[go: up one dir, main page]

EP1397162A2 - Antibiotique soluble dans l'eau comportant un sucre amine, sous forme de conjugue polysaccharide - Google Patents

Antibiotique soluble dans l'eau comportant un sucre amine, sous forme de conjugue polysaccharide

Info

Publication number
EP1397162A2
EP1397162A2 EP02762293A EP02762293A EP1397162A2 EP 1397162 A2 EP1397162 A2 EP 1397162A2 EP 02762293 A EP02762293 A EP 02762293A EP 02762293 A EP02762293 A EP 02762293A EP 1397162 A2 EP1397162 A2 EP 1397162A2
Authority
EP
European Patent Office
Prior art keywords
antibiotic
starch
hydroxyethyl starch
derivative
polysaccharide
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Withdrawn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
EP02762293A
Other languages
German (de)
English (en)
Inventor
Klaus Sommermeyer
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.)
Fresenius Kabi Deutschland GmbH
Original Assignee
Fresenius Kabi Deutschland GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fresenius Kabi Deutschland GmbH filed Critical Fresenius Kabi Deutschland GmbH
Publication of EP1397162A2 publication Critical patent/EP1397162A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B35/00—Preparation of derivatives of amylopectin
    • C08B35/06—Ether-esters
    • 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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/56—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • 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
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B31/00—Preparation of derivatives of starch
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B31/00—Preparation of derivatives of starch
    • C08B31/02—Esters
    • C08B31/04—Esters of organic acids, e.g. alkenyl-succinated starch
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B31/00—Preparation of derivatives of starch
    • C08B31/08—Ethers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B31/00—Preparation of derivatives of starch
    • C08B31/08—Ethers
    • C08B31/12—Ethers having alkyl or cycloalkyl radicals substituted by heteroatoms, e.g. hydroxyalkyl or carboxyalkyl starch
    • C08B31/125—Ethers having alkyl or cycloalkyl radicals substituted by heteroatoms, e.g. hydroxyalkyl or carboxyalkyl starch having a substituent containing at least one nitrogen atom, e.g. cationic starch
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B31/00—Preparation of derivatives of starch
    • C08B31/16—Ether-esters
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B33/00—Preparation of derivatives of amylose
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B33/00—Preparation of derivatives of amylose
    • C08B33/02—Esters
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B33/00—Preparation of derivatives of amylose
    • C08B33/04—Ethers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B33/00—Preparation of derivatives of amylose
    • C08B33/06—Ether-esters
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B35/00—Preparation of derivatives of amylopectin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B35/00—Preparation of derivatives of amylopectin
    • C08B35/02—Esters
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B35/00—Preparation of derivatives of amylopectin
    • C08B35/04—Ethers

