AU2006314942A1 - Lipopeptide compositions - Google Patents

Lipopeptide compositions Download PDF

Info

Publication number
AU2006314942A1
AU2006314942A1 AU2006314942A AU2006314942A AU2006314942A1 AU 2006314942 A1 AU2006314942 A1 AU 2006314942A1 AU 2006314942 A AU2006314942 A AU 2006314942A AU 2006314942 A AU2006314942 A AU 2006314942A AU 2006314942 A1 AU2006314942 A1 AU 2006314942A1
Authority
AU
Australia
Prior art keywords
amphomycin
cyclodextrin
derivatives
friulimicin
lipopeptide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
AU2006314942A
Inventor
Harald Labischinski
Stefan Pelzer
Horst Priefert
Andreas Vente
Sven-Eric Wohlert
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merlion Pharmaceuticals GmbH
Original Assignee
Merlion Pharmaceuticals GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merlion Pharmaceuticals GmbH filed Critical Merlion Pharmaceuticals GmbH
Publication of AU2006314942A1 publication Critical patent/AU2006314942A1/en
Abandoned legal-status Critical Current

Links

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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nanotechnology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

New lipopeptide compositions. Field of the invention. The invention relates to new pharmaceutical compositions containing lipopeptides, to the use 5 of such compositions, to methods for the produc tion thereof and to the use thereof as drugs. Background of the invention and prior art. Secondary metabolites, which are produced by living organisms, in particular microorganisms, 10 and the chemical variants derived therefrom are successfully used as active agents in medicine. Particularly for the control of infectious dis eases, the use of secondary metabolites has proven effective. A large portion of the antibiotics used 15 today were isolated from bacteria in the soil, the so-called actinomycetes. Due to the development of resistances against the respectively used drugs, there is a permanent demand of new antibiotic ac tive agents with novel activity mechanisms. In 20 spite of their excellent antibiotic and other pharmacological properties, for many secondary me tabolites the use as a drug is at last unsuccess ful because of the in most cases also very dis tinct toxic properties for man. 25 Antibiotics from the class of the lipopep tides, which are characterized by a linear or cy clic peptide portion or a combination of both, with naturally and/or non-naturally derivatized and/or non-derivatized amino acids, with which a 30 saturated or unsaturated acyl residue is con nected, which optionally may be interrupted by one or several phenyl or cycloalkyl groups or con nected with such groups or interrupted by one or several oxygen or nitrogen atoms, have been found in the past as very effective against fungi and 5 Gram-positive bacteria. For the majority of these compounds, however, toxic properties are also known. The compound daptomycin belonging to the class of the A-21978C lipopeptides for instance damages 10 the skeletal muscle (Oleson et al. 2000, Anti microbial agents and chemotherapy, Vol. 44 No 11; 2948 - 2953), and a series of further lipopep tides, for instance lichenysin (Grangemard I. et al., Applied Biochemistry and Biotechnology, Vol 15 ume 90, Number 3, 2001, pp. 199-210(12)), surfac tin A (Hanka Symmank, Peter Franke, Wolfram Saenger and Frank Bernhard, Modification of bio logically active peptides: production of a novel lipohexapeptide after engineering of Bacillus sub 20 tilis surfactin synthetase), FR131535 and echino candin (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 25 like lipopeptide: synthesis and biological proper ties), Fengycin (J. of Antibiotics 29 (1986) 888 901), iturin A (Aranda FJ, Teruel JA, Ortiz A., Biochem Biophys Acta. 2005 Jul 15;1713(1):51-6. Further aspects on the hemolytic activity of the 30 antibiotic lipopeptide iturin A), and lipopeptides (DE 19807972) similar to amphomycin and friuli micin act in a hemolytic manner. An essential problem for the application of these lipopeptides as drugs is however the elimi 35 nation of the toxicological properties without im pairing the antibiotic activity of the substances.
For the application of these substances as drugs, it is therefore necessary to find pharmaceutical compositions, which compared to the pure substance have improved pharmacological properties. It is 5 known, for instance, that the hemolytic properties of a substance or of an ion are reduced in the presence of the serum albumin, and this is caused by the interaction with the serum albumin ("mask ing effect") (Caffrey JM Jr, Smith HA, Schmitz JC, 10 Merchant A, Frieden E.: Hemolysis of rabbit eryth rocytes in the presence of copper ions. Inhibition by albumin and ceruloplasmin. Biol Trace Elem Res. 1990 Apr 25; (1):11-9). This masking effect with the serum albumin causes however in many cases 15 also the loss of the desired properties of mole cules, and thus also of the antibiotic activity of lipopeptides as illustrated in example 1 of this invention. It is known in the art to use cyclodextrins in 20 pharmaceutical compositions. Due to their circular structure, cyclodextrins have a hydrophilic exte rior and hydrophobic inner pocket. By enclosing in particular hydrophobic sections of the molecules, cyclodextrins can achieve a "molecular encapsula 25 tion" or "masking" of active agents, which are used for instance as a protective envelope of sen sitive molecules in cosmetic and pharmaceutical formulations. Thereby, improved solubilities of substances, but also reduced toxicities, such as 30 for instance a reduction of the hemolytic proper ties of molecules (J. Pharmacobiodyn. 1983 6(6): 408-14. Protective mechanism of beta cyclodextrin for the hemolysis induced with phenothiazine neu roleptics in vitro. Irie T, Sunada M, Otagiri M, 35 Uekama K.) are obtained.
Technical object of the invention. It is therefore the technical object of the invention to provide new pharmaceutical composi tions with antibacterially, antivirally and/or an 5 timycotically acting lipopeptides, the tolerance of which is improved while maintaining the physio clogical effectiveness such that even with very high concentrations, which will for example occur during infusions for short times at the place of 10 application, only little toxic side effects will be encountered. Basics of the invention and embodiments. For achieving this technical object, the in vention teaches a pharmaceutical composition com 15 prising as an active agent an antibacterially, antivirally, and/or antimycotically acting lipo peptide in a physiologically effective dose and a physiologically tolerated cyclodextrin or a cyclo dextrin derivative. 20 The invention is based on the surprising find ing that specially by using cyclodextrins or cyclodextrin derivatives not only a reduction of the hemolytic properties of antibiotically acting lipopeptides is achieved, but that rather at the 25 same time the antibiotic effect of the lipopep tides is maintained, whereas on the other hand for instance a masking with HSA will lead to a reduced or completely suppressed antibiotic effect. The lipopeptide preferably has a structure ac 30 cording to formula I, Y-X-Dab-Pip-MeAsp-Asp-Gly-Asp-Gly-Dab-Va l-Pro formula I wherein X = one of the amino acids Asn or Asp, 5 wherein Y = a straight-chain or branched, satu rated or unsaturated aliphatic acyl residue with 6 to 22 carbon atoms, which optionally is inter rupted by one or several phenyl or cycloalkyl groups or connected with such groups or inter 10 rupted by one or several oxygen atoms. The amino acids of the peptide portion of the molecules may be derivatized (US 2005/0153876 Al). In the case that X = Asn, it is friulimicin or a friulimicin derivative. In the case that that X = Asp, it is 15 amphomycin or an amphomycin derivative. Y may in particular be:
(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-,
CH
3
(CH
2
)
1 0 CO-, CH 3
(CH
2
)
1 1 CO-, CH 3
(CH
2
)
1 2 CO-, 20 CH 3
(CH
2
)
1 3 CO-, CH 3
(CH
2
)
1 4 CO-, CH 3
(CH
2
)
1 5 CO-,
CH
3
CH(CH
3
)(CH
2
)
8 CO-, CH 3 CH (CH 3 ) (CH 2 ) 9 CO-,
CH
3 CH (CH 3 ) (CH 2 ) 1 0 CO-, CH 3 CH (CH 3 ) (CH 2 ) 1 1 CO-,
CH
3 CH (CH 3 ) (CH 2 ) 12CO
-
, H 2 C=CH (CH 2 ) 8 CO-,
H
2 C=CH (CH 2
)
9 CO-, CH 3
(CH
2
)
7 CH=CHCO- (trans), 25 CH 3
(CH
2
)
8 CH=CHCO-(trans), CH 3
(CH
2
)
1 2
CH=CHCO
(trans), CH 3
(CH
2
)
3 CH=CH (CH 2
)
7 CO- (cis),
CH
3
(CH
2 ) 3
CRH=CRH(CR
2 ) 7CO- (trans)
CH
3
(CH
2 ) 3
CH=CH(CH
2 ) 8 CO- (trans)
CH
3
(CH
2
)
5
CH=CH(CH
2
)
7
CO
- (cis) 30 CH 3
(CH
2
)
5
CH=CH(CH
2
)
7 CO- (trans)
CH
3
(CH
2 ) 5
CH=CH(CH
2 ) 8 CO- (cis)
CH
3
(CH
2 ) 1 0 CH=CH (CH 2 ) 4 CO- (cis)
CH
3
(CH
2
)
1 0 CH=CH (CH 2
)
4 CO- (trans)
CH
3
(CH
2
)
7
CH=CH(CH
2
)
7 CO- (cis)
CH
3
(CH
2
)
7
CH=CH(CH
2 )7CO- trans) ,
CH
3
(CH
2 ) 5 CH=CH (CH2) 9CO- trans) ,
CH
3
(CH
2 ) 3 (CH 2
C
H = CH) 2 (CH 2 ) 7 CO- (cis) ,
CH
3
(CH
2
)
3
(CH
2 CH=CH)2 (CH 2
)
2 C O - trans) , 5 CH 3
(CH
2 )3(CH 2 CH=CH) 2 (CH 2 ) 9 C O - (cis) ,
CH
3
(CH
2 CH=CH)3(CH2) 7CO- (cis) ,
CH
3
(CH
2 )3(CH 2 CH=CH) 3 (CH2) 4 C O - (cis) ,
CH
3
(CH
2
CH=CH)
4 (CH2)4CO- (cis),
CH
3
(CH
2 ) 3 (CH 2 CH=CH )4 (CR 2 ) 3CO- (cis) , 10 CH3(CH 2 CH=CH ) 6
(CH
2 )2CO- (cis), H 2 C=CH (CH 3
)
8 CO-,
CH
3
(CH
2 ) 3 CH=CH (CH2) 7CO-, CH3 (CH 2 ) 7 CH=CH (CH 2 ) 7CO-,
CH
3
(CH
2
)
4
CH=CH-CH=CH-(CH
2 )8CO-,
(CH
3
)
2 C=CHCH2 [CH 2
C(CH
3 ) =CHCH 2 ] 2CO-, Phe-Phe-CH2CO-, Phe- (CH 2 ) 9CO
-
, Phe-O- (CH 2 ) 10CO-, CH 3
(CH
2
)
7 -Phe-CO-, 15 Phe-Phe-CO-, 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-, CH3CH 2 Phe-(CH 2
)
2 -Phe-CO-, Phe-Phe-(CH 2
)
2 -Phe-CO-, Phe
(CH
2 ) 2 -Phe- (CH 2 ) 2 -Phe-CO-, CH3 (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 20 (CH 2 ) 6
CH=CHCH
2 CO- (cis) , (CH 3 ) 2CH (CH 2 ) 6 CH=CHCH2CO (trans), (CH 3 )2CH(CH 2
)
7
CH=CHCH
2 CO- (cis),
(CH
3 ) 2 CH (CH 2 ) 7 CH=CHCH2CO- (trans)
CH
3 CH2(CHCH 3 ) (CH 2 ) 5CH=CHCH2CO- (cis) CH3CH 2
(CHCH
3 ) (CH 2 ) 5 CH=CHCH2CO- (trans) 25 CH3CH 2
