CN101370524A - Lipopeptide compositions - Google Patents
Lipopeptide compositions Download PDFInfo
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- CN101370524A CN101370524A CNA2006800511655A CN200680051165A CN101370524A CN 101370524 A CN101370524 A CN 101370524A CN A2006800511655 A CNA2006800511655 A CN A2006800511655A CN 200680051165 A CN200680051165 A CN 200680051165A CN 101370524 A CN101370524 A CN 101370524A
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- cyclodextrin
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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
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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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- 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
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- 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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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
Technical field
The application, its preparation method that the present invention relates to contain new pharmaceutical composition, the said composition of lipopeptid with and as the application of medicine.
Background technology and prior art
By the secondary metabolites of live body (especially microorganism) generation, and deutero-thus chemical variant successfully is used as activating agent in pharmacy.Especially for the control of infectious disease, the use that has confirmed secondary metabolites is effective.Used now most of antibiotic is isolating in the antibacterial (so-called actinomycetes) from soil.Owing to the medicine that uses is respectively produced drug resistance, so need have the antibiotics activating agent of new active mechanism lastingly.Although many secondary metabolitess have good antibiotic and other pharmacological characteristics, so because in most of the cases they to the people also have very significantly toxicity they finally successfully as medicine.
Have found that; antibiotic antifungal and gram positive bacteria very effectively with lipopeptid class of following character: described lipopeptide antibiotic be characterised in that have linear peptide or cyclic peptide part or its both; contain natural and/or non-natural is deutero-and/or not deutero-aminoacid; be connected with saturated or unsaturated acyl group residue on the described aminoacid, can randomly insert one or several phenyl or cycloalkyl on this lipopeptide antibiotic or be connected with such group or insert one or several oxygen atom or nitrogen-atoms.Yet the great majority of known these chemical compounds have toxicity.
For example, the A-21978C lipopeptide compound reaches the handkerchief Tobramycin can damage skeletal muscle (Oleson etc., 2000, Antimicrobial Agents Chemotherapy, Vol.44 No 11:2948-2953), many other lipopeptids, zearin (lichenysin) (Grangemard I. etc. for example, Applied Biochemistry and Biotechnology, Volume 90, Number 3,2001, pp199-210 (12)), plain A (surfactin A) (the Hanka Symmank of surface activity, Peter Franke, Wolfram Saenger and Frank Bermhard, Modification ofbiologically active peptides:production of a novel lipohexapeptide afterengineering of Bacillus subtilis surfactin synthetase), FR131535 and echinocandin (Fujie A, Iwamoto T, Sato B, Muramatsu H, Kasahara C, Furuta T, Hori Y, Hino M, Hashimoto S., Bioorg Med Chem Lett.2001 Feb 12; 11 (3): 399-402.FR131535, a novel water-soluble echinocandin-likelipopeptide:synthesis and biological properties), fragrant shepherd's purse element (Fengycin) (J.of Antibiotics 29 (1986) 888-901), iraq subtilis actinomycin A (Aranda FJ, TeruelJA, Ortiz A., Biochem Biophys Acta.2005 Jul 15; 1713 (1): 51-6.Further aspects on the hemolytic activity of the antibiotic lipopeptideiturin A) and the lipopeptid (DE 19807972) and the friulimicin that are similar to amfomycin work in the haemolysis mode.
But with the key issue that these lipopeptids are applied as medicine is to eliminate the toxicity of described material and do not slacken its antibacterial activity.Therefore, be with these materials as medicine, just must obtain comparing with pure material has the pharmaceutical composition of improved pharmacological characteristics.For example, known in the presence of sero-abluminous, material or ionic haemolysis character can reduce, this is by causing (" masking effect ") (Caffrey JM Jr with sero-abluminous interaction, Smith HA, Schmitz JC, Merchant A, Frieden E.:Hemolysis of rabbit erythrocytes in thepresence of copper ions.Inhibition by albumin and ceruloplasmin.BiolTrace Eiern Res.1990 Apr; 25 (1): 11-9).Yet in many cases, this masking effect that is produced by serum albumin also can cause the forfeiture of the desirable characteristics of molecule, and, as shown in the embodiment of the invention 1, also can therefore lose the antibacterial activity of lipopeptid.
It is known in the art using cyclodextrin in pharmaceutical composition.Cyclodextrin is because of its circulus possess hydrophilic property surface and hydrophobicity inner chamber.In the specific hydrophobic parts of molecule, cyclodextrin can be with activating agent " molecule package " that is " sheltering " by package, and described activating agent for example can be used in cosmetics and the pharmaceutical compositions with the form of the protectiveness bag-sealing matter of sensitivity molecule.Thus, can improve solubility of substances, and reduction toxicity, (J.Pharmacobiodyn.1983 6 (6): 408-14.Protective mechanism ofbeta-cyclodextrin for the hemolysis induced with phenothiazineneuroleptics in vitro.Irie T for example to reduce the haematolysis property of molecule, Sunada M, Otagiri M, Uekama K).
Technical purpose of the present invention
Therefore, technical purpose of the present invention provides so new pharmaceutical composition: it contains the lipopeptid with antibiotic, antiviral and/or antifungic action, its toleration raising keeps physiological function simultaneously, like this, even very little toxic and side effects also only appears in very high concentration (for example can this situation occur in the transfusion part short time when transfusion).
Main points of the present invention and embodiment
In order to realize this technical purpose, the present invention instructs a kind of pharmaceutical composition, it comprises the lipopeptid of, antiviral antibiotic as having of effective dose on the physiology of activating agent and/or antifungic action, and cyclodextrin that can tolerate on the physiology or cyclodextrin derivative.
The present invention is based on following surprising discovery: especially by utilizing cyclodextrin or cyclodextrin derivative, the haematolysis property of the lipopeptid with antibacterial action is reduced, and can keep the effects of antibiotics of described lipopeptid simultaneously, yet, on the other hand, for example utilize HAS to shelter and to reduce or to suppress fully effects of antibiotics.
