - (CH ₂ ) ₉ -SO ₂ -GLY-AMPHOMYCIN, CH ₃ - (CH ₂ ) ₁₅ -SO ₂ -PH-AMPHOMYCIN, CH ₃ - (CH _{2) 13} -NH-C (O) -AMPHOMYCIN-9-GLY-LYS, CH ₃ - (CH _{2) 13} -NH-C (= O) -AMPHOMYCIN-9- (β-ALA), CH ₃ - ( CH ₂ ) ₁₃ -NH-C (OO) -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 - (CH ₂ ) ₁₀ -NH-C (= O) - (β-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 ) ₁₀ -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 (= O) - (β-ALA) -AMPHOMYCIN, C ₁₂ - (M-AMINOBENZOYL) -AMPHOMYCIN, C ₁₃ - (M-AMINOBENZOYL) -AMPHOMYCIN, BORONATE-PINACOL-ESTER-RESIN, 4'-OCTYL-BIPHENYL- 4-CARBOXYL-AMPHOMYCIN, C ₁₃ - (P-APA) -AMPHOMYCIN, C ₁₄ - (P-APA) -AMPHOMYCIN, CH ₃ - (CH ₂ ) ₁₅ -NH-C (= O) - (M-PHENYL ACETYL) -AMPHOMYCIN, C ₁₄ - (M-APA) -AMPHOMYCIN, C ₁₃ - (P-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, CH ₃ - (CH ₂ ) ₁₃ - NH-C (= O) -GLY-AMPHOMYCIN, 1-DODECYL-1H- (1,2,3) -TRIAZOLE-4-C ARBOXYLIC ACID, 1-DODECYL-1H- (1,2,3) -TRIAZOLE-4-CARBOXYL-AMPHOMYCIN, C ₁₅ - (M-APA) -AMPHOMYCIN, C ₁₃ - (ASP- (OME)) - AMPHOMYCIN, C ₁₅ - (P-APA) -AMPHOMYCIN, C ₁₅ - (ASP- (OME)) - AMPHOMYCIN, C ₁₁ - (ASP- (OTBU)) - AMPHOMYCIN, C ₁₃ - (ASP- (OTBU)) - AMPHOMYCIN, C ₁₁ - (ASP- (OME)) - AMPHOMYCIN, C ₁₅ - (ASP- (OME)) - AMPHOMYCIN, C ₁₅ -AMPHOMYCIN-9-C (= O) -NH- (O-CF ₃ -PHENYL), N, N'-DI-C ₆ - (M, M-DIAMINOBENZOYL) -AMPHOMYCIN, N, N'-DI-C ₁₂ - (M, M-DIAMINOBENZOYL) -AMPHOMYCIN, CH ₃ - (CH ₂ ) ₇ -NH-C (= O) - (β-ALA) - AMPHOMYCIN, (4-PHENYL-BENZOYL) -AMPHOMYCIN, (2- (PHENYLMETHYL) -BENZOYL-AMPHOMYCIN, N, N-DIETHYL-PABA-AMPHOMYCIN, (3,4,5-TRIMETHOXYBENZOYL) -RMPHOMYCIN, (4-TBUTYLBENZOYL) -AMPHOMYCIN , (3- (PHENOXY) -BENZOYL) -AMPHOMYCIN, C ₁₅ -AMPHOMYCIN-9- (D-DAP), β-ISOMER CH ₃ - (CH ₂ ) ₁₃ -NH-C (= O) -AMPHOMYCIN, β- ISOMER CH ₃ - (CH ₂ ) ₁₀ -NH-C (= O) - (GABA) -AMPHOMYCIN, LYS-GLY-AMPHOMYCIN-9-C ₁₅ , LYS-GLY-AMPHOMYCIN-9-C ₁₃ , (11- ( PHENOXY) ANDECANOYL) -AMPHOMYCIN, NC ₁₂ - ((1S, 4S) -4-AMINOCYCLOHEXYLCARBOXYLIC ACID), C _1-2 - ((1S, 4S) -4-AMINOCYCLOHEXYLCARBOXYL) -AMPHOMYCIN, (2-DODECANOYLAMINO-THIAZOLE-4 -YL) -ACETIC ACID, (2-DODECANOYLAMINO-THIAZOLE-4-YL) ACETYL-AMPHOMYCIN, 8-DODECYLOXY-QUINOLINE-2-CARBOXYLIC ACID, (8-DODECYLOXY-QUINOLINE-2-CARBONYL) -AMPHOMYCIN, β-ISOMER (8-DODECYLOXY-QUINOLINE-2-CARBONYL) -AMPHOMYCIN, C ₁₅ -A MPHOMYCIN-9-PHE, C ₁₅ -AMPHOMYCIN-9-C ₁₅ , C ₁₅ -AMPHOMYCIN-9 - ([2- (2-METHOXY-ETHOXY) -ETHOXY] -ACETYL), C ₁₀ -SAR-AMPHOMYCIN, C ₁₄ -SAR-AMPHOMYCIN, C ₈ -SAR-AMPHOMYCIN, C ₁₅ -AMPHOMYCIN-9-C ₁₂ , C ₁₅ -AMPHOMYCIN-9- (11-PHENOXYUNDE-CANOYL), C ₁₅ -AMPHOMYCIN-9- (3-FURAN-2 -YL-ACRYLOYL), C ₁₅ -AMPHOMYCIN-9- (3- (BENZENESULFONYL) PROPIONOYL), C ₁₅ -AMPHOMYCIN-9- (4- (PYRENE-2-YL) BUTYROYL), C ₁₅ -AMPHOMYCIN-9-SUC , C ₁₅ -AMPHOMYCIN-9-PRO-LYS, BOC-AMPHOMYCIN, AMPHOMYCIN-9- (β-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 ) ₁₀ -NH-C (= O) - (M-PHENYLACETYL) -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- (β-ALA), (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN -9-GLY, (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN-9-SAR, (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN-9- (β-ALA), (12-ACETYLAMINODODECANOYL) -AMPHOMYCIN, and (12-AMINODODECOYL) -AMPHOMYCIN ". Reference is made to US 2005/0153876 A1, "Compositions of Lipopeptide Antibiotic Derivatives and Methods of Use" of Migenix Inc., Canada, for the structure, terminology and synthesis of such lipopeptides the formula Ia fall,