(CHCH
3 ) (CH 2 ) 7CH=CHCH2CO- (cis)
CH
3
CH
2
(CHCH
3 ) (CH 2 ) 7CH=CHCH2CO- (trans)
CH
3
CH
2
(CHCH
3 ) (CH 2
)
7 CH=CHCH2CO- (cis) CH3(CH 2
)
8 CH=CHCO-(cis), CH3(CH 2 )8CH=CHCO- (trans),
CH
3
(CH
2
)
9 CH=CHCO- (cis), CH 3
(CH
2
)
8 CH=CHCO- (trans), 30 CH 3
(CH
2 )7CH=CHCO- (cis), CH 3
(CH
2
)
7 CH=CHCO- (trans), wherein Phe is a benzene ring being not substituted or substituted one time or two to four times by C1-8 alkyl, and wherein -Phe- is ortho, metha, or para bonding. 35 For producing such lipopeptides in detail, reference is made for instance to the documents DE 198 07 972 Al, EP 0 629 636 Al, EP 0 688 789 Al and US 2005/0153876 Al. The lipopeptide may be selected, independently from formula I, from the group comprising "ampho 5 mycin, amphomycin derivatives, friulimicin, friulimicin B, friulimicin derivatives, daptomy cin, daptomycin derivatives, aspartocin, asparto cin derivatives, glumamycin, glumamycin deriva tives, crystallomycin, crystallomycin derivatives, 10 zaomycin, zaomycin derivatives, tsushimycin, tsu shimyin derivatives, laspartomycin, laspartomycin derivatives, brevistin, brevistin derivatives, cerexin B, cerexin B derivatives, syringomycin and its derivatives, antibiotic A-30912 and its de 15 rivatives, antibiotic A-54145 and its derivatives and antibiotic A-21978C and its derivatives" The lipopeptide may furthermore be selected, independently from formula I, from the group com prising "C 15 -AMPHOMYCIN, Cs 15 -AMPHOMYCIN-9-GLY, C 15 20 AMPHOMYCIN-9-GLY-LYS, C 15 -AMPHOMYCIN-9-LEU, Cl0 AMPHOMYCIN, C 11 -AMPHOMYCIN, C 12 -AMPHOMYCIN, C 13
-AM
PHOMYCIN, C 14 -AMPHOMYCIN, C 16 -AMPHOMYCIN, C 17
-AM
PHOMYCIN, C 1 8 -AMPHOMYCIN, OLEOYL-AMPHOMYCIN, CH 3 (CH 2
)
11 -O-P-PH-C(=O)-AMPHOMYCIN, CH 3
-(CH
2
)
15
-O-P
25 PH-C(=O)AMPHOMYCIN, HO-(CH 2
)
15 -C(=O) -AMPHOMYCIN,
CH
3
-(CH
2
)
9 -0-P-PH-C(=O)-AMPHOMYCIN, CH 3
-(CH
2
)
7 -0-P PH-C(=O)-AMPHOMYCIN, CH 3
(CH
2
)
11
-NH-SUCCINYL-AMPHO
MYCIN, C 12 -P-HYDRAZINBENZOIC ACID-AMPHOMYCIN, C 15 AMPHOMYCIN-9-GABA, C 14 -AMPHOMYCIN-9-GLY, C 15
-AM
30 PHOMYCIN-9-SAR, C 15 -AMPHOMYCIN-9-AHX, C 15
-AMPHOMY
CIN-9-INA, C 15 -AMPHOMYCIN-9-(P-N0 2 -PHE), C 15
-AMPHO
MYCIN-9-GLY-PHE, C 15 -AMPHOMYCIN-9-GLU, C 15
-AMPHO
MYCIN-9-(P-F-PHE), C1 5 -AMPHOMYCIN-9- (B-CHA), Cis 5 AMPHOMYCIN-9-HPHE, C 15 -AMPHOMYCIN-9-GLY-GLY-GLY, 35 C 15 -AMPHOMYCIN-9-C(=0)-(CH 2
)
10
-NH
2 , C 15
-AMPHOMYCIN
9-(8-CYANO-ALA), C 15 -AMPHOMYCIN-9-ILE, C 15
-AMPHO-
MYCIN-9-GLY-VAL, C 15 -AMPHOMYCIN-9-ASN, C 15
-AMPHO
MYCIN-9-TYR, C 1 5 -AMPHOMYC IN- 9-TRP, C 1 5
-AMPHOMYCIN
9-PHG, C 15 -AMPHOMYCIN-9-GLY-GLY, C 1 5 -AMPHOMYCIN-9 GLN, C 15 -AMPHOMYCIN-9-THR, C 15 -AMPHOMYCIN-9-PRO 5 GLY, C 15 -AMPHOMYCIN-9-GLY-LEU, C 15 -AMPHOMYCIN-9 TYR (ET), C 15 -AMPHOMYCIN-9-GLY-SUC, C 15
-AMPHOMY
CIN-9-GLY-AC, C 13 -AMPHOMYCIN- 9-GABA, C 14
-AMPHOMY
CIN-9-GLY-LYS, C 15 -AMPHOMYCIN-9-TYR (ME), C 13
-AM
PHOMYCIN-9-GLY, C 1 3 -AMPHOMYCIN-9- (8-ALA), C 1 3
-AM
10 PHOMYCIN-9-SAR, C 13 -AMPHOMYCIN-9-AHX, C 12
-AMPHOMY
CIN-9-GABA, C 1 2 -AMPHOMYCIN-9-GLY, C 1 4
-AMPHOMYCIN
9-(8-ALA), C 14 -AMPHOMYCIN-9-SAR, C 1 4 -AMPHOMYCIN-9 AHX, C 14 -AMPHOMYCIN-9-GABA, C 13 -AMPHOMYCIN-9-ALA,
C
13 -AMPHOMYCIN-9-(D-ALA), C 13 -AMPHOMYCIN-9-(D 15 PRO), C 15 -AMPHOMYCIN-9-(D-ALA), C 1 5 -AMPHOMYCIN-9 (D-PRO), C 15 -AMPHOMYCIN-9-GLY-GABA, C 1 5
-AMPHOMY
CIN-9-GLY-(D-ALA), C 15 -AMPHOMYCIN-9-(8-ALA)-AHX,
C
15 -AMPHOMYCIN-9-GABA-VAL, C 15 -AMPHOMYCIN-9-GABA AHX, C 12 -AMPHOMYCIN-9- (8-ALA), C 12 -AMPHOMYCIN-9 20 SAR, C 1 6 -AMPHOMYCIN-9-SAR, Clo-AMPHOMYCIN-9- ( ALA), Co 10 -AMPHOMYCIN-9-SAR, C 17 -AMPHOMYCIN-9-SAR,
C
1 6 -AMPHOMYCIN-9- (8-ALA), C 1 7 -AMPHOMYCIN-9- (8 ALA), C 1 5 -AMPHOMYCIN-9-GLY-C 6 , C 1 5 -AMPHOMYCIN-9 ALA, CH 3
-(CH
2
)
1 5 -NH-C(=O)-AMPHOMYCIN-9-GLY, CH 3 25 (CH 2 ) 1 5
-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
)
1 1 -O-P-PH-C(=0)-AMPHOMYCIN-9-GLY,
C
12 -(P-TRANS-CINNAMYL)-AMPHOMYCIN-9-GLY, CH 3 (CH 2 ) 1 1 -O-P-PH-C) -GLY-AMPHOMYCIN-9-GLY, C 14
-PABA
30 GLY-AMPHOMYCIN-9-GLY, CH 3
(CH
2
)
1 1 -NH-C(=0)-AMPHOMY CIN-9-GLY, C 15 -AMPHOMYCIN-9-AHX-GLY, C 15
-AMPHOMY
CIN-9-GABA-GABA, C 1 5 -AMPHOMYCIN-9-HPRO, C 1 5
-AMPHO
MYCIN-9-(D-PIP), CH 3
-(CH
2
)
1 1 -NH-C(=0)-AMPHOMYCIN 9-(8-ALA), CH 3
-(CH
2
)
1 1 -NH-C(=0)-AMPHOMYCIN-9-SAR, 35 CH 3 - (CH 2 ) 1 5
-SO
2 -GLY-AMPHOMYCIN, CH 3 - (CH 2 ) 9
-SO
2
-PHE
AMPHOMYCIN, CH 3
-(CH
2
)
9
-SO
2 -GLY-AMPHOMYCIN-9-LYS,
CH
3 - (CH 2 ) 9
-SO
2 -GLY-AMPHOMYCIN-9-GLY, C 1 2
-GLY-AMPHO
MYCIN, C 8 -(P-APA)-AMPHOMYCIN, C 1 4
-GLY-AMPHOMYCIN,
C
1 6 -GLY-AMPHOMYOIN, C 1 8 -GLY-AMPHOMYCIN, C 1 2 - (P AMINOPHENYLPROPANOYL)-AMPHOMYCIN, 0 12
-(P-AMINO
PHENYLPROPANOYL)
2 -AMPHOMYCIN, CH 3 - (CH 2 ) 9
-O-P-PH
C(=O)-GLY-AMPHOMYCIN, C 1 2 - (M-APA) -AMPHOMYCIN, C1 5 5 [ASP-(OTBU)]-AMPHOMYCIN, Cl 0 -(M-APA)-AMPHOMYCIN,
CH
3 - (0H 2 ) 7 - (CH 3 - (CH 2 ) 5 ) CH-C (=O )-GLY-AMPHOMYCIN, C1 5 -PHG-AMPHOMYCIN, 0 15 -(D-PHE)-AMPHOMYCTN, PH-O (0H 2 ) 1 1 -GLY-AMPHOMYCIN, Cio-(L-BBTA)-AMPHOMYCIN,
C
12 -(P-APA)-AMPHOMYCIN, C 12
-(P-AMINO-TRANS-CINNA
10 MYL)-AMPHOMYCIN, 0H 3 - (CH 2 ) 1 1 -O-P-PH-C (=O) -GLY-AM PHOMYCIN, CH 3 - (CH 2 ) 9 - (P-APA) -AMPHOMYCIN, C 1 2
-PABA
GLY-AMPHOMYCIN, C 1 5 -AMPHOMYCIN-9- (D-ORN), C 1 4
-AM
PHOMYCIN-9-GLY-LYS, C 1 4 -AMPHOMYCIN-9-LYS, C 1 4
-AM
PHOMYCIN-9-ORN, C 1 3 -AMPHOMYCIN-9-GLY-LYS, C 1 5
-AM
15 PHOMYCIN-9-LYS, C 1 5 -AMPHOMYCIN- 9-ORN, C 1 5
-AMPHOMY
CIN- 9-GDAB, C 1 5 -AMPHOMYCIN- 9-DAP, C 1 3
-AMPHOMYCIN
9 -L Y S, C 13 -AMPHOMYCIN--9-ORN, C 1 3 -AMPHOMYCIN-9 GDAB, C 13 -AMPHOMYCIN-9-DAP, C 1 2 -AMPHOMYCIN-9-LYS,
C
1 2 -AMPHOMYCIN- 9-GDAB, C 14 -AMPHOMYCIN- 9-GDAB, C 1 4 20 AMPHOMYCIN-9-DAP, C 1 6 -AMPHOMYCTN-9-GLY-LYS, C 1
-
AMPHOMYCIN-9-GLY-LYS, C 12 -AMPHOMYCIN-9-GLY-LYS,
C
1 5 -AMPHOMYCIN- 9-SAR-ORN, C 1 5 -AMPHOMYCIN-9-SAR GDAB, C 15 -AMPHOMYC IN- 9- SAR- DAP, C 1 5 -AMPHOMYC IN- 9 (B-ALA) , C 1 5 -AMPHOMYCIN-9- (B-ALA) -ORN, B-ISOMER OF 25 C 1 5 -AMPHOMYCIN-9- (B-ALA) , ANHYDROISOMER OF C 1 5
-AM
PHOMYCTN-9-(B-ALA), C 15 -AMPHOMYCIN-9-(D-PRO)--(D LYS) , C 1 5 -AMPHOMYCIN-9-GLY-(D-LYS), C, 5
-AMPHOMY
CIN-9-GLY-ORN, C 1 5 -AMPHOMYCIN- 9-GLY-GDAB, C 15
-AM
PHOMYCIN-9- (B-ALA) -LYS, C 15 -AMPHOMYCIN-9-GABA-LYS, 30 C 1 5 -AMPHOMYCIN- 9-GLY-DAP, C 1 5 -AMPHOMYCIN-9-GLY HLYS, C 15 -AMPHOMYCIN- 9-GABA-GDAB, C 1 5
-AMPHOMYCIN
9-PRO, CIS-AMPHOMYCIN- 9-AIB, C 1 5 -AMPHOMYCIN- 9-ME C Y S, C 15 -AMPHOMYCIN-9-NVL, C 1 5 -AMPHOMYCIN-9-ABU,
C
1 5 -AMPHOMYCIN-9-CIT, C 1 5 -AMPHOMYCIN-9- (ME) 2 ARG, 35 C 1 5 -AMPH-OMYCIN-9-HYP, C 1 5 -AMPHOMYCIN-9- (P-APA) ,
C
1 5 -AMPHOMYCIN-9-VAL, C 1 5 -AMPHOMYCIN-9- (ME) 3 LYS,
C
1 5 -AMPHOMYCIN-9-NLE, C 1 5 -AMPHOMYCIN-9-LYS, C 1 5
-AM
PHOMYCIN-9-(B -ALA)-(5-AVA), C, 5 -AMPHOMYCIN-9-(13- ALA) -VAL, 8-ISOMER OF C 15 -AMPHOMYCIN-9-(13-ALA) VAL, C 15 -AMPHOMYCIN-9-(S-AVA)-(Z-ALA), C 1 5
-AMPHO
MYCIN-9-GLY-LYS-GLY, C 15 -AMPHOMYCIN-9-GLY-LYS-LYS,
C
1 5 -AMPHOMYC IN- 9-GLY-GLY-LYS, 0 1 5 -AMPHOMYCIN-9 5 LYS-GLY, C 1 5 -AMPHOMYCIN-9-LYS-LYS, C 1 5 -AMPHOMYC TN 9-LYS-LYS-LYS, 0 1 5 -AMPHOMYCIN-9-GLY- (D-LEJ), C, 5 AMPHOMYCIN- 9-GLY-AHX, C, 5 -AMPHOMYCIN-9-SAR-AHX, Cls-AMPHOMYCIN-9-SAR-LYS, C, 5 -AMPHOMYCTN-9-DAP- (3 N-(13-ALA)), C 1 5 -AMPHOMYCIN-9-C 6 , C 1 5 -AMPHOMYCIN-9 10 PLA, C 15 -AMPHOMYCTN-9-PCA, C 1 5 -AMPHOMYCIN-9- (CAR BAMOYL-LEU) , C 1 5 -AMPHOMYCIN-9-C 8 , C 1 5 -AMPHOMYCTN-9 CHEXYL, C 1 5 -AMPHOMYCIN-9-C 4 , C 1 5 -AMPHOMYCIN-9- (2 NORBORNANEACETYL), C 15 -AMPHOMYCIN-9-(N-BENZOYL TYR-PABA), C 15 -AMPHOMYCIN-9-((S)-(+)-5-OXO-2-TET 15 RAHYDROFURANCARBONYL) , C 1 5 -AMPHOMYCIN-9-PHENYLPRO PYNYL, C 15 -AMPHOMYCIN-9-(CARBAMOYL-3-ALA), C 1 5
-AM
PHOMYCTN-9-AORYL, C 1 5 -AMPHOMYCIN-9- (1-NAPTHYLACE TYL), C 1 5 -AMPHOMYCIN-9-(4-PHENOXYBENZOYL), C 15
-AM
PHOMYCIN-9-(2-NAPTHYLACETYL), C 15 -AMPHOMYCIN-9-(2 20 FURYL), C 1 5 -AMPHOMYCIN-9-CROTONYL, C 1 5
-AMPHOMYCIN
9-(3,4-(METHYLENEDIOXY)PHENYLACETYL), C 15
-AMPHOMY
CIN-9-Cl 0 , C 15 -AMPHOMYCIN-9- (y-OXO-5-ACENAPTHENE BUTANYL), C 15 -AMPHOMYCIN-9-HYDROCINNAMYL, C 1 5
-AM
PHOMYCIN-9 (a-KETOBUTYL) , C 1 5 -AMPHOMYCIN-9-GERANYL, 25 C 1 5 -AMPHOMYCTN-9-(O-ANISYL), C 1 5 -AMPHOMYCIN-9 PHENYLECATYL, C 15 -AMPHOMYCIN-9(2-BUTYNYL), C1 5
-AM
PHOMYCIN-9-(3,5-BIS(CF 3 )PHENYLACETYL), C 1 5
-AMPHO
MYCIN-9-(3,4-METHYLENEDIOXY-CINNAMYL), C 15
-AMPHO
MYCIN-9-(TRANS-CINNAMYL), C 15 -AMPHOMYCIN-9-ACE 30 TOXYACETYL, C 1 5 -AMPHOMYCIN-9-(l-ADAMANTANYLCAR BONYL), .C 15 -AMPHOMYCIN-9-(4-COTININECARBONYL),
C
1 5 -AMPHOMYCIN-9- (4-FLUOROBENZOLYL) , C 1 5
-AMPHOMY
CIN-9-(S-ACETYLTHIOGLYCOYL), C 1 5 -AMPHOMYCTN-9-(4 BUTOXYBENZOYL), C 1 5 -AMPHOMYCTN-9-(6-OXOHEPTANOYL), 35 0 15 -AMPHOMYCIN-9-OLEATE, C 1 5 -AMPHOMYCIN--9- (4 PENYLBENZOYL), C 15 -AMPHOMYCIN-9-(3-PHENOXYBEN ZOYL) , C 1 5 -AMPHOMYCIN-9- (C (=O) -(CH 2 ) 2 -PIPERIDINE,
C
1 5 -AMPHOMYCIN-9(N,N'-DIMETHYL-GABA), C 1 5
-AMPHOMY-
CIN-9-(N-ETHYL-GLY), C 1 5 -AMPHOMYCIN-9-SAR-(N,N-DI METHYL-GLY), C 15 -AMPHOMYCIN-9-(N-BENZYL-GLY), C15 AMPH0MYCIN-9-(N,N-DIETHYL-3-ALA), Cl 0
-AMPHOMYCIN
9-co, C 1 5 -AMPHOMYCIN9(N-METHYL-GABA), CH 3 5 (CH 2 ) 1 5 -NH-C (=0) -AMPHOMYCIN, C 1 5 -AMPHOMYCIN-9-PGLU,
CH
3
(CH
2 ) 1 1 -NH-C (=0) -AMPHOMYCIN, CH 3 - (CH 2 ) 7
-NH
C(=0)-AMPHOMYCTN, CH 3 - (CH 2
)
1 3 -NH-C (=O) -AMPHOMYCIN,
CH
3 - (CH 2 ) 1 1 -NH-C (=O) AMPHOMYCIN, C 1 5
-AMPHOMYCIN
C(=O)-NH-N-BJTYL, C 15
-AMPHOMYCIN-C(=O)-NH-CYCLO
10 HEXYL, C 15 -AMPHOMYCIN-C(=0)-NH-FURFURYL, 0 1 5
-AM
PHOMYCIN-C (=0) -NH-2-FLUOROBENZYL, 0 15
-AMPHOMYCIN
C (=0) -NH-M-CF 3 -PHENYL, C 1 5 -AMPHOMYCIN-C (=0) -NH-P
CF
3 -PHENYL, C 1 5 -AMPHOMYCIN-C(=O)-NH-3-FLUORO PHENYL, C 1 5 -AMPHOMYCN-(D-SER), C 1 5 -AMPH0MYCIN- (D 15 TYR), C 1 5 -AMPHOMYCIN-(D-TRP), C 1 3 -AMPHOMYCIN-9 GLU, C 15 -AMPHOMYCIN-9-(4-HYDR0XYBENZYL), C 15
-AM
PHOMYCIN-9-N,N-DI-(P-HYDROXYBENZYL), CIS-AMPHOMY CIN-9(N,N-DIMETHYLGLYCINE), CH 3 - (CH 2 ) 9 -S0 2
-GLY-AM
PHOMYCIN, CH 3 - (CH 2 ) 1 5 -30 2 -PHE-AMPHOMYCIN, CR 3 20 (CH 2 ) 1 3 -NH-C (=0)-AMPHOMYCIN-9-GLY-LYS, CH 3 - (CH 2
)
1 3 NH-C(=0)-AMPHOMYCIN-9-(3-ALA), CH 3 - (CH 2
)
1 3
-NH
C(=0)-AMPHOMYCIN-9-GLY, C 12 -PABA-AMPHOMYCTN-9-(B ALA), C 1 6 -(P-APA)-AMPHOMYCTN, C 8 -PABA-AMPHOMYCTN, Cl 0 -PABA-AMPHOMYCIN, Cll-PABA-AMPHOMYCIN, C 1 3
-PABA