Described lipopeptid preferably has the structure of formula I,
Formula I
In the formula; one of X=aminoacid Asn or Asp; Y=has the straight or branched of 6 to 22 carbon atoms, saturated or undersaturated aliphatic acyl radical residue, and it can at random insert one or several phenyl or cycloalkyl or be connected with such group or insert one or several oxygen atom.But the aminoacid derivatization of the peptide moiety of described molecule (US 2005/0153876A1).Under the situation of X=Asn, it is friulimicin or friulimicin derivant.Under the situation of X=Asp, it is amfomycin or amfomycin derivant.Y specifically can be:
(CH
3)
2CH(CH
2)
7CH＝CHCH
2CO-，CH
3(CH
2)
6CO-，CH
3(CH
2)
7CO-，
CH
3(CH
2)
8CO-，CH
3(CH
2)
9CO-，CH
3(CH
2)
10CO-，
CH
3(CH
2)
11CO-，CH
3(CH
2)
12CO-，CH
3(CH
2)
13CO-，
CH
3(CH
2)
14CO-，CH
3(CH
2)
15CO-，CH
3CH(CH
3)(CH
2)
8CO-，
CH
3CH(CH
3)(CH
2)
9CO-，CH
3CH(CH
3)(CH
2)
10CO-，
CH
3CH(CH
3)(CH
2)
11CO-，CH
3CH(CH
3)(CH
2)
12CO-，
H
2C＝CH(CH
2)
8CO-，H
2C＝CH(CH
2)
9CO-，CH
3(CH
2)
7CH=CHCO-(trans), CH3(CH
2)
8CH=CHCO-(trans), CH3(CH
2)
12CH=CHCO-(trans), CH3(CH
2)
3CH＝CH(CH
2)
7CO-(cis), CH3(CH
2)
3CH＝CH(CH
2)
7CO-(trans), CH3(CH
2)
3CH＝CH(CH
2)
8CO-(trans), CH3(CH
2)
5CH＝CH(CH
2)
7CO-(cis), CH3(CH
2)
5CH＝CH(CH
2)
7CO-(trans), CH3(CH
2)
5CH＝CH(CH
2)
8CO-(cis), CH3(CH
2)
10CH＝CH(CH
2)
4CO-(cis), CH3(CH
2)
10CH＝CH(CH
2)
4CO-(trans), CH3(CH
2)
7CH＝CH(CH
2)
7CO-(cis), CH3(CH
2)
7CH＝CH(CH
2)
7CO-(trans), CH3(CH
2)
5CH＝CH(CH
2)
9CO-(trans), CH3(CH
2)
3(CH
2CH＝CH)
2(CH
2)
7CO-(cis), CH3(CH
2)
3(CH
2CH＝CH)
2(CH
2)
2CO-(trans), CH3(CH
2)
3(CH
2CH＝CH)
2(CH
2)
9CO-(cis), CH3(CH
2CH＝CH)
3(CH
2)
7CO-(cis), CH3(CH
2)
3(CH
2CH＝CH)
3(CH
2)
4CO-(cis), CH3(CH
2CH＝CH)
4(CH
2)
4CO-(cis), CH3(CH
2)
3(CH
2CH＝CH)
4(CH
2)
3CO-(cis), CH3(CH
2CH＝CH)
6(CH
2)
2CO-(cis), H2C＝CH(CH
3)
8CO-，
CH
3(CH
2)
3CH＝CH(CH
2)
7CO-，CH
3(CH
2)
7CH＝CH(CH
2)
7CO-，
CH
3(CH
2)
4CH＝CH-CH＝CH-(CH
2)
8CO-，
(CH
3)
2C＝CHCH
2[CH
2C(CH
3)＝CHCH
2]
2CO-，Phe-Phe-CH
2CO-，
Phe-(CH
2)
9CO-，Phe-O-(CH
2)
10CO-，CH
3(CH
2)
7-Phe-CO-，
Phe-Phe-CO-，CH
3(CH
2)
6-Phe-CO-，CH
3(CH
2)
6-O-Phe-CO，
CH
3(CH
2)
7-O-Phe-CO-，Phe-(CH
2)
2-Phe-CO-，
CH
3CH
2-Phe-(CH
2)
2-Phe-CO-，Phe-Phe-(CH
2)
2-Phe-CO-，
Phe- (CH
2)
2-Phe-(CH
2)
2-Phe-CO-，
CH
3(CH
2)
3-Phe-(CH
2)
2-Phe-CO-，
CH
3(CH
2)
5-O-Phe-(CH
2)
2-Phe-CO-， (CH
3)
2CH
(CH
2)
6CH＝CHCH
2CO-(cis), (CH3)
2CH(CH
2)
6CH＝CHCH
2CO-(trans), (CH3)
2CH(CH
2)
7CH＝CHCH
2CO-(cis), (CH3)
2CH(CH
2)
7CH＝CHCH
2CO-(trans), CH3CH
2(CHCH
3)(CH
2)
5CH＝CHCH
2CO-(cis), CH3CH
2(CHCH
3)(CH
2)
5CH＝CHCH
2CO-(trans), CH3CH
2(CHCH
3)(CH
2)
7CH＝CHCH
2CO-(cis), CH3CH
2(CHCH
3)(CH
2)
7CH＝CHCH
2CO-(trans), CH3CH
2(CHCH
3)(CH
2)
7CH＝CHCH
2CO-(cis), CH3(CH
2)
8CH=CHCO-(cis), CH3(CH
2)
8CH=CHCO-(trans), CH3(CH
2)
9CH=CHCO-(cis), CH3(CH
2)
8CH=CHCO-(trans), CH3(CH
2)
7CH=CHCO-(cis), CH3(CH
2)
7CH=CHCO-(trans),
Wherein, Phe is unsubstituted or is replaced the phenyl ring of 1 time or 2 to 4 times by the C1-8 alkyl that-Phe-represents ortho position, a position or para-linkage.
The method of the lipopeptid that concrete preparation is such can be referring to for example document DE 198 07 972 A1, EP 0 629 636 A1, EP 0 688 789 A1 and US 2005/0153876 A1.
Lipopeptid can not be subject to formula I and be selected from the group that comprises following material: amfomycin, the amfomycin derivant, friulimicin, friulimicin B, the friulimicin derivant, reach the handkerchief Tobramycin, reach handkerchief Tobramycin derivant, aspartocin (Aspartocin), the aspartocin derivant, Dermokalixan, the Dermokalixan derivant, crystallomycin, the crystallomycin derivant, zaomycin, the zaomycin derivant, tsushimycin, the tsushimycin derivant, aspartomycin, the aspartomycin derivant, brevimycin, the brevimycin derivant, Cerexin B, the Cerexin B derivant, syringomycin and derivant thereof, antibiotic A-30912 and derivant thereof, antibiotic A-54145 and derivant thereof, and antibiotic A-21978C and derivant thereof.
Lipopeptid can not be subject to formula I and further be selected from the group that comprises following material:
About synthetic, structure and its term of these lipopeptids, can be referring to " the Compositions of Lipopeptide Antibiotic Derivatives andMethods of use thereof " of document US 2005/0153876 A1, Canadian Migenix Inc..Above is the included lipopeptid of formula Ia,
Formula Ia
Wherein in formula Ia, R3 also can with residue L bonding,
Wherein R1 is OH or NH
2,
Wherein L be at least one aminoacid, at least one replacement aminoacid ,-R '-(CO)-,-R '-(CO)-(NR ')-or-O-Ph-(CO)-, wherein R ' is identical or different independently of each other respectively, and residue can be defined such as R3 or R5, and/or wherein L when R3 and residue L bonding, be identical or different and be independently of each other respectively at least one aminoacid, at least one replacement aminoacid ,-(CO)-,-R '-(CO)-,-SO
2-,-(CS)-,-(PO)-,-O-(PO)-,-O-(CO)-R '-O-(CO) (NR ')-,-NH-(CO)-,-NR '-(CO)-,-R '-(CO)-,-R '-(CO)-(NR ')-or-O-Ph-(CO)-, wherein R ' is identical or different independently of each other respectively, and residue can be defined such as R3 or R5, wherein the L of Dab9 preferably-(CO)-
Wherein R2 be-OR5 ,-SR5, NR5R5 ,-(CO)-R5 ,-(CO)-O-R5 ,-(CO)-NHR4 ,-(CO)-NR4R4 ,-(CS)-NHR4 ,-(CS)-NR4R4 ,-(CNR4)-NHR4 or-(CNR4)-NR4R4, R5-(CO), SO
2R5 ,-(SO)-R5 ,-(PO) (OR5) 2 ,-(PO) (OR5), COOH, SO
3H ,-PO
3H ,-F ,-Cl ,-Br ,-I or trihalomethyl group,
Wherein R3 be-H ,-OR5 ,-SR5 ,-NR5R5 ,-CN ,-NO
2,-N
3,-(CO)-R5 ,-(CO)-O-R5 ,-(CO)-NR5R5 ,-(CS)-NR5R5 ,-(CNR5)-NR5R5 ,-(CO)-H ,-R5-(CO) ,-SO
2R5 ,-(PO) (OR5) 2 ,-(PO) (OR5) ,-CO
2H ,-SO
3H ,-PO
3H,-F,-Cl,-Br,-I, trihalomethyl group, the C1-C25 alkyl, the C1-C25 alkyl that replaces, the C1-C25 alkyl of mixing, the assorted alkyl of the C1-C25 that replaces, the C5-C10 aryl, C5-C15 aryl aryl, the C5-C15 aryl aryl that replaces, the C5-C15 diaryl, the C5-C15 diaryl that replaces, 5-10 unit heteroaryl, the 5-10 unit heteroaryl that replaces, the C6-C26 aryl alkyl, the C6-C26-aryl alkyl that replaces, 6-26 unit heteroaryl alkyl, the 6-26 unit heteroaryl alkyl that replaces, at least one aminoacid, or the aminoacid of at least one replacement
Wherein R4 is identical or different C7-C10 alkyl independently of each other, the C17-C26 aryl alkyl, 17-26 unit heteroaryl alkyl, straight or branched, saturated or single unsaturated or polyunsaturated C7-C25 alkyl, the primary amine or the secondary amine that can be replaced by hydroxyl arbitrarily, the aminoacid of at least one aminoacid or at least one replacement
Wherein R5 is identical or different C1-C10-alkyl independently of each other, the C5-C10-aryl, 5-10 unit heteroaryl, C6-C26 aryl alkyl, 6-26 unit heteroaryl alkyl, straight or branched, saturated or single unsaturated or polyunsaturated C5-C25 alkyl, the primary amine or the secondary amine that can be replaced by hydroxyl arbitrarily, the aminoacid of at least one aminoacid or at least one replacement, or its any combination.When being aminoacid, R3 can be glycine, Beta-alanine, GABA, 5-aminovaleric acid, 6-aminocaprolc acid, gDAB, Orn, Dap, hLys, sarcosine, lysine, glycine-lysine or sarcosine-lysine.L is glycine, sarcosine, phenylglycine, phenylalanine, neighbour-methylaspartic acid, neighbour-tert-butyl group aspartic acid, p-aminophenyl acetyl group, (right-the aminophenyl propiono) specifically
nAnd n=1 or 2, m-aminophenyl base acetyl group, (-the aminophenyl propiono)
nAnd n=1 or 2, adjacent aminophenyl acetyl group, (o-amino-phenyl-propiono)
nAnd n=1 or 2, GABA, para-amino benzoic acid (PABA), gavaculine, ortho-aminobenzoic acid, to hydrazino-benzoic acid, a hydrazino-benzoic acid, adjacent hydrazino-benzoic acid, right-amino-trans-cinnamyl ,-amino-trans-cinnamyl, neighbour-amino-trans-cinnamyl, right-aminophenyl acetic acid ,-aminophenyl acetic acid, L-BBTA or its any combination.