where in formula Ia R3 can also be bonded via a radical L,
where R ₁ is OH or NH ₂ ,
wherein L is at least one amino acid, at least one substituted amino acid, -R '- (CO) -, -R' - (CO) - (NR ') -, or -O-Ph- (CO) -, wherein R' each independently of one another are the same or different and a radical as may be defined as R3 or R5, and / or where L - when R3 is linked via a radical L identical or different and independently 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 '- (CO) -, -R' - (CO) - (NR ') -, or - O-Ph- (CO) -, where R 'are each independently the same or different and a radical, such as may be defined as R3 or R5, where L in Dab9 is preferably - (CO) -,
wherein R2-OR5, -SR5, NR5R5, - (CO) -R5, - (CO) -O-R5, - (CO) -NHR4, - (CO) -NR4R4, - (CS) -NHR4, - (CS ) -NR4R4, - (CNR4) -NHR 4 or - (CNR4) -NR4R4, R5- (CO), SO ₂ R 5, - (SO) -R 5, - (PO) (oR 5) 2, - (PO) (oR 5 ), COOH, SO ₃ H, -PO ₃ H, -F, -Cl, -Br, -I, or trihalomethyl, is
where R 3 is -H, -OR 5, -SR 5, -NR 5 R 5, -CN, -NO ₂ , -N ₃ , - (CO) -R 5, - (CO) -O-R 5, - (CO) -NR 5 R 5, - ( CS) -NR5R5, - (CNR5) -NR5R5, - (CO) -H, -R 5 (CO), _-SO2 R5, - (PO) (OR 5) _2, - (PO) (OR 5), -CO ₂ H, -SO ₃ H, -PO ₃ H, -F, -Cl, -Br, -I, trihalomethyl, Cl-C25-alkyl, substituted C1-C25 alkyl, C1-C25 heteroalkyl, substituted C1-C25 Heteroalkyl, C5-C10-aryl, C5-C15-arylaryl, substituted C5-C15-arylaryl, C5-C15-biaryl, substituted C5-C15-biaryl, 5-10-membered heteroaryl, substituted 5-10-membered heteroaryl, C6-C26 is arylalkyl, substituted C6-C26 arylalkyl, 6-26-membered heteroarylalkyl, substituted 6-26-membered heteroarylalkyl, at least one amino acid, or at least one substituted amino acid,
wherein R4 is independently or differently C7-C10 alkyl, C17-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,
where R5 is, independently of one another, identical or different C1-C10-alkyl, C5-C10-aryl, 5-10-membered heteroaryl, C6-C26-arylalkyl, 6-26-membered heteroaryl-allyl, straight-chain 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, ot-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, o-hydrazinobenzoic acid, p-amino-trans-cinnamyl, m-aminotrans-cinnamyl, o-amino-trans-cinnamyl, p-aminophenylacetic acid, m-aminophenylacetic acid, L-BBTA, or any combination thereof.