25 AMPHOMYCIN, CH 3
(CH
2 ) l 0 -NH-C (=0) - (1-ALA) -AMPHOMY CIN, CH 3 - (CH 2 ) 1 5 -NH-C(=0) - (P- PHENYLACETYL) AMPHOMYCIN, CH 3 - (CH 2 ) 7 -NH-C(=O) - (P-PHENYLACETYL) AMPHOMYCIN, CH 3 - (CH 2 ) 1 3 -NH-C (=0) - (P-PHENYLACETYL) AMPHOMYCIN, CH 3 - (CH 2 ) l-NH-C (=) - (P-PHENYLACETYL) 30 AMPH-OMYCIN, CH 3 - (CH 2 ) 1 3 -NH-C (=0) -(GABA) AMPHOMYCIN, CH 3 - (CH 2 ) 1 3 -NH-C (=0) -(M-PHENYLACETYL) AMPHOMYCIN, Cl 0 -(M-AMINOBENZOYL)-AMPHOMYCIN, C 11 (M-AMINOBENZOYL)-AMPHOMYCIN, CH 3 - (CH 2 ) 1 3 -NH-C (=0) (1-ALA)-AMPHOMYCIN, C 12
-(M-AMINOBENZOYL)
35 AMPHOMYCIN, C 13 -(M-AMINOBENZOYL)-AMPHOMYCIN, BORONAT-PINACOL-ESTER-RESIN, 4' -OCTYL-BIPHENYL-4 CARBOXYL-AMPHOMYCIN, C 1 3 - (P-APA) AMPHOMYCIN, C14 (P-APA)-AMPHOMYCIN, CH 3 - (CH 2 ) 1 5 -NH-C (=0) -(M- PHENYLACETYL)-AMPHOMYCIN, C 14 -(M-APA)-AMPHOMYCIN,
C
13 -(P-APA)-AMPHOMYCIN, CH 3
-(CH
2 ) 1 0 o-NH-C(=O)-GABA AMPHOMYCIN, N,N'-DI-C 8
-(M,M-DIAMINOBENZOYL)
AMPHOMYCIN, CH 3
-(CH
2
)
7 -NH-C(=O) - (M-PHENYLACETYL) 5 AMPHOMYCIN, CH 3 -
(CH
2
)
1 3 -NH-C(=O)-GLY-AMPHOMYCIN, 1-DODECYL-1H-(1,2,3)-TRIAZOLE-4-CARBOXYLIC ACID, 1-DODECYL-1H-(1,2,3)-TRIAZOLE-4-CARBOXYL AMPHOMYCIN, C 1 5 -(M-APA)-AMPHOMYCIN, C 1 3
-(ASP
(OME))-AMPHOMYCIN, C 1 5 -(PAPA)-AMPHOMYCIN, C15 10 (ASP-(OME))-AMPHOMYCIN, Cii-(ASP(OTBU))-AMPHO MYCIN, C 13 -(ASP-(OTBU))-AMPHOMYCIN, Cil (ASP(OME))-AMPHOMYCIN, C 15 -ASP-(OME))-AMPHOMYCIN,
C
1 5 -AMPHOMYCIN-9-C(=O)-NH-(O-CF 3 -PHENYL), N,N'-DI
C
6 -(M,MDIAMINOBENZOYL)-AMPHOMYCIN, N,N'-DI-C 12 15 (M,MDIAMINOBENZOYL)-AMPHOMYCIN, CH 3 - ( CH 2 ) 7 -NH C(=O)-(8-ALA)-AMPHOMYCIN, (4-PHENYLBENZOYL)-AMPHO MYCIN, (2-PHENYLMETHYL)-BENZOYL-AMPHOMYCIN, N,N DIETHYL-PABA-AMPHOMYCIN, (3,4,5-TRIMETHOXYBEN ZOYL)-AMPHOMYCIN, (4-TBUTYLBENZOYL)-AMPHOMYCIN, 20 (3-(PHENOXY)-BENZOYL)-AMPHOMYCIN, C 15
-AMPHOMYCIN
9-(D-DAP), 8-ISOMER OF CH 3 - (CH 2
)
1 3
-NH-C(=O)-AMPHO
MYCIN, B-ISOMER OF CH 3
-(CH
2 ) 1 0 o-NH-C(=O) - (GABA)-AM PHOMYCIN, LYS-GLY-AMPHOMYCIN-9-C 1 5 , LYS-GLY-AMPHO MYCIN-9-C 1 3, (11-(PHENOXY)UNDECANOYL)-AMPHOMYCIN, 25 N-C 12 -((1S,4S)-4-AMINOCYCLOHEXYLCARBOXYLIC ACID),
C
1
-
2 -((IS,4S)-4-AMINOCYCLOHEXYLCARBOXYL)-AMPHOMY CIN, (2-DODECANOYLAMINO-THIAZOL-4-YL)-ACETIC ACID, (2-DODECANOYLAMINO-THIAZOL-4-YL) ACETYL-AMPHOMY CIN, 8-DODECYLOXY-QUINOLINE-2-CARBOXYLIC ACID, (8 30 DODECYLOXY-QUINOLINE-2-CARBONYL)-AMPHOMYCIN, 8 ISOMER OF (8-DODECYLOXY-QUINOLINE-2-CARBONYL)-AM PHOMYCIN, C 15 -AMPHOMYCIN-9-PHE, C 15 -AMPHOMYCIN-9
C
15 , C 15 -AMPHOMYCIN-9-([2-(2-METHOXY-ETHOXY)-ETH OXY]-ACETYL), Co 10 -SAR-AMPHOMYCIN, C 1 4
-SAR-AMPHOMY
35 CIN, C 8 -SAR-AMPHOMYCIN, C 1 5 -AMPHOMYCIN-9-C 1 2 , C 15 AMPHOMYCIN-9-(11-PHENOXYUNDE-CANOYL), C 15
-AMPHOMY
CIN-9-(3FURAN-2-YL-ACRYLOYL), C 15 -AMPHOMYCIN-9 (3(BENZENESULPHONYL)PROPIONOYL), C 15 -AMPHOMYCIN-9- (4-(PYREN-2-YL)BUTYROYL), C 15 -AMPHOMYCIN-9-SUC,
C
15 -AMPHOMYCIN-9-PRO-LYS, BOC-AMPHOMYCIN, AMPHOMY CIN-9-(3-ALA), AMPHOMYCIN-9-SAR, GLY-AMPHOMYCIN-9 FMOC, C6-GLY-AMPHOMYCIN-9-FMOC, C 8
-GLY-AMPHOMYCIN
5 9-FMOC, C 10 -GLY-AMPHOMYCIN-9-FMOC, C 8
-(M-APA)-AM
PHOMYCIN, CH 3
-(CH
2
)
1 0 -NH-C(=O) - (M-PHENYLACETYL) AMPHOMYCIN, 1-ADAMANTANE-(=O)-AMPHOMYCIN, (10 METHYL-UNDEC-2-ENOYL)-AMPHOMYCIN, (10-METHYL-DO DEC-2-ENOYL)-AMPHOMYCIN, (12-METHYL-TETRADEC-2 10 ENOYL)-ASPARTOCIN, (10-METHYL-DODEC-2-ENOYL)-AM PHOMYCIN-9-GLY, (10-METHYL-DODEC-2-ENOYL)-AMPHOMY CIN-9-SAR, (10-METHYL-DODEC-2-ENOYL)-AMPHOMYCIN 9(8-ALA), (12-METHYL-TETRADEC-2-ENOYL)-ASPARTOCIN 9-GLY, (12-METHYL-TETRADEC-2-ENOYL)-ASPARTOCIN-9 15 SAR, (12-METHYL-TETRADEC-2-ENOYL)-ASPARTOCIN-9-(8 ALA), (12-ACETYLAMINODODECANOYL)-AMPHOMYCIN, and (12-AMINODODECOYL)-AMPHOMYCIN". With regard to the structure, the terminology thereof and the synthe sis of such lipopeptides, reference is made to the 20 document US 2005/0153876 Al, "Compositions of Lipopeptide Antibiotic Derivatives and Methods of Use thereof" of Migenix Inc., Canada. The above are lipopeptides, which are covered by formula Ia, COOH 0 O COR N O 25 N N H O HN o RNm, R2-L- 0 COOK 0/ NH 0 HOOC NH 0 3 O H 0 0 NH I
I
Formula Ia wherein in formula Ia R3 may also be bound by a residue L, 5 wherein R1 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' is respectively independently from each other identical or 10 different, and a residue such as R3 or R5can be defined, and/or wherein L - when R3 is bound by a residue L is identical or different and respec tively independent from each other at least one amino acid, at least one substituted amino acid, 15 (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)-, wherein R' is respectively independently from each other identical or different and a residue such as R3 or 20 R5can be defined, wherein L for Dab9 is preferably - (CO)-, wherein 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), 25 S0 2 R5, -(SO)-R5, -(PO)(0R5)2, - (PO)(OR5) , COOH,
SO
3 H, -PO 3 H, -F, -Cl, -Br, -I, or trihalomethyl, wherein R3 is -H, -OR5, -SR5, -NR5R5, -CN, -NO 2 , N 3 , -(CO)-R5, -(CO)-O-R5, -(CO)-NR5R5, -(CS) NR5R5, -(CNR5)-NR5R5, -(CO)-H, -R5-(CO), -S0 2 R5 , 30 -(PO)(OR5) 2 , - (PO) (OR5) , - CO 2 H, - S0 3 H, -PO 3 H, -F, -Cl, -Br, -I, trihalomethyl, C1-C25 alkyl, substituted C1-C25 alkyl, Cl-C25 heteroalkyl, sub stituted 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 arylalkyl, substituted C6-C26 arylalkyl, 6 26-membered heteroarylalkyl, substituted 6-26-mem 5 bered heteroarylalkyl, at least one amino acid, or at least one substituted amino acid, wherein R4 is independently from each other iden tical or different C7-C10 alkyl, C17-C26 arylal kyl, 17-26-membered heteroarylalkyl, straight 10 chain or branched, saturated or singly or multiply unsaturated C7-C25 alkyl, optionally hydroxy-sub stituted, primary or secondary amine, at least one amino acid or at least one substituted amino acid, wherein RS is independently from each other iden 15 tical or different C1-C10 alkyl, C5-C10 aryl, 5 10-membered heteroaryl, C6-C26 arylalkyl, 6-26 membered heteroarylalykl, straight-chain or branched, saturated or singly or multiply unsatu rated C5-C25 alkyl, optionally hydroxy-substi 20 tuted, 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, P-alanine, GABA, 5 aminopentanoic acid, 6-aminohexanoic acid, gDAB, 25 Orn, Dap, hLys, sarcosine, lysine, glycine-lysine, or sarcosine-lysine. L may in particular be gly cine, sarcosine, phenylglycine, phenylalanine, o methylaspartic acid, o-t-butyl aspartic acid, p aminophenylacetyl, (p-aminophenylpropanoyl) n with 30 n = 1 or 2, m-aminophenylacetyl, (m aminophenyl propanoyl) 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 35 hydrazinobenzoic acid, o-hydrazinobenzoic acid, p amino-trans-cinnamyl, m-amino-trans-cinnamyl, o amino-trans-cinnamyl, p-aminophenylacetic acid, maminophenylacetic acid, L-BBTA, or any combination thereof. It is possible that the pharmaceutical compo sition includes several different lipopeptides in 5 a physiologically effective dose each. Then it is a combination preparation or a wide band prepara tion. In detail, the lipopeptide may be present in a free form or as an alkali or alkaline earth salt, 10 preferably as a Na or Ca salt, in particular as a di-Ca salt (Ca 2 Cl 2 salt), or as an ammonium salt. The lipopeptide is added in the pharmaceutical composition preferably in a total amount (referred to the amount of all employed lipopeptides) from 15 0.01 to 80 wt.%, in particular from 0.05 to 50 wt.%, preferably from 0.1 to 30 wt.%, wherein the amount figures are referred to the completed com position. In principle, all physiologically tolerated 20 cyclodextrins and cyclodextrin derivatives can be employed. Cyclodextrins are cyclic oligosaccha rides, which are composed of alpha-l,4-linked glu cose components. Usually, six to eight glucose components (a, 8, or y-cyclodextrin) are connected 25 with each other in a cyclodextrin molecule. Be sides the naturally occurring, unmodified cyclo dextrins, there is a large number of chemically modified cyclodextrin derivatives, which are physiologically tolerated and can be used for the 30 purpose of the invention. The cyclodextrin or cyclodextrin derivative preferably is an a or 1 cyclodextrin and may in particular have the gen eral formula II, OR1
CH
2 O 5 H H O H H OR3 n Formula II 10 wherein R1, R2, and R3 may be identical or differ ent and an arbitrary physiologically tolerated residue, preferably -H, C1-C8 alkyl, -SO 2 0H, PO(OH) 2 , or -CO-R4 with R4 = C1-C8 alkyl, wherein the Cl-C8 alkyl may be single or multiple at iden 15 tical or at different C atoms with -OH, -COOH, CONHR5, -NHCOR6, -S0 2 0H, -PO(OH) 2 , or tetrazol-5 yl with R5 = -H or Cl-C4 alkyl and R6 = carboxyl phenyl, wherein n = 6, 7 or 8, wherein RI, R2 and R3 may be randomized in different glucopyranose 20 units, wherein an oxygen atom or several oxygen atoms of the glucopyranose units, in particular the oxygen atom at C6, may be substituted by sul fur atoms, including physiologically tolerated salts of such cyclodextrins. Preferably, the glu 25 copyranose units are a-D or a-L-glucopyranose units. C1-C8 alkyl comprises in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl and ter tiary butyl. On average, 1 to 3, preferably 1 to 2 of the residues Rl, R2 and R3 may be different from H. Preferably, in particular R1 is different from -H. 1, 2, 3, 4, 5, 6, or if applicable 7 of the residues R1 of a cyclodextrin molecule may be different from -H. R2 and R3 may then be -H. In 5 addition, however, 1, 2, 3, 4, 5, 6, or if appli cable 7 of the residues R3 of a cyclodextrin mole cule may also be different from -H. In detail, the cyclodextrin or cyclodextrin derivative may be selected from the group consist 10 ing of "a-cyclodextrin, 3-cyclodextrin, hydroxy (C1-C8 alkyl)-c-cyclodextrin, hydroxy-(Cl-C8 al kyl)-8-cyclodextrin, (2-hydroxypropyl)-B-cyclodex trin, (2-hydroxypropyl)-a-cyclodextrin, sulfo-(C1 C8 alkyl)-ether-a-cyclodextrin, sulfo-(C1-C8 al 15 kyl)-ether-8-cyclodextrin, sulfobutylether-a-cy clodextrin, sulfobutylether-3-cyclodextrin". For the derivatives, in particular the residue at the oxygen atom of the C6 atom is different from -H. The cyclodextrin or cyclodextrin derivative 20 may be present in the pharmaceutical composition in an amount from 0.01 to 99 wt.