EP1951311A1 - Compositions a base de lipopeptide - Google Patents

Compositions a base de lipopeptide

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Publication number
EP1951311A1
EP1951311A1 EP06805527A EP06805527A EP1951311A1 EP 1951311 A1 EP1951311 A1 EP 1951311A1 EP 06805527 A EP06805527 A EP 06805527A EP 06805527 A EP06805527 A EP 06805527A EP 1951311 A1 EP1951311 A1 EP 1951311A1
Authority
EP
European Patent Office
Prior art keywords
amphomycin
cyclodextrin
derivatives
lipopeptide
weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06805527A
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German (de)
English (en)
Inventor
Harald Labischinski
Stefan Pelzer
Horst Priefert
Andreas Vente
Sven-Eric Wohlert
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merlion Pharmaceuticals GmbH
Original Assignee
Merlion Pharmaceuticals GmbH
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Filing date
Publication date
Application filed by Merlion Pharmaceuticals GmbH filed Critical Merlion Pharmaceuticals GmbH
Publication of EP1951311A1 publication Critical patent/EP1951311A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • the invention relates to novel pharmaceutical compositions containing lipopeptides, to the use of such compositions, to processes for their preparation and to their use as medicaments.
  • Antibiotics from the class of lipopeptides that are characterized by being of a linear or cyclic peptide moiety, or a combination of both, with natural and / or unnatural, derivatized and / or non-derivatized amino acids to which a saturated or unsaturated acyl moiety is attached, optionally substituted by one or more phenyl or the like
  • Cycloalkyl groups may be interrupted or connected to such groups or interrupted by one or more oxygen or nitrogen atoms, have proven in the past to be extremely effective against fungi and Gram-positive bacteria. For the majority of these compounds, however, toxic properties are also known.
  • the compound daptomycin which is one of the class of A-21978C lipopeptides, damages skeletal muscle
  • cyclodextrins in pharmaceutical compositions. Due to their circular structure, cyclodextrins have a hydrophilic outside and a hydrophobic inside pocket. By enveloping in particular hydrophobic regions of the molecules, cyclodextrins can achieve a "molecular encapsulation" or “masking" of active substances, which is used, for example, as a protective coating of sensitive molecules in cosmetic and pharmaceutical formulations. This allows improved solubilities of Substances, but also reduced toxicities, such as a reduction in the hemolytic properties of molecules (J. Pharmacobiodyn.
  • the invention is therefore based on the technical problem of providing new pharmaceutical compositions with antibacterial, antiviral and / or antimycotic lipopeptides available whose compatibility is improved to the extent of preserving the physiological efficacy that even at very high concentrations, for example, in Infusions typically occur at short notice at the site of application, with only minor toxic side effects.
  • the invention teaches a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient an antibacterial, antiviral, and / or antimycotic lipopeptide in a physiologically effective dose and a physiologically acceptable cyclodextrin or a cyclodextrin derivative.
  • the invention is based on the surprising finding that, especially by using cyclodextrins or cyclodextrin derivatives, not only a reduction in the haemolytic properties of antibiotically acting lipopeptides is achieved, but rather that at the same time the antibiotic effect of the lipopeptides is retained while, for example, a masking with HSA leads to a reduced or completely suppressed antibiotic effect.
  • the lipopeptide preferably has a structure according to formula I,
  • X one of the amino acids Asn or Asp
  • Y a straight-chain or branched, saturated or unsaturated aliphatic acyl radical having 6 to 22 carbon atoms, optionally interrupted by or linked to one or more phenyl or cycloalkyl groups or may be interrupted by one or more oxygen atoms.
  • the amino acids of the peptide portion of the molecule can be derivatized (US2005 / 0153876 A1).
  • X Asn, it is friulimicin or a friulimicin derivative.