It is possible, that the pharmaceutical composition has several different lipopeptides each containing physiologically effective dose. Then it is about a combination preparation or a broadband preparation.

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.

The Lipopeptide is preferred in the pharmaceutical composition in a total amount (based on the amount of all lipopeptides used) 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 indicated is based on the finished composition.

wobei R1, R2, und R3 gleich oder verschieden und ein beliebiger physiologisch verträglicher Rest sein kann, vorzugsweise -H, C1-C8-Alkyl, -SO₂OH, -PO(OH)₂, oder -CO-R4 mit R4 = C1-C8-Alkyl ist, wobei das C1-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 C1-C4-Alkyl und R6 = carboxylphenyl sein kann, wobei n = 6, 7 oder 8, wobei R1, 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. C1-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 R1, R2 und R3 verschieden von H sein. Vorzugsweise ist insbesondere R1 verschieden von -H. Dabei können 1, 2, 3, 4, 5, 6, oder ggf. 7 der Reste R1 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.In principle, all physiologically acceptable cyclodextrins and cyclodextrin derivatives can be used. Cyclodextrins are cyclic oligosaccharides composed of alpha-1,4 linked glucose units. Usually, six to eight glucose units (α-, β-, or γ-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 and may in particular have the general formula II, 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 = C ₁ C 8 -alkyl, wherein the C 1 -C 8 -alkyl is 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, where R1, R2 and R3 can 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 R1, R2 and R3 can be different from H. Preferably, R1 is different from -H. In this case, 1, 2, 3, 4, 5, 6, or optionally 7 of the radicals R1 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.

in the 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) -β-cyclodextrin, (2-hydroxypropyl) -α-cyclodextrin, sulpho (C 1 -C 8 -alkyl) ether-α-cyclodextrin, Sulpho (C1-C8-alkyl) ether-β-cyclodextrin, Sulphobutylether-α-cyclodextrin, Sulphobutyl ether-β-cyclodextrin. "In the derivatives In particular, the remainder of the oxygen atom of the C6 atom is different from -H.

The Cyclodextrin or cyclodextrin derivative may be used in the pharmaceutical Composition in an amount of 0.01 to 99% by weight, in particular from 0.05 to 80% by weight, preferably 0.1 to 50% by weight, based on the finished composition, be present.

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. As counter-ions for ionic compounds are, for example Ca ^++, CaCl ^+, Na ^+, K ^+, Li ⁺ or cyclohexylammonium, and 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 ), Formulations for dry powder inhalation, transdermal systems, as well as preparations with protracted drug release, in the preparation of conventional auxiliaries such as carriers, blasting, binding, coating, swelling, lubricants or lubricants, flavoring agents, sweeteners and solubilizers, are used , As adjuvants may be, for example, 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 monohydric or polyhydric alcohols, for example glycerol. 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.

When thinner Polyglycols, ethanol, water and buffer solutions come into question. Suitable buffer substances are, for example, N, N'-dibenzylethylenediamine, Diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, Diethylamine, phosphate, sodium bicarbonate, or sodium carbonate. But it can also be without a diluent to be worked.