%, in particular from 0.05 to 80 wt.%, preferably 0.1 to 50 wt.%, referred to the completed composition. Preferably, the lipopeptide in the pharmaceu 25 tical composition is mixed with the cyclodextrin or cyclodextrin derivative in a molar ratio lipo peptide/cyclodextrin from 100:1 to 1:500, prefera bly 10:1 to 1:50, most preferably 2:1 to 1:10, op tionally under addition of additional and/or aux 30 iliary substances in galenically common additions. Usually, the pharmaceutical composition will comprise further additional and/or auxiliary sub stances, in particular galenic auxiliary sub stances, the selection of which depends from the selected form of administration. The galenic preparation of the pharmaceutical composition ac cording to the invention may be made in a way be ing usual for this technology. As counter ions for 5 ionic compounds may for instance be used Ca++, CaCl+, Na+, K+, Li+ or cyclohexylammonium or Cl-, Br-, acetate, trifluoroacetate, propionate, lac tate, oxalate, malonate, maleinate, citrate, ben zoate, salicylate etc. Suitable solid or liquid 10 galenic forms of preparation are instance granu lates, powders, dragees, tablets, (micro) cap sules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions (IV, IP, IM, SC) or fine dispersions (aerosols), forms of 15 preparation for dry powder inhalation, transdermal systems, and preparations with protracted release of active ingredient, for the production of which usual means are used, such as carrier substances, explosives, binding, coating, swelling, sliding or 20 lubricating agents, tasting agents, sweeteners and solution mediators. As auxiliary substances are named here magnesium carbonate, titanium dioxide, lactose, mannite and other sugars, talcum, milk protein, gelatin, starch, cellulose and deriva 25 tives, 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 multi-valent alcohols, for instance glyc erin. A pharmaceutical composition according to 30 the invention can be produced by that at least one combination of substances used according to the invention is mixed in a defined dose with a phar maceutically suitable and physiologically well tolerated carrier and possibly further suitable 35 active, additional or auxiliary substances, and is prepared in the desired form of administration. Preferred are solutions for injection in the usual preparation.
As dilution agents, polyglycols, ethanol, wa ter and buffer solutions can be used. Suitable buffer solutions are for instance N,N'-diben zylethylendiamine, diethanolamine, ethylendiamine, 5 N-methylglucamine, N-benzylphenethylamine, di ethylamine, phosphate, sodium bicarbonate, or so dium carbonate. It is however also possible not to use any dilution agent at all. Physiologically tolerated salts, whether of 10 the lipopeptide, or of the cyclodextrins or cyclo dextrin derivatives, are salts with inorganic or organic acids, such as hydrochloric acid, sulfuric acid, acetic acid, citric acid, p-toluolsulfonic acid, or with inorganic or organic bases, such as 15 NaOH, KOH, Mg(OH) 2 , diethanolamine, ethylendia mine, or with amino acids, such as arginine, ly sine, glutamine acid etc. or with inorganic salts, such as CaC1 2 , NaCl or the free ions thereof, such 2-2 as Ca 2 , Nat, C1 , S04 - or combinations thereof. 20 They are also produced by using standard methods. In detail, a pharmaceutical composition ac cording to the invention may comprise: A) 0.01 to 80 wt.%, in particular 0.05 to 50 wt.%, preferably 0.1 to 30 wt.% lipopeptide, B) 0.01 to 99 wt.%, in 25 particular 0.05 to 80 wt.%, preferably 0.1 to 50 wt.% cyclodextrin or cyclodextrin derivative, C) 0.1 to 99.8 wt.%, in particular 1 to 80 wt.%, preferably 1 to 50 wt.% additional and/or auxil iary substances and optionally dilution agents, 30 wherein the components A) to C) also add up to 100 % and wherein the lipopeptide in a physiologically effective dose is mixed with the cyclodextrin or cyclodextrin derivative in a molar ratio lipopep tide/cyclodextrin from 1:500 to 10:1, preferably 35 1:100 to 10:1, most preferably 1:100 to 2:1, optionally under addition of additional and/or aux iliary substances in galenically usual additions. As far as above and below statements are made with regard to wt.%, molar ratios and/or doses, 5 they always refer to the so-called free acid of the lipopeptide, provided it is used in a salt form. Counter ions of salt forms are not taken into account, but are substituted by the atomic weight of hydrogen. Counter ions are rather used 10 as additional or auxiliary substances. The invention relates further to the use of a pharmaceutical composition according to the inven tion for the production of a drug for the treat ment and/or prophylaxis of viral, bacterial and/or 15 parasitary infectious diseases and/or of fungal diseases. Examples of such diseases or applica tions are: infections of the respiratory tract, infections of the skin and the soft parts, infec tions of the urinary tract, infections of the 20 gallbladder tract, sepsis, endocarditis, meningi tis, op prophylaxis, wound infections or intraab dominal infections. It is preferred that the drug is galenically prepared for the oral administration or for the 25 injection. The invention furthermore relates to a method for the treatment of a bacterial, viral or parasi tary infectious disease or a fungal disease, wherein a person, which has fallen ill with the 30 disease or is in danger of falling ill therewith, is administered a physiologically effective dose of a drug according to the invention. 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 lipopeptide over a period from 1 to 60 days, pref erably 1 to 30 days. Packing units with a multitude of administra tion units may be provided, wherein every admini 5 stration unit is prepared for an administration within the above treatment plan. For example, a packing unit may contain nl = 5 to n2 = 500 ad ministration units, wherein every administration unit contains ml = 1/5 to m2 = 1 daily dose of 10 lipopeptide. The packing unit is then prepared for a treatment plan, which provides 1 to 5 admini strations per day over a period of ol to o2 days, wherein o is then calculated by ol = nl * m2 and 02 = n2 * ml, or o and m are given and n is calcu 15 lated as n = o/m. In the following, the invention is explained in more detail by comparative examples and not limiting examples according to the invention. Example 1: Minimization of the friulimicin B-in 20 duced hemolysis by human serum albumin (HSA); comparative example. Na 2 friulimicin B was dissolved in a concen tration of 6,400 mg/l in 0.9 % NaCl solution with 20, 15, 10, 5, 1 or 0 % HSA. By dilution with 0.9 25 % NaCl and the respective HSA concentrations, fur ther stock solutions of 3,200, 1,600, 800, 200 and 100 mg/l Na 2 friulimicin were prepared for every one of the listed HSA concentrations. After pre incubation for 2 hours at ambient temperature, 40 30 pl of the friulimicin B/HSA mixture were mixed with 40 pl of fresh venal human blood and then in cubated at 37 oC for 180 min. As a negative con trol, mixtures of full blood were prepared with the different HSA concentrations in 0.9 % NaC1, as a standard for the complete hydrolysis a mixture von 40 pl of fresh venal human blood were prepared with 40 pl water. Subsequently, the degree of the 5 hemolysis induced by the incubation was determined as follows: The samples were cautiously mixed ei ther with water (standard) or with 1 ml 0.9 % NaCl. After centrifugation of the samples at 2,500 RFC (5 min), the absorption of the supernatant was 10 determined in the spectral photometer at 540 nm. Before the measurement of the samples, the spec tral photometer was calibrated with the respective negative control described above. For the determi nation of the degree of hemolysis of the different 15 reaction batches, the measured value of the stan dard with complete hemolysis was set to 100 %. The measured values of the different reaction batches were related to the value of this standard and given in percent. Table 1 shows the result of the 20 hemolysis test with Na 2 friulimicin B and differ ent HSA concentrations performed with human blood. The statements of the concentration of the HSA (in % wt./vol.) and of the Na 2 friulimicin B (in mg/l, free acid) refer to the final concentrations in 25 the reaction batch. Table 1 Hemolytic activity as a function of the Na 2 friulimicin B concentration (mg/l) in presence of different HSA concentrations in vitro (in %) 30 Friulimicin concentration in mg/l 0 100 200 800 1600 3200 Batch with 0 % HSA 0 4.6 5.2 6.5 11.8 13.6 Batch with 2.5 % HSA 0 0.7 2 2.7 3.2 3.9 Batch with 5 % HSA 0 0.1 1 1.9 1.7 1.7 35 Batch with 7.5 % HSA 0 0 0.4 1.6 1.5 1.3 Batch with 10 % HSA 0 0 0.3 0.5 0.8 0.3 HSA suppresses with a good efficiency the hemolysis induced by Na 2 friulimicin B beginning from a concentration of approx. 2.5 %. The follow ing determination of the content of free hemoglo 5 bin in the serum showed that after pre-incubation with 5 % - 10 % HSA (wt./vol., final concentration in the reaction batch) the friulimicin B-induced hemolysis could significantly be minimized. The determination of the antibiotic activity 10 of such Na 2 friulimicin B/HSA compositions in vi tro with Staphylococcus aureus and Enterococcus faecalis, measured according to the following ex amples according to the invention, showed however, as illustrated in Table 2, also a strong reduction 15 of the antibiotic activity. Table 2 Determination of the minimum inhibitory concentra tion (MIC) of Na 2 friulimicin in presence of HSA MIC value 20 Medium addition [pg/ml] S. aureus ATCC 29213 0 % HSA 2 S. aureus ATCC 29213 4 % HSA 8 E. faecalis ATCC 29212 0 % HSA 4 E. faecalis ATCC 29212 4 % HSA >64 25 Example 2: Minimization of the hemolysis induced by Na 2 by the addition of cyclodex trins. This example shows the effect of different modified or unmodified cyclodextrins on the hemo 30 lytic effect induced by lipopeptides. Herein, Na 2 friulimicin B serves as an example molecule for the antibiotics of the lipopeptides. Na 2 friulimicin B was dissolved in a concen tration of 3,200 mg/1 in 0.9 % NaCl solution. By 5 dilution with 0.9 % NaCI, further stock solutions of 1,600, 800, 200, 100 and 50 mg/1 Na 2 friuli micin were produced. 