CA2630497A1 - Lipopeptide compositions - Google Patents
Lipopeptide compositions Download PDFInfo
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- CA2630497A1 CA2630497A1 CA002630497A CA2630497A CA2630497A1 CA 2630497 A1 CA2630497 A1 CA 2630497A1 CA 002630497 A CA002630497 A CA 002630497A CA 2630497 A CA2630497 A CA 2630497A CA 2630497 A1 CA2630497 A1 CA 2630497A1
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- Prior art keywords
- amphomycin
- cyclodextrin
- derivatives
- friulimicin
- lipopeptide
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- 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
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- 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
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- 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
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- 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
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- Engineering & Computer Science (AREA)
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- 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)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Organic Chemistry (AREA)
- Nanotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Biotechnology (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a pharmaceutical composition comprising as active ingredient a lipopeptide in physiologically effective dose, and a cyclodextrin or a cyclodextrin derivative.
Description
New lipopeptide compositions.
Field of the invention.
The invention relates to new pharmaceutical compositions containing lipopeptides, to the use 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, 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 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 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.
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 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 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 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-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-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-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(l):51-6.
Further aspects on the hemolytic activity of the 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-nation of the toxicological properties without im-pairing the antibiotic activity of the substances.
Field of the invention.
The invention relates to new pharmaceutical compositions containing lipopeptides, to the use 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, 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 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 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.
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 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 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 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-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-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-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(l):51-6.
Further aspects on the hemolytic activity of the 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-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 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, 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 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 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-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 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, Uekama K.) are obtained.
1990 Apr 25; (1):11-9). This masking effect with the serum albumin causes however in many cases 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 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-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 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, 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-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 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-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.
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 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-cording to formula I, Y-X-Dab-Pip-MeAsp-Asp-Gly-Asp-Gly-Dab-Val-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-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 amphomycin or an amphomycin derivative. Y may in particular be:
( CH3 ) 2CH ( CH2 ) 7CH=CHCH2C0-, CH3 ( CH2 ) 6C0-, CH3 ( CH2 ) 7CO-, CH3 ( CH2 ) 8C0-, CH3 ( CH2 ) 9C0-, CH3 ( CH2 ) ioCO- ~ CH3 ( CH2 ) 11C0-, CH3 ( CH2 ) 12C0- , CH3 ( CH2 ) 13C0-, CH3 ( CH2 ) 14C0-, CH3 ( CH2 ) 15C0-, CH3CH (CH3 )( CH2 ) 8C0-, CH3CH ( CH3 )( CH2 ) 9C0-, CH3CH ( CH3 ) ( CH2 ) 1 0 C 0 - , CH3CH (CH3 )( CH2 ) 11C0-, CH3CH ( CH3 )( CH2 ) 12C0-, H2C=CH (CH2 ) gC0-, H2C=CH(CH2)9C0-, CH3(CH2)7CH=CHCO- (trans), CH3 ( CH2 ) 8CH=CHCO- ( trans ), CH3 ( CH2 ) 12CH=CHCO-(trans), CH3(CH2)3CH=CH(CH2)7CO- (cis CH3 ( CH2 ) 3CH=CH ( CH2 ) 7CO- ( t rans ), CH3 ( CH2 ) 3CH=CH ( CH2 ) 8C0- ( t rans ), CH3 ( CH2 ) 5CH=CH ( CH2 ) 7CO- ( ci s), CH3 ( CH2 ) 5CH=CH ( CH2 ) 7C0- ( t rans ), CH3 ( CH2 ) 5CH=CH ( CHz ) 8C0- ( ci s), CH3 (CH2) loCH=CH (CH2) 4C0- (cis) , CH3 ( CH2 ) 10CH=CH ( CH2 ) 4C0- ( t rans ), CH3(CH2)7CH=CH(CH2)7CO- (cis), CH3(CH2)7CH=CH(CH2)7CO- (trans), CH3 ( CH2 ) 5CH=CH ( CH2 ) 9C0- ( t rans ), CH3(CH2)3(CH2CH=CH)2(CH2)7CO- (cis), CH3(CH2)3(CH2CH=CH)2(CH2)2CO- (trans), CH3 (CH2 ) 3 ( CH2CH=CH ) 2 ( CH2 ) 9C0- ( ci s), CH3 ( CH2CH=CH ) 3( CH2 ) 7CO- ( ci s), CH3(CH2)3(CH2CH=CH)3(CH2)4C0- (cis), CH3(CH2CH=CH)4(CH2)4C0- (cis), CH3(CH2)3(CH2CH=CH)4(CH2)3C0- (cis), CH3(CH2CH=CH)6(CH2)2CO- (cis), H2C=CH(CH3)8C0-, CH3(CH2)3CH=CH(CH2)7CO-, CH3(CH2)7CH=CH(CH2)7CO-, CH3 (CH2) 4CH=CH-CH=CH- (CH2) 8C0-, (CH3)2C=CHCH2[CH2C(CH3)=CHCH2]2C0-, Phe-Phe-CH2C0-, Phe- ( CH2 ) 9C0-, Phe-0- (CH2 ) 10C0-, CH3 ( CH2 ) 7-Phe-CO-, Phe-Phe-CO-, CH3(CH2)6-Phe-CO-, CH3(CH2)6-0-Phe-C0, CH3(CH2)7-0-Phe-CO-, Phe-(CH2)2-Phe-CO-, CH3CH2-Phe-(CH2)2-Phe-CO-, Phe-Phe-(CH2)z-Phe-CO-, Phe-(CH2)2-Phe-(CH2)2-Phe-CO-, CH3(CH2 )3-Phe-(CH2)2-Phe-CO-, CH3(CH2)5-0-Phe-(CH2)2-Phe-CO-, (CH3) 2CH
( CHz ) 6CH=CHCH2C0- ( ci s), (CH3 ) 2CH ( CH2 ) 6CH=CHCH2C0-(trans), (CH3)2CH(CH2)7CH=CHCH2C0- (cis), (CH3)2CH(CHZ)7CH=CHCH2C0- (trans), CH3CH2 ( CHCH3 ) ( CHz ) 5CH=CHCH2CO- ( cis CH3CH2(CHCH3)(CH2)5CH=CHCH2CO- (trans CH3CH2(CHCH3)(CH2hCH=CHCH2C0- (cis), CH3CH2(CHCH3)(CH2)7CH=CHCH2C0- (trans CH3CH2 ( CHCH3 ) ( CH2 ) 7CH=CHCH2C0- ( ci s CH3(CH2)8CH=CHCO-(cis), CH3(CH2)8CH=CHCO- (trans), CH3 ( CH2 ) 9CH=CHCO- ( ci s ) , CH3 ( CH2 ) 8CH=CHCO- ( t rans ), CH3 (CH2) 7CH=CHCO- (cis), CH3 (CH2) 7CH=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.
For producing such lipopeptides in detail, reference is made for instance to the documents DE
It is therefore the technical object of the invention to provide new pharmaceutical composi-tions with antibacterially, antivirally and/or an-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 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-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.
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 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-cording to formula I, Y-X-Dab-Pip-MeAsp-Asp-Gly-Asp-Gly-Dab-Val-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-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 amphomycin or an amphomycin derivative. Y may in particular be:
( CH3 ) 2CH ( CH2 ) 7CH=CHCH2C0-, CH3 ( CH2 ) 6C0-, CH3 ( CH2 ) 7CO-, CH3 ( CH2 ) 8C0-, CH3 ( CH2 ) 9C0-, CH3 ( CH2 ) ioCO- ~ CH3 ( CH2 ) 11C0-, CH3 ( CH2 ) 12C0- , CH3 ( CH2 ) 13C0-, CH3 ( CH2 ) 14C0-, CH3 ( CH2 ) 15C0-, CH3CH (CH3 )( CH2 ) 8C0-, CH3CH ( CH3 )( CH2 ) 9C0-, CH3CH ( CH3 ) ( CH2 ) 1 0 C 0 - , CH3CH (CH3 )( CH2 ) 11C0-, CH3CH ( CH3 )( CH2 ) 12C0-, H2C=CH (CH2 ) gC0-, H2C=CH(CH2)9C0-, CH3(CH2)7CH=CHCO- (trans), CH3 ( CH2 ) 8CH=CHCO- ( trans ), CH3 ( CH2 ) 12CH=CHCO-(trans), CH3(CH2)3CH=CH(CH2)7CO- (cis CH3 ( CH2 ) 3CH=CH ( CH2 ) 7CO- ( t rans ), CH3 ( CH2 ) 3CH=CH ( CH2 ) 8C0- ( t rans ), CH3 ( CH2 ) 5CH=CH ( CH2 ) 7CO- ( ci s), CH3 ( CH2 ) 5CH=CH ( CH2 ) 7C0- ( t rans ), CH3 ( CH2 ) 5CH=CH ( CHz ) 8C0- ( ci s), CH3 (CH2) loCH=CH (CH2) 4C0- (cis) , CH3 ( CH2 ) 10CH=CH ( CH2 ) 4C0- ( t rans ), CH3(CH2)7CH=CH(CH2)7CO- (cis), CH3(CH2)7CH=CH(CH2)7CO- (trans), CH3 ( CH2 ) 5CH=CH ( CH2 ) 9C0- ( t rans ), CH3(CH2)3(CH2CH=CH)2(CH2)7CO- (cis), CH3(CH2)3(CH2CH=CH)2(CH2)2CO- (trans), CH3 (CH2 ) 3 ( CH2CH=CH ) 2 ( CH2 ) 9C0- ( ci s), CH3 ( CH2CH=CH ) 3( CH2 ) 7CO- ( ci s), CH3(CH2)3(CH2CH=CH)3(CH2)4C0- (cis), CH3(CH2CH=CH)4(CH2)4C0- (cis), CH3(CH2)3(CH2CH=CH)4(CH2)3C0- (cis), CH3(CH2CH=CH)6(CH2)2CO- (cis), H2C=CH(CH3)8C0-, CH3(CH2)3CH=CH(CH2)7CO-, CH3(CH2)7CH=CH(CH2)7CO-, CH3 (CH2) 4CH=CH-CH=CH- (CH2) 8C0-, (CH3)2C=CHCH2[CH2C(CH3)=CHCH2]2C0-, Phe-Phe-CH2C0-, Phe- ( CH2 ) 9C0-, Phe-0- (CH2 ) 10C0-, CH3 ( CH2 ) 7-Phe-CO-, Phe-Phe-CO-, CH3(CH2)6-Phe-CO-, CH3(CH2)6-0-Phe-C0, CH3(CH2)7-0-Phe-CO-, Phe-(CH2)2-Phe-CO-, CH3CH2-Phe-(CH2)2-Phe-CO-, Phe-Phe-(CH2)z-Phe-CO-, Phe-(CH2)2-Phe-(CH2)2-Phe-CO-, CH3(CH2 )3-Phe-(CH2)2-Phe-CO-, CH3(CH2)5-0-Phe-(CH2)2-Phe-CO-, (CH3) 2CH
( CHz ) 6CH=CHCH2C0- ( ci s), (CH3 ) 2CH ( CH2 ) 6CH=CHCH2C0-(trans), (CH3)2CH(CH2)7CH=CHCH2C0- (cis), (CH3)2CH(CHZ)7CH=CHCH2C0- (trans), CH3CH2 ( CHCH3 ) ( CHz ) 5CH=CHCH2CO- ( cis CH3CH2(CHCH3)(CH2)5CH=CHCH2CO- (trans CH3CH2(CHCH3)(CH2hCH=CHCH2C0- (cis), CH3CH2(CHCH3)(CH2)7CH=CHCH2C0- (trans CH3CH2 ( CHCH3 ) ( CH2 ) 7CH=CHCH2C0- ( ci s CH3(CH2)8CH=CHCO-(cis), CH3(CH2)8CH=CHCO- (trans), CH3 ( CH2 ) 9CH=CHCO- ( ci s ) , CH3 ( CH2 ) 8CH=CHCO- ( t rans ), CH3 (CH2) 7CH=CHCO- (cis), CH3 (CH2) 7CH=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.