  • Y are in particular:
  • (CH 3 ) 2 CH (CH 2 ) 7 CH CHCH 2 CO-, CH 3 (CH 2 ) 6 CO-, CH 3 (CH 2 ) 7 CO-, CH 3 (CH 2 ) 8 CO-, CH 3 (CH 2) 9 CO- 5 CH 3 (CH 2 KoCO-, CH 3 (CH 2) X1 CO-,
  • the lipopeptide can be selected independently of the formula I from the group consisting of "amphomycin, amphomycin derivatives, friulimicin, friulimicin B, friulimicin derivatives, daptomycin, daptomycin derivatives, aspartocin, aspartocin derivatives, glumamycin, glumamycin derivatives, crystallomycin , Crystallomycin Derivatives, Zaomycin, Zaomycin Derivatives, Tsushimycin, Tsushimyin Derivatives, Laspartomycin, Laspartomycin Derivatives, Brevistin, Brevistin Derivatives, Cerexin B, Cerexin B Derivatives, Syringomycin and Its Derivatives, Antibiotic A-30912 and its Derivatives, Antibiotic A-54145 and its derivatives as well as Antibiotic A-21978C and its derivatives ".
  • AMINOPHENYLPROPANOYL) 2 -AMPHOMYCIN, CH 3 - (CH 2) 9 -O-P-PH-C ( 0) - GLY-amphomycin, Ci 2 - (M-APA) -AMPHOMYCIN, C 5 - [ASP (OtBu)] AMPHOMYCIN, C 10 - (M-APA) -AMPHOMYCIN, CH 3 - (CH 2 ) 7 ) (CH 3 -
  • Acetoxyacetyl, C 15 -AMPHOMYCIN-9- (1-adamantanylcarbonyl), C 15 -AMPHOMYCIN-9- (4-COTININECARBONYL), C 15 -AMPHOMYCIN-9- (4- FLUOROBENZOLYL), C 15 -AMPHOMYCIN-9- (S -ACETYLTHIOGLYCOYL), Ci 5 -AMPHOMYCIN-9- (4-BUTOXYBENZOYL), C 15 -AMPHOMYCIN-S- (6- OXOHEPTANOYL), C I5 -AMPHOMYCIN-9-OLEATE, C 15 -AMPHOMYCIN-9- (4- PENYLBENZOYL), C 15 -AMPHOMYCIN-9- (3-PHENOXYBENZOYL), C 15 - AMPHOMYCIN-9- (C ( O) - (CH 2 ) 2-PIPERIDINE, C 15
  • AMPHOMYCIN, 1-ADAMANTANE O) -AMPHOMYCIN, (10-METHYL-ANDEC-2-ENOYL) -AMPHOMYCIN, (10-METHYL-DODEC-2-ENOYL) -AMPHOMYCIN, (12-METHYL-TETRADEC-2 ENOYL) -ASPARTOCIN, (10-METHYL-DODEC-2-ENOYL) -AMPHOMYCIN-9-GLY, (10-METHYL-DODEC-2-ENOYL) -AMPHOMYCIN-9-SAR, (10-METHYL-DODEC-2 ENOYL) -AMPHOMYCIN-9- (jß-ALA), (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN-9-GLY, (12-METHYL-TETRADEC-2-ENOYL) -ASPARTOCIN-9-SAR, ( 12-METHYL-TETRADEC-2
  • R3 can also be bonded via a radical L, where Rl is OH or NH 2 , L being at least one amino acid, at least one substituted amino acid, -R'- (CO) -, -R'- (CO) - (NR ') -, or -O-Ph- (CO) -, wherein R' are each independently the same or different and a radical, as may be defined as R3 or R5, and / or wherein L - when R3 identical or different and independently of one another at least one amino acid, at least one substituted amino acid, - (CO) -, -R "- (CO) -, -SO 2 -, - (CS) -, - (PO) - , -O- (PO) -, -O- (CO) - R - O- (CO) (NR -) -, -NH- (CO) -, - NR'- (CO) -, -R ' I
  • R3 may be glycine, ⁇ -alanine, GABA, 5-aminopentanoic acid, 6-aminohexanoic acid, gDAB, Orn, Dap, hLys, sarcosine, lysine, glycine-lysine, or sarcosine-lysine.
  • Aminophenylacetic acid m-aminophenylacetic acid, L-BBTA, or any combination thereof.