20 pl each of these stock so lutions were carefully mixed with 20 pl1 0.9 % NaCl or 2 % solutions of (2-Hydroxypropyl)-y-cyclodex 10 trin (HP-y-CD), (2-Hydroxypropyl)-B-cyclodextrin (HP-B-CD) or a-cyclodextrin (a-CD) in 0.9 % NaCl. The pre-incubation and test execution for the de termination of the hemolytic activity with fresh venal human blood was made according to Example 1. 15 Experiments at a final concentration of 0.5 % (wt./vol.) of the different cyclodextrins and the stated final concentrations of the Na 2 friulimicin B (in mg/l, free acid) provided the results shown in Table 3. 20 Table 3 Hemolytic activity as a function of the Na 2 friulimicin concentration in presence of different cyclodextrins in vitro (in %) Cyclodextrin conc. Friulimicin concentration in mg/l 25 0 50 100 200 800 1600 without cyclodextrin addition 0 2.3 5.1 5.9 8.3 9.4 0.5 % (wt./vol.) o-CD 0 0 0 0.1 0.4 1.2 0.5 % (wt./vol.) HP-f-CD 0 0 0.3 0.6 4.4 5.3 0.5 % (wt./vol.) HP-y-CD 0 2 4.8 5.8 6.6 8.6 30 The determination of the content of free hemo globin in the serum showed that after pre-incuba tion with 0.5 % HP-y-CD, there could not be found any significant reduction of the hemolysis induced by Na 2 friulimicin B. y-cyclodextrins have, due to their sugar structure, a larger volume in their hydrophobic inner pocket, compared to a and 8-cy clodextrins. Surprisingly, however, after the pre incubation with 0.5 % HP-3-CD and a-CD a signifi 5 cant reduction of the hemolysis induced by di-so dium friulimicin B could be detected. Example 3: Minimization of the Ca 2 C1 2 friulimicin B-induced hemolysis by the addition of modified 8-cyclodextrins. 10 This example shows the effect of 8-cyclodex trins on the hemolytic effect induced by lipopep tides in presence of high concentrations of the lipopeptide. Herein, Ca 2 C1 2 friulimicin B serves as an example molecule for the antibiotics of the 15 class of the lipopeptides and sulfobutylether-8 cyclodextrin (SBE-8-CD) as well as HP-3-CD as ex amples for modified 8-cyclodextrins. Ca 2 Cl 2 friulimicin B was dissolved in a concen tration of 100, 50, 40, 30, 20, 10 and 5 g/l in 20 20, 15, 12.5, 10, 7.5 % SBE-B3-CD in 0.9 % NaCl so lution or 12.5 % HP-8-CD in 0.9 % NaCl solution, respectively. The pre-incubation and test execu tion for the determination of the hemolytic activ ity with fresh venal human blood were made accord 25 ing to Example 1. Different therefrom, the incuba tion of the final reaction batches was performed with blood for 60 min at 37 oC. The results are shown in Table 4. Statements of the Ca 2 C1 2 friuli micin B (in mg/l, free acid) and of the cyclodex 30 trins refer to the final concentrations in the re action batch. Table 4 Hemolytic activity as a function of the Ca 2 Cl 2 friulimicin concentration in presence of different cyclodextrins in vitro (in %) Cyclodextrin conc. Friulimicin concentration in g/l 5 0 5 10 15 20 25 without cyclodextrin addition 0 76 87 91 93 97 7.5 % (wt./vol.) SBE-3-CD 0 0 1 3 18 63 10 % (wt./vol.) SBE-B-CD 0 0 1 3 13 42 12.5 % (wt./vol.) SBE-3-CD 0 0 0 1 4 12 10 15 % (wt./vol.) SBE-B-CD 0 0 0 1 1 4 Surprisingly, it could be found that HP-B-CD, in particular however also SBE-8-CD itself sup press at very high concentrations of the hemolyti cally very active Ca 2 C1 2 salt of friulimicin B the 15 hemolysis induced by the active agent. These re sults show that even with extreme active agent concentrations, which occur for a short time only immediately at injection or infusion positions, the hemolytic effect of Ca 2 C1 2 friulimicin B can 20 significantly be suppressed after pre-incubation with modified 8-cyclodextrins over a period of one hour. Example 4: Minimization of the daptomycin-induced hemolysis by the addition of modified 25 B-cyclodextrins. This example shows the effect of a sulfoal kylether cyclodextrin on the hemolytic effect in duced by the lipopeptide daptomycin with isolated erythrocytes in the presence of CaCl 2 . 30 Daptomycin was dissolved in a solution of 0 % or 2.5 % SBE-3-CD in 0.9 % NaC1, 2.5 mM CaCl 2 . For performing the hemolysis tests, erythrocytes from fresh venal human blood, which was collected in heparinized sample tubes, were isolated. For this purpose, the erythrocytes were sedimented by cen trifugation at 2,500 RFC (5 min). The erythrocytes 5 were washed three times with 0.9 % NaCl and after the final centrifugation received in a volume of 0.9 % NaCl, which corresponded to the initial vol ume of the blood sample. 40 pl of the erythrocytes were reacted with 40 pl of the above reaction 10 batches and incubated for 5 hours at 37 oC under continuous careful shaking. The further execution of the test for the determination of the hemolytic activity was made according to Example 1. The re sults are shown in Table 5. Statements of the con 15 centrations of SBE-3-CD (in % wt./vol.) and of the daptomycin (in mg/l, free acid) refer to the final concentrations in the reaction batch. Table 5 Hemolytic activity as a function of the daptomycin 20 concentration in presence of SBE-8-CD in vitro (in %) Cyclodextrin conc. Daptomycin conc. in (mg/l) 0 1,600 3,200 6,400 12,800 0% 0 1.7 6.5 7.6 7.8 25 1.25 % (wt./vol.) 0 0 0.1 0.1 0 SBE-3-CD SBE-3-CD suppressed also in the experiment with isolated erythrocytes the cell lysis induced by a lipopeptide, here daptomycin. This experiment 30 shows that SBE-8-CD can suppress toxic properties of very different lipopeptides. The hemolytic properties of the daptomycin are based on an imme diate interaction with the erythrocyte membrane. Similar mechanisms cause the toxic effect de 35 scribed for daptomycin on the skeletal muscle, so that a formulation of daptomycin or its deriva tives with cyclodextrins minimizes this toxic ef fect, too. Example 5: Effects of the additions of cyclodex 5 trins on the antibiotic activity of Ca 2 C1 2 friulimicin B. The effects of cyclodextrins on the antibiotic activity von Ca 2 Cl 2 friulimicin B were investi gated by in vitro experiments about the growth in 10 hibition of Gram-positive bacteria. Herein, the minimum inhibitory concentration for the growth inhibition was determined by cultivation of the bacteria on nutritious agar (agar dilution) ac cording to the CLSI (previously NCCLS) rules (Na 15 tional Committee for Clinical Laboratory Stan dards. 2003. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aero bically; approved standard - 6th ed. Document M7 A6. Clinical and Laboratory Standards Institute, 20 Wayne, PA, USA). Different molar mixture ratios of the lipopeptide Ca 2 Cl 2 friulimicin B were tested with SBE-8-CD in Ca ions-adjusted MUller-Hinton medium. The Gram-positive strains tested for the cultivation methods were: 25 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 employed quantities of cells per spot (in 30 tended value: 5*103 - 5*104 CFU) were: S. carnosus ATCC 51365 5.5 * 10 3 CFU S. aureus ATCC 29213 7.6 * 103 CFU S. aureus ATCC 33592 2.2 * 104 CFU S. epidermidis ATCC 12228 1.1 * 10 4 CFU Table 6 Antibiotic activity (MIC in pg/ml) of Ca 2 C12 5 friulimicin B as a function of the SBE-B-CD quan tity (given is the molar ratio of the quantities) in vitro Friulimicin : SBE-3-CD 1:0 1:2.5 1:4 10 S. carnosus ATCC51365 0.5 0.5 0.5 S. aureus ATCC29213 0.5 0.5 0.5 S. aureus ATCC33592 1 1 1 S. epidermidis ATCC12228 0.5 0.5 0.5 Surprisingly, the cyclodextrin does not nega 15 tively affect in these experiments the antibiotic activity of Ca 2 C1 2 friulimicin B, although by the molecular interaction of the cyclodextrins with friulimicin at the same molar ratios the hemolytic property of the lipopeptide can nearly completely 20 be suppressed. Example 6: Inhibition of the hemolytic activity of different lipopeptides by cyclodex trins. This example shows the effect of a sulfoal 25 kylether cyclodextrin on the hemolytic effect in duced by different lipopeptides. The lipopeptides were dissolved in a concentration von 6,400 mg/l in 0.9 % NaCl solution. By dilution with a volume 0.9 % NaCl or 0.9 % NaCl/10 % SBE-B-CD were re 30 spectively produced stock solutions of 3,200 mg/l lipopeptide (free acid) with or without 5 % SBE-B CD. The pre-incubation and the execution of the test for the determination of the hemolytic activ ity with fresh venal human blood were made accord ing to Example 1 and supplied the results shown in Table 7. There is shown the percentage inhibition 5 of the lipopeptide-induced hemolysis by the pres ence von 2.5 % SBE-8-CD at a lipopeptide concen tration of 1,600 mg/l. The tested lipopeptides are friulimicin derivatives and amphomycin deriva tives, the acyl residue of which was modified. All 10 lipopeptides have a structure according to formula I Y-X-Dab-Pip-MeAsp-Asp-Gly-Asp-Gly-Dab-Val-Pro ----------------------------------------------- I formula I 15 wherein the investigated lipopeptides are charac terized as follows: X Y Amphomycin Asp 10-methyldodec-3-ene acid Friulimicin B Asn 12-methyltridec-3-ene acid 20 CBS000201 Asn 12-methyltridecanoic acid CBS000205 Asn 15-phenyl-n-pentadecancarbonic acid CBS000203 Asn stearic acid CBS000204 Asn y-linolenic acid CBS000217 Asn 4-[2-(4-Phenethyl-phenyl)-ethyl] 25 benzoic acid and Y was linked by amidation with the extracircu lar Asn or Asp of the peptide. In detail, for the production of such lipopeptides is for instance made reference to the document EP 0 688 789 Al. 30 Table 7 Inhibition of the hemolytic activity of different lipopeptides at a concentration of 1,600 mg/l in presence of 2.5 % SBE-8-CD 5 Lipopeptide Reduction of the hemolysis in % Amphomycin 99.6 % Ca 2 Cl 2 friulimicin B 99.2 % CBS000201 95.7 % CBS000205 74.9 % 10 CBS000203 41.3 % CBS000204 87.0 % CBS000217 99.5 % These results show that cyclodextrins are sub stantially independently from the acyl and pepti 15 dyl residue of lipopeptides capable to reduce the hemolysis. Example 7: Production of a Ca 2 C1 2 friulimicin B injection solution. 100 mg Ca 2 Cl 2 friulimicin B and 770 mg SBE-8-CD 20 are dissolved in a sterile 0.9 % NaCl solution, filtrated through a polyethersulfone membrane (0.2 pm, non-pyrogenic) and lyophilized. The whole ly ophilisate is then dissolved in 10 ml water for injection solutions, filled into a sterile ampule. 25 Then the ampule is sealed with a septum. Example 8: Minimization of the hemolysis induced by Ca 2 C1 2 friulimicin B by the addition of different concentrations of sulfo butylether-8-cyclodextrin (SBE-B-CD).