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-mycin, amphomycin derivatives, friulimicin, friulimicin B, friulimicin derivatives, daptomy-cin, daptomycin derivatives, aspartocin, asparto-cin derivatives, glumamycin, glumamycin deriva-tives, crystallomycin, crystallomycin derivatives, 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-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 "C15-AMPHOMYCIN, C15-AMPHOMYCIN-9-GLY, C15-AMPHOMYCIN-9-GLY-LYS, C15-AMPHOMYCIN-9-LEU, Clo -AMPHOMYCIN, C11-AMPHOMYCIN, C12-AMPHOMYCIN, C13-AM-PHOMYCIN, C14-AMPHOMYCIN, C16-AMPHOMYCIN, C17-AM-PHOMYCIN, C18-AMPHOMYCIN, OLEOYL-AMPHOMYCIN, CH3-(CH2) 11-0-P-PH-C (=0) -AMPHOMYCIN, CH3- (CH2) 15-0-P-PH-C(=0)AMPHOMYCIN, HO-(CH2)15-C(=0)-AMPHOMYCIN, CH3- (CH2) 9-0-P-PH-C (=0) -AMPHOMYCIN, CH3- (CH2) 7-0-P-PH-C(=0)-AMPHOMYCIN, CH3(CH2)11-NH-SUCCINYL-AMPHO-MYCIN, C12-P-HYDRAZINBENZOIC ACID-AMPHOMYCIN, C15-AMPHOMYCIN-9-GABA, C14-AMPHOMYCIN-9-GLY, C15-AM-PHOMYCIN-9-SAR, C15-AMPHOMYCIN-9-AHX, C15-AMPHOMY-CIN-9-INA, C15-AMPHOMYCIN-9-(P-N02-PHE), C15-AMPHO-MYCIN-9-GLY-PHE, C15-AMPHOMYCIN-9-GLU, C15-AMPHO-MYCIN-9-(P-F-PHE), C15-AMPHOMYCIN-9-(13-CHA), C15-AMPHOMYCIN-9-HPHE, C15-AMPHOMYCIN-9-GLY-GLY-GLY, C15-AMPHOMYCIN-9-C (=0) - (CH2) 10-NH2, C15-AMPHOMYCIN-9-(B-CYANO-ALA), C15-AMPHOMYCIN-9-ILE, C15-AMPHO-MYCIN-9-GLY-VAL, C15-AMPHOMYCIN-9-ASN, C15-AMPHO-MYCIN-9-TYR, C15-AMPHOMYCIN-9-TRP, C15-AMPHOMYCIN-9-PHG, C15-AMPHOMYCIN-9-GLY-GLY, C15-AMPHOMYCIN-9-GLN, C15-AMPHOMYCIN-9-THR, C15-AMPHOMYCIN-9-PRO-GLY, C15-AMPHOMYCIN-9-GLY-LEU, C15-AMPHOMYCIN-9-TYR (ET), C15-AMPHOMYCIN-9-GLY-SUC, C15-AMPHOMY-CIN-9-GLY-AC, C13-AMPHOMYCIN-9-GABA, C14-AMPHOMY-CIN-9-GLY-LYS, C15-AMPHOMYCIN-9-TYR (ME), C13-AM-PHOMYCIN-9-GLY, C13-AMPHOMYCIN-9-(13-ALA), C13-AM-PHOMYCIN-9-SAR, C13-AMPHOMYCIN-9-AHX, C12-AMPHOMY-CIN-9-GABA, C12-AMPHOMYCIN-9-GLY, C14-AMPHOMYCIN-9-(8-ALA), C14-AMPHOMYCIN-9-SAR, C14-AMPHOMYCIN-9-AHX, C14-AMPHOMYCIN-9-GABA, C13-AMPHOMYCIN-9-ALA, C13-AMPHOMYCIN-9-(D-ALA), C13-AMPHOMYCIN-9-(D-PRO), C15-AMPHOMYCIN-9-(D-ALA), C15-AMPHOMYCIN-9-(D-PRO), C15-AMPHOMYCIN-9-GLY-GABA, C15-AMPHOMY-CIN-9-GLY- (D-ALA) , C15-AMPHOMYCIN-9- (8-ALA) -AHX, C15-AMPHOMYCIN-9-GABA-VAL, C15-AMPHOMYCIN-9-GABA-AHX, C12-AMPHOMYCIN-9-(I3-ALA), C12-AMPHOMYCIN-9-SAR, C16-AMPHOMYCIN-9-SAR, Clp-AMPHOMYCIN-9- (1~-ALA), Clp-AMPHOMYCIN-9-SAR, C17-AMPHOMYCIN-9-SAR, C16-AMPHOMYCIN-9- (f3-ALA) , C17-AMPHOMYCIN-9- (13-ALA), C15-AMPHOMYCIN-9-GLY-C6r C15-AMPHOMYCIN-9-ALA, CH3- (CH2) 15-NH-C (=0) -AMPHOMYCIN-9-GLY, CH3-(CH2) 15-SO2-AMPHOMYCIN-9-GLY, C2-PABA-AMPHOMYCIN, C12-(P-APA)-AMPHOMYCIN-9-GLY, C12-PABA-AMPHOMYCIN-9-GLY, CH3-(CH2)11-0-P-PH-C(=O)-AMPHOMYCIN-9-GLY, C12-(P-TRANS-CINNAMYL)-AMPHOMYCIN-9-GLY, CH3-(CH2)11-O-P-PH-C)-GLY-AMPHOMYCIN-9-GLY, C14-PABA-GLY-AMPHOMYCIN-9-GLY, CH3 (CH2) 11-NH-C (=O) -AMPHOMY-CIN-9-GLY, C15-AMPHOMYCIN-9-AHX-GLY, C15-AMPHOMY-CIN-9-GABA-GABA, C15-AMPHOMYCIN-9-HPRO, C15-AMPHO-MYCIN-9-(D-PIP), CH3-(CH2)11-NH-C(=O)-AMPHOMYCIN-9- (f3-ALA), CH3- (CH2) 11-NH-C (=O) -AMPHOMYCIN-9-SAR, CH3- (CH2) 15-SOZ-GLY-AMPHOMYCIN, CH3- (CH2) 9-S02-PHE-AMPHOMYCIN, CH3-(CH2)9-S02-GLY-AMPHOMYCIN-9-LYS, CH3- (CH2) 9-SO2-GLY-AMPHOMYCIN-9-GLY, C12-GLY-AMPHO-MYCIN, C8-(P-APA)-AMPHOMYCIN, C14-GLY-AMPHOMYCIN, C16-GLY-AMPHOMYCIN, C18-GLY-AMPHOMYCIN, C12-(P-AMINOPHENYLPROPANOYL)-AMPHOMYCIN, C12-(P-AMINO-PHENYLPROPANOYL)2-AMPHOMYCIN, CH3-(CH2)g-O-P-PH-C(=0)-GLY-AMPHOMYCIN, C12- (M-APA) -AMPHOMYCIN, C15-[ASP-(OTBU)]-AMPHOMYCIN, Cip-(M-APA)-AMPHOMYCIN, CH3- ( CH2 ) 7- (CH3- ( CH2 ) 5 ) CH-C ( =0 ) -GLY-AMPHOMYC IN, C15-PHG-AMPHOMYCIN, C15-(D-PHE)-AMPHOMYCIN, PH-O-(CH2) 11-GLY-AMPHOMYCIN, Clp- (L-BBTA) -AMPHOMYCIN, C12-(P-APA)-AMPHOMYCIN, C12-(P-AMINO-TRANS-CINNA-MYL) -AMPHOMYCIN, CH3- (CH2) 11-0-P-PH-C (=0) -GLY-AM-PHOMYCIN, CH3-(CH2)9-(P-APA)-AMPHOMYCIN, C12-PABA-GLY-AMPHOMYCIN, C15-AMPHOMYCIN-9-(D-ORN), C14-AM-PHOMYCIN-9-GLY-LYS, C14-AMPHOMYCIN-9-LYS, C14-AM-PHOMYCIN-9-ORN, C13-AMPHOMYCIN-9-GLY-LYS, C15-AM-PHOMYCIN-9-LYS, C15-AMPHOMYCIN-9-ORN, C15-AMPHOMY-CIN-9-GDAB, C15-AMPHOMYCIN-9-DAP, C13-AMPHOMYCIN-9-LYS, C13-AMPHOMYCIN-9-ORN, C13-AMPHOMYCIN-9-GDAB, C13-AMPHOMYCIN-9-DAP, C12-AMPHOMYCIN-9-LYS, C12-AMPHOMYCIN-9-GDAB, C14-AMPHOMYCIN-9-GDAB, C19-AMPHOMYCIN-9-DAP, C16-AMPHOMYCIN-9-GLY-LYS, Cl~-AMPHOMYCIN-9-GLY-LYS, C12-AMPHOMYCIN-9-GLY-LYS, C15-AMPHOMYCIN-9-SAR-ORN, C15-AMPHOMYCIN-9-SAR-GDAB, C15-AMPHOMYCIN-9-SAR-DAP, C15-AMPHOMYCIN-9-(13-ALA) , C15-AMPHOMYCIN-9- (8-ALA) -ORN, B-ISOMER OF
C15-AMPHOMYCIN-9- (3-ALA) , ANHYDROISOMER OF C15-AM-PHOMYCIN-9-(B-ALA), C15-AMPHOMYCIN-9-(D-PRO)-(D-LYS), C15-AMPHOMYCIN-9-GLY-(D-LYS), C15-AMPHOMY-CIN-9-GLY-ORN, C15-AMPHOMYCIN-9-GLY-GDAB, C15-AM-PHOMYCIN-9-(13-ALA)-LYS, C15-AMPHOMYCIN-9-GABA-LYS, C15-AMPHOMYCIN-9-GLY-DAP, C15-AMPHOMYCIN-9-GLY-HLYS, C15-AMPHOMYCIN-9-GABA-GDAB, C15-AMPHOMYCIN-9-PRO, C15-AMPHOMYCIN-9-AIB, C15-AMPHOMYCIN-9-ME-CYS, C15-AMPHOMYCIN-9-NVL, C15-AMPHOMYCIN-9-ABU, C15-AMPHOMYCIN-9-CIT, C15-AMPHOMYCIN-9-(ME)2ARG, C15-AMPHOMYCIN-9-HYP, C15-AMPHOMYCIN-9-(P-APA), C15-AMPHOMYCIN-9-VAL, C15-AMPHOMYCIN-9-(ME)3LYS, C15-AMPHOMYCIN-9-NLE, C15-AMPHOMYCIN-9-LYS, C15-AM-PHOMYCIN-9-(B-ALA)-(5-AVA), C15-AMPHOMYCIN-9-(B-ALA) -VAL, 13-ISOMER OF C15-AMPHOMYCIN-9- (B-ALA) -VAL, C15-AMPHOMYCIN-9- (S-AVA) - (13-ALA) , C15-AMPHO-MYCIN-9-GLY-LYS-GLY, C15-AMPHOMYCIN-9-GLY-LYS-LYS, C15-AMPHOMYCIN-9-GLY-GLY-LYS, C15-AMPHOMYCIN-9-5 LYS-GLY, C15-AMPHOMYCIN-9-LYS-LYS, C15-AMPHOMYCIN-9-LYS-LYS-LYS, C15-AMPHOMYCIN-9-GLY-(D-LEU), C15-AMPHOMYCIN-9-GLY-AHX, C15-AMPHOMYCIN-9-SAR-AHX, C15-AMPHOMYCIN-9-SAR-LYS, C15-AMPHOMYCIN-9-DAP-(f3-N- (13-ALA) ) , C15-AMPHOMYCIN-9-C6, C15-AMPHOMYCIN-9-10 PLA, C15-AMPHOMYCIN-9-PCA, C15-AMPHOMYCIN-9-(CAR-BAMOYL-LEU), C15-AMPHOMYCIN-9-C8, C15-AMPHOMYCIN-9-CHEXYL, C15-AMPHOMYCIN-9-C4, C15-AMPHOMYCIN-9-(2-NORBORNANEACETYL), C15-AMPHOMYCIN-9-(N-BENZOYL-TYR-PABA), C15-AMPHOMYCIN-9-((S)-(+)-5-OXO-2-TET-RAHYDROFURANCARBONYL), C15-AMPHOMYCIN-9-PHENYLPRO-PYNYL, C15-AMPHOMYCIN-9-(CARBAMOYL-I3-ALA), C15-AM-PHOMYCIN-9-ACRYL, C15-AMPHOMYCIN-9-(l-NAPTHYLACE-TYL) , C15-AMPHOMYCIN-9- (4-PHENOXYBENZOYL) , C15-AM-PHOMYCIN-9-(2-NAPTHYLACETYL), C15-AMPHOMYCIN-9-(2-FURYL), C15-AMPHOMYCIN-9-CROTONYL, C15-AMPHOMYCIN-9-(3,4-(METHYLENEDIOXY)PHENYLACETYL), C15-AMPHOMY-CIN-9-Clo, C15-AMPHOMYCIN-9-(~-OXO-5-ACENAPTHENE-BUTANYL), C15-AMPHOMYCIN-9-HYDROCINNAMYL, C15-AM-PHOMYCIN-9(11-KETOBUTYL), C15-AMPHOMYCIN-9-GERANYL, C15-AMPHOMYCIN-9- (0-ANISYL) , C15-AMPHOMYCIN-9-PHENYLECATYL, C15-AMPHOMYCIN-9(2-BUTYNYL), C15-AM-PHOMYCIN-9- (3, 5-BIS (CF3) PHENYLACETYL) , C15-AMPHO-MYCIN-9-(3,4-METHYLENEDIOXY-CINNAMYL), C15-AMPHO-MYCIN-9-(TRANS-CINNAMYL), C15-AMPHOMYCIN-9-ACE-TOXYACETYL, C15-AMPHOMYCIN-9-(l-ADAMANTANYLCAR-BONYL), C15-AMPHOMYCIN-9-(4-COTININECARBONYL), C15-AMPHOMYCIN-9-(4-FLUOROBENZOLYL), C15-AMPHOMY-CIN-9-(S-ACETYLTHIOGLYCOYL), C15-AMPHOMYCIN-9-(4-BUTOXYBENZOYL), C15-AMPHOMYCIN-9-(6-OXOHEPTANOYL), C15-AMPHOMYCIN-9-OLEATE, C15-AMPHOMYCIN-9-(4-PENYLBENZOYL), C15-AMPHOMYCIN-9-(3-PHENOXYBEN-ZOYL), C15-AMPHOMYCIN-9-(C(=0)-(CH2)2-PIPERIDINE, C15-AMPHOMYCIN-9(N,N'-DIMETHYL-GABA), C15-AMPHOMY-CIN-9-(N-ETHYL-GLY), C15-AMPHOMYCIN-9-SAR-(N,N-DI-METHYL-GLY), C15-AMPHOMYCIN-9-(N-BENZYL-GLY), C15-AMPHOMYCIN-9-(N,N-DIETHYL-3-ALA), C10-AMPHOMYCIN-9-Clo, C15-AMPHOMYCIN-9-(N-METHYL-GABA), CH3-(CH2) 