  • the pharmaceutical composition contains several different lipopeptides in each physiologically effective dose. Then it is a combination preparation or a broadband preparation.
  • the lipopeptide may be free or as an alkali or alkaline earth salt, preferably as a sodium or calcium salt, in particular as a di-calcium salt (Ca 2 Cl 2 salt), or as an ammonium salt.
  • an alkali or alkaline earth salt preferably as a sodium or calcium salt, in particular as a di-calcium salt (Ca 2 Cl 2 salt), or as an ammonium salt.
  • the lipopeptide is preferably present in the pharmaceutical composition in a total amount (based on the amount of all lipopeptides used) of from 0.01 to 80% by weight, in particular from 0.05 to 50% by weight, preferably from 0.1 to 30% by weight added, the amount being based on the finished composition.
  • Cyclodextrins are cyclic oligosaccharides composed of alpha-1,4 linked glucose units. Usually, six to eight glucose units (.alpha., .Beta. Or .gamma.-cyclodextrin) are linked together in a cyclodextrin molecule. In addition to the naturally occurring, unmodified cyclodextrins, there are a variety of chemically modified cyclodextrin derivatives that are physiologically compatible and can be used in the invention.
  • the cyclodextrin or cyclodextrin derivative is preferably an ⁇ - or ⁇ -
  • Cyclodextrin and may in particular have the general formula II,
  • the glucopyranose units are ⁇ -D or ⁇ -L-glucose pyranose units.
  • C 1 -C 8 -alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
  • 1 to 3, preferably 1 to 2, of the radicals R 1, R 2 and R 3 can be different from H.
  • R 1 is different from -H.
  • 1, 2, 3, 4, 5, 6, or optionally 7 of the radicals Rl of a cyclodextrin molecule may be different from -H.
  • R2 and R3 can then be -H.
  • 1, 2, 3, 4, 5, 6, or optionally 7 of the radicals R3 of a cyclodextrin molecule may be different from -H.
  • the cyclodextrin or cyclodextrin derivative may be selected from the group consisting of ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxy (C 1 -C 8 -alkyl) - ⁇ -cyclodextrin, hydroxy (C 1 -C 8 -alkyl) - ⁇ -cyclodextrin , (2-hydroxypropyl) - / 3-cyclodextrin, (2-hydroxypropyl) - ⁇ -cyclodextrin, sulpho- (C 1 -C 8 -alkyl) -ether- ⁇ -cyclodextrin, sulpho- (C 1 -C 8 -alkyl) -ether- ⁇ -cyclodextrin, Sulphobutyl ether- ⁇ -cyclodextrin, sulphobutyl ether- ⁇ -cyclodextrin. "In the case of the derivatives, in particular the radical on the oxygen
  • the cyclodextrin or cyclodextrin derivative may be present in the pharmaceutical composition in an amount of 0.01 to 99% by weight, more preferably 0.05 to 80% by weight, preferably 0.1 to 50% by weight, based on the final composition be.
  • the lipopeptide in the pharmaceutical composition with the cyclodextrin or cyclodextrin derivative in a lipopeptide / cyclodextrin molar ratio is from 100: 1 to 1: 500, preferably 10: 1 to 1:50, most preferably 2: 1 to 1:10, optionally with addition of additives and / or excipients in galenically customary amounts, mixed.
  • the pharmaceutical composition will contain other additives and / or adjuvants, in particular galenic adjuvants, the selection of which depends on the selected dosage form.
  • galenic preparation of the pharmaceutical composition according to the invention can be carried out in the usual way.
  • counterions for ionic compounds are Ca ++ , CaCl + , Na + , K + , Li + or cyclohexylammonium, or Cl " , Br " , acetate, trifluoroacetate, propionate, lactate, oxalate, malonate, maleate, citrate, benzoate , Salicylate, etc. in question.
  • Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection (iV, ip, im, sc) or nebulization (aerosols), dry powder inhalation preparations, transdermal systems, and sustained-release preparations prepared by conventional means such as excipients, disintegrants, binders, coating, swelling or lubricants, flavoring agents, Sweeteners and solubilizers, find use.
  • adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile Water and mono- or polyhydric alcohols, such as glycerol, called.