This example shows the effect of different ra tios of cyclodextrins to lipopeptides on the hemo lytic effect induced by the lipopeptides. Herein, Ca 2 C1 2 friulimicin B serves as an example molecule 5 for the antibiotics of the class of the lipopep tides and sulfobutylether-3-cyclodextrin (SBE-3 CD) as an example molecule for the cyclodextrins. Ca 2 Cl 2 friulimicin B was dissolved in a concen tration of 2,500 mg/1l in 0.9 % NaCl solution. To 10 different batches of this 0.9 % NaCl solution were added different SBE-f-CD concentrations, so that the following molar ratios (SBE-8-CD : friulimicin B) were generated: 0:1; 1:10; 1:5; 1:1; 2.5:1; 5:1; 10:1. 15 The pre-incubation and the execution of the test for the determination of the hemolytic activ ity with fresh venal human blood were made accord ing to Example 1. In Table 8 is shown, which share of the hemolysis induced by 2,500 mg/l Ca 2 Cl 2 20 friulimicin B in absence of SBE-8-CD is reduced by the addition of SBE-8-CD in the mentioned molar ratios. Statements of the content of Ca 2 C1 2 friulimicin B (in mg/1) refer to the final concentrations of 25 the free acid of the friulimicin B in the reaction batch. The statements of the molar ratios respec tively refer to the free acids of friulimicin B and SBE-8-CD. Table 8 30 Reduction of the hemolysis induced by 2,500 mg/l Ca 2 C1 2 friulimicin B by SBE-8-CD in vitro (in %) Molar ratio Reduction of the SBE-8-CD : friulimicin B induced hemolysis 0 : 1 0 % 1 : 10 11 % 1 : 5 28 % 5 1 : 1 80 % 2.5 : 1 96 % 5 : 1 98 % 10 : 1 100 % Surprisingly it could be found that SBE-8-CD 10 suppressed already in substoechiometric concentra tions the hemolysis induced by Ca 2 C1 2 friulimicin B even at a friulimicin B concentration of 2,500 mg/l during an incubation duration of 3 hours. Example 9: Effect of cyclodextrins on the hemo 15 lytic activity of a cyclic peptide. This example concerns the inhibition of the hemolytic activity of different lipopeptides by cyclodextrins and shows the effect of a sulfoal kylether cyclodextrin on the hemolytic effect in 20 duced by the cyclic peptide tyrocidin. Tyrocidin was dissolved in a concentration of 6,400 mg/l in 0.9 % NaCl solution. By dilution with a volume of 0.9 % NaCl or 0.9 % NaCl/10 % SBE-B-CD, stock so lutions of 3,200 mg/l tyrocidin with or without 5 25 % SBE-B-CD, respectively, were prepared. The pre incubation the execution of the test for the de termination of the hemolytic activity with fresh venal human blood were made according to Example 1. The evaluation of this experiment showed that 30 the hemolysis induced by 1,600 mg/l tyrocidin in presence of 2.5 % SBE-B-CD is increased by 178 %. The addition of cyclodextrins thus does not sup press for every hemolytically acting substance the lysis of the erythrocytes.
Example 10: Minimization of the hemolysis induced by Ca 2 Cl 2 friulimicin B with canine blood by sulfobutylether-8-cyclodex trin (SBE-8-CD). 5 This example shows the effect of 3-cyclodex trins on the lipopeptide-induced hemolytic effect with blood of different organisms. Herein, Ca 2 C12 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopeptides 10 and sulfobutylether-3-cyclodextrin (SBE-8-CD) as examples for modified 8-cyclodextrins. The experi ments were made with canine blood. Ca 2 C1 2 friulimicin B was dissolved in 0.9 % NaCl solution with and without addition of SBE-8 15 CD. In the batch with SBE-B-CD there was a molar ratio (SBE-f-CD : friulimicin B) of 2,5 : 1. The pre-incubation and the execution of the test for the determination of the hemolytic activity with venal canine blood were made according to Example 20 1. The results are shown in Table 9. Statements of the content of Ca 2 Cl 2 friulimicin B (in mg/l) re fer to the final concentrations of the free acid of the friulimicin B in the reaction batch. The statements of the molar ratio refer to the free 25 acids of friulimicin B and SBE-5-CD, respectively. Table 9 Reduction of the hemolysis induced by Ca 2 Cl 2 friulimicin B by SBE-3-CD in vitro with canine blood (in %) 30 Friulimicin B Reduction of the hemolysis by the concentration addition of SBE-8-CD 800 55 % 5,000 100 % The example shows that SBE-3-CD in a molar ra tio of 2.5 : 1 (SBE-3-CD : friulimicin B) sup presses the lysis induced by Ca 2 Cl 2 friulimicin B of erythrocytes in canine blood. 5 Example 11: Minimization of the hemolysis induced by Ca 2 C1 2 friulimicin B with blood of macaques (Macaca fascicularis) by sul fobutylether-8-cyclodextrin (SBE-8 CD). 10 This example shows the effect of B-cyclodex trins on the hemolytic effect induced by lipopep tides with the blood of different organisms. Herein, Ca 2 C1 2 friulimicin B serves as an example molecule for the antibiotics of the class of the 15 lipopeptides and sulfobutylether-8-cyclodextrin (SBE-B-CD) as an example for cyclodextrins. The experiments were made with the blood of macaques. Ca 2 C1 2 friulimicin B was dissolved in 0.9 % NaCl solution with and without addition of SBE-8 20 CD. In the batch with SBE-8-CD, there was a molar ratio (SBE-8-CD : friulimicin B) of 5 : 1. The pre-incubation and the execution of the test for the determination of the hemolytic activity with venal macaque blood were made according to Example 25 1. Statements of the content of Ca 2 C1 2 friulimicin B (in mg/l) refer to the final concentrations of the free acid of the friulimicin B in the reaction batch. The statements of the molar ratio refer to the free acids of friulimicin B and SBE-8-CD, re 30 spectively. Table 10 Reduction of the hemolysis induced by Ca 2 C1 2 friulimicin B by SBE-B-CD in vitro with blood of macaques (in %) Friulimicin B Reduction of the hemolysis by the 5 concentration addition of SBE-B-CD 3,200 92 % 6,400 99 % The example shows that SBE-B-CD in a molar ra tio of 5 : 1 (SBE-B-CD : friulimicin B) suppresses 10 the lysis induced by Ca 2 C1 2 friulimicin B of erythrocytes in the blood of macaques. Example 12: Influence of the antibiotic activity of lipopeptides by cyclodextrins in vivo. 15 This example shows the effect of 3-cyclodex trins on the antibiotic activity of lipopeptides in vivo. Herein, Ca 2 C1 2 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopeptides and sulfobutylether-8-cyclo 20 dextrin (SBE-8-CD) as examples for modified f cyclodextrins. Shown are the results of a study with an intranasal lung infection model in the mouse. Ca 2 C1 2 friulimicin B was dissolved in 0.9 % 25 NaCl solution with and without addition of SBE-3 CD. In the batch with SBE-8-CD , there was a molar ratio (SBE-f3-CD : friulimicin B) of 2,5 : 1. The statements of the Ca 2 C1 2 friulimicin B concentra tion (in mg/l) refer to the final concentrations 30 of the free acid of the friulimicin B in the reac tion batch. The statements of the molar ratios refer to the free acids of friulimicin B and SBE-B3 CD, respectively. Female mice (CFW-1 (Harlan Winkelmann, Ger many)) were infected intranasally with Streptococ 5 cus pneumoniae L3TV (1*10 CFU/mouse). 1 and 4 hours after the infection, the animals were subcu taneously administered a total dose of 20 mg Ca 2 C1 2 friulimicin B / kg with and without SBE-3 CD (5 %). 24 hours after the infection, a determi 10 nation of the number of germs in the lung was per formed by plating-out of a tissue disintegration on agar plates in a manner the man skilled in the art is familiar with. The evaluation of this study showed that surprisingly SBE-8-CD increases the 15 antibiotic effect of Ca 2 Cl1 2 friulimicin B (Mann Whitney Test p = 0.0159). Example 13: Influence of the acute toxicity of lipopeptides by cyclodextrins in vivo. This example shows the effect of 3-cyclodex 20 trins on the acute toxic effects in mice caused by high concentrations of lipopeptides. Herein, Ca 2 C1 2 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopep tides and sulfobutylether-3-cyclodextrin (SBE-3 25 CD) as examples for modified [-cyclodextrins. Ca 2 C1 2 friulimicin B was dissolved in 0.9 % NaCl solution with and without addition of SBE-3 CD. In the batch with SBE-13-CD, there was a molar ratio (SBE-B-CD : friulimicin B) of 2.5 : 1. The 30 statements of the Ca 2 Cl 2 friulimicin B concentra tion (in mg/l) refer to the final concentrations of the free acid of the friulimicin B in the reac tion batch. The statements of the molar ratio refer to the free acids of friulimicin B and SBE-5 CD, respectively. Female mice (CFW-1 (Harlan Winkelmann, Ger many)) were administered once (iv) the Ca 2 C1 2 5 friulimicin B solutions with and without SBE-8-CD. The mortality rate of the animals within 24 hours was determined. It is shown in Table 11. Table 11 Mortality rate of mice after one-time iv admini 10 stration of Ca 2 C1 2 friulimicin B with and without SBE-8-CD (in %) Friulimicin B Friulimicin B with addition without addition Mortality rate of SBE-3-CD of SBE-8-CD within 24 hours 15 300 mg/kg 0 % (0/3) 350 mg/kg 66 % (2/3) 400 mg/kg 100 % (3/3) 300 mg/kg 0 % (0/3) 400 mg/kg 0 % (0/3) 20 The example shows that the acute toxicity of Ca 2 Cl 2 friulimicin B by the presence of SBE-3-CD in a molar ratio of 2,5 : 1 (SBE-B-CD : friuli micin B) is reduced.