15-NH-C (=0) -AMPHOMYCIN, C15-AMPHOMYCIN-9-PGLU, CH3 ( C H 2 ) 11-NH-C ( = 0 ) -AMPHOMYCIN, CH3- (CH2) 7-NH-C (=0) -AMPHOMYCIN, CH3- (CH2) 13-NH-C (=0) -AMPHOMYCIN, CH3-(CH2)11-NH-C(=0)AMPHOMYCIN, C15-AMPHOMYCIN-C(=0)-NH-N-BUTYL, C15-AMPHOMYCIN-C(=0)-NH-CYCLO-HEXYL, C15-AMPHOMYCIN-C(=0)-NH-FURFURYL, C15-AM-PHOMYCIN-C(=0)-NH-2-FLUOROBENZYL, C15-AMPHOMYCIN-C(=0)-NH-M-CF3-PHENYL, C15-AMPHOMYCIN-C(=0)-NH-P-CF3-PHENYL, C15-AMPHOMYCIN-C(=0)-NH-3-FLUORO-PHENYL, C15-AMPHOMYCIN-(D-SER), C15-AMPHOMYCIN-(D-TYR), C15-AMPHOMYCIN- (D-TRP) , C13-AMPHOMYCIN-9-GLU, C15-AMPHOMYCIN-9-(4-HYDROXYBENZYL), C15-AM-PHOMYCIN-9-N,N-DI-(P-HYDROXYBENZYL), C15-AMPHOMY-CIN-9(N,N-DIMETHYLGLYCINE), CH3-(CH2)g-S02-GLY-AM-PHOMYCIN, CH3-(CH2)15-S02-PHE-AMPHOMYCIN, CH3-(CH2) 13-NH-C (=0) -AMPHOMYCIN-9-GLY-LYS, CH3- (CH2) 13-NH-C (=0) -AMPHOMYCIN-9- (15-ALA) , CH3- (CH2) 13-NH-C(=0)-AMPHOMYCIN-9-GLY, C12-PABA-AMPHOMYCIN-9-(3-ALA), C16-(P-APA)-AMPHOMYCIN, C8-PABA-AMPHOMYCIN, Clo-PABA-AMPHOMYCIN, C11-PABA-AMPHOMYCIN, C13-PABA-AMPHOMYCIN, CH3 (CH2) lp-NH-C (=0) - (8-ALA) -AMPHOMY-CIN, CH3-(CH2)15-NH-C(=0)-(P-PHENYLACETYL)-AMPHOMYCIN, CH3-(CH2)7-NH-C(=0)-(P-PHENYLACETYL)-AMPHOMYCIN, CH3-(CH2)13-NH-C(=0)-(P-PHENYLACETYL)-AMPHOMYCIN, CH3-(CH2)lp-NH-C(=0)-(P-PHENYLACETYL)-AMPHOMYCIN, CH3- (CH2) 13-NH-C (=0) - (GABA) -AMPHOMYCIN, CH3-(CH2)13-NH-C(=0)-(M-PHENYLACETYL)-AMPHOMYCIN, Clp-(M-AMINOBENZOYL)-AMPHOMYCIN, C11-(M-AMINOBENZOYL)-AMPHOMYCIN, CH3-(CH2)13-NH-C(=0)-(3-ALA) -AMPHOMYCIN, C12- (M-AMINOBENZOYL) -AMPHOMYCIN, C13-(M-AMINOBENZOYL)-AMPHOMYCIN, BORONAT-PINACOL-ESTER-RESIN, 4'-OCTYL-BIPHENYL-4-CARBOXYL-AMPHOMYCIN, C13-(P-APA)AMPHOMYCIN, C14-(P-APA) -AMPHOMYCIN, CH3- (CH2) 15-NH-C (=0) - (M-PHENYLACETYL)-AMPHOMYCIN, C14-(M-APA)-AMPHOMYCIN, C13- (P-APA) -AMPHOMYCIN, CH3- (CH2) 10-NH-C (=0) -GABA-AMPHOMYCIN, N,N'-DI-C8-(M,M-DIAMINOBENZOYL)-AMPHOMYCIN, CH3-(CH2)7-NH-C(=O)-(M-PHENYLACETYL)-AMPHOMYCIN, CH3-(CH2)13-NH-C(=0)-GLY-AMPHOMYCIN, 1-DODECYL-IH-(1,2,3)-TRIAZOLE-4-CARBOXYLIC ACID, 1-DODECYL-IH-(1,2,3)-TRIAZOLE-4-CARBOXYL-AMPHOMYCIN, C15-(M-APA)-AMPHOMYCIN, C13-(ASP-(OME) ) -AMPHOMYCIN, C1S- (PAPA) -AMPHOMYCIN, G15-(ASP-(OME))-AMPHOMYCIN, C11-(ASP(OTBU))-AMPHO-MYCIN, C13- (ASP- (OTBU) ) -AMPHOMYCIN, C1i-(ASP(OME))-AMPHOMYCIN, C15-ASP-(OME))-AMPHOMYCIN, C15-AMPHOMYCIN-9-C(=0)-NH-(0-CF3-PHENYL), N,N'-DI-C6-(M,MDIAMINOBENZOYL)-AMPHOMYCIN, N,N'-DI-C12-(M,MDIAMINOBENZOYL)-AMPHOMYCIN, CH3-(CH2)7-NH-C(=0)-(I3-ALA)-AMPHOMYCIN, (4-PHENYLBENZOYL)-AMPHO-MYCIN, (2-PHENYLMETHYL)-BENZOYL-AMPHOMYCIN, N,N-DIETHYL-PABA-AMPHOMYCIN, (3,4,5-TRIMETHOXYBEN-ZOYL)-AMPHOMYCIN, (4-TBUTYLBENZOYL)-AMPHOMYCIN, (3-(PHENOXY)-BENZOYL)-AMPHOMYCIN, C15-AMPHOMYCIN-9- (D-DAP) , I~-ISOMER OF CH3- ( C H 2 ) 13-NH-C ( = 0 ) -AMPHO-MYCIN, 1~-ISOMER OF CH3- (CH2) lp-NH-C (=0) -(GABA) -AM-PHOMYCIN, LYS-GLY-AMPHOMYCIN-9-C15, LYS-GLY-AMPHO-MYCIN-9-C13, (11-(PHENOXY)UNDECANOYL)-AMPHOMYCIN, N-C12-((1S,4S)-4-AMINOCYCLOHEXYLCARBOXYLIC ACID), C1_2-((1S,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-DODECYLOXY-QUINOLINE-2-CARBONYL)-AMPHOMYCIN, 13-ISOMER OF (8-DODECYLOXY-QUINOLINE-2-CARBONYL)-AM-PHOMYCIN, C15-AMPHOMYCIN-9-PHE, C15-AMPHOMYCIN-9-C15, C15-AMPHOMYCIN-9-([2-(2-METHOXY-ETHOXY)-ETH-OXY]-ACETYL), Clp-SAR-AMPHOMYCIN, C14-SAR-AMPHOMY-CIN, Cg-SAR-AMPHOMYCIN, C15-AMPHOMYCIN-9-C12, C15-AMPHOMYCIN-9-(11-PHENOXYUNDE-CANOYL), C15-AMPHOMY-CIN-9-(3FURAN-2-YL-ACRYLOYL), C15-AMPHOMYCIN-9-(3(BENZENESULPHONYL)PROPIONOYL), C15-AMPHOMYCIN-9-(4-(PYREN-2-YL)BUTYROYL), C15-AMPHOMYCIN-9-SUC, C15-AMPHOMYCIN-9-PRO-LYS, BOC-AMPHOMYCIN, AMPHOMY-CIN-9-(f3-ALA), AMPHOMYCIN-9-SAR, GLY-AMPHOMYCIN-9-FMOC, C6-GLY-AMPHOMYCIN-9-FMOC, C8-GLY-AMPHOMYCIN-9-FMOC, Clp-GLY-AMPHOMYCIN-9-FMOC, C8-(M-APA)-AM-PHOMYCIN, CH3-(CH2)lp-NH-C(=0)-(M-PHENYLACETYL)-AMPHOMYCIN, 1-ADAMANTANE-(=O)-AMPHOMYCIN, (10-METHYL-UNDEC-2-ENOYL)-AMPHOMYCIN, (10-METHYL-DO-DEC-2-ENOYL)-AMPHOMYCIN, (12-METHYL-TETRADEC-2-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-SAR, (12-METHYL-TETRADEC-2-ENOYL)-ASPARTOCIN-9-(13-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 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, CvOx COR' 0 H
H ~ 0 HN
O (a ~
HOOC NH
~
H
N
N
H
NH
The lipopeptide may be selected, independently from formula I, from the group comprising "ampho-mycin, amphomycin derivatives, friulimicin, friulimicin B, friulimicin derivatives, daptomy-cin, daptomycin derivatives, aspartocin, asparto-cin derivatives, glumamycin, glumamycin deriva-tives, crystallomycin, crystallomycin derivatives, 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-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 "C15-AMPHOMYCIN, C15-AMPHOMYCIN-9-GLY, C15-AMPHOMYCIN-9-GLY-LYS, C15-AMPHOMYCIN-9-LEU, Clo -AMPHOMYCIN, C11-AMPHOMYCIN, C12-AMPHOMYCIN, C13-AM-PHOMYCIN, C14-AMPHOMYCIN, C16-AMPHOMYCIN, C17-AM-PHOMYCIN, C18-AMPHOMYCIN, OLEOYL-AMPHOMYCIN, CH3-(CH2) 11-0-P-PH-C (=0) -AMPHOMYCIN, CH3- (CH2) 15-0-P-PH-C(=0)AMPHOMYCIN, HO-(CH2)15-C(=0)-AMPHOMYCIN, CH3- (CH2) 9-0-P-PH-C (=0) -AMPHOMYCIN, CH3- (CH2) 7-0-P-PH-C(=0)-AMPHOMYCIN, CH3(CH2)11-NH-SUCCINYL-AMPHO-MYCIN, C12-P-HYDRAZINBENZOIC ACID-AMPHOMYCIN, C15-AMPHOMYCIN-9-GABA, C14-AMPHOMYCIN-9-GLY, C15-AM-PHOMYCIN-9-SAR, C15-AMPHOMYCIN-9-AHX, C15-AMPHOMY-CIN-9-INA, C15-AMPHOMYCIN-9-(P-N02-PHE), C15-AMPHO-MYCIN-9-GLY-PHE, C15-AMPHOMYCIN-9-GLU, C15-AMPHO-MYCIN-9-(P-F-PHE), C15-AMPHOMYCIN-9-(13-CHA), C15-AMPHOMYCIN-9-HPHE, C15-AMPHOMYCIN-9-GLY-GLY-GLY, C15-AMPHOMYCIN-9-C (=0) - (CH2) 10-NH2, C15-AMPHOMYCIN-9-(B-CYANO-ALA), C15-AMPHOMYCIN-9-ILE, C15-AMPHO-MYCIN-9-GLY-VAL, C15-AMPHOMYCIN-9-ASN, C15-AMPHO-MYCIN-9-TYR, C15-AMPHOMYCIN-9-TRP, C15-AMPHOMYCIN-9-PHG, C15-AMPHOMYCIN-9-GLY-GLY, C15-AMPHOMYCIN-9-GLN, C15-AMPHOMYCIN-9-THR, C15-AMPHOMYCIN-9-PRO-GLY, C15-AMPHOMYCIN-9-GLY-LEU, C15-AMPHOMYCIN-9-TYR (ET), C15-AMPHOMYCIN-9-GLY-SUC, C15-AMPHOMY-CIN-9-GLY-AC, C13-AMPHOMYCIN-9-GABA, C14-AMPHOMY-CIN-9-GLY-LYS, C15-AMPHOMYCIN-9-TYR (ME), C13-AM-PHOMYCIN-9-GLY, C13-AMPHOMYCIN-9-(13-ALA), C13-AM-PHOMYCIN-9-SAR, C13-AMPHOMYCIN-9-AHX, C12-AMPHOMY-CIN-9-GABA, C12-AMPHOMYCIN-9-GLY, C14-AMPHOMYCIN-9-(8-ALA), C14-AMPHOMYCIN-9-SAR, C14-AMPHOMYCIN-9-AHX, C14-AMPHOMYCIN-9-GABA, C13-AMPHOMYCIN-9-ALA, C13-AMPHOMYCIN-9-(D-ALA), C13-AMPHOMYCIN-9-(D-PRO), C15-AMPHOMYCIN-9-(D-ALA), C15-AMPHOMYCIN-9-(D-PRO), C15-AMPHOMYCIN-9-GLY-GABA, C15-AMPHOMY-CIN-9-GLY- (D-ALA) , C15-AMPHOMYCIN-9- (8-ALA) -AHX, C15-AMPHOMYCIN-9-GABA-VAL, C15-AMPHOMYCIN-9-GABA-AHX, C12-AMPHOMYCIN-9-(I3-ALA), C12-AMPHOMYCIN-9-SAR, C16-AMPHOMYCIN-9-SAR, Clp-AMPHOMYCIN-9- (1~-ALA), Clp-AMPHOMYCIN-9-SAR, C17-AMPHOMYCIN-9-SAR, C16-AMPHOMYCIN-9- (f3-ALA) , C17-AMPHOMYCIN-9- (13-ALA), C15-AMPHOMYCIN-9-GLY-C6r