It respectively is several different lipopeptid of effective dose on the physiology that described pharmaceutical composition can comprise.At this moment, described pharmaceutical composition is a compound formulation, that is wide range (wide band) preparation.
Particularly, described lipopeptid can free form or is existed as alkali metal salt or alkali salt, preferably as Na or Ca salt, especially as two Ca salt (Ca
2Cl
2Salt) or as ammonium salt exist.
The total amount of lipopeptid in described pharmaceutical composition (amount that refers to all lipopeptids of using) is preferably 0.01 to 80 weight %, especially is 0.05 to 50 weight %, more preferably is 0.1 to 30 weight %, and described amount is for whole compositions.
In principle, can use the cyclodextrin and the cyclodextrin derivative that can tolerate on all physiology.Cyclodextrin is the ring-type oligosaccharide, and by α-1, the dextrose components that 4-connects constitutes.Usually, in cyclodextrin molecular, 6 to 8 dextrose components (α, β or gamma-cyclodextrin) interconnect.Except the cyclodextrin naturally occurring, that unmodified is crossed, also have the cyclodextrin derivative of a large amount of chemical modifications, its be can tolerate on the physiology and can be used for purpose of the present invention.Cyclodextrin or cyclodextrin derivative be alpha-cyclodextrin or beta-schardinger dextrin-preferably, and can have general formula I I particularly,
Formula II
Wherein R1, R2 and R3 can be identical or different, are the residues that can tolerate on any physiology, preferably-H, C1-C8-alkyl ,-SO
2OH ,-PO (OH)
2, or-CO-R4 (wherein R4=C1-C8-alkyl), wherein said C1-C8 alkyl can on its identical or different carbon atom, have one or more-OH ,-COOH ,-CONHR5 ,-NHCOR6 ,-SO
2OH ,-PO (OH)
2, or tetrazolium-5-base, wherein, R5=-H or C1-C4 alkyl, the R6=carbonyl phenyl, n=6,7 or 8, wherein R1, R2 can be arranged in different glucopyranose units randomly with R3, and one or several oxygen atom of described glucopyranose units (the particularly oxygen atom of C6) can be replaced by sulphur atom.Described cyclodextrin also comprises the salt that can tolerate on the physiology of this cyclodextrin.Preferably, described glucopyranose units is α-D or α-L-glucopyranose units.The C1-C8 alkyl specifically comprises methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group and the tert-butyl group.Usually, the 1-3 among residue R1, R2 and the R3 (being 1-2 better) can be different from H.Good especially is that R1 is not-H.1,2,3,4,5,6 or 7 (if feasible) residue R1 of cyclodextrin molecular can be different from-H.At this moment, R2 and R3 can be-H.In addition, and 1,2,3,4,5,6 or 7 (if feasible) residue R3 of cyclodextrin molecular also can be different from-H.
Particularly, described cyclodextrin or cyclodextrin derivative can be selected from: alpha-cyclodextrin, beta-schardinger dextrin-, hydroxyl-(C1-C8 alkyl)-alpha-cyclodextrin, hydroxyl-(C1-C8 alkyl)-beta-schardinger dextrin-, (2-hydroxypropyl)-beta-schardinger dextrin-, (2-hydroxypropyl)-alpha-cyclodextrin, sulfo group-(C1-C8 alkyl)-ether-alpha-cyclodextrin, sulfo group-(C1-C8 alkyl)-ether-beta-schardinger dextrin-, sulfo group butyl ether-alpha-cyclodextrin, sulfo group butyl ether-beta-schardinger dextrin-.For derivant, particularly the residue on the oxygen atom that connected of its C6 atom is different from-H.
Described cyclodextrin or cyclodextrin derivative can be with 0.01 to 99 weight % of total composition, 0.05 to 80 weight % especially, and the amount of preferred 0.1 to 50 weight % is present in the pharmaceutical composition.
Preferably, can at random in the galenic conventional additives, add under the situation of substance and/or auxiliary substance, with 100:1 to 1:500, preferred 10:1 to 1:50, the mol ratio of lipopeptid/cyclodextrin of 2:1 to 1:10 most preferably, the lipopeptid in the pharmaceutical composition and cyclodextrin or cyclodextrin derivative is mixed.
Usually, pharmaceutical composition also comprises substance and/or auxiliary substance, galenic auxiliary substance especially, and selected method of application is depended in the selection of described material.The galenical of pharmaceutical composition of the present invention can adopt this technology mode commonly used to be prepared.For example can use the counter ion of following ionic compound: Ca
++, CaCl
+, Na
+, K
+, Li
+, or hexamethylene ammonium or Cl
-, Br
-, acetate, trifluoroacetic acid root, propionate, lactate, oxalate, malonate, maleic acid, citrate, benzoate anion, salicylate etc.The suitable solid of preparation or liquid galenic form are dosage form, the transdermal system of for example granule, powder, dragee, tablet, (little) capsule, suppository, syrup, juice, suspensoid, Emulsion, drop or injectable solution (IV, IP, IM, SC) or fine dispersions (aerosol), Foradil Aerolizer formoterol fumarate and the preparation that prolongs release of active ingredients, common method is used in its preparation, such as carrier mass, explosive (dash forward and release agent), binding agent, coating materials, extender, antiseize paste or lubricant, flavoring agent, sweeting agent and solution regulator.What be called auxiliary substance at this is magnesium carbonate, titanium dioxide, lactose, mannitol and other sugar, Talcum, lactoprotein, gelatin, starch, cellulose and derivant thereof, animal oil and vegetable oil are such as cod liver oil, Oleum helianthi, Oleum Arachidis hypogaeae semen or Oleum sesami, and Polyethylene Glycol and ratio of solvent such as sterilized water and monobasic or polyhydric alcohol be glycerol for example.Pharmaceutical preparation of the present invention can be prepared by the following method: at least a combinations of substances that the present invention is used is mixed mutually with well-tolerated carrier on prescribed dose and pharmaceutically suitable and the physiology and possible other suitable active substances, substance or auxiliary substance, and is mixed with required administration form.In common dosage forms, preferred injection solution.