Physiologically acceptable salts, be it the lipopeptide, be it the cyclodextrin or cyclodextrin derivative, are 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, ethylenediamine, 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.

in the Individually, a pharmaceutical composition according to the invention 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 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 Additives and / or auxiliaries and optionally diluents, wherein the Components A) to C) always add to 100 and wherein the lipopeptide in a physiologically effective dose with the cyclodextrin or Cyclodextrin derivative in a molar ratio of 1: 500 to 10: 1, preferably 1: 100 to 10: 1, most preferably 1: 100 to 2: 1, optionally with the addition of additives and / or auxiliaries in galenic usual Additional quantities, is mixed.

The The invention further relates to the use of a pharmaceutical according to the invention Composition for the manufacture of a medicament for treatment and / or prophylaxis of viral, bacterial and / or parasitic infectious diseases and / or fungal diseases. Examples of possible diseases or applications are: respiratory infections, skin and soft tissue infections, urinary tract infections, Bile duct infections, sepsis, endocarditis, meningitis, surgical prophylaxis, Wound infections or intra-abdominal infections.

Prefers It is when the medicine for oral administration or injection galenically prepared.

The The invention further relates to a method for treating a bacterial, viral or parasitic infectious disease or a fungal disease, being a person suffering from the disease is or is about to become ill, a physiologically effective Dose of a medicament according to the invention becomes. The daily dose may range from 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.

It can Packing units provided with a plurality of delivery units be, each gift unit to the gift within the above Treatment plan is prepared. For example, a packaging unit n1 = 5 to n2 = 500 units of administration, each unit of administration m1 = 1/5 to m2 = 1 daily dose of lipopeptide. The Packing unit is then for set up a treatment plan, which gives 1 to 5 doses a day over a Duration from o1 to o2 days, where o is then calculated as o1 = n1 · m2 and o2 = n2 * m1, or for given o and m, n is calculated as n = o / m.

in the Below, the invention by comparative examples and not limiting examples according to the invention explained in more detail.

Example 1: Minimization friulimicin B-induced hemolysis by human serum albumin (HSA);

Comparative example

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 were prepared further stock solutions of 3200, 1600, 800, 200 and 100 mg / l Na ₂ friulimicin 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 of 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. Here, the data on the concentration of HSA (in% w / v) and of Na ₂ -friulimicin B (in mg / l) refer to the final concentrations in the reaction mixture.

Table 1 Hemolytic activity as a function of the Na ₂ -frirulimicin B concentration (mg / l) in the presence of various HSA concentrations in vitro (in%)

HSA suppresses with good efficiency the Na ₂ -friulimicin B-induced hemolysis from a concentration of about 2.5%. Subsequent determination of serum free 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.

The Determining the antibiotic activity of such Nazi friulimicin B / HSA compositions in vitro with Staphylococcus aureus and Enterococcus Faecalis measured according to the following examples of the invention, however, as shown in Table 2, also showed a strong Reduction of antibiotic activity.

Table 2 Determination of minimum inhibitory concentration (MIC) of Na ₂ -frululimicin in the presence of HSA

Example 2: Minimization of Na ₂ -Friulimicin B-Induced Hemolysis by Addition of Cyclodextrins

This Example shows the effect of various modified or unmodified Cyclodextrins on the by lipopeptide-induced hemolytic Effect. Here Na2-Friulimicin B serves as an example molecule for the antibiotics the lipopeptides.

Na 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 / l Na ₂ -frululimicin were prepared. In each case 20 μl of these stock solutions were each mixed with 20 μl of 0.9% NaCl or 2% solutions of (2-hydroxypropyl) -γ-cyclodextrin (HP-γ-CD), (2-hydroxypropyl) -β-cyclodextrin (HP-β CD) or α-cyclodextrin (α-CD) in 0.9% NaCl mixed carefully. 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 final concentrations of Na ₂ -friulimicin B (in mg / l) gave the results shown in Table 3.

Table 3 Hemolytic activity as a function of the Na ₂ -fibrulicin concentration in the presence of various cyclodextrins in vitro (in%)

The determination of the serum free hemoglobin content showed that no significant reduction in Na ₂ -friulimicin B-induced hemolysis was detectable after preincubation with 0.5% HP-γ-CD. 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, after pre-incubation with 0.5% HP-β-CD and α-CD, a significant reduction in di-sodium-friulimicin B-induced hemolysis could be detected.