C15-AMPHOMYCIN-9-ALA, CH3- (CH2) 15-NH-C (=0) -AMPHOMYCIN-9-GLY, CH3-(CH2) 15-SO2-AMPHOMYCIN-9-GLY, C2-PABA-AMPHOMYCIN, C12-(P-APA)-AMPHOMYCIN-9-GLY, C12-PABA-AMPHOMYCIN-9-GLY, CH3-(CH2)11-0-P-PH-C(=O)-AMPHOMYCIN-9-GLY, C12-(P-TRANS-CINNAMYL)-AMPHOMYCIN-9-GLY, CH3-(CH2)11-O-P-PH-C)-GLY-AMPHOMYCIN-9-GLY, C14-PABA-GLY-AMPHOMYCIN-9-GLY, CH3 (CH2) 11-NH-C (=O) -AMPHOMY-CIN-9-GLY, C15-AMPHOMYCIN-9-AHX-GLY, C15-AMPHOMY-CIN-9-GABA-GABA, C15-AMPHOMYCIN-9-HPRO, C15-AMPHO-MYCIN-9-(D-PIP), CH3-(CH2)11-NH-C(=O)-AMPHOMYCIN-9- (f3-ALA), CH3- (CH2) 11-NH-C (=O) -AMPHOMYCIN-9-SAR, CH3- (CH2) 15-SOZ-GLY-AMPHOMYCIN, CH3- (CH2) 9-S02-PHE-AMPHOMYCIN, CH3-(CH2)9-S02-GLY-AMPHOMYCIN-9-LYS, CH3- (CH2) 9-SO2-GLY-AMPHOMYCIN-9-GLY, C12-GLY-AMPHO-MYCIN, C8-(P-APA)-AMPHOMYCIN, C14-GLY-AMPHOMYCIN, C16-GLY-AMPHOMYCIN, C18-GLY-AMPHOMYCIN, C12-(P-AMINOPHENYLPROPANOYL)-AMPHOMYCIN, C12-(P-AMINO-PHENYLPROPANOYL)2-AMPHOMYCIN, CH3-(CH2)g-O-P-PH-C(=0)-GLY-AMPHOMYCIN, C12- (M-APA) -AMPHOMYCIN, C15-[ASP-(OTBU)]-AMPHOMYCIN, Cip-(M-APA)-AMPHOMYCIN, CH3- ( CH2 ) 7- (CH3- ( CH2 ) 5 ) CH-C ( =0 ) -GLY-AMPHOMYC IN, C15-PHG-AMPHOMYCIN, C15-(D-PHE)-AMPHOMYCIN, PH-O-(CH2) 11-GLY-AMPHOMYCIN, Clp- (L-BBTA) -AMPHOMYCIN, C12-(P-APA)-AMPHOMYCIN, C12-(P-AMINO-TRANS-CINNA-MYL) -AMPHOMYCIN, CH3- (CH2) 11-0-P-PH-C (=0) -GLY-AM-PHOMYCIN, CH3-(CH2)9-(P-APA)-AMPHOMYCIN, C12-PABA-GLY-AMPHOMYCIN, C15-AMPHOMYCIN-9-(D-ORN), C14-AM-PHOMYCIN-9-GLY-LYS, C14-AMPHOMYCIN-9-LYS, C14-AM-PHOMYCIN-9-ORN, C13-AMPHOMYCIN-9-GLY-LYS, C15-AM-PHOMYCIN-9-LYS, C15-AMPHOMYCIN-9-ORN, C15-AMPHOMY-CIN-9-GDAB, C15-AMPHOMYCIN-9-DAP, C13-AMPHOMYCIN-9-LYS, C13-AMPHOMYCIN-9-ORN, C13-AMPHOMYCIN-9-GDAB, C13-AMPHOMYCIN-9-DAP, C12-AMPHOMYCIN-9-LYS, C12-AMPHOMYCIN-9-GDAB, C14-AMPHOMYCIN-9-GDAB, C19-AMPHOMYCIN-9-DAP, C16-AMPHOMYCIN-9-GLY-LYS, Cl~-AMPHOMYCIN-9-GLY-LYS, C12-AMPHOMYCIN-9-GLY-LYS, C15-AMPHOMYCIN-9-SAR-ORN, C15-AMPHOMYCIN-9-SAR-GDAB, C15-AMPHOMYCIN-9-SAR-DAP, C15-AMPHOMYCIN-9-(13-ALA) , C15-AMPHOMYCIN-9- (8-ALA) -ORN, B-ISOMER OF
C15-AMPHOMYCIN-9- (3-ALA) , ANHYDROISOMER OF C15-AM-PHOMYCIN-9-(B-ALA), C15-AMPHOMYCIN-9-(D-PRO)-(D-LYS), C15-AMPHOMYCIN-9-GLY-(D-LYS), C15-AMPHOMY-CIN-9-GLY-ORN, C15-AMPHOMYCIN-9-GLY-GDAB, C15-AM-PHOMYCIN-9-(13-ALA)-LYS, C15-AMPHOMYCIN-9-GABA-LYS, C15-AMPHOMYCIN-9-GLY-DAP, C15-AMPHOMYCIN-9-GLY-HLYS, C15-AMPHOMYCIN-9-GABA-GDAB, C15-AMPHOMYCIN-9-PRO, C15-AMPHOMYCIN-9-AIB, C15-AMPHOMYCIN-9-ME-CYS, C15-AMPHOMYCIN-9-NVL, C15-AMPHOMYCIN-9-ABU, C15-AMPHOMYCIN-9-CIT, C15-AMPHOMYCIN-9-(ME)2ARG, C15-AMPHOMYCIN-9-HYP, C15-AMPHOMYCIN-9-(P-APA), C15-AMPHOMYCIN-9-VAL, C15-AMPHOMYCIN-9-(ME)3LYS, C15-AMPHOMYCIN-9-NLE, C15-AMPHOMYCIN-9-LYS, C15-AM-PHOMYCIN-9-(B-ALA)-(5-AVA), C15-AMPHOMYCIN-9-(B-ALA) -VAL, 13-ISOMER OF C15-AMPHOMYCIN-9- (B-ALA) -VAL, C15-AMPHOMYCIN-9- (S-AVA) - (13-ALA) , C15-AMPHO-MYCIN-9-GLY-LYS-GLY, C15-AMPHOMYCIN-9-GLY-LYS-LYS, C15-AMPHOMYCIN-9-GLY-GLY-LYS, C15-AMPHOMYCIN-9-5 LYS-GLY, C15-AMPHOMYCIN-9-LYS-LYS, C15-AMPHOMYCIN-9-LYS-LYS-LYS, C15-AMPHOMYCIN-9-GLY-(D-LEU), C15-AMPHOMYCIN-9-GLY-AHX, C15-AMPHOMYCIN-9-SAR-AHX, C15-AMPHOMYCIN-9-SAR-LYS, C15-AMPHOMYCIN-9-DAP-(f3-N- (13-ALA) ) , C15-AMPHOMYCIN-9-C6, C15-AMPHOMYCIN-9-10 PLA, C15-AMPHOMYCIN-9-PCA, C15-AMPHOMYCIN-9-(CAR-BAMOYL-LEU), C15-AMPHOMYCIN-9-C8, C15-AMPHOMYCIN-9-CHEXYL, C15-AMPHOMYCIN-9-C4, C15-AMPHOMYCIN-9-(2-NORBORNANEACETYL), C15-AMPHOMYCIN-9-(N-BENZOYL-TYR-PABA), C15-AMPHOMYCIN-9-((S)-(+)-5-OXO-2-TET-RAHYDROFURANCARBONYL), C15-AMPHOMYCIN-9-PHENYLPRO-PYNYL, C15-AMPHOMYCIN-9-(CARBAMOYL-I3-ALA), C15-AM-PHOMYCIN-9-ACRYL, C15-AMPHOMYCIN-9-(l-NAPTHYLACE-TYL) , C15-AMPHOMYCIN-9- (4-PHENOXYBENZOYL) , C15-AM-PHOMYCIN-9-(2-NAPTHYLACETYL), C15-AMPHOMYCIN-9-(2-FURYL), C15-AMPHOMYCIN-9-CROTONYL, C15-AMPHOMYCIN-9-(3,4-(METHYLENEDIOXY)PHENYLACETYL), C15-AMPHOMY-CIN-9-Clo, C15-AMPHOMYCIN-9-(~-OXO-5-ACENAPTHENE-BUTANYL), C15-AMPHOMYCIN-9-HYDROCINNAMYL, C15-AM-PHOMYCIN-9(11-KETOBUTYL), C15-AMPHOMYCIN-9-GERANYL, C15-AMPHOMYCIN-9- (0-ANISYL) , C15-AMPHOMYCIN-9-PHENYLECATYL, C15-AMPHOMYCIN-9(2-BUTYNYL), C15-AM-PHOMYCIN-9- (3, 5-BIS (CF3) PHENYLACETYL) , C15-AMPHO-MYCIN-9-(3,4-METHYLENEDIOXY-CINNAMYL), C15-AMPHO-MYCIN-9-(TRANS-CINNAMYL), C15-AMPHOMYCIN-9-ACE-TOXYACETYL, C15-AMPHOMYCIN-9-(l-ADAMANTANYLCAR-BONYL), C15-AMPHOMYCIN-9-(4-COTININECARBONYL), C15-AMPHOMYCIN-9-(4-FLUOROBENZOLYL), C15-AMPHOMY-CIN-9-(S-ACETYLTHIOGLYCOYL), C15-AMPHOMYCIN-9-(4-BUTOXYBENZOYL), C15-AMPHOMYCIN-9-(6-OXOHEPTANOYL), C15-AMPHOMYCIN-9-OLEATE, C15-AMPHOMYCIN-9-(4-PENYLBENZOYL), C15-AMPHOMYCIN-9-(3-PHENOXYBEN-ZOYL), C15-AMPHOMYCIN-9-(C(=0)-(CH2)2-PIPERIDINE, C15-AMPHOMYCIN-9(N,N'-DIMETHYL-GABA), C15-AMPHOMY-CIN-9-(N-ETHYL-GLY), C15-AMPHOMYCIN-9-SAR-(N,N-DI-METHYL-GLY), C15-AMPHOMYCIN-9-(N-BENZYL-GLY), C15-AMPHOMYCIN-9-(N,N-DIETHYL-3-ALA), C10-AMPHOMYCIN-9-Clo, C15-AMPHOMYCIN-9-(N-METHYL-GABA), CH3-(CH2) 15-NH-C (=0) -AMPHOMYCIN, C15-AMPHOMYCIN-9-PGLU, CH3 ( C H 2 ) 11-NH-C ( = 0 ) -AMPHOMYCIN, CH3- (CH2) 7-NH-C (=0) -AMPHOMYCIN, CH3- (CH2) 13-NH-C (=0) -AMPHOMYCIN, CH3-(CH2)11-NH-C(=0)AMPHOMYCIN, C15-AMPHOMYCIN-C(=0)-NH-N-BUTYL, C15-AMPHOMYCIN-C(=0)-NH-CYCLO-HEXYL, C15-AMPHOMYCIN-C(=0)-NH-FURFURYL, C15-AM-PHOMYCIN-C(=0)-NH-2-FLUOROBENZYL, C15-AMPHOMYCIN-C(=0)-NH-M-CF3-PHENYL, C15-AMPHOMYCIN-C(=0)-NH-P-CF3-PHENYL, C15-AMPHOMYCIN-C(=0)-NH-3-FLUORO-PHENYL, C15-AMPHOMYCIN-(D-SER), C15-AMPHOMYCIN-(D-TYR), C15-AMPHOMYCIN- (D-TRP) , C13-AMPHOMYCIN-9-GLU, C15-AMPHOMYCIN-9-(4-HYDROXYBENZYL), C15-AM-PHOMYCIN-9-N,N-DI-(P-HYDROXYBENZYL), C15-AMPHOMY-CIN-9(N,N-DIMETHYLGLYCINE), CH3-(CH2)g-S02-GLY-AM-PHOMYCIN, CH3-(CH2)15-S02-PHE-AMPHOMYCIN, CH3-(CH2) 13-NH-C (=0) -AMPHOMYCIN-9-GLY-LYS, CH3- (CH2) 13-NH-C (=0) -AMPHOMYCIN-9- (15-ALA) , CH3- (CH2) 13-NH-C(=0)-AMPHOMYCIN-9-GLY, C12-PABA-AMPHOMYCIN-9-(3-ALA), C16-(P-APA)-AMPHOMYCIN, C8-PABA-AMPHOMYCIN, Clo-PABA-AMPHOMYCIN, C11-PABA-AMPHOMYCIN, C13-PABA-AMPHOMYCIN, CH3 (CH2) lp-NH-C (=0) - (8-ALA) -AMPHOMY-CIN, CH3-(CH2)15-NH-C(=0)-(P-PHENYLACETYL)-AMPHOMYCIN, CH3-(CH2)7-NH-C(=0)-(P-PHENYLACETYL)-AMPHOMYCIN, CH3-(CH2)13-NH-C(=0)-(P-PHENYLACETYL)-AMPHOMYCIN, CH3-(CH2)lp-NH-C(=0)-(P-PHENYLACETYL)-AMPHOMYCIN, CH3- (CH2) 13-NH-C (=0) - (GABA) -AMPHOMYCIN, CH3-(CH2)13-NH-C(=0)-(M-PHENYLACETYL)-AMPHOMYCIN, Clp-(M-AMINOBENZOYL)-AMPHOMYCIN, C11-(M-AMINOBENZOYL)-AMPHOMYCIN, CH3-(CH2)13-NH-C(=0)-(3-ALA) -AMPHOMYCIN, C12- (M-AMINOBENZOYL) -AMPHOMYCIN, C13-(M-AMINOBENZOYL)-AMPHOMYCIN, BORONAT-PINACOL-ESTER-RESIN, 4'-OCTYL-BIPHENYL-4-CARBOXYL-AMPHOMYCIN, C13-(P-APA)AMPHOMYCIN, C14-(P-APA) -AMPHOMYCIN, CH3- (CH2) 15-NH-C (=0) - (M-PHENYLACETYL)-AMPHOMYCIN, C14-(M-APA)-AMPHOMYCIN, C13- (P-APA) -AMPHOMYCIN, CH3- (CH2) 10-NH-C (=0) -GABA-AMPHOMYCIN, N,N'-DI-C8-(M,M-DIAMINOBENZOYL)-AMPHOMYCIN, CH3-(CH2)7-NH-C(=O)-(M-PHENYLACETYL)-AMPHOMYCIN, CH3-(CH2)13-NH-C(=0)-GLY-AMPHOMYCIN, 1-DODECYL-IH-(1,2,3)-TRIAZOLE-4-CARBOXYLIC ACID, 