As diluent, can use Polyethylene Glycol, ethanol, water and buffering solution.Suitable buffer solution is N for example, N '-dibenzyl-ethylenediamin, diethanolamine, ethylenediamine, N-methylglucosamine, N-benzyl-1-phenylethylamine, diethylamine, phosphate, sodium bicarbonate or sodium carbonate.And, also can fully need not any diluent.
The salt that can tolerate on the physiology of lipopeptid or cyclodextrin, cyclodextrin derivative all is and mineral acid or the organic acid salt such as hydrochloric acid, sulphuric acid, acetic acid, citric acid, p-methyl benzenesulfonic acid, or with inorganic base or organic base such as NaOH, KOH, Mg (OH)
2, diethanolamine, ethylenediamine salt, or with the salt of aminoacid such as arginine, lysine, glutamic acid etc., or with inorganic salt such as CaCl
2, NaCl or its dissociated ion be such as Ca
2+, Na
+, Cl
-, SO
4 2-Or the salt of its combination.They also utilize the method for standard to make.
Particularly, pharmaceutical composition of the present invention can comprise: A) 0.01 to 80 weight %, especially 0.05 to 50 weight %, the lipopeptid of 0.1 to 30 weight % preferably, B) 0.01 to 99 weight %, especially 0.05 to 80 weight %, the cyclodextrin of preferred 0.1 to 50 weight % or cyclodextrin derivative, C) 0.1 to 99.8 weight %, especially 1 to 80 weight %, the substance of preferred 1 to 50 weight % and/or auxiliary substance and optional diluent, wherein component A) to C) add up to 100%, and wherein under the situation of the substance in randomly adding the galenic conventional additives and/or auxiliary substance, with 1:500 to 10:1, preferred 1:100 to 10:1, the lipopeptid of 1:100 to 2:1/cyclodextrin mol ratio is most preferably mixed the described lipopeptid of effective dose on the physiology with cyclodextrin or cyclodextrin derivative.
With regard to weight % cited above and below, mol ratio and/or dosage, they refer to the so-called free acid of described lipopeptid all the time, and condition is that its form with salt is used.The counter ion of salt form is irrespective, but generation is with the atomic weight of hydrogen.Some is as substance or auxiliary substance in the counter ion.
The invention further relates to pharmaceutical composition of the present invention preparation be used for the treatment of and/or the medicine of pre-anti-virus, antibacterial and/or parasitic infection disease and/or fungal disease in application.The example of these diseases or application is: respiratory tract infection, skin and soft tissue infection, urinary tract infection, prevention, wound infection or the intra-abdominal infection of the infection of gallbladder road, septicemia, endocarditis, meningitis, primary osteoporosis (op).
Preferably, make described medicine for oral use or the injection galenical.
In addition, the invention still further relates to the method that is used for the treatment of antibacterial, virus or parasitic infection disease or fungal disease, wherein give and suffered from the medicine of the present invention that people this disease or that be in the danger of suffering from this disease uses effective dose on the physiology.At 1 to 60 day, preferably 1 to 30 day time, daily dose can be 1 to 50000mg, and preferred 50 to 30000mg, most preferably 100 to 20000mg lipopeptids.
Can be made into and contain the unitary packaging unit of a plurality of administrations, prepare each position, administration unit for the administration in the above-mentioned treatment plan.For example, packaging unit can contain n1=5 to n2=500 administration unit, and wherein each administration unit contains the lipopeptid of m1=1/5 to m2=1 daily dose.Prepare described packaging unit by treatment plan then, this packaging unit can provide by a definite date o1 to o2 sky, 1 to 5 time administration every day, and wherein o calculates by o1=n1*m2 and o2=n2*m1, or given o and m and calculate n according to n=o/m.
Below, by explaining the present invention in more detail by comparative example and non-limiting example of the present invention.
Embodiment 1: make by the inductive haemolysis of friulimicinB by human serum albumin (HSA) to minimize; The comparative example
With Na
2Friulimicin B with the concentration of 6400mg/l be dissolved in contain 20%, 15%, 10%, 5%, 1% or the 0.9% NaCl solution of 0%HSA in.To each cited HSA concentration, the diluent preparation that reuse contains 0.9% NaCl and each HSA concentration contains 3200,1600,800,200 and the Na of 100mg/l
2The stock solution of friulimicin.Preincubate is after 2 hours at ambient temperature, and people's venous blood that 40 μ l friulimicin B/HSA mixture and 40 μ l are fresh mixes, and hatches 180 minutes at 37 ℃ then.With the 0.9% NaCl liquid preparation whole blood mixture of different HAS concentration,, will be used for the standard substance of complete hydrolysis with the mixture conduct of 40 μ l water and the preparation of 40 μ l Freshman venous blood as negative control.Subsequently, following mensuration is hatched inductive haemolysis degree by above-mentioned: carefully sample is mixed with water (standard) or 1ml 0.9%NaCI.Sample is measured the absorbance of supernatant at the 540nm place in spectrophotometer behind 2500 RFC centrifugal (5 minutes).Before the measuring samples, proofread and correct spectrophotometer with above-mentioned each negative control.When measuring the haemolysis degree of differential responses batch, the measured value of the standard substance of complete hemolysis is made as 100%.The measured value of differential responses batch is associated with the numerical value of these standard substance and provides with percentage rate.Table 1 shows the Na that utilizes human blood to carry out
2The result of the friulimicin B and the hemolytic test of different HSA concentration.In the table, HSA concentration (% represents with weight/volume) and Na
2Friulimicin B (representing free acid with mg/l) is meant the final concentration in reaction batch.
Table 1
In the presence of different HSA concentration as Na
2The external hemolytic activity (representing) of the function of friulimicin B concentration (mg/l) with %
Friulimicin concentration is represented with mg/l
0 100 200 800 1600 3200
Contain batches 0 4.6 5.2 6.5 11.8 13.6 of 0%HSA
Contain batches 0 0.7 2 2.7 3.2 3.9 of 2.5%HSA
Contain batches 0 0.1 1 1.9 1.7 1.7 of 5%HSA
Contain batches 00 0.4 1.6 1.5 1.3 of 7.5%HSA
Contain batches 00 0.3 0.5 0.8 0.3 of 10%HSA
Concentration from about 2.5%, HSA suppresses Na efficiently
2The inductive haemolysis of friulimicin B.The Determination on content of free hemoglobin shows in the following serum: behind 5% to 10% HSA (weight/volume, the final concentration in the reaction batch) preincubate, can significantly minimize the inductive haemolysis of friulimicinB.
Yet, as shown in table 2, these Na that in the following embodiment of the present invention, record
2Friulimicin B/BSA compositions shows also that to the external antibiotic activity resulting of staphylococcus aureus (Staphylococcus aureus) and enterococcus faecalis (Enterococcus faecalis) its antibiotic activity significantly reduces.
Table 2
Na in the presence of HSA
2The mensuration of the minimal inhibitory concentration of friulimicin (MIC)
The MIC value
Culture medium is added [μ g/ml]
Staphylococcus aureus ATCC 29,213 0 % HSA 2
Staphylococcus aureus ATCC 29,213 4 % HSA 8
Enterococcus faecalis ATCC 29,212 0 % HSA 4
Enterococcus faecalis ATCC 29,212 4 % HSA〉64
Embodiment 2: make Na by adding cyclodextrin
2The inductive haemolysis of friulimicin B minimizes
This embodiment shows the influence of cyclodextrin different modifications or unmodified to the inductive haemolysis of lipopeptid.At this, Na
2Friulimicin B is as the example molecule of lipopeptide antibiotics.