  • a pharmaceutical composition according to the invention can be prepared by mixing at least one substance combination used according to the invention in a defined dose with a pharmaceutically suitable and physiologically acceptable carrier and optionally further suitable active ingredients, additives or excipients with a defined dose and prepared to the desired administration form. Preference is given to solutions for injection in the customary preparation.
  • Suitable diluents are polyglycols, ethanol, water and buffer solutions.
  • Suitable buffer substances are, for example, N, N'-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, sodium bicarbonate or sodium carbonate, but it is also possible to work without a diluent.
  • Physiologically acceptable salts be it the lipopeptide, be it the cyclodextrin or cyclodextrin derivative Salts with inorganic or organic acids, such as hydrochloric acid, sulfuric acid, acetic acid, citric acid, p-toluenesulfonic acid, or with inorganic or organic bases, such as NaOH, KOH, Mg (OH) 2 / diethanolamine, ethylenediarine, or with amino acids, such as arginine, lysine , Glutamic acid, etc. or with inorganic salts such as CaCl 2 , NaCl or their free ions such as Ca 2+ , Na + , Cl " , SO 4 2" or combinations thereof. They are manufactured according to standard methods.
  • inorganic or organic acids such as hydrochloric acid, sulfuric acid, acetic acid, citric acid, p-toluenesulfonic acid, or with inorganic or organic bases, such as NaOH, KOH,
  • a pharmaceutical composition according to the invention may contain: A) 0.01 to 80% by weight, in particular 0.05 to 50% by weight, preferably 0.1 to 30% by weight, lipopeptide, B) 0.01 to 99% by weight %, in particular 0.05 to 80% by weight, preferably 0.1 to 50% by weight of cyclodextrin or cyclodextrin derivative, C) 0.1 to 99.8% by weight, in particular 1 to 80% by weight, preferably 1 to 50% by weight of additives and / or auxiliaries and optionally diluents, wherein the components A) to C) always add up to 100% and wherein the lipopeptide in a physiologically effective dose with the cyclodextrin or cyclodextrin derivative in a molar ratio lipopeptide / cyclodextrin from 1: 500 to 10: 1, preferably 1: 100 to 10: 1, most preferably 1: 100 to 2: 1, optionally with the addition of additional and / or
  • the invention further relates to the use of a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment and / or prophylaxis of viral, bacterial and / or parasitic infectious diseases and / or fungal diseases.
  • a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment and / or prophylaxis of viral, bacterial and / or parasitic infectious diseases and / or fungal diseases. Examples of eligible diseases or
  • Areas of application are: respiratory tract infections, skin and soft tissue infections, urinary tract infections, bile duct infections, sepsis, endocarditis, meningitis, surgical prophylaxis, wound infections or intra-abdominal infections.
  • the medicament is prepared galenically for oral administration or for injection.
  • the invention further relates to a method for the treatment of a bacterial, viral or parasitic infectious disease or a fungal disease, wherein a person suffering from the disease or threatens to fall ill, a physiologically effective dose of a medicament according to the invention is presented.
  • the daily dose may be from 1 to 50,000 mg, preferably 50 to 30,000 mg, most preferably from 100 to 20,000 mg, of lipopeptide over a period of 1 to 60 days, preferably 1 to 30 days.
  • Packaging units with a plurality of delivery units may be provided, each delivery unit being for administration within the above treatment plan is prepared.
  • a delivery unit being for administration within the above treatment plan is prepared.
  • HSA Human Serum Albumin
  • Na 2 -Friulimicin B was dissolved in a concentration of 6400 mg / l in 0.9% NaCl solution with 20, 15, 10, 5, 1 or 0% HSA.
  • 0.9% NaCl and the respective HSA concentrations further stock solutions of 3200, 1600, 800, 200 and 100 mg / l Na 2 -frululimicin were prepared for each of the listed HSA concentrations.
  • 40 ⁇ l each of the friulimicin B / HSA mixture was mixed with 40 ⁇ l fresh human venous blood and then incubated at 37 ° C for 180 min.