Definitions

  • the present invention relates to water-soluble, orally or parenterally administrable preparations of antibiotics having an amino sugar in the form of a conjugate with a polysaccharide based on starch or starch derivatives, in particular hydroxyethyl starch and hydroxypropyl starch, and a process for their cost-effective production in high yield. Hydroxyethyl starch is particularly preferred as the polysaccharide.
  • Antibiotics with an amino sugar are in particular amphotericin B, daunorubicin and doxorubicin, all of which have an amino group in the C 3 position of the amino sugar portion.
  • Amphotericin B is mainly administered parenterally, daunorubicin and doxorubicin must be used IV. be administered.
  • Amphotericin B is a polyen antibiotic isolated from Streptomyces nodosus. Chemically, it is a macrocyclic lactone (macrolide) with 7 conjugated double bonds in an all-trans configuration within a 38-membered lactone ring, to which the amino sugar D-mycosamine is bound via an O-glycosidic bond.
  • Amphotericin B is amphoteric and has lipophilic and hydrophilic regions in the molecule, which enable it to form complexes with the sterols contained in the cytoplasmic membrane of fungi, which leads to a disturbance in cell permeability. Since bacterial membranes do not contain sterols, the antibiotic effect of Amphotericin B is selectively directed against fungi.
  • Amphotericin B Because of the broad spectrum of action of Amphotericin B, which covers practically all human pathogenic fungi, it is the method of choice for systemic treatment of mycotic infections in humans. Especially in patients whose immune system is impaired, e.g. in HIV or cancer patients, the treatment of the associated invasive fungal infections has increased significantly in recent years.
  • Amphotericin B is sometimes associated with rather massive side effects.
  • amphotericin B i.v. applied usually with a daily dose of 0.5 to 0.7 mg / kg body weight.
  • the dosage must be adjusted or adjusted individually.
  • patients with a weakened immune system usually need higher doses than usual, e.g. 1 mg / kg body weight daily, which can be increased up to 1.5 mg / kg in difficult forms - if tolerable.
  • the parenteral duration of use can extend from a few weeks to several months.
  • Amphotericin B Because of its toxicity and side effects, Amphotericin B should therefore only be administered in life-threatening circumstances. On the other hand, however, it is caused by disorders caused by the immune system - e.g. in AIDS or after organ transplants - mycoses often the only effective remedy.
  • amphotericin as a whole has pronounced hydrophobic properties, so that it is practically insoluble in water in the physiological pH range. It is difficult to dissolve even in organic solvents. Therefore, the current commercial preparations are relatively complicated pharmaceutical forms, which have additional disadvantages.
  • a suitable solution mediator e.g. Na deoxycholate
  • the solubility in water can be increased.
  • the BRISTOL-MYERS SQUIBB originator preparation intended for infusion available in Germany under the trade name "Amphotericin B”
  • Amphotericin B the stock solution thus obtained can only be used with electrolyte-free carrier solutions, e.g. a 5% glucose solution, diluted to the desired final concentration.
  • This preparation also has a low therapeutic index, i.e. the window between the effective and toxic dose is very narrow.
  • this preparation is not very effective in certain clinical pictures because the active substance does not reach the site of the mycotic infection or only in too small a concentration, so that amphotericin B does not or only has its characteristic antifungal activity can unfold insufficiently.
  • amphotericin B preparations which represent lipid formulations, for example lipid complexes with amphotericin B, colloidal dispersions of cholesteryl sulfate with amphotericin B and liposomally packaged amphotericin B. All of these medicinal forms are shown Although a larger therapeutic index and a higher tolerance, in particular a lower nephrotoxicity compared to a conventional amphotericin B deoxycholate formulation, which is why they can also be administered in higher doses, the side effects described above cannot be avoided entirely at high doses ,
  • amphotericin B As a further method of converting amphotericin B into a water-soluble form for injection purposes, the formation of an amphotericin B-arabinogalactan conjugate is described in the literature (Antimicrobial Agents and Chemotherapy, Vol. 43 No. 8, 1999, 1975-1981).
  • Arabinogalactan is a water-soluble polysaccharide obtained from larch from arabinose and galactose units in a ratio of 1: 6.
  • Amphotericin B binds to arabinogalactan in 4 steps. Arabinogalactan is first subjected to periodate oxidation, with vicinal hydroxyl groups of the sugar units being converted into dialdehydes with ring cleavage.
  • the aminos group of mycosamine from amphotericin B is coupled to an aldehyde group to form an imine (Schiff base) and finally the imine group is converted into an amine group by means of Na borohydride. Group and unreacted aldehyde groups converted into hydroxyl groups.
  • the coupling reaction is carried out at pH 11. This pH value is a compromise between the yield of the conjugate formed on the one hand and the toxicity of the conjugate on the other. Below pH 10, amphotericin B is water-insoluble and the yields are low. From pH 12, amphotericin B is relatively readily water-soluble, which enables higher yields, but the product obtained is toxic. Toxicity was also observed when the final step of Na borohydride reduction was omitted.
  • the antibiotics daunorubicin and doxorubicin belong to the group of anthracyclines and differ only by a hydroxyl group. They are soluble in water. Doxorubicin is obtained from cultures of the fungus Streptomyces peuceticus var. Caesius, Daunomycin from Streptomyces peuceticus or coeruleorubidus.