Example 3: Minimization of Ca ₂ Cl ₂ -frulimicin B-induced hemolysis by the addition of modified β-cyclodextrins

This example demonstrates the effect of β-cyclodextrins on the lipopeptide-induced hemolytic effect in the presence of high concentrations of the lipopeptide. 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) and HP-β-CD as examples of modified β-cyclodextrins.

Ca ₂ Cl ₂ -frulimicin B was added in concentrations of 100, 50, 40, 30, 20, 10 and 5 g / l in 20, 15, 12.5, 10, 7.5% SBE-β-CD in 0.9% NaCl solution or 12.5% HP-β-CD dissolved 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. Data of the Ca ₂ Cl ₂ -frulimicin B (in mg / l) and the cyclodextrins relate to the final concentrations in the reaction mixture.

Table 4 Hemolytic activity as a function of the Ca ₂ Cl ₂ -frulimicin concentration in the presence of various cyclodextrins in vitro (in%)

Surprisingly, it was found that HP-β-CD, but in particular SBE-β-CD suppress even at very high concentrations of haemolytically very active Ca ₂ Cl ₂ salt of friulimicin B induced by the drug hemolysis. These results show that even at extreme drug concentrations that occur only for a short time directly at injection or infusion sites, after preincubation with modified β-cyclodextrins, the hemolytic effect of Ca ₂ Cl ₂ -frulimicin B over a period of one hour are significantly suppressed can.

Example 4: Minimization the daptomycin-induced hemolysis by the addition of modified β-cyclodextrins

This example demonstrates the effect of a sulphoalkylethercyclodextrin on the hemolytic effect induced by the lipopeptide daptomycin on isolated erythrocytes in the presence of CaCl ₂ .

Daptomycin was dissolved in a solution of 0% or 2.5% SBE-β-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 corresponded to the starting volume of the blood sample. 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, the concentrations of SBE-β-CD (in% w / v) and of daptomycin (in mg / l) are based on the final concentrations in the reaction mixture.

Table 5 Hemolytic activity as a function of daptomycin concentration in the presence of SBE-β-CD in vitro (in%)

SBE-β-CD also suppresses the cell lysis induced by a lipopeptide, here daptomycin, in an experiment with isolated erythrocytes. This experiment shows that SBE-β-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 a formulation of Daptomycin or its derivatives with cyclodextrins also minimizes this toxic effect.

Example 5 Effects of Addition of Cyclodextrins on the Antibiotic Activity of Ca ₂ Cl ₂ Friulimicin B.

The effects of cyclodextrins on the antibiotic activity of Ca ₂ Cl ₂ friulimicin B were investigated by in vitro experiments on the growth inhibition of gram-positive bacteria. The minimum inhibitory concentration for growth inhibition was determined by cultivating the bacteria on nutrient agar (agar dilution) 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; 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 -frulimicin B with SBE-β-CD were tested in Ca-ion-adjusted Müller-Hinton medium. The gram-positive strains tested for the cultivation methods were:
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 cell quantities used per spot (nominal value: 5 × 10 ³ -5 × 10 ⁴ CFU) were at:
S. carnosus ATCC 51365 5.5x10 ³ CFU
S. aureus ATCC 29213 7.6 x 10 ³ CFU
S. aureus ATCC 33592 2.2x10 ⁴ CFU
S. epidermidis ATCC 12228 1.1 x 10 ⁴ CFU

Table 6 Antibiotic activity (MIC in μg / ml) of Ca ₂ Cl ₂ -frulimicin B as a function of the amount of SBE-β-CD (the molar ratio is indicated) in vitro

Surprisingly, 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 the hemolytic activity different lipopeptides by cyclodextrins

auf, wobei die untersuchten Lipopeptide folgendermaßen charakterisiert sind:

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 0 688 789 A1 verwiesen.This example demonstrates the effect of a sulphoalkylethercyclodextrin on the hemolytic effect induced by various lipopeptides. The lipopeptides were 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-β-CD, stock solutions of 3200 mg / l lipopeptide with or without 5% SBE-β-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-β-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. Formula I

with the lipopeptides investigated being characterized as follows:

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 literature reference 0 688 789 A1.

Inhibition of the hemolytic activity of various lipopeptides at a concentration of 1600 mg / l in the presence of 2.5% SBE-β-CD

These Results show that cyclodextrins essentially independent of the acyl and peptidyl moiety of a lipopeptide are capable of hemolysis to reduce.