1-DODECYL-IH-(1,2,3)-TRIAZOLE-4-CARBOXYL-AMPHOMYCIN, C15-(M-APA)-AMPHOMYCIN, C13-(ASP-(OME) ) -AMPHOMYCIN, C1S- (PAPA) -AMPHOMYCIN, G15-(ASP-(OME))-AMPHOMYCIN, C11-(ASP(OTBU))-AMPHO-MYCIN, C13- (ASP- (OTBU) ) -AMPHOMYCIN, C1i-(ASP(OME))-AMPHOMYCIN, C15-ASP-(OME))-AMPHOMYCIN, C15-AMPHOMYCIN-9-C(=0)-NH-(0-CF3-PHENYL), N,N'-DI-C6-(M,MDIAMINOBENZOYL)-AMPHOMYCIN, N,N'-DI-C12-(M,MDIAMINOBENZOYL)-AMPHOMYCIN, CH3-(CH2)7-NH-C(=0)-(I3-ALA)-AMPHOMYCIN, (4-PHENYLBENZOYL)-AMPHO-MYCIN, (2-PHENYLMETHYL)-BENZOYL-AMPHOMYCIN, N,N-DIETHYL-PABA-AMPHOMYCIN, (3,4,5-TRIMETHOXYBEN-ZOYL)-AMPHOMYCIN, (4-TBUTYLBENZOYL)-AMPHOMYCIN, (3-(PHENOXY)-BENZOYL)-AMPHOMYCIN, C15-AMPHOMYCIN-9- (D-DAP) , I~-ISOMER OF CH3- ( C H 2 ) 13-NH-C ( = 0 ) -AMPHO-MYCIN, 1~-ISOMER OF CH3- (CH2) lp-NH-C (=0) -(GABA) -AM-PHOMYCIN, LYS-GLY-AMPHOMYCIN-9-C15, LYS-GLY-AMPHO-MYCIN-9-C13, (11-(PHENOXY)UNDECANOYL)-AMPHOMYCIN, N-C12-((1S,4S)-4-AMINOCYCLOHEXYLCARBOXYLIC ACID), C1_2-((1S,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-DODECYLOXY-QUINOLINE-2-CARBONYL)-AMPHOMYCIN, 13-ISOMER OF (8-DODECYLOXY-QUINOLINE-2-CARBONYL)-AM-PHOMYCIN, C15-AMPHOMYCIN-9-PHE, C15-AMPHOMYCIN-9-C15, C15-AMPHOMYCIN-9-([2-(2-METHOXY-ETHOXY)-ETH-OXY]-ACETYL), Clp-SAR-AMPHOMYCIN, C14-SAR-AMPHOMY-CIN, Cg-SAR-AMPHOMYCIN, C15-AMPHOMYCIN-9-C12, C15-AMPHOMYCIN-9-(11-PHENOXYUNDE-CANOYL), C15-AMPHOMY-CIN-9-(3FURAN-2-YL-ACRYLOYL), C15-AMPHOMYCIN-9-(3(BENZENESULPHONYL)PROPIONOYL), C15-AMPHOMYCIN-9-(4-(PYREN-2-YL)BUTYROYL), C15-AMPHOMYCIN-9-SUC, C15-AMPHOMYCIN-9-PRO-LYS, BOC-AMPHOMYCIN, AMPHOMY-CIN-9-(f3-ALA), AMPHOMYCIN-9-SAR, GLY-AMPHOMYCIN-9-FMOC, C6-GLY-AMPHOMYCIN-9-FMOC, C8-GLY-AMPHOMYCIN-9-FMOC, Clp-GLY-AMPHOMYCIN-9-FMOC, C8-(M-APA)-AM-PHOMYCIN, CH3-(CH2)lp-NH-C(=0)-(M-PHENYLACETYL)-AMPHOMYCIN, 1-ADAMANTANE-(=O)-AMPHOMYCIN, (10-METHYL-UNDEC-2-ENOYL)-AMPHOMYCIN, (10-METHYL-DO-DEC-2-ENOYL)-AMPHOMYCIN, (12-METHYL-TETRADEC-2-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-SAR, (12-METHYL-TETRADEC-2-ENOYL)-ASPARTOCIN-9-(13-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 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, CvOx COR' 0 H
H ~ 0 HN
O (a ~
HOOC NH
~
H
N
N
H
NH
Formula Ia wherein in formula Ia R3 may also be bound by a residue L, wherein Rl is OH or NH2, wherein L is at least one amino acid, at least one substituted amino acid, -R'-(CO)-, -R'-(CO)-(NR')-, or -O-Ph-(C0)-, wherein R' is respectively independently from each other identical or 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, -1 5 ( CO ) - , - R ' - ( CO ) - , - S O 2 - , - ( CS ) - , - ( P O ) - , -0- ( PO ) -, -0- (CO) - R' -0- (CO) (NR' ) -, -NH- (CO) -, -NR' - (CO) -, -R'-(CO)-, -R'-(CO)-(NR')-, or -0-Ph-(CO)-, wherein R' is respectively independently from each other identical or different and a residue such as R3 or R5can be defined, wherein L for Dab9 is preferably - (CO) -, wherein R2 is -ORS, -SR5, NR5R5, -(CO)-R5, -(CO)-0-R5, - (CO) NHR4, - (CO) -NR4R4, - (CS) -NHR4, - (CS) -NR4R4, -(CNR4)-NHR4 or -(CNR4)-NR4R4, R5-(CO), S02R5, - (SO) -R5, - (PO) (OR5) 2, - (PO) (OR5) , COOH, SO3H, -PO3H, -F, -Cl, -Br, -I, or trihalomethyl, wherein R3 is -H, -OR5, -SR5, -NR5R5, -CN, -NO2, -N3, - (CO) -R5, - (CO) -O-R5, - (C0) -NR5R5, - (CS) -NR5R5, -(CNR5)-NR5R5, -(CO)-H, -R5-(CO), -S02R5 , - (PO) (OR5) zr - (PO) (OR5) , - CO2H, - SO3H, -P03H, -F, -Cl, -Br, -I, trihalomethyl, C1-C25 alkyl, substituted C1-C25 alkyl, C1-C25 heteroalkyl, sub-stituted Cl-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-ClO 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 R5 is independently from each other iden-15 tical or different Cl-C10 alkyl, C5-ClO 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-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, 8-alanine, GABA, 5-aminopentanoic acid, 6-aminohexanoic acid, gDAB, 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 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-hydrazinobenzoic acid, o-hydrazinobenzoic acid, p-amino-trans-cinnamyl, m-amino-trans-cinnamyl, o-amino-trans-cinnamyl, p-aminophenylacetic acid, m-aminophenylacetic acid, L-BBTA, or any combination thereof.
It is possible that the pharmaceutical compo-sition includes several different lipopeptides in 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, preferably as a Na or Ca salt, in particular as a di-Ca salt (Ca2C12 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 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 cyclodextrins and cyclodextrin derivatives can be employed. Cyclodextrins are cyclic oligosaccha-rides, which are composed of alpha-1,4-linked glu-cose components. Usually, six to eight glucose components (~, 8, or ~-cyclodextrin) are connected 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 purpose of the invention. The cyclodextrin or cyclodextrin derivative preferably is an ~ or f~-cyclodextrin and may in particular have the gen-eral formula II, ~ OR1 ~
N
_ p H H
ORz ~{ 0-OR
n _--------"'....-- /,/
Formula II
wherein Rl, R2, and R3 may be identical or differ-ent and an arbitrary physiologically tolerated residue, preferably -H, C1-C8 alkyl, -SOzOH, -PO(OH)zr or -CO-R4 with R4 = C1-C8 alkyl, wherein the Cl-C8 alkyl may be single or multiple at iden-tical or at different C atoms with -OH, -COOH, -CONHR5, -NHCOR6, - SOzOH, -PO(OH)2r or tetrazol-5-yl with R5 = -H or C1-C4 alkyl and R6 = carboxyl-phenyl, wherein n = 6, 7 or 8, wherein R1, R2 and R3 may be randomized in different 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 sul-fur atoms, including physiologically tolerated salts of such cyclodextrins. Preferably, the glu-copyranose units are ~-D or ~-L-glucopyranose units. Cl-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 Rl of a cyclodextrin molecule may be different from -H. R2 and R3 may then be -H. In 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-ing of "~-cyclodextrin, B-cyclodextrin, hydroxy-(Cl-C8 alkyl)-D-cyclodextrin, hydroxy-(Cl-C8 al-kyl)-B-cyclodextrin, (2-hydroxypropyl)-8-cyclodex-trin, (2-hydroxypropyl)-~-cyclodextrin, sulfo-(Cl-C8 alkyl)-ether-LI-cyclodextrin, sulfo-(Cl-C8 al-kyl)-ether-B-cyclodextrin, sulfobutylether-LI-cy-clodextrin, sulfobutylether-B-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 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-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-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 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 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 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 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-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 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 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)2r diethanolamine, ethylendia-mine, or with amino acids, such as arginine, ly-sine, glutamine acid etc. or with inorganic salts, such as CaC12r NaCl or the free ions thereof, such as Ca2+, Na+, Cl-, S042- or combinations thereof.