  • the measurement value of the standard with complete hemolysis was set as 100%.
  • the measured values of the various reaction batches are set in relation to the value of this standard and expressed as a percentage.
  • Table 1 shows the result of the hemolysis experiment with Na 2 friulimicin B and various HSA concentrations performed on human blood.
  • the data on the concentration of HSA (in% w / v) and of Na 2 -friulimicin B (in mg / l, free acid) refer to the final concentrations in the reaction mixture.
  • HSA suppresses with good efficiency Na 2 -friulimicin B-induced hemolysis from one concentration of about 2.5%.
  • the subsequent determination of free serum hemoglobin content showed that after preincubation with 5% -10% HSA (w / v), final concentration in the reaction mixture, friulimicin B-induced hemolysis could be significantly minimized.
  • This example demonstrates the effect of various modified or unmodified cyclodextrins on the lipopeptide-induced hemolytic effect. This serves Na 2 -Friulimicin B as an example molecule for the Antibiotics of lipopeptides.
  • Na 2 -Friulimicin B was dissolved in a concentration of 3200 mg / l in 0.9% NaCl solution.
  • 0.9% NaCl further stock solutions of 1600, 800, 200, 100 and 50 mg / 1 Na 2 -frululimicin were prepared.
  • 20 .mu.l of these stock solutions each containing 20 .mu.l 0.9% NaCl or 2% solutions of (2-hydroxypropyl) - ⁇ -cyclodextrin (HP-y-CD), (2-hydroxypropyl) - / 3-cyclodextrin ( HP- / 3-CD) or ⁇ -cyclodextrin ( ⁇ -CD) mixed gently in 0.9% NaCl.
  • the pre-incubation and experimental procedure for the determination of the hemolytic activity with fresh human venous blood was carried out according to example 1.
  • Example 3 Minimization of Ca 2 Cl 2 -frulimicin B-induced hemolysis by the addition of modified / 3-cyclodextrins
  • Ca 2 Cl 2 -friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and
  • Ca 2 Cl 2 -frulimicin B was dissolved in concentrations of 100, 50, 40, 30, 20, 10 and 5 g / l in 20, 15, 12.5, 10, 7.5%
  • Daptomycin was dissolved in a solution of 0% or 2.5% SBE- / 3-CD in 0.9% NaCl, 2.5 mM CaCl 2 .
  • erythrocytes were isolated from fresh venal human blood collected in heparinized sample tubes. For this purpose, the erythrocytes were sedimented by centrifugation at 2500 RFC (5 min). The erythrocytes were washed three times with 0.9% NaCl and taken after the final centrifugation in a volume of 0.9% NaCl, which corresponds to the initial volume of the
  • Blood sample corresponded. 40 .mu.l of the erythrocytes were mixed with 40 .mu.l of the reaction mixtures described above and incubated for 5 hours at 37 ° C with constant gentle shaking. The further experiment to determine the hemolytic activity was carried out according to Example 1. The results are shown in Table 5. Here, data on the concentrations of SBE- / 3-CD (in% w / v) and of daptomycin (in mg / l, free acid) refer to the final concentrations in the reaction mixture.
  • SBE- / 3-CD also suppresses the cell lysis induced by a lipopeptide, here daptomycin, in an experiment with isolated erythrocytes.
  • This experiment shows that SBE- / 3-CD can suppress toxic properties of very different lipopeptides.
  • the hemolytic properties of daptomycin are due to an immediate interaction with the erythrocyte membrane. Similar mechanisms underlie the toxic effect on skeletal muscle described for daptomycin so that formulation of daptomycin or its derivatives with cyclodextrins also minimizes this toxic effect.
  • Staphylococcus carnosus ATCC 51365 (DSM 20501) Staphylococcus aureus ATCC 29213 (DSM 2569) Staphylococcus aureus ATCC 33592 (DSM 11729) Staphylococcus epidermidis ATCC 12228 (DSM 1798)
  • the amounts of cells used per spot were: S. carnosus ATCC 51365 5.5 ⁇ 10 3 CFU S. aureus ATCC 29213 7.6 ⁇ 10 3 CFU S. aureus ATCC 33592 2.2 X 10 4 CFU S. epidermidis ATCC 12228 1.1 X 10 4 CFU
  • Example 7 Preparation of a Ca 2 Cl 2 -frulimicin B injection solution.