With Na
2Friulimicin B is dissolved in the 0.9% NaCl solution with the concentration of 3200mg/l.Utilize 0.9% NaCl to dilute, refabrication contains 1600,800,200,100 and the Na of 50mg/l
2The stock solution of friulimicin.With each 20 μ l of these stock solutions carefully with 0.9% NaCl or contain 2% (2-hydroxypropyl)-gamma-cyclodextrin (((0.9% NaCl solution, the 20 μ L of α-CD) mix for HP-β-CD) or alpha-cyclodextrin for HP-γ-CD), (2-hydroxypropyl)-beta-schardinger dextrin-.According to the method for embodiment 1, utilize Freshman venous blood preincubate and test to measure hemolytic activity.The ultimate density of different rings dextrin is 0.5% (weight/volume), Na
2Friulimicin B (representing free acid with mg/l) provides the result shown in the table 3 for the test under the condition of described ultimate density.
Table 3
In the presence of the different rings dextrin as Na
2The external hemolytic activity (representing) of the function of friulimicin concentration with %
Cyclodextrin concentration Friulimicin concentration is represented with mg/l
0 50 100 200 800 1600
Do not contain cyclodextrin additive 0 2.3 5.1 5.9 8.3 9.4
0.5% (weight/volume) α-CD 000 0.1 0.4 1.2
0.5% (weight/volume) HP-β-CD 00 0.3 0.6 4.4 5.3
0.5% (weight/volume) HP-γ-CD 02 4.8 5.8 6.6 8.6
The mensuration of free content of hemoglobin shows in the serum: after utilizing HP-γ-CD preincubate of 0.5%, fail to find by Na
2The inductive hemolytic any remarkable reduction of friulimicin B.With α-compare with beta cyclodextrin, gamma-cyclodextrin is because its sugared structure and have bigger volume in its hydrophobic interior chamber.Yet, surprisingly, utilize 0.5% HP-β-CD and α-CD preincubate after, can detect by Na
2The inductive hemolytic remarkable reduction of friulimicin B.
Embodiment 3: make Ca by the beta-schardinger dextrin-that adds modified
2Cl
2The inductive haemolysis of friulimicin B minimizes
This embodiment shows that beta-schardinger dextrin-is to the influence of the inductive haemolysis of lipopeptid in the presence of the high concentration lipopeptid.At this, Ca
2Cl
2Friulimicin B is as the example molecule of lipopeptide antibiotic, and (SBE-β-CD) and HP-β-CD are as the example of the beta-schardinger dextrin-of modifying for sulfo group butyl ether-beta-schardinger dextrin-.
With Ca
2Cl
2Friulimicin B respectively with 100,50,40,30,20,10 and the concentration of 5g/l be dissolved in contain 20%, 15%, 12.5%, 10%, in the 0.9% NaCl solution of 7.5%SBE-β-CD or contain in the 0.9% NaCl solution of 12.5% HP-β-CD.According to the method for embodiment 1, utilize Freshman venous blood preincubate and test to measure hemolytic activity.Different with embodiment 1, under 37 ℃ with blood batch hatching 60 minutes to end reaction.The results are shown in table 4.In the table, Ca
2Cl
2The concentration of friulimicin B (representing free acid with mg/l) and cyclodextrin refers to the ultimate density in its reaction batch.
Table 4
In the presence of the different rings dextrin as Ca
2Cl
2The external hemolytic activity (representing) of the function of friulimicin concentration with %
Cyclodextrin concentration Friulimicin concentration is represented with g/l
0 5 10 15 20 25
Do not contain cyclodextrin additive 0 76 87 91 93 97
7.5% (weight/volume) SBE-β-CD 0013 18 63
10% (weight/volume) SBE-β-CD 0013 13 42
12.5% (weight/volume) SBE-β-CD 00014 12
15% (weight/volume) SBE-β-CD 000114
Surprisingly, can find: at the Ca of the high friulimicinB of the hemolytic activity of unusual high concentration
2Cl
2Under the condition that salt exists, HP-β-CD, particularly SBE-β-CD itself also can suppress the inductive haemolysis of described activating agent.These results show, even in (this situation only occurs in the short time in injection or transfusion part) under the high surfactant concentration, after 1 hour, can significantly suppress Ca at the beta-schardinger dextrin-preincubate of using modified
2Cl
2The haemolysis of friulimicin B.
Embodiment 4: make by the beta-schardinger dextrin-that adds modified to reach the inductive haemolysis of handkerchief Tobramycin and minimize
This embodiment shows at CaCl
2Exist down, the sulfoalkyl ether cyclodextrin that utilizes isolated erythrocyte to carry out reaches the influence of the inductive haemolysis of handkerchief Tobramycin to lipopeptid.
To reach the handkerchief Tobramycin and be dissolved in 0 or 2.5% SBE-β-CD at 0.9% NaCl, 2.5mMCaCl
2In solution in.In order to carry out hemolytic test, separating red corpuscle from Freshman venous blood, this erythrocyte is collected in the sample cell of heparinization.For this purpose, under 2500RFC centrifugal 5 minutes, the deposition erythrocyte.With 0.9% NaCl flushing erythrocyte 3 times, be contained in volume after centrifugal and be equivalent among 0.9% NaCl of blood sample initial volume at last.The above-mentioned reaction batch reaction of 40 μ l erythrocyte and 40 μ l, and under the condition of continuously careful jolting, under 37 ℃, hatched 5 hours.According to the method for embodiment 1, measure the further test of hemolytic activity.The results are shown in table 5.In the table, SBE-β-CD (% represents with weight/volume) and reach handkerchief Tobramycin (representing free acid with mg/l) concentration and refer to the final concentration in the reaction batch.
Table 5
Conduct reaches the external hemolytic activity (representing with %) of the function of handkerchief Tobramycin concentration in the presence of SBE-β-CD
Cyclodextrin concentration reaches handkerchief Tobramycin concentration and represents with mg/l
0 1,600 3,200 6,400 12,800
0％ 0 1.7 6.5 7.6 7.8
1.25% (weight/volume) 00 0.1 0.1 0
SBE-β-CD
In this test that utilizes isolated erythrocyte to carry out, SBE-β-CD also suppresses the inductive molten born of the same parents of lipopeptid (referring to reach the handkerchief Tobramycin at this).This test shows that SBE-β-CD can suppress the toxicity of very different lipopeptid.The haematolysis property that reaches the handkerchief Tobramycin based on the interaction at once of erythrocyte membrane.Similar mechanism can cause and reach the toxic action of handkerchief Tobramycin to skeletal muscle that therefore, the preparation that reaches handkerchief Tobramycin or derivatives thereof and cyclodextrin also can make this toxic action minimize.
Embodiment 5: add cyclodextrin to Ca
2Cl
2The influence of friulimicin B antibiotic activity
By the growth inhibiting in vitro tests of gram positive bacteria, the research cyclodextrin is to Ca
2Cl
2The influence of friulimicin B antibiotic activity.At this, antibacterial culturing is measured required minimal inhibitory concentration (agar dilution) (the National Committee for Clinical Laboratory Standards.2003.Methods for dilution antimicrobial susceptibility tests for bacteria thatgrow aerobically of inhibition growth on Nutrient agar according to CLSI (claiming NCCLS) rule before; Approved Standard-6th ed.Document M7-A6.Clinical and Laboratory Standards Institute, Wayne, PA, USA).In the M ü ller-Hinton culture medium that the Ca ion was regulated, with the SBE-β-CD and the lipopeptid Ca of different mole mixture ratio examples
2Cl
2Friulimicin B tests together.The Gram-positive strain that is used for testing in the described cultural method is:
Staphylococcus carnosus ATCC 51365 (DSM 20501)
Staphylococcus aureus ATCC 29213 (DSM 2569)
Staphylococcus aureus ATCC 33592 (DSM 11729)
Staphylococcus epidermidis ATCC 12228 (DSM 1798)
Cell concentration (the desired value: 5*10 that each speckle is used
3To 5*10
4CFU) be
Staphylococcus carnosus ATCC 51365 5.5*10
3CFU
Staphylococcus aureus ATCC 29213 7.6*10
3CFU
Staphylococcus aureus ATCC 33592 2.2*10
4CFU
Staphylococcus epidermidis ATCC 12228 1.1*10
4CFU
Table 6
Measure the Ca of the function of (mol ratio of the amount of being that provides) as SBE-β-CD
2Cl
2The external antibiotic activity of friulimicinB (MIC represents with μ g/ml)
Friulimicin：SBE-β-CD
1:0 1:2.5 1:4
Staphylococcus carnosus ATCC 51,365 0.5 0.5 0.5
Staphylococcus aureus ATCC 29,213 0.5 0.5 0.5
Staphylococcus aureus ATCC 33,592 111
Staphylococcus epidermidis ATCC 12,228 0.5 0.5 0.5
Surprisingly, though the haematolysis property of lipopeptid can almost completely be suppressed by the interaction of molecules of the cyclodextrin of identical molar ratio and friulimicin, cyclodextrin does not influence to negativity Ca in these trials
2Cl
2The antibiotic activity of friulimicin B.