It is possible that the pharmaceutical compo-sition includes several different lipopeptides in 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, preferably as a Na or Ca salt, in particular as a di-Ca salt (Ca2C12 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 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 cyclodextrins and cyclodextrin derivatives can be employed. Cyclodextrins are cyclic oligosaccha-rides, which are composed of alpha-1,4-linked glu-cose components. Usually, six to eight glucose components (~, 8, or ~-cyclodextrin) are connected 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 purpose of the invention. The cyclodextrin or cyclodextrin derivative preferably is an ~ or f~-cyclodextrin and may in particular have the gen-eral formula II, ~ OR1 ~
N
_ p H H
ORz ~{ 0-OR
n _--------"'....-- /,/
Formula II
wherein Rl, R2, and R3 may be identical or differ-ent and an arbitrary physiologically tolerated residue, preferably -H, C1-C8 alkyl, -SOzOH, -PO(OH)zr or -CO-R4 with R4 = C1-C8 alkyl, wherein the Cl-C8 alkyl may be single or multiple at iden-tical or at different C atoms with -OH, -COOH, -CONHR5, -NHCOR6, - SOzOH, -PO(OH)2r or tetrazol-5-yl with R5 = -H or C1-C4 alkyl and R6 = carboxyl-phenyl, wherein n = 6, 7 or 8, wherein R1, R2 and R3 may be randomized in different 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 sul-fur atoms, including physiologically tolerated salts of such cyclodextrins. Preferably, the glu-copyranose units are ~-D or ~-L-glucopyranose units. Cl-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 Rl of a cyclodextrin molecule may be different from -H. R2 and R3 may then be -H. In 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-ing of "~-cyclodextrin, B-cyclodextrin, hydroxy-(Cl-C8 alkyl)-D-cyclodextrin, hydroxy-(Cl-C8 al-kyl)-B-cyclodextrin, (2-hydroxypropyl)-8-cyclodex-trin, (2-hydroxypropyl)-~-cyclodextrin, sulfo-(Cl-C8 alkyl)-ether-LI-cyclodextrin, sulfo-(Cl-C8 al-kyl)-ether-B-cyclodextrin, sulfobutylether-LI-cy-clodextrin, sulfobutylether-B-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 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-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-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 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 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 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 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-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 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 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)2r diethanolamine, ethylendia-mine, or with amino acids, such as arginine, ly-sine, glutamine acid etc. or with inorganic salts, such as CaC12r NaCl or the free ions thereof, such as Ca2+, Na+, Cl-, S042- 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 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, 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 1:100 to 10:1, most preferably 1:100 to 2:1, op-tionally 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, 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 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 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 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 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 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-stration unit is prepared for a'n 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 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 o2 = n2 * ml, or o and m are given and n is calcu-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-duced hemolysis by human serum albumin (HSA); comparative example.
Na2 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 % NaCl and the respective HSA concentrations, fur-ther stock solutions of 3,200, 1,600, 800, 200 and 100 mg/l Na2 friulimicin were prepared for every one of the listed HSA concentrations. After pre-incubation for 2 hours at ambient temperature, 40 ~1 of the friulimicin B/HSA mixture were mixed with 40 ~1 of fresh venal human blood and then in-cubated at 37 C for 180 min. As a negative con-trol, mixtures of full blood were prepared with the different HSA concentrations in 0.9 % NaCI, as a standard for the complete hydrolysis a mixture von 40 01 of fresh venal human blood were prepared with 40 01 water. Subsequently, the degree of the 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 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 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 hemolysis test with Na2 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 Na2 friulimicin B (in mg/l, free acid) refer to the final concentrations in the reaction batch.
Table 1 Hemolytic activity as a function of the Na2 friulimicin B concentration (mg/1) in presence of different HSA concentrations in vitro (in %) Friulimicin concentration in mg/1 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 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 Na2 friulimicin B beginning from a concentration of approx. 2.5 %. The follow-ing determination of the content of free hemoglo-bin in the serum showed that after pre-incubation with 5 0- 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 of such Na2 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 of the antibiotic activity.
Table 2 Determination of the minimum inhibitory concentra-tion (MIC) of Na2 friulimicin in presence of HSA
MIC value Medium addition [Elg/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 Example 2: Minimization of the hemolysis induced by Na2 by the addition of cyclodex-trins.
This example shows the effect of different modified or unmodified cyclodextrins on the hemo-lytic effect induced by lipopeptides. Herein, Na2 friulimicin B serves as an example molecule for the antibiotics of the lipopeptides.
Na2 friulimicin B was dissolved in a concen-tration of 3,200 mg/1 in 0.9 % NaCl solution. By 5 dilution with 0.9 % NaCl, further stock solutions of 1,600, 800, 200, 100 and 50 mg/1 Na2 friuli-micin were produced. 20 ~1 each of these stock so-lutions were carefully mixed with 20 01 0.9 % NaCl or 2 % solutions of (2-Hydroxypropyl)-D-cyclodex-10 trin (HP-O-CD), (2-Hydroxypropyl)-13-cyclodextrin (HP-l3-CD) or 0-cyclodextrin (0-CD) in 0.9 % NaC1.
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 Na2 friulimicin B (in mg/1, free acid) provided the results shown in Table 3.
20 Table 3 Hemolytic activity as a function of the Na2 friulimicin concentration in presence of different cyclodextrins in vitro (in %) Cyclodextrin conc. Friulimicin concentration in mg/1 without cyclodextrin addition 0 2.3 5.1 5.9 8.3 9.4 0.5 0(wt./vol.) ~-CD 0 0 0 0.1 0.4 1.2 0.5 0(wt./vol.) HP-8-CD 0 0 0.3 0.6 4.4 5.3 0.5 0(wt./vol.) HP-D-CD 0 2 4.8 5.8 6.6 8.6 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 Na2 friulimicin B. ~-cyclodextrins have, due to their sugar structure, a larger volume in their hydrophobic inner pocket, compared to ~ and B-cy-clodextrins. Surprisingly, however, after the pre-incubation with 0.5 % HP-B-CD and ~-CD a signifi-cant reduction of the hemolysis induced by di-so-dium friulimicin B could be detected.
Example 3: Minimization of the Ca2C12 friulimicin B-induced hemolysis by the addition of modified B-cyclodextrins.
This example shows the effect of B-cyclodex-trins on the hemolytic effect induced by lipopep-tides in presence of high concentrations of the lipopeptide. Herein, Ca2C12 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopeptides and sulfobutylether-8-cyclodextrin (SBE-B-CD) as well as HP-8-CD as ex-amples for modified B-cyclodextrins.
Ca2C12 friulimicin B was dissolved in a concen-tration of 100, 50, 40, 30, 20, 10 and 5 g/l in 20, 15, 12.5, 10, 7.5 % SBE-8-CD in 0.9 % NaCl so-lution or 12.5 % HP-8-CD in 0.9 % NaC1 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-ing to Example 1. Different therefrom, the incuba-tion of the final reaction batches was performed with blood for 60 min at 37 C. The results are shown in Table 4. Statements of the Ca2Cl2 friuli-micin B (in mg/1, free acid) and of the cyclodex-trins refer to the final concentrations in the re-action batch.
Table 4 Hemolytic activity as a function of the Ca2C12 friulimicin concentration in presence of different cyclodextrins in vitro (in %) Cyclodextrin conc. Friulimicin concentration in g/l without cyclodextrin addition 0 76 87 91 93 97 7.5 0(wt./vol.) SBE-B-CD 0 0 1 3 18 63 0(wt./vol.) SBE-B-CD 0 0 1 3 13 42 12.5 0(wt./vol.) SBE-B-CD 0 0 0 1 4 12 10 15 0(wt./vol.) SBE-B-CD 0 0 0 1 1 4 Surprisingly, it could be found that HP-8-CD, in particular however also SBE-f~-CD itself sup-press at very high concentrations of the hemolyti-cally very active Ca2C12 salt of friulimicin B the 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 Ca2C12 friulimicin B can 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 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 CaC12.
Daptomycin was dissolved in a solution of 0 %
or 2.5 % SBE-B-CD in 0.9 % NaCl, 2.5 mM CaC12. 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 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 ~1 of the erythrocytes were reacted with 40 ~1 of the above reaction batches and incubated for 5 hours at 37 C 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-centrations of SBE-8-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 concentration in presence of SBE-B-CD in vitro (in %) Cyclodextrin conc. Daptomycin conc. in (mg/1) 0 1,600 3,200 6,400 12,800 0% 0 1.7 6.5 7.6 7.8 1.25 a(wt./vol.) 0 0 0.1 0.1 0 SBE-13-CD suppressed also in the experiment with isolated erythrocytes the cell lysis induced by a lipopeptide, here daptomycin. This experiment shows that SBE-B-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-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-trins on the antibiotic activity of Ca2C12 friulimicin B.
The effects of cyclodextrins on the antibiotic activity von Ca2C12 friulimicin B were investi-gated by in vitro experiments about the growth in-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-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, Wayne, PA, USA). Different molar mixture ratios of the lipopeptide Ca2Cl2 friulimicin B were tested with SBE-13-CD in Ca ions-adjusted Muller-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 employed quantities of cells per spot (in-tended value: 5*103 - 5*104 CFU) were:
S. carnosus ATCC 51365 5.5 * 103 CFU
S. aureus ATCC 29213 7.6 * 103 CFU
S. aureus ATCC 33592 2.2 * 109 CFU
S. epidermidis ATCC 12228 1.1 * 109 CFU
Table 6 Antibiotic activity (MIC in ~g/ml) of Ca2C12 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 Ca2C12 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-13-CD were re-30 spectively produced stock solutions of 3,200 mg/1 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 of the lipopeptide-induced hemolysis by the pres-ence von 2.5 % SBE-B-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 lipopeptides have a structure according to formula I
Y-X-Dab-Pip-MeAsp-Asp-Gly-Asp-Gly-Dab-Val-Pro -------------------------------------formula I
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 CBS000201 Asn 12-methyltridecanoic acid CBS000205 Asn 15-phenyl-n-pentadecancarbonic acid CBS000203 Asn stearic acid CBS000204 Asn LI-linolenic acid CBS000217 Asn 4-[2-(4-Phenethyl-phenyl)-ethyl]-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 A1.
Table 7 Inhibition of the hemolytic activity of different lipopeptides at a concentration of 1,600 mg/1 in presence of 2.5 % SBE-B-CD
Lipopeptide Reduction of the hemolysis in %
Amphomycin 99.6 %
Ca2C12 friulimicin B 99.2 %
CBS000201 95.7 %
CBS000205 74.9 %
CBS000203 41.3 %
CBS000204 87.0 %
CBS000217 99.5 %
These results show that cyclodextrins are sub-stantially independently from the acyl and pepti-dyl residue of lipopeptides capable to reduce the hemolysis.
Example 7: Production of a Ca2C12 friulimicin B
injection solution.
100 mg Ca2C12 friulimicin B and 770 mg SBE-13-CD
are dissolved in a sterile 0.9 % NaCl solution, filtrated through a polyethersulfone membrane (0.2 ~m, non-pyrogenic) and lyophilized. The whole ly-ophilisate is then dissolved in 10 ml water for injection solutions, filled into a sterile ampule.
Then the ampule is sealed with a septum.
Example 8: Minimization of the hemolysis induced by Ca2C12 friulimicin B by the addition of different concentrations of sulfo-butylether-l3-cyclodextrin (SBE-B-CD).
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 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, 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 1:100 to 10:1, most preferably 1:100 to 2:1, op-tionally 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, 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 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 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 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 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 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-stration unit is prepared for a'n 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 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 o2 = n2 * ml, or o and m are given and n is calcu-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-duced hemolysis by human serum albumin (HSA); comparative example.
Na2 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 % NaCl and the respective HSA concentrations, fur-ther stock solutions of 3,200, 1,600, 800, 200 and 100 mg/l Na2 friulimicin were prepared for every one of the listed HSA concentrations. After pre-incubation for 2 hours at ambient temperature, 40 ~1 of the friulimicin B/HSA mixture were mixed with 40 ~1 of fresh venal human blood and then in-cubated at 37 C for 180 min. As a negative con-trol, mixtures of full blood were prepared with the different HSA concentrations in 0.9 % NaCI, as a standard for the complete hydrolysis a mixture von 40 01 of fresh venal human blood were prepared with 40 01 water. Subsequently, the degree of the 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 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 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 hemolysis test with Na2 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 Na2 friulimicin B (in mg/l, free acid) refer to the final concentrations in the reaction batch.
Table 1 Hemolytic activity as a function of the Na2 friulimicin B concentration (mg/1) in presence of different HSA concentrations in vitro (in %) Friulimicin concentration in mg/1 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 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 Na2 friulimicin B beginning from a concentration of approx. 2.5 %. The follow-ing determination of the content of free hemoglo-bin in the serum showed that after pre-incubation with 5 0- 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 of such Na2 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 of the antibiotic activity.
Table 2 Determination of the minimum inhibitory concentra-tion (MIC) of Na2 friulimicin in presence of HSA
MIC value Medium addition [Elg/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 Example 2: Minimization of the hemolysis induced by Na2 by the addition of cyclodex-trins.
This example shows the effect of different modified or unmodified cyclodextrins on the hemo-lytic effect induced by lipopeptides. Herein, Na2 friulimicin B serves as an example molecule for the antibiotics of the lipopeptides.