Claims (18)

1. A pharmaceutical composition comprising as an active agent a lipopeptide in a physiologically effective dose as well as a cyclodextrin or a 5 cyclodextrin derivative.
2. The 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-Pro 10 formula I wherein X = one of the amino acids Asn or Asp, wherein Y = a straight-chain or branched, satu rated or unsaturated aliphatic acyl residue with 6 15 to 22 carbon atoms, which optionally is inter rupted by one or several phenyl or cycloalkyl groups or connected with such groups or inter rupted by one or several oxygen atoms, or a physiologically tolerated salt of such a compound. 20
3. The pharmaceutical composition according to claim 1 or 2, wherein the lipopeptide is selected from the group comprising "amphomycin and amphomy cin derivatives"
4. The pharmaceutical composition according to 25 one of claims 1 to 3, wherein the lipopeptide is selected from the group comprising "amphomycin, amphomycin derivatives, friulimicin, friulimicin B, friulimicin derivatives, daptomycin, daptomycin derivatives, aspartocin, aspartocin derivatives, glumamycin, glumamycin derivatives, crystallomy 5 cin, crystallomycin derivatives, zaomycin, zaomy cin derivatives, tsushimycin, tsushimyin deriva tives, laspartomycin, laspartomycin derivatives, brevistin, brevistin derivatives, cerexin B, cer exin B derivatives, syringomycin and its deriva 10 tives, antibiotic A-30912 and its derivatives, an tibiotic A-54145 and its derivatives and antibi otic A-21978C and its derivatives".
5. The pharmaceutical composition according to one of claims 1 to 4, comprising several different 15 lipopeptides in a physiologically effective dose each.
6. The pharmaceutical composition according to one of claims 1 to 5, wherein the lipopeptide is present as an alkali or alkaline earth salt, pref 20 erably as a Na or calcium salt, in particular as a di-calcium salt (Ca 2 Cl 2 salt), or as an ammonium salt, or wherein the lipopeptide is neutral, or wherein the lipopeptide is present as a cationic part of a salt, wherein in the last alternative as 25 a counter ion preferably an ion from the group comprising "hydrochloride, sulfonate, nitrate, phosphate, succinate, maleate, citrate, tartrate, lactate, gluconate and sulfonate" can be employed.
7. The pharmaceutical composition according to 30 one of claims 1 to 6, comprising the lipopeptide in a total quantity from 0.001 to 20 wt.%, in par- ticular from 0.05 to 20 wt.%, preferably from 0.1 to 5 wt.%.
8. The pharmaceutical composition according to one of claims 1 to 7, wherein the cyclodextrin or 5 cyclodextrin derivative is an a or P-cyclodextrin and preferably has the general formula II F ~OR1 CH 2 O H H 10 Lo R2 H 0 O H O L H OR 3 n Formula II 15 wherein Rl, R2, and R3 may be identical or differ ent and an arbitrary physiologically tolerated residue, preferably -H, C1-C8 alkyl, -SO 2 OH, PO(OH) 2 , or -CO-R4 with R4 = C1-C8 alkyl, wherein the Cl-C8 alkyl may be single or multiple at iden 20 tical or at different C atoms with -OH, -COOH, CONHR5, -NHCOR6, -S0 2 OH, -PO(OH) 2 , or tetrazol-5 yl with R5 = -H or Cl-C4 alkyl and R6 = carboxyl phenyl, wherein n = 6 or 7 25 wherein RI, R2 and R3 may be randomized in differ ent glucopyranose units, wherein an oxygen atom or several oxygen atoms of the glucopyranose units, in particular the oxygen atom at C6, may be substituted by sulfur atoms, including physiologically tolerated salts of such 5 cyclodextrins.
9. The pharmaceutical composition according to one of claims 1 to 8, wherein the cyclodextrin or cyclodextrin derivative is selected from the group comprising "a-cyclodextrin, 6-cyclodextrin, hy 10 droxy-(Cl-C8 alkyl)-a-cyclodextrin, hydroxy-(Cl-C8 alkyl)-8-cyclodextrin, (2-hydroxypropyl)-3-cyclo dextrin, (2-hydroxypropyl)-c-cyclodextrin, sulfo (Cl-C8 alkyl)-ether-a-cyclodextrin, sulfo-(Cl-C8 alkyl)-ether-B-cyclodextrin, sulfobutylether-c 15 cyclodextrin, sulfobutylether-8-cyclodextrin"
10. The pharmaceutical composition according to one of claims 1 to 9, comprising the cyclodextrin or cyclodextrin derivative in a quantity from 0.001 to 50 wt.%, in particular from 0.01 to 30 20 wt.%, preferably 0.1 to 20 wt.%.
11. The pharmaceutical composition according to one of claims 1 to 9, comprising further addi tional and/or auxiliary substances, in particular galenic auxiliary substances. 25
12. The pharmaceutical composition according to claim 11, comprising A) 0.001 to 20 wt.%, in particular 0.05 to 20 wt.%, preferably 0.1 to 5 wt.% lipopeptide, B) 0.001 to 79.9 wt.%, in particular 0.01 to 30 wt.%, preferably 0.1 to 20 wt.% cyclodextrin or cyclodextrin derivative, C) 0.1 to 99.998 wt.%, in particular 50 to 99.98 5 wt.%, preferably 95 to 99.98 wt.% additional and/or auxiliary substances and optionally dilu tion agents, wherein the components A) to C) always add up to 100 %. 10
13. The use of a pharmaceutical composition ac cording to one of claims 1 to 12 for the produc tion of a drug for the treatment and/or prophy laxis of viral and/or bacterial and/or parasitary infectious diseases and/or of fungal diseases. 15
14. The use according to claim 13, wherein the drug is galenically prepared for the oral admini stration or for the injection by mixture with galenic auxiliary and carrier substances.
15. A method for the treatment of a bacterial, vi 20 ral or parasitary infectious disease and/or a fun gal disease, wherein a person, which has fallen ill with the disease or is in danger of falling ill therewith, is administered a physiologically effective dose of a drug according to one of 25 claims 1 to 12.
16. The method according to claim 15, wherein the person is administered a daily dose from 1 to 50,000 mg, preferably 50 to 30,000 mg, most pref- erably from 100 to 20,000 mg lipopeptide over a period from 1 to 60 days, preferably 1 to 30 days.
17. A packing unit with a multitude of administra tion units, wherein each administration unit is 5 prepared for the administration within a treatment plan according to one of claims 15 or 16.
18. The method for the production of a pharmaceu tical composition according to one of claims 1 to 12, wherein the lipopeptide in a physiologically 10 effective dose is mixed with the cyclodextrin or cyclodextrin derivative in a molar ratio lipopep tide/cyclodextrin from 100:1 to 1:500, preferably 10:1 to 1:50, most preferably 2:1 to 1:10, option ally under addition of additional and/or auxiliary 15 substances in galenically usual additions.
AU2006314942A 2005-11-21 2006-11-20 Lipopeptide compositions Abandoned AU2006314942A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102005056194.2 2005-11-21
DE102005056194A DE102005056194A1 (en) 2005-11-21 2005-11-21 New lipopeptide compositions
PCT/DE2006/002064 WO2007057005A1 (en) 2005-11-21 2006-11-20 Lipopeptide compositions