Example 7: Preparation of a Ca ₂ Cl ₂ -frulimicin B injection solution.

100 mg of Ca ₂ Cl ₂ -frulimicin B and 770 mg of 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.

Claims (18)

Pharmaceutical composition containing as Active ingredient a lipopeptide in physiologically effective dose as well a cyclodextrin or a cyclodextrin derivative. A pharmaceutical composition according to claim 1, wherein the lipopeptide has a structure according to formula I Formula I

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 one or more phenyl or cycloalkyl groups or connected to such groups or by one or more oxygen atoms may be interrupted, or a physiologically acceptable salt of such a compound. A pharmaceutical composition according to claim 1 or 2, wherein the lipopeptide is selected is from the group consisting of "amphomycin and amphomycin derivatives. Pharmaceutical composition according to one of claims 1 to 3, wherein the lipopeptide is selected 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 ". Pharmaceutical composition according to one of claims 1 to 4, containing several different lipopeptides in each physiological effective dose. Pharmaceutical composition according to one of claims 1 to 5, wherein the lipopeptide is present as alkali or alkaline earth salt, preferably as sodium or calcium salt, in particular as di-calcium salt (Ca ₂ Cl ₂ salt), or as 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 preferably an ion from the group consisting of "hydrochloride, sulfonate, nitrate, phosphate, succinate, maleate, citrate, tartrate, lactate , Gluconate and sulfonate "may be used. Pharmaceutical composition according to one of claims 1 to 6, containing the lipopeptide in a total amount of 0.01 to 80 % By weight, in particular from 0.05 to 50% by weight, preferably from 0.1 to 30% by weight. A pharmaceutical composition according to any one of claims 1 to 7, wherein the cyclodextrin or cyclodextrin derivative is an α- or β-cyclodextrin and preferably has the general formula II 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 = C ₁ C 8 -alkyl, wherein the C 1 -C 8 -alkyl is 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 or 7, wherein R1, 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. Pharmaceutical composition according to one of claims 1 to 8, wherein the cyclodextrin or cyclodextrin derivative is selected from the group consisting of "α-cyclodextrin, β-cyclodextrin, Hydroxy (C1-C8-alkyl) -α-cyclodextrin, Hydroxy- (C 1 -C 8 -alkyl) -β-cyclodextrin, (2-hydroxypropyl) -β-cyclodextrin, (2-hydroxypropyl) -α-cyclodextrin, Sulpho (C1-C8-alkyl) ether-α-cyclodextrin, Sulpho- (C 1 -C 8 -alkyl) ether-β-cyclodextrin, sulphobutyl ether-α-cyclodextrin, Sulphobutylether-β-cyclodextrin ". Pharmaceutical composition according to one of claims 1 to 9, containing the cyclodextrin or cyclodextrin derivative in one Amount of from 0.01 to 99% by weight, in particular from 0.05 to 80% by weight, preferably 0.1 to 50% by weight. Pharmaceutical composition according to one of claims 1 to 9, containing further additives and / or adjuvants, in particular galenic adjuvants. Pharmaceutical composition according to claim 11 containing A) 0.01 to 80% by weight, in particular 0.05 to 50% by weight, preferably 0.1 to 30% by weight, of lipopeptide, B) 0.01 to 99% by weight, especially 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, especially 1 to 80% by weight, preferably 1 to 50% by weight additional and / or Excipients as well as optional diluents, in which the components A) to C) always add up to 100. Use of a pharmaceutical composition according to one of the 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. Use according to claim 13, wherein the medicament prepared for oral administration or injection. Method of treating a bacterial, viral or parasitic Infectious disease and / or fungal disease, whereby a person, sick or at risk of contracting the disease a physiologically effective dose of a drug after a the claims 1 to 12 is presented. 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 presented. Packaging unit with a plurality of delivery units, each donation unit being a gift within a treatment plan according to one of the claims 15 or 16 is prepared. Process for the preparation of a pharmaceutical A 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 of 1: 500 to 10: 1, preferably 1: 100 to 10: 1, most preferably 1: 100 up to 2: 1, optionally with the addition of additives and / or auxiliaries in galenic usual Additional quantities, is mixed.