  • Ca 2 Cl 2 -friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and suibutyl ether- ⁇ -cyclodextrin (SBE-jS-CD) as an example molecule for the cyclodextrins.
  • Data on the content of Ca 2 Cl 2 -friulimicin B (in tng / 1) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture.
  • the molar ratio in each case refers to the free acids of friulimicin B and SBE- / 3-CD.
  • This example relates to the inhibition of haemolytic activity of various lipopeptides by cyclodextrins and shows the effect of a sulphoalkylethercyclodextrin on the cyclic peptide tyrocidine-induced hemolytic effect.
  • Tyrocidine was dissolved in a concentration of 6400 mg / l in 0.9% NaCl solution.
  • SBE- / 3-CD By dilution with a volume of 0.9% NaCl or 0.9% NaCl / 10% SBE- / 3-CD respectively stock solutions of 3200 mg / 1 Tyrocidin were prepared with or without 5% SBE-ß-CD.
  • the pre-incubation and experimental procedure for the determination of the hemolytic activity with fresh venale human blood was carried out according to the example 1.
  • This example demonstrates the effect of ⁇ -cyclodextrins on the lipopeptide-induced hemolytic effect on the blood of various organisms.
  • Ca 2 Cl 2 - Friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and sulfobutyl ether- ⁇ -cyclodextrin (SBE- / 3-CD) as examples of modified ⁇ -cyclodextrins.
  • SBE- / 3-CD sulfobutyl ether- ⁇ -cyclodextrin
  • Ca 2 Cl 2 -frulimicin B was dissolved in 0.9% NaCl solution with and without the addition of SBE- / 3-CD.
  • SBE- / 3-CD was a molar ratio (SBE- / 3-CD: Friulimicin B) of 2.5: 1 before.
  • the preincubation and experimental procedure for the determination of hemolytic activity with venal canine blood were carried out according to Example 1. The results are shown in Table 9.
  • Data on the content of Ca 2 Cl 2 -frulimicin B (in mg / l) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture.
  • the details of the molar ratio relate in each case to the free acids of friulimicin B and SBE- ⁇ -CD.
  • SBE- / 3-CD in a molar ratio of 2.5: 1 SBE-ß-CD: Friulimicin B suppresses the Ca 2 Cl 2 -frulimicin B-induced lysis of erythrocytes in dog blood.
  • This example demonstrates the effect of / 3-cyclodextrins on the lipopeptide-induced hemolytic effect on the blood of various organisms.
  • Ca 2 Cl 2 - Friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and sulfobutyl ether-ß-cyclodextrin (SBE- / 3-CD) as an example of cyclodextrins.
  • SBE- / 3-CD sulfobutyl ether-ß-cyclodextrin
  • Ca 2 Cl 2 -frulimicin B was dissolved in 0.9% NaCl solution with and without the addition of SBE- / 3-CD. In the mixture with SBE- ⁇ -CD, a molar ratio (SBE / 3-CD: friulimicin B) of 5: 1 was present.
  • the preincubation and experimental procedure for the determination of hemolytic activity with venal macaque blood were carried out according to Example 1.
  • Data on the content of Ca 2 Cl 2 -frulimicin B (in mg / l) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture. The details of the molar ratio relate in each case to the free acids of friulimicin B and SBE- ⁇ -CD.
  • the example shows that SBE- ⁇ -CD in a molar ratio of 5: 1 (SBE- / 3-CD: Friulimicin B) by Ca2Cl 2 -Friulimicin B suppresses induced lysis of erythrocytes in blood of macaques.
  • This example demonstrates the effect of / 3-cyclodextrins on the antibiotic activity of lipopeptides in vivo.
  • Ca 2 Cl 2 -friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and sulfobutyl ether
  • SBE- ⁇ -CD ⁇ -cyclodextrin
  • Ca 2 Cl 2 -frululimicin B was dissolved in 0.9% NaCl solution with and without addition of SBE- ⁇ -CD.