  • daunorubicin and doxorubicin are able to inhibit DNA and RNA synthesis with the formation of very stable, long-lasting DNA intercalation complexes.
  • cytochrome P-450 reductase and NADPH they form semiquinone radicals, which in turn trigger further radical reactions (superoxide anion and hadroxyl radicals). This gives these antibiotics a pronounced cytostatic effect, which is why they are used as cytostatics in cancer therapy.
  • antibiotics are only insufficiently absorbed after oral administration, they must be (strictly) IV. in short infusions over 10 to 15 minutes. They are distributed quickly in the organism, with the highest concentrations in the heart, lungs, spleen and kidneys being detected.
  • the object of the present invention is therefore to provide pharmaceutical forms for such amino sugar-containing antibiotics in which the specific toxic side effects are reduced, which ensure a more uniform, controlled distribution in the organism and thus allow a higher dosage and which are nevertheless easy to use.
  • Another object of the invention is to provide an inexpensive method for producing these dosage forms with a high yield.
  • Starch or starch derivatives can be solved with such antibiotics.
  • composition is a water-soluble antibiotic derivative containing an aminosugar
  • polysaccharide portion of the conjugate is linked to the amino group at C 3 of the amino sugar of the antibiotic to form a peptide bond.
  • starch or starch derivatives are amylose (unbranched only with ⁇ -l, 4-glycosidic linkage) and / or amylopectin (branched, additionally with ⁇ -l, 6-glycosidic linkage) and in particular hydroxyalkylated starch.
  • amylose or amylopectin commercially available so-called "soluble" starch is used. The latter can also be in hydroxyethylated and hydroxypropylated form.
  • the average molecular weight can be in the range between 2000 and 2 ⁇ 10 6 daltons.
  • the average degree of polymerization should, however, be at least 15 and in a preferred one Embodiment range up to about 3000 (corresponding to an average molecular weight of about 5 • 10 5 ).
  • the use of hydroxyethyl starch is particularly preferred.
  • the molecular weight of the HES should preferably be above the kidney threshold for HES, ie above 70,000 Daltons.
  • a HES of specification 130 / with an average molecular weight of 130,000 daltons is particularly preferred.
  • the degree of substitution MS is preferably in the range from 0.1 to 0.8. In a preferred embodiment, the degree of substitution is in the range from 0.3 to 0.5.
  • the preferred C 2 / C 6 ratio is in the range from 2 to 12, in a particularly preferred embodiment in the range from 5 to 11.
  • HES can be both unbranched are present only with predominantly ⁇ -1,4-glycosidic linkages and also branched with both ⁇ -1,4-glycosidic linkages and also ⁇ -1,6-glycosidic linkages.
  • the binding of the polysaccharide to the amino group of the amino sugar of the antibiotic is carried out by oxidizing the free, reducing aldehyde group of the terminal polysaccharide molecule, preferably with J 2, to form an aldonic acid group, which in turn contains a free hydroxyl group of the terminal sugar unit. preferably on the C 4 atom of the terminal sugar unit, a lactone ring is formed which can then form a peptide bond with the amino group of the amino sugar of the antibiotic.
  • the coupling reaction according to the invention of the oxidation product at the reducing end of HES with the amino group of the amino sugar can also be used high yield in an organic solvent, for example DMSO, in which, for example, the antibiotic amphotericin B is soluble.
  • the conjugate obtained surprisingly also proved to be non-toxic, so that it can also be administered orally.
  • the conjugate can be dissolved or diluted to the desired applicable final concentration with electrolyte-containing solvents or mixtures (e.g. a mixture of isotonic saline and glucose solution).
  • higher doses e.g. For the amphotericin B conjugate, apply daily doses of up to 15 mg of amphotericin B.
  • hydroxyethyl starch can in any case be administered intravenously as a plasma expander in large doses, when HES and amphotericin B are coupled, unreacted portions of HES are physiologically harmless and therefore do not need to be separated from the reaction product, which is of great economic advantage in the synthesis.
  • amphotericin B no final hydrogenation is required in order to make the conjugate formed less toxic.
  • unbound hydroxyethyl starch itself on amphotericin B is even a solubilizing one Exerts an effect, whereby an additional stabilization of the antifungal active ingredient can be achieved with excess HES.
  • an antibiotic-HES conjugate according to the invention is that the polysccharide portion is degradable by serum ⁇ -amylase. This degradation is described in detail in the relevant literature on the pharmacokinetics of the HES used as plasma expanders.
  • the peptide bond between the polysaccharide component and the antibiotic in vivo is in principle accessible to an enzymatic attack.
  • amphotericin B As was shown from studies on Candida albicans, known as the leading microorganism from the spectrum of the possible fungal infection germs, the conjugates of amphotericin B according to the invention had comparable efficacies to the lipid formulations. In the hemolysis test on sheep erythrocytes it was possible to demonstrate that the in vitro toxicity of an amphotericin B-HES conjugate is significantly lower than that of commercial amphotericin B deoxycholate formulations.
  • a significant advantage of an antibiotic-HES conjugate according to the invention can be seen in the fact that the pharmacokinetic properties of the conjugate obtained can be adjusted practically tailored to the needs of a particular patient by suitable selection of molecular weight, degree of substitution, substitution pattern