Publications (1)

Publication Number Publication Date
AU2006314942A1 true AU2006314942A1 (en) 2007-05-24

Family

ID=37763891

Family Applications (1)

Application Number Title Priority Date Filing Date
AU2006314942A Abandoned AU2006314942A1 (en) 2005-11-21 2006-11-20 Lipopeptide compositions

Country Status (7)

Country Link
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 (2)

* Cited by examiner, † Cited by third party
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

Family Cites Families (6)

* Cited by examiner, † Cited by third party
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.
DE19807972A1 (en) * 1998-02-25 1999-08-26 Hoechst Marion Roussel De Gmbh New stable, water soluble calcium salts of cyclic lipopeptide antibiotics, useful as antibacterial agents
CA2726789A1 (en) * 2000-02-05 2001-11-08 Theravance, Inc. Cyclodextrin containing glycopeptide antibiotic compositions
US7527807B2 (en) * 2000-06-21 2009-05-05 Cubist Pharmaceuticals, Inc. Compositions and methods for increasing the oral absorption of antimicrobials
JP4969013B2 (en) * 2000-06-21 2012-07-04 キュービスト ファーマスーティカルズ インコーポレイテッド Compositions and methods for improving oral absorption of antimicrobial agents
US6699505B2 (en) * 2000-10-17 2004-03-02 Massachusetts Institute Of Technology Method of increasing the efficacy of antibiotics by compexing with cyclodextrins

Also Published As

Publication number Publication date
MX2008006476A (en) 2008-09-26
EP1951311A1 (en) 2008-08-06
WO2007057005A1 (en) 2007-05-24
DE102005056194A1 (en) 2007-07-12
CA2630497A1 (en) 2007-05-24
CN101370524A (en) 2009-02-18

Similar Documents

Publication Publication Date Title
CN1033738C (en) Stable pharmaceutical preparation containing granulocyte colony stimulating factor and process for producing same
CA2532475C (en) Formulation for a protein pharmaceutical without added human serum albumin (hsa)
EP1372735B1 (en) Conjugate of hydroxyalkyl starch and an active agent
EP0091782A2 (en) Inclusion compound of Lankacidin-group antibiotic and use thereof
de Belder Dextran
RU94006023A (en) Physiologically active composition on the base of lyophilized, modified by polyalkylene oxide complexes of protein and peptide with cyclodextrin and method for its production
JPH07509719A (en) Human growth hormone aqueous preparation
EP0175667B1 (en) Macrophage-activating composition and a process for its manufacture
US7795207B2 (en) Lipopeptide compositions
JP3100058B2 (en) Stable pharmaceutical composition containing fibroblast growth factor
AU2006314942A1 (en) Lipopeptide compositions
JP4571829B2 (en) Anti-Chlamydia composition
DE3942141A1 (en) K2P PRO STABILIZATION
DE60022759T2 (en) ERYTHROPOIETIN FORMULATIONS OF THE MULTI-DOSE TYPE
Zunino et al. Steric influence of the orientation of the primary amino group at position 3 of the sugar moiety of anthracycline antibiotics in DNA binding properties
WO1999043357A1 (en) Indolicidin and cationic peptides conjugated with polymers
CN112755175A (en) Antibacterial peptide liquid composition and preparation thereof
Nakano et al. Biological characterization of Pseudomonas aeruginosa endotoxin released by antibiotic treatment in vitro
JPH0253799A (en) Novel peptide and antimicrobial agent
EP1994938A1 (en) New lipoglycodepsipeptide compositions
JP2002542201A (en) Pseudomycin antifungal compositions and methods of use
HU218103B (en) Pharmaceutical composition containing non-glycosylated recombinant human interleukin-2 and process for producing it
RU2391354C1 (en) Complex of biologically active recombinant protein with polysialic acid
JPH02152987A (en) Novel peptide and antibacterial agent
JPH0657662B2 (en) Pharmaceutical preparations and medicinal products of non-glycosylated t-PA derivative K1K2Ppro and methods for producing the same

Legal Events

Date Code Title Description
MK1 Application lapsed section 142(2)(a) - no request for examination in relevant period