Embodiment 6: cyclodextrin is to the inhibition of the hemolytic activity of different lipopeptids
This embodiment shows the influence of sulfoalkyl ether cyclodextrin to the inductive haemolysis of different lipopeptids.The concentration of lipopeptid with 6400mg/l is dissolved in the 0.9% NaCl solution.0.9% NaCl or 0.9% NaCl/10%SBE-β-CD with certain volume dilutes respectively, contained or do not contain the stock solution of the 3200mg/l lipopeptid (free acid) of 5%SBE-β-CD.According to the method for embodiment 1, with Freshman venous blood preincubate and measure the test of hemolytic activity, obtain in the result shown in the table 7.Show in the table that 2.5%SBE-β-CD was to the inductive hemolytic inhibition percentage rate of lipopeptid when lipopeptid concentration was 1600mg/l.The lipopeptid of surveying is friulimicin derivant and amfomycin derivant, and its acyl residue is a modified.All lipopeptids have the structure of formula I:
Formula I
Wherein the feature of the lipopeptid of studying is as follows:
X Y
Amfomycin Asp 10-methyl 12 carbon-3-olefin(e) acid
Friulimicin B Asn 12-methyl 13 carbon-3-olefin(e) acid
CBS000201 Asn 12-methyl tridecanoic acid
CBS000205 Asn 15-phenyl-just-pentadecanoic acid
CBS000203 Asn stearic acid
CBS000204 Asn gamma-Linolenic acid
CBS000217 Asn 4-[2-(4-phenethyl-phenyl)-ethyl]-benzoic acid
And Y is connected with the outer shroud Asn or the Asp of described peptide by amidatioon.Particularly, for example list of references EP0 688 789 A1 prepare such lipopeptid.
Table 7
2.5%SBE-β-CD is the inhibition of hemolytic activity of the different lipopeptids of 1600mg/l to concentration
Lipopeptid haemolysis reduces %
Amfomycin 99.6%
Ca
2Cl
2 friulimicin B 99.2％
CBS000201 95.7％
CBS000205 74.9％
CBS000203 41.3％
CBS000204 87.0％
CBS000217 99.5％
These results show that cyclodextrin goes up substantially that the acyl group that is not subjected to lipopeptid and peptidyl residue influence and the hemolytic activity that can reduce lipopeptid.
Embodiment 7:Ca
2Cl
2The preparation of friulimicin B injection solution
With 100mg Ca
2Cl
2Friulimicin B and 770mg SBE-β-CD are dissolved in the aseptic 0.9% NaCl solution, filter and lyophilizing by poly (ether sulfone) film (0.2 μ m, non-pyrogen).Then whole lyophilized products are dissolved in the 10ml injection solution water, in the aseptic ampoule of packing into.Use the diaphragm seal ampoule then.
Embodiment 8: (SBE-β-CD) makes Ca to the sulfo group butyl ether-beta-schardinger dextrin-by adding variable concentrations
2Cl
2The inductive haemolysis of friulimicin B minimizes
This embodiment shows different cyclodextrin: the influence of the inductive haemolysis of comparison lipopeptid of lipopeptid.At this, Ca
2Cl
2Friulimicin B is as the example molecule of lipopeptide antibiotic, and (SBE-β-CD) is as the example molecule of cyclodextrin for sulfo group butyl ether-beta-schardinger dextrin-.
With Ca
2Cl
2Friulimicin B is dissolved in the 0.9% NaCl solution with the concentration of 2500mg/l.In this 0.9% NaCl solution of different batches, add the SBE-β-CD of variable concentrations, produce following mol ratio (SBE-β-CD:friulimicin B): 0:1; 1:10; 1:5; 1:1; 2.5:1; 5:1; 10:1.
According to the method for embodiment 1, with Freshman venous blood preincubate and measure the test of hemolytic activity.Table 8 shows, under the situation of no SBE-β-CD by 2500mg/l Ca
2Cl
2Friulimicin B induces and how many hemolytic activities of producing can reduce when adding SBE-β-CD with above-mentioned mol ratio.
Ca
2Cl
2The content of friulimicin B (representing with mg/l) refers to the ultimate density of the free acid of the B of friulimicin described in the reaction batch.Described mol ratio is respectively with regard to the free acid of friulimicin B and the SBE-β-CD.
Table 8
SBE-β-CD external to 2500mg/l Ca
2Cl
2The inductive hemolytic reduction of friulimicin B (representing) with %
Mol ratio is induced hemolytic reduction
SBE-β-CD:friulimicin B
0:1 0％
1:10 11％
1:5 28％
1:1 80％
2.5:1 96％
5:1 98％
10:1 100％
Surprisingly, can find: between 3 hours incubation period, even be under the condition of 2500mg/l in the concentration of friulimicin B, SBE-β-CD suppresses Ca with substoichiometric concentration
2Cl
2The inductive haemolysis of friulimicin B.
Embodiment 9: cyclodextrin is to the influence of cyclic peptide hemolytic activity
This embodiment relates to the inhibition of cyclodextrin to the hemolytic activity of different lipopeptids, and shows the influence of sulfoalkyl ether cyclodextrin to the inductive haemolysis of cyclic peptide tyrocidine.The concentration of tyrocidine with 6400mg/l is dissolved in the 0.9% NaCl solution.By diluting with 0.9% NaCl or 0.9%NaCl/10%SBE-β-CD, preparation contains or does not contain the stock solution of the 3200mg/l tyrocidine of 5%SBE-β-CD respectively.According to the method for embodiment 1, with Freshman venous blood preincubate and measure the test of hemolytic activity.The evaluation of this test shows: in the presence of 2.5%SBE-β-CD, the inductive haemolysis of 1600mg/l tyrocidine has improved 178%.Therefore, add the erythrocyte lysis that cyclodextrin can not suppress all hemolytic activity material.
Embodiment 10: (SBE-β-CD) makes Ca by sulfo group butyl ether-beta-schardinger dextrin-
2Cl
2The haemolysis of the inductive dog blood of friulimicinB minimizes
This embodiment shows the influence of beta-schardinger dextrin-to the haemolysis of the inductive different organism blood of lipopeptid.At this, Ca
2Cl
2Friulimicin B is as the example molecule of lipopeptide antibiotic, and (SBE-β-CD) is as the example of the beta-schardinger dextrin-of modified for sulfo group butyl ether-beta-schardinger dextrin-.Utilize dog blood to carry out this test.
With Ca
2Cl
2Friulimicin B is dissolved in and adds and do not add in the 0.9%NaCl solution of SBE-β-CD.Contain SBE-β-CD batch in, mol ratio (SBE-β-CD:friulimicin B) is 2.5:1.According to the method for embodiment 1, with dog venous blood preincubate and measure the test of hemolytic activity.The results are shown in the table 9.Described Ca
2Cl
2Friulimicin B content (representing with mg/l) is meant the ultimate density of friulimicin B free acid in this reaction batch.Described mol ratio is respectively with regard to the free acid of friulimicin B and the SBE-β-CD.