  • SBE- / 3-CD was a molar ratio (SBE- / 3-CD: Friulimicin B) of 2.5: 1 before.
  • the data for the Ca 2 Cl 2 -frulimicin B concentration (in mg / l) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture.
  • the details of the molar ratio relate in each case to the free acids of friulimicin B and SBE- ⁇ -CD.
  • Ca 2 Cl 2 -friulimicin B serves as an example molecule for the antibiotics from the class of lipopeptides and sulfobutyl ether-J ⁇ -cyclodextrin (SBE-J ⁇ -CD) as examples of modified ⁇ -cyclodextrins.
  • Ca 2 Cl 2 -frulimicin B was dissolved in 0.9% NaCl solution with and without the addition of SBE- / 3-CD.
  • SBE-jß-CD was a molar ratio (SBE-jß-CD: Friulimicin B) of 2.5: 1 before.
  • the data for the Ca 2 Cl 2 -frulimicin B concentration (in mg / l) refer to the final concentrations of the free acid of friulimicin B in the reaction mixture.
  • the details of the molar ratio relate in each case to the free acids of friulimicin B and SBE- ⁇ -CD.
  • the Ca 2 Cl 2 -frulimicin B solutions with and without SBE- / 3-CD were administered once to female mice (CFW-I (Harlan Winkelmann, Germany)) (iv).
  • the mortality rate of the animals within 24 hours was determined. It is shown in Table 11.
  • the example shows that the acute toxicity of Ca 2 Cl 2 -friulimicin B is reduced by the presence of SBE- ⁇ -CD in a molar ratio of 2.5: 1 (SBE- / 3-CD: friulimicin B).

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Abstract

L'invention concerne une composition pharmaceutique comprenant en tant qu'ingrédient actif un lipopeptide en une dose active physiologiquement, ainsi qu'une cyclodextrine ou un dérivé de cyclodextrine.
EP06805527A 2005-11-21 2006-11-20 Compositions a base de lipopeptide Withdrawn EP1951311A1 (fr)

Applications Claiming Priority (2)

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DE102005056194A DE102005056194A1 (de) 2005-11-21 2005-11-21 Neue Lipopeptid Zusammensetzungen
PCT/DE2006/002064 WO2007057005A1 (fr) 2005-11-21 2006-11-20 Compositions a base de lipopeptide

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EP1951311A1 true EP1951311A1 (fr) 2008-08-06

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WO2014044803A1 (fr) * 2012-09-24 2014-03-27 Dsm Sinochem Pharmaceuticals Netherlands B.V. Procédé de production d'un peptide cyclique
WO2020229369A1 (fr) * 2019-05-10 2020-11-19 Xellia Pharmaceuticals Aps Formulations aqueuses de daptomycine

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DE4411025A1 (de) * 1994-03-30 1995-10-05 Hoechst Ag Lipopeptid-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung
DE19807972A1 (de) * 1998-02-25 1999-08-26 Hoechst Marion Roussel De Gmbh Lipopeptidantibiotika-Calciumsalze, Verfahren zu ihrer Herstellung und Verwendung
AU2001259306A1 (en) * 2000-05-02 2001-11-12 Advanced Medicine, Inc. Pharmaceutical compositions containing a glycopeptide antibiotic and a cyclodextrin
US7527807B2 (en) * 2000-06-21 2009-05-05 Cubist Pharmaceuticals, Inc. Compositions and methods for increasing the oral absorption of antimicrobials
UA82824C2 (uk) * 2000-06-21 2008-05-26 К'Юбіст Фармасьютікалз, Інк. Композиція і спосіб поліпшення перорального всмоктування протимікробних засобів
WO2002032459A2 (fr) * 2000-10-17 2002-04-25 Massachusetts Institute Of Technology Procede permettant d'ameliorer l'efficacite des antibiotiques par complexion avec des cyclodextrines

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AU2006314942A1 (en) 2007-05-24
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CA2630497A1 (fr) 2007-05-24
CN101370524A (zh) 2009-02-18

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