Na2 friulimicin B was dissolved in a concen-tration of 3,200 mg/1 in 0.9 % NaCl solution. By 5 dilution with 0.9 % NaCl, further stock solutions of 1,600, 800, 200, 100 and 50 mg/1 Na2 friuli-micin were produced. 20 ~1 each of these stock so-lutions were carefully mixed with 20 01 0.9 % NaCl or 2 % solutions of (2-Hydroxypropyl)-D-cyclodex-10 trin (HP-O-CD), (2-Hydroxypropyl)-13-cyclodextrin (HP-l3-CD) or 0-cyclodextrin (0-CD) in 0.9 % NaC1.
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 Na2 friulimicin B (in mg/1, free acid) provided the results shown in Table 3.
20 Table 3 Hemolytic activity as a function of the Na2 friulimicin concentration in presence of different cyclodextrins in vitro (in %) Cyclodextrin conc. Friulimicin concentration in mg/1 without cyclodextrin addition 0 2.3 5.1 5.9 8.3 9.4 0.5 0(wt./vol.) ~-CD 0 0 0 0.1 0.4 1.2 0.5 0(wt./vol.) HP-8-CD 0 0 0.3 0.6 4.4 5.3 0.5 0(wt./vol.) HP-D-CD 0 2 4.8 5.8 6.6 8.6 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 Na2 friulimicin B. ~-cyclodextrins have, due to their sugar structure, a larger volume in their hydrophobic inner pocket, compared to ~ and B-cy-clodextrins. Surprisingly, however, after the pre-incubation with 0.5 % HP-B-CD and ~-CD a signifi-cant reduction of the hemolysis induced by di-so-dium friulimicin B could be detected.
Example 3: Minimization of the Ca2C12 friulimicin B-induced hemolysis by the addition of modified B-cyclodextrins.
This example shows the effect of B-cyclodex-trins on the hemolytic effect induced by lipopep-tides in presence of high concentrations of the lipopeptide. Herein, Ca2C12 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopeptides and sulfobutylether-8-cyclodextrin (SBE-B-CD) as well as HP-8-CD as ex-amples for modified B-cyclodextrins.
Ca2C12 friulimicin B was dissolved in a concen-tration of 100, 50, 40, 30, 20, 10 and 5 g/l in 20, 15, 12.5, 10, 7.5 % SBE-8-CD in 0.9 % NaCl so-lution or 12.5 % HP-8-CD in 0.9 % NaC1 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-ing to Example 1. Different therefrom, the incuba-tion of the final reaction batches was performed with blood for 60 min at 37 C. The results are shown in Table 4. Statements of the Ca2Cl2 friuli-micin B (in mg/1, free acid) and of the cyclodex-trins refer to the final concentrations in the re-action batch.
Table 4 Hemolytic activity as a function of the Ca2C12 friulimicin concentration in presence of different cyclodextrins in vitro (in %) Cyclodextrin conc. Friulimicin concentration in g/l without cyclodextrin addition 0 76 87 91 93 97 7.5 0(wt./vol.) SBE-B-CD 0 0 1 3 18 63 0(wt./vol.) SBE-B-CD 0 0 1 3 13 42 12.5 0(wt./vol.) SBE-B-CD 0 0 0 1 4 12 10 15 0(wt./vol.) SBE-B-CD 0 0 0 1 1 4 Surprisingly, it could be found that HP-8-CD, in particular however also SBE-f~-CD itself sup-press at very high concentrations of the hemolyti-cally very active Ca2C12 salt of friulimicin B the 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 Ca2C12 friulimicin B can 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 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 CaC12.
Daptomycin was dissolved in a solution of 0 %
or 2.5 % SBE-B-CD in 0.9 % NaCl, 2.5 mM CaC12. 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 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 ~1 of the erythrocytes were reacted with 40 ~1 of the above reaction batches and incubated for 5 hours at 37 C 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-centrations of SBE-8-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 concentration in presence of SBE-B-CD in vitro (in %) Cyclodextrin conc. Daptomycin conc. in (mg/1) 0 1,600 3,200 6,400 12,800 0% 0 1.7 6.5 7.6 7.8 1.25 a(wt./vol.) 0 0 0.1 0.1 0 SBE-13-CD suppressed also in the experiment with isolated erythrocytes the cell lysis induced by a lipopeptide, here daptomycin. This experiment shows that SBE-B-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-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-trins on the antibiotic activity of Ca2C12 friulimicin B.
The effects of cyclodextrins on the antibiotic activity von Ca2C12 friulimicin B were investi-gated by in vitro experiments about the growth in-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-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, Wayne, PA, USA). Different molar mixture ratios of the lipopeptide Ca2Cl2 friulimicin B were tested with SBE-13-CD in Ca ions-adjusted Muller-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 employed quantities of cells per spot (in-tended value: 5*103 - 5*104 CFU) were:
S. carnosus ATCC 51365 5.5 * 103 CFU
S. aureus ATCC 29213 7.6 * 103 CFU
S. aureus ATCC 33592 2.2 * 109 CFU
S. epidermidis ATCC 12228 1.1 * 109 CFU
Table 6 Antibiotic activity (MIC in ~g/ml) of Ca2C12 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 Ca2C12 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-13-CD were re-30 spectively produced stock solutions of 3,200 mg/1 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 of the lipopeptide-induced hemolysis by the pres-ence von 2.5 % SBE-B-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 lipopeptides have a structure according to formula I
Y-X-Dab-Pip-MeAsp-Asp-Gly-Asp-Gly-Dab-Val-Pro -------------------------------------formula I
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 CBS000201 Asn 12-methyltridecanoic acid CBS000205 Asn 15-phenyl-n-pentadecancarbonic acid CBS000203 Asn stearic acid CBS000204 Asn LI-linolenic acid CBS000217 Asn 4-[2-(4-Phenethyl-phenyl)-ethyl]-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 A1.
Table 7 Inhibition of the hemolytic activity of different lipopeptides at a concentration of 1,600 mg/1 in presence of 2.5 % SBE-B-CD
Lipopeptide Reduction of the hemolysis in %
Amphomycin 99.6 %
Ca2C12 friulimicin B 99.2 %
CBS000201 95.7 %
CBS000205 74.9 %
CBS000203 41.3 %
CBS000204 87.0 %
CBS000217 99.5 %
These results show that cyclodextrins are sub-stantially independently from the acyl and pepti-dyl residue of lipopeptides capable to reduce the hemolysis.
Example 7: Production of a Ca2C12 friulimicin B
injection solution.
100 mg Ca2C12 friulimicin B and 770 mg SBE-13-CD
are dissolved in a sterile 0.9 % NaCl solution, filtrated through a polyethersulfone membrane (0.2 ~m, non-pyrogenic) and lyophilized. The whole ly-ophilisate is then dissolved in 10 ml water for injection solutions, filled into a sterile ampule.
Then the ampule is sealed with a septum.
Example 8: Minimization of the hemolysis induced by Ca2C12 friulimicin B by the addition of different concentrations of sulfo-butylether-l3-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, Ca2C12 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopep-tides and sulfobutylether-B-cyclodextrin (SBE-8-CD) as an example molecule for the cyclodextrins.
Ca2C12 friulimicin B was dissolved in a concen-tration of 2,500 mg/l in 0.9 % NaCl solution. To different batches of this 0.9 % NaCl solution were added different SBE-B-CD concentrations, so that the following molar ratios (SBE-B-CD : friulimicin B) were generated: 0:1; 1:10; 1:5; 1:1; 2.5:1;
5.1; 10.1.
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 Ca2C1z friulimicin B in absence of SBE-B-CD is reduced by the addition of SBE-3-CD in the mentioned molar ratios.
Statements of the content of Ca2C12 friulimicin B (in mg/1) refer to the final concentrations of 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-B-CD.
Table 8 Reduction of the hemolysis induced by 2,500 mg/1 Ca2C12 friulimicin B by SBE-B-CD in vitro (in %) Molar ratio Reduction of the SBE-8-CD : friulimicin B induced hemolysis 0 : 1 0 0 1 : 10 11 %
1 : 5 28 %
1 1 80 %
2.5 : 1 96 %
5 : 1 98 %
: 1 100 %
Surprisingly it could be found that SBE-B-CD
10 suppressed already in substoechiometric concentra-tions the hemolysis induced by Ca2C12 friulimicin B even at a friulimicin B concentration of 2,500 mg/1 during an incubation duration of 3 hours.
Example 9: Effect of cyclodextrins on the hemo-lytic activity of a cyclic peptide.
This example concerns the inhibition of the hemolytic activity of different iipopeptides by cyclodextrins and shows the effect of a sulfoal-kylether cyclodextrin on the hemolytic effect in-duced by the cyclic peptide tyrocidin. Tyrocidin was dissolved in a concentration of 6,400 mg/i in 0.9 % NaCl solution. By dilution with a volume of 0.9 % NaCl or 0.9 % NaCl/10 % SBE-8-CD, stock so-lutions of 3,200 mg/1 tyrocidin with or without 5 % SBE-3-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 the hemolysis induced by 1,600 mg/1 tyrocidin in presence of 2.5 % SBE-13-CD is increased by 178 0.
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 Ca2Cl2 friulimicin B with canine blood by sulfobutylether-3-cyclodex-trin (SBE-8-CD).
5 This example shows the effect of f3-cyclodex-trins on the lipopeptide-induced hemolytic effect with blood of different organisms. Herein, Ca2C12 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopeptides 10 and sulfobutylether-8-cyclodextrin (SBE-3-CD) as examples for modified B-cyclodextrins. The experi-ments were made with canine blood.
Ca2C12 friulimicin B was dissolved in 0.9 %
NaCl solution with and without addition of SBE-8-15 CD. In the batch with SBE-8-CD there was a molar ratio (SBE-B-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 Ca2C12 friulimicin B (in mg/1) 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-B-CD, respectively.
Table 9 Reduction of the hemolysis induced by Ca2C12 friulimicin B by SBE-B-CD in vitro with canine blood (in %) 30 Friulimicin B Reduction of the hemolysis by the concentration addition of SBE-B-CD
800 55 %
5, 000 100 0 The example shows that SBE-13-CD in a molar ra-tio of 2.5 : 1(SBE-B-CD : friulimicin B) sup-presses the lysis induced by CaZCl2 friulimicin B
of erythrocytes in canine blood.
Example 11: Minimization of the hemolysis induced by Ca2C12 friulimicin B with blood of macaques (Macaca fascicularis) by sul-fobutylether-l3-cyclodextrin (SBE-8-CD) .
This example shows the effect of B-cyclodex-trins on the hemolytic effect induced by lipopep-tides with the blood of different organisms.
Herein, Ca2C12 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopeptides and sulfobutylether-3-cyclodextrin (SBE-B-CD) as an example for cyclodextrins. The experiments were made with the blood of macaques.
CazC12 friulimicin B was dissolved in 0.9 0 NaCl solution with and without addition of SBE-13-CD. In the batch with SBE-8-CD, there was a molar ratio (SBE-f3-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 1. Statements of the content of Ca2C12 friulimicin B (in mg/1) 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-f3-CD, re-spectively.
Table 10 Reduction of the hemolysis induced by Ca2C12 friulimicin B by SBE-B-CD in vitro with blood of macaques (in %) Friulimicin B Reduction of the hemolysis by the concentration addition of SBE-13-CD
3, 200 92 %
6, 400 99 %
The example shows that SBE-1~-CD in a molar ra-tio of 5. 1(SBE-B-CD : friulimicin B) suppresses the lysis induced by CazCl2 friulimicin B of erythrocytes in the blood of macaques.
Example 12: Influence of the antibiotic activity of lipopeptides by cyclodextrins in vivo.
This example shows the effect of B-cyclodex-trins on the antibiotic activity of lipopeptides in vivo. Herein, Ca2C12 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopeptides and sulfobutylether-8-cyclo-dextrin (SBE-B-CD) as examples for modified 13-cyclodextrins. Shown are the results of a study with an intranasal lung infection model in the mouse.
CazC12 friulimicin B was dissolved in 0.9 %
NaCl solution with and without addition of SBE-f3-CD. In the batch with SBE-13-CD , there was a molar ratio (SBE-8-CD : friulimicin B) of 2,5 . 1. The statements of the Ca2C12 friulimicin B concentra-tion (in mg/1) refer to the final concentrations of the free acid of the friulimicin B in the reac-tion batch. The statements of the molar ratios re-fer to the free acids of friulimicin B and SBE-13-CD, respectively.
Female mice (CFW-1 (Harlan Winkelmann, Ger-many)) were infected intranasally with Streptococ-cus pneumoniae L3TV (1*106 CFU/mouse). 1 and 4 hours after the infection, the animals were subcu-taneously administered a total dose of 20 mg Ca2C12 friulimicin B / kg with and without SBE-8-CD (5 0). 24 hours after the infection, a determi-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-3-CD increases the antibiotic effect of Ca2Cl2 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 13-cyclodex-trins on the acute toxic effects in mice caused by high concentrations of lipopeptides. Herein, Ca2C12 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopep-tides and sulfobutylether-B-cyclodextrin (SBE-t~-CD) as examples for modified B-cyclodextrins.