Table 9
Externally make Ca by SBE-β-CD
2Cl
2The inductive dog blood of friulimicin B haemolysis reduces (representing with %)
Friulimicin B adds the haemolysis reduction that SBE-β-CD causes
Concentration
800 55％
5 000 100％
This embodiment shows that mol ratio is that SBE-β-CD of 2.5:1 (SBE-β-CD:friulimicin B) suppresses Ca
2Cl
2The molten born of the same parents of the inductive dog erythrocyte of friulimicin B.
Embodiment 11: (SBE-β-CD) makes Ca by sulfo group butyl ether-beta-schardinger dextrin-
2Cl
2The haemolysis of the inductive stump-tailed macaque of friulimicinB (machin) blood minimizes
This embodiment shows the influence of beta-schardinger dextrin-to the haemolysis of the inductive different organism blood of lipopeptid.At this, Ca
2Cl
2Friulimicin B is as the example molecule of lipopeptide antibiotic, and (SBE-β-CD) is as the example of beta-schardinger dextrin-for sulfo group butyl ether-beta-schardinger dextrin-.Utilize stump-tailed macaque blood to carry out this test.
With Ca
2Cl
2Friulimicin B is dissolved in and adds and do not add in the 0.9%NaCl solution of SBE-β-CD.Contain SBE-β-CD batch in, mol ratio (SBE-β-CD:friulimicin B) is 5:1.According to the method for embodiment 1, with stump-tailed macaque venous blood preincubate and measure the test of hemolytic activity.Described Ca
2Cl
2Friulimicin B content (representing with mg/l) is meant the ultimate density of friulimicin B free acid in the reaction batch.Described mol ratio is respectively with regard to the free acid of friulimicin B and the SBE-β-CD.
Table 10
Externally make Ca by SBE-β-CD
2Cl
2The inductive stump-tailed macaque blood of friulimicin B haemolysis reduces (representing with %)
Friulimicin B adds the haemolysis reduction that SBE-β-CD causes
Concentration
3 200 92％
6 400 99％
This embodiment shows that mol ratio is that SBE-β-CD of 5:1 (SBE-β-CD:friulimicin B) suppresses Ca
2Cl
2The molten born of the same parents of the inductive stump-tailed macaque erythrocyte of friulimicin B.
Embodiment 12: cyclodextrin is in vivo to the active influence of lipopeptide antibiotics
This embodiment shows that beta-schardinger dextrin-is in vivo to the active influence of lipopeptide antibiotics.At this, Ca
2Cl
2Friulimicin B is as the example molecule of lipopeptide antibiotic, and (SBE-β-CD) is as the example of the beta-schardinger dextrin-of modified for sulfo group butyl ether-beta-schardinger dextrin-.Also shown result to the research of intranasal pulmonary infection mouse model.
With Ca
2Cl
2Friulimicin B is dissolved in and adds and do not add in the 0.9%NaCl solution of SBE-β-CD.Contain SBE-β-CD batch in, mol ratio (SBE-β-CD:friulimicin B) is 2.5:1.Described Ca
2Cl
2Friulimicin B concentration (representing with mg/l) is meant the ultimate density of friulimicin B free acid in this reaction batch.Described mol ratio is respectively with regard to the free acid of friulimicin B and the SBE-β-CD.
Utilize streptococcus pneumoniae (Streptococus pneumoniae) L3TV intranasal infection female mice (CFW-1 (Harlan Winkelmann, Germany)) (1*10
6CFU/ mice).Infected back 1 hour and 4 hours, the accumulated dose of containing and not containing SBE-β-CD (5%) for the animal subcutaneous administration is 20mg Ca
2Cl
2Friulimicin B/kg.Infected back 24 hours, and, measured the bacterial population in the lung by organizing the analyte plane to be seeded on the agar plate in mode well known to those skilled in the art.The evaluation of this research shows that SBE-β-CD strengthens Ca surprisingly
2Cl
2The antibiotic effect of friulimicinB (Mann Whitney checks p=0.0159).
Embodiment 13: cyclodextrin is in vivo to the influence of lipopeptid acute toxicity
This embodiment shows the influence of acute toxic action in the mice body that beta-schardinger dextrin-causes the high concentration lipopeptid.At this, Ca
2Cl
2Friulimicin B is as the example molecule of lipopeptide antibiotic, and (SBE-β-CD) is as the example of the beta-schardinger dextrin-of modified for sulfo group butyl ether-beta-schardinger dextrin-.
With Ca
2Cl
2Friulimicin B is dissolved in and adds and do not add in the 0.9%NaCl solution of SBE-β-CD.Contain SBE-β-CD batch in, mol ratio (SBE-β-CD:friulimicin B) is 2.5:1.Described Ca
2Cl
2Friulimicin B concentration (representing with mg/l) is meant the ultimate density of friulimicin B free acid in this reaction batch.Described mol ratio is respectively with regard to the free acid of friulimicin B and the SBE-β-CD.
Give in female mice (CFW-1 (Harlan Winkelmann, the Germany)) disposable vein and (iv) use the Ca that contains and do not contain SBE-β-CD
2Cl
2Friulimicin B solution.Measure the mortality rate of animal in 24 hours.As shown in table 11.
Table 11
(iv) use the Ca that contains and do not contain SBE-β-CD in the disposable vein
2Cl
2Mortality of mice behind the friulimicin B (representing) with %
Friulimicin B Friulimicin B
Add SBE-β-CD and do not add mortality rate in SBE-β-CD 24 hours
300mg/kg 0％(0/3)
350mg/kg 66％(2/3)
400mg/kg 100％(3/3)
300mg/kg 0％(0/3)
400mg/kg 0％(0/3)
This embodiment shows that mol ratio (SBE-β-CD:friulimicin B) reduces Ca for the existence of SBE-β-CD of 2.5:1
2Cl
2The acute toxicity of friulimicin B.
Claims (17)
1. pharmaceutical composition, it comprises lipopeptid and the cyclodextrin or the cyclodextrin derivative as activating agent of effective dose on the physiology.
2. pharmaceutical composition according to claim 1, wherein said lipopeptid have the salt that can tolerate on the physiology of the structure of formula I or this chemical compound:
Formula I
In the formula; one of X=aminoacid Asn or Asp; Y=has the straight or branched of 6 to 22 carbon atoms, saturated or undersaturated aliphatic acyl radical residue, and it can at random insert one or several phenyl or cycloalkyl or be connected with such group or insert one or several oxygen atom.
3. pharmaceutical composition according to claim 1 and 2, wherein said lipopeptid are selected from the group that comprises amfomycin and amfomycin derivant.
4. according to each described pharmaceutical composition in the claim 1 to 3, wherein said lipopeptid is selected from and comprises following group: amfomycin, the amfomycin derivant, friulimicin, friulimicinB, the friulimicin derivant, reach the handkerchief Tobramycin, reach handkerchief Tobramycin derivant, aspartocin, the aspartocin derivant, Dermokalixan, the Dermokalixan derivant, crystallomycin, the crystallomycin derivant, zaomycin, the zaomycin derivant, tsushimycin, the tsushimycin derivant, aspartomycin, the aspartomycin derivant, brevimycin, the brevimycin derivant, Cerexin B, the Cerexin B derivant, syringomycin and derivant thereof, antibiotic A-30912 and derivant thereof, antibiotic A-54145 and derivant thereof, and antibiotic A-21978C and derivant thereof.
5. according to each described pharmaceutical composition in the claim 1 to 4, it comprises respectively is several different lipopeptid of effective dose on the physiology.
6. according to each described pharmaceutical composition in the claim 1 to 5, wherein said lipopeptid exists as alkali metal salt or alkali salt, preferably as Na salt or calcium salt, especially as two calcium salt (Ca
2Cl
2Salt), or exist as ammonium salt, or wherein said lipopeptid is neutral, or wherein said lipopeptid is as the cationic moiety existence of salt, wherein under the situation that described lipopeptid exists as the cationic moiety of salt, can preferably use to be selected from the ion that comprises following group as counter ion: salt acid group, sulfonate radical, nitrate anion, phosphate radical, amber acid radical, maleate, citrate, tartrate anion, lactate, glucose acid group and sulfonate radical.
7. according to each described pharmaceutical composition in the claim 1 to 6, it comprises total amount is 0.001 to 20 weight %, 0.05 to 20 weight % especially, the lipopeptid of preferred 0.1 to 5 weight %.
8. according to each described pharmaceutical composition in the claim 1 to 7, wherein said cyclodextrin or cyclodextrin derivative are alpha-cyclodextrin or beta-schardinger dextrin-and preferably have general formula I I, comprise the salt that can tolerate on the physiology of these cyclodextrin:
Formula II
In the formula, R1, R2 and R3 can be identical or different, and can be the residues that can tolerate on the physiology arbitrarily, preferably-H, C1-C8 alkyl ,-SO
2OH ,-PO (OH)
2, or-CO-R4, R4=C1-C8 alkyl wherein, described C1-C8 alkyl can on identical or different carbon atom, have one or more-OH ,-COOH ,-CONHR5 ,-NHCOR6 ,-SO
2OH ,-PO (OH)
2, or tetrazolium-5-base, described R5=-H or C1-C4 alkyl, the R6=carboxyl phenyl,
N=6 or 7,
R1, R2 can be arranged in different glucopyranose units randomly with R3,
An oxygen atom or several oxygen atom of described glucopyranose units particularly at the oxygen atom at C6 place, can be replaced by sulphur atom.
9. according to each pharmaceutical composition in the claim 1 to 8, wherein said cyclodextrin or cyclodextrin derivative are selected from the group that comprises following material: alpha-cyclodextrin, beta-schardinger dextrin-, hydroxyl-(C1-C8 alkyl)-alpha-cyclodextrin, hydroxyl-(C1-C8 alkyl)-beta-schardinger dextrin-, (2-hydroxypropyl)-beta-schardinger dextrin-, (2-hydroxypropyl)-alpha-cyclodextrin, sulfo group-(C1-C8 alkyl)-ether-alpha-cyclodextrin, sulfo group-(C1-C8 alkyl)-ether-beta-schardinger dextrin-, sulfo group butyl ether-alpha-cyclodextrin, sulfo group butyl ether-beta-schardinger dextrin-.
10. according to each described pharmaceutical composition in the claim 1 to 9, it comprises 0.001 to 50 weight %, 0.01 to 30 weight % especially, described cyclodextrin or the cyclodextrin derivative of preferred 0.1 to 20 weight %.
11. according to each described pharmaceutical composition in the claim 1 to 9, it further comprises substance and/or auxiliary substance, especially the galenic auxiliary substance.
12. pharmaceutical composition according to claim 11, it comprises
A) 0.001 to 20 weight %, especially 0.05 to 20 weight %, the lipopeptid of preferred 0.1 to 5 weight %,
B) 0.001 to 79.9 weight %, especially 0.01 to 30 weight %, the cyclodextrin of preferred 0.1 to 20 weight % or cyclodextrin derivative,
C) 0.1 to 99.998 weight %, especially 50 to 99.98 weight %, the substance of preferred 95 to 99.98 weight % and/or auxiliary substance and optional diluent,
Component A wherein) to C) always add up to 100%.
13. in the claim 1 to 12 each described pharmaceutical composition preparation be used for the treatment of and/or the medicine of pre-anti-virus and/or antibacterial and/or parasitic infection disease and/or fungal disease in application.
14. application according to claim 13, wherein said medicine is used for galenical oral or injection by mixing with galenic auxiliary substance and carrier mass to be mixed with.
15. a method for the treatment of antibacterial, virus or parasitic infection disease and/or fungal disease, wherein give suffered from this disease or be in each described medicine in the claim 1 to 12 that people in the danger of suffering from this disease uses effective dose on the physiology.
16. method according to claim 15, wherein giving daily dose to described people is 1 to 50000mg, and preferred 50 to 30000mg, 100 to 20000mg lipopeptid most preferably, administration time 1 to 60 day, preferred 1 to 30 day.
17. one kind has the unitary packing unit of a plurality of administrations, wherein each administration unit is prepared for the administration in the treatment plan described in each in claim 15 or 16.
18. method for preparing each described pharmaceutical composition in the claim 1 to 12, wherein, can at random in the galenic conventional additives, add under the situation of substance and/or auxiliary substance, with 100:1 to 1:500, preferred 10:1 to 1:50, the mol ratio of lipopeptid/cyclodextrin of 2:1 to 1:10 most preferably, the lipopeptid of effective dose on the physiology is mixed with cyclodextrin or cyclodextrin derivative.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005056194A DE102005056194A1 (en) | 2005-11-21 | 2005-11-21 | New lipopeptide compositions |
| DE102005056194.2 | 2005-11-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101370524A true CN101370524A (en) | 2009-02-18 |
Family
ID=37763891
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800511655A Pending CN101370524A (en) | 2005-11-21 | 2006-11-20 | Lipopeptide compositions |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1951311A1 (en) |
| CN (1) | CN101370524A (en) |
| AU (1) | AU2006314942A1 (en) |
| CA (1) | CA2630497A1 (en) |
| DE (1) | DE102005056194A1 (en) |
| MX (1) | MX2008006476A (en) |
| WO (1) | WO2007057005A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104768966A (en) * | 2012-09-24 | 2015-07-08 | 中化帝斯曼制药有限公司荷兰公司 | Method for producing a cyclic peptide |
| CN113811290A (en) * | 2019-05-10 | 2021-12-17 | 埃克斯利亚制药有限公司 | Aqueous daptomycin formulations |
Family Cites Families (6)
| 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 |
| CA2408008C (en) * | 2000-05-02 | 2011-01-18 | Theravance, Inc. | Pharmaceutical compositions containing a glycopeptide antibiotic and a cyclodextrin |
| PL218223B1 (en) * | 2000-06-21 | 2014-10-31 | Cubist Pharmaceuticals | Compositions and methods for improving 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 |
| WO2002032459A2 (en) * | 2000-10-17 | 2002-04-25 | Massachusetts Institute Of Technology | Method of increasing the efficacy of antibiotics by complexing with cyclodextrins |
-
2005
- 2005-11-21 DE DE102005056194A patent/DE102005056194A1/en not_active Ceased
-
2006
- 2006-11-20 MX MX2008006476A patent/MX2008006476A/en not_active Application Discontinuation
- 2006-11-20 CN CNA2006800511655A patent/CN101370524A/en active Pending
- 2006-11-20 EP EP06805527A patent/EP1951311A1/en not_active Withdrawn
- 2006-11-20 WO PCT/DE2006/002064 patent/WO2007057005A1/en active Application Filing
- 2006-11-20 CA CA002630497A patent/CA2630497A1/en not_active Abandoned
- 2006-11-20 AU AU2006314942A patent/AU2006314942A1/en not_active Abandoned
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104768966A (en) * | 2012-09-24 | 2015-07-08 | 中化帝斯曼制药有限公司荷兰公司 | Method for producing a cyclic peptide |
| 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 |
| CN113811290A (en) * | 2019-05-10 | 2021-12-17 | 埃克斯利亚制药有限公司 | Aqueous daptomycin formulations |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2008006476A (en) | 2008-09-26 |
| CA2630497A1 (en) | 2007-05-24 |
| EP1951311A1 (en) | 2008-08-06 |
| WO2007057005A1 (en) | 2007-05-24 |
| DE102005056194A1 (en) | 2007-07-12 |
| AU2006314942A1 (en) | 2007-05-24 |
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