CazC12 friulimicin B was dissolved in 0.9 %
NaCl solution with and without addition of SBE-8-CD. In the batch with SBE-I3-CD, there was a molar ratio (SBE-B-CD . friulimicin B) of 2.5 . 1. The statements of the Ca2Clz friulimicin B concentra-tion (in mg/1) refer to the final concentrations of the free acid of the friulimicin B in the reac-tion batch. The statements of the molar ratio re-fer to the free acids of friulimicin B and SBE-B-CD, respectively.
Female mice (CFW-1 (Harlan Winkelmann, Ger-many)) were administered once (iv) the Ca2C12 friulimicin B solutions with and without SBE-B-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-stration of Ca2C12 friulimicin B with and without SBE-3-CD (in %) .
Friulimicin B Friulimicin B
with addition without addition Mortality rate of SBE-l3-CD of SBE-13-CD within 24 hours 300 mg/kg 0 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) The example shows that the acute toxicity of CazC12 friulimicin B by the presence of SBE-f3-CD
in a molar ratio of 2,5 . 1(SBE-f3-CD . friuli-micin B) is reduced.
Ca2C12 friulimicin B was dissolved in a concen-tration of 2,500 mg/l in 0.9 % NaCl solution. To different batches of this 0.9 % NaCl solution were added different SBE-B-CD concentrations, so that the following molar ratios (SBE-B-CD : friulimicin B) were generated: 0:1; 1:10; 1:5; 1:1; 2.5:1;
5.1; 10.1.
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 Ca2C1z friulimicin B in absence of SBE-B-CD is reduced by the addition of SBE-3-CD in the mentioned molar ratios.
Statements of the content of Ca2C12 friulimicin B (in mg/1) refer to the final concentrations of 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-B-CD.
Table 8 Reduction of the hemolysis induced by 2,500 mg/1 Ca2C12 friulimicin B by SBE-B-CD in vitro (in %) Molar ratio Reduction of the SBE-8-CD : friulimicin B induced hemolysis 0 : 1 0 0 1 : 10 11 %
1 : 5 28 %
1 1 80 %
2.5 : 1 96 %
5 : 1 98 %
: 1 100 %
Surprisingly it could be found that SBE-B-CD
10 suppressed already in substoechiometric concentra-tions the hemolysis induced by Ca2C12 friulimicin B even at a friulimicin B concentration of 2,500 mg/1 during an incubation duration of 3 hours.
Example 9: Effect of cyclodextrins on the hemo-lytic activity of a cyclic peptide.
This example concerns the inhibition of the hemolytic activity of different iipopeptides by cyclodextrins and shows the effect of a sulfoal-kylether cyclodextrin on the hemolytic effect in-duced by the cyclic peptide tyrocidin. Tyrocidin was dissolved in a concentration of 6,400 mg/i in 0.9 % NaCl solution. By dilution with a volume of 0.9 % NaCl or 0.9 % NaCl/10 % SBE-8-CD, stock so-lutions of 3,200 mg/1 tyrocidin with or without 5 % SBE-3-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 the hemolysis induced by 1,600 mg/1 tyrocidin in presence of 2.5 % SBE-13-CD is increased by 178 0.
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 Ca2Cl2 friulimicin B with canine blood by sulfobutylether-3-cyclodex-trin (SBE-8-CD).
5 This example shows the effect of f3-cyclodex-trins on the lipopeptide-induced hemolytic effect with blood of different organisms. Herein, Ca2C12 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopeptides 10 and sulfobutylether-8-cyclodextrin (SBE-3-CD) as examples for modified B-cyclodextrins. The experi-ments were made with canine blood.
Ca2C12 friulimicin B was dissolved in 0.9 %
NaCl solution with and without addition of SBE-8-15 CD. In the batch with SBE-8-CD there was a molar ratio (SBE-B-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 Ca2C12 friulimicin B (in mg/1) 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-B-CD, respectively.
Table 9 Reduction of the hemolysis induced by Ca2C12 friulimicin B by SBE-B-CD in vitro with canine blood (in %) 30 Friulimicin B Reduction of the hemolysis by the concentration addition of SBE-B-CD
800 55 %
5, 000 100 0 The example shows that SBE-13-CD in a molar ra-tio of 2.5 : 1(SBE-B-CD : friulimicin B) sup-presses the lysis induced by CaZCl2 friulimicin B
of erythrocytes in canine blood.
Example 11: Minimization of the hemolysis induced by Ca2C12 friulimicin B with blood of macaques (Macaca fascicularis) by sul-fobutylether-l3-cyclodextrin (SBE-8-CD) .
This example shows the effect of B-cyclodex-trins on the hemolytic effect induced by lipopep-tides with the blood of different organisms.
Herein, Ca2C12 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopeptides and sulfobutylether-3-cyclodextrin (SBE-B-CD) as an example for cyclodextrins. The experiments were made with the blood of macaques.
CazC12 friulimicin B was dissolved in 0.9 0 NaCl solution with and without addition of SBE-13-CD. In the batch with SBE-8-CD, there was a molar ratio (SBE-f3-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 1. Statements of the content of Ca2C12 friulimicin B (in mg/1) 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-f3-CD, re-spectively.
Table 10 Reduction of the hemolysis induced by Ca2C12 friulimicin B by SBE-B-CD in vitro with blood of macaques (in %) Friulimicin B Reduction of the hemolysis by the concentration addition of SBE-13-CD
3, 200 92 %
6, 400 99 %
The example shows that SBE-1~-CD in a molar ra-tio of 5. 1(SBE-B-CD : friulimicin B) suppresses the lysis induced by CazCl2 friulimicin B of erythrocytes in the blood of macaques.
Example 12: Influence of the antibiotic activity of lipopeptides by cyclodextrins in vivo.
This example shows the effect of B-cyclodex-trins on the antibiotic activity of lipopeptides in vivo. Herein, Ca2C12 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopeptides and sulfobutylether-8-cyclo-dextrin (SBE-B-CD) as examples for modified 13-cyclodextrins. Shown are the results of a study with an intranasal lung infection model in the mouse.
CazC12 friulimicin B was dissolved in 0.9 %
NaCl solution with and without addition of SBE-f3-CD. In the batch with SBE-13-CD , there was a molar ratio (SBE-8-CD : friulimicin B) of 2,5 . 1. The statements of the Ca2C12 friulimicin B concentra-tion (in mg/1) refer to the final concentrations of the free acid of the friulimicin B in the reac-tion batch. The statements of the molar ratios re-fer to the free acids of friulimicin B and SBE-13-CD, respectively.
Female mice (CFW-1 (Harlan Winkelmann, Ger-many)) were infected intranasally with Streptococ-cus pneumoniae L3TV (1*106 CFU/mouse). 1 and 4 hours after the infection, the animals were subcu-taneously administered a total dose of 20 mg Ca2C12 friulimicin B / kg with and without SBE-8-CD (5 0). 24 hours after the infection, a determi-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-3-CD increases the antibiotic effect of Ca2Cl2 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 13-cyclodex-trins on the acute toxic effects in mice caused by high concentrations of lipopeptides. Herein, Ca2C12 friulimicin B serves as an example molecule for the antibiotics of the class of the lipopep-tides and sulfobutylether-B-cyclodextrin (SBE-t~-CD) as examples for modified B-cyclodextrins.
CazC12 friulimicin B was dissolved in 0.9 %
NaCl solution with and without addition of SBE-8-CD. In the batch with SBE-I3-CD, there was a molar ratio (SBE-B-CD . friulimicin B) of 2.5 . 1. The statements of the Ca2Clz friulimicin B concentra-tion (in mg/1) refer to the final concentrations of the free acid of the friulimicin B in the reac-tion batch. The statements of the molar ratio re-fer to the free acids of friulimicin B and SBE-B-CD, respectively.
Female mice (CFW-1 (Harlan Winkelmann, Ger-many)) were administered once (iv) the Ca2C12 friulimicin B solutions with and without SBE-B-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-stration of Ca2C12 friulimicin B with and without SBE-3-CD (in %) .
Friulimicin B Friulimicin B
with addition without addition Mortality rate of SBE-l3-CD of SBE-13-CD within 24 hours 300 mg/kg 0 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) The example shows that the acute toxicity of CazC12 friulimicin B by the presence of SBE-f3-CD
in a molar ratio of 2,5 . 1(SBE-f3-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 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 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 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.
Y-X-Dab-Pip-MeAsp-Asp-Gly-Asp-Gly-Dab-Val-Pro 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 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.
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 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-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-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 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-erably as a Na or calcium salt, in particular as a di-calcium salt (Ca2Cl2 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 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 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 cyclodextrin derivative is an ~ or .beta.-cyclodextrin and preferably has the general formula II
wherein R1, R2, and R3 may be identical or differ-ent and an arbitrary physiologically tolerated residue, preferably -H, C1-C8 alkyl, -SO2OH, -PO (OH) 2, or -CO-R4 with R4 = C1-C8 alkyl, wherein the C1-C8 alkyl may be single or multiple at iden-tical or at different C atoms with -OH, -COOH, -CONHR5, -NHCOR6, - S0 2OH, -PO(OH)2, or tetrazol-5-yl with R5 = -H or C1-C4 alkyl and R6 = carboxyl-phenyl, wherein n = 6 or 7 wherein R1, 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 cyclodextrins.
wherein R1, R2, and R3 may be identical or differ-ent and an arbitrary physiologically tolerated residue, preferably -H, C1-C8 alkyl, -SO2OH, -PO (OH) 2, or -CO-R4 with R4 = C1-C8 alkyl, wherein the C1-C8 alkyl may be single or multiple at iden-tical or at different C atoms with -OH, -COOH, -CONHR5, -NHCOR6, - S0 2OH, -PO(OH)2, or tetrazol-5-yl with R5 = -H or C1-C4 alkyl and R6 = carboxyl-phenyl, wherein n = 6 or 7 wherein R1, 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 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 "~-cyclodextrin, .beta.-cyclodextrin, hy-droxy-(C1-C8 alkyl)-~-cyclodextrin, hydroxy-(C1-C8 alkyl)-3-cyclodextrin, (2-hydroxypropyl)-.beta.-cyclo-dextrin, (2-hydroxypropyl)-~-cyclodextrin, sulfo-(C1-C8 alkyl)-ether-~-cyclodextrin, sulfo-(C1-C8 alkyl)-ether-B-cyclodextrin, sulfobutylether-~-cyclodextrin, sulfobutylether-.beta.-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 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.
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 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 %.
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.
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-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 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 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 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 substances in galenically usual additions.
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| 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 |
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| CA2630497A1 true CA2630497A1 (en) | 2007-05-24 |
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| CA002630497A Abandoned CA2630497A1 (en) | 2005-11-21 | 2006-11-20 | Lipopeptide compositions |
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| EP (1) | EP1951311A1 (en) |
| CN (1) | CN101370524A (en) |
| AU (1) | AU2006314942A1 (en) |
| CA (1) | CA2630497A1 (en) |
| DE (1) | DE102005056194A1 (en) |
| MX (1) | MX2008006476A (en) |
| WO (1) | WO2007057005A1 (en) |
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| CN104768966B (en) * | 2012-09-24 | 2018-11-02 | 中化帝斯曼制药有限公司荷兰公司 | The method for producing cyclic peptide |
| JP2022532045A (en) * | 2019-05-10 | 2022-07-13 | クセリア ファーマシューティカルズ エーピーエス | Daptomycin aqueous preparation |
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| 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 |
| WO2001097851A2 (en) * | 2000-06-21 | 2001-12-27 | Cubist Pharmaceuticals, Inc. | Compositions and methods to improve the oral absorption of antimicrobial agents |
| US7527807B2 (en) * | 2000-06-21 | 2009-05-05 | Cubist Pharmaceuticals, Inc. | Compositions and methods for increasing the oral absorption of antimicrobials |
| US6699505B2 (en) * | 2000-10-17 | 2004-03-02 | Massachusetts Institute Of Technology | Method of increasing the efficacy of antibiotics by compexing with cyclodextrins |
-
2005
- 2005-11-21 DE DE102005056194A patent/DE102005056194A1/en not_active Ceased
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2006
- 2006-11-20 CN CNA2006800511655A patent/CN101370524A/en active Pending
- 2006-11-20 WO PCT/DE2006/002064 patent/WO2007057005A1/en active Application Filing
- 2006-11-20 CA CA002630497A patent/CA2630497A1/en not_active Abandoned
- 2006-11-20 AU AU2006314942A patent/AU2006314942A1/en not_active Abandoned
- 2006-11-20 MX MX2008006476A patent/MX2008006476A/en not_active Application Discontinuation
- 2006-11-20 EP EP06805527A patent/EP1951311A1/en not_active Withdrawn
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| EP1951311A1 (en) | 2008-08-06 |
| CN101370524A (en) | 2009-02-18 |
| WO2007057005A1 (en) | 2007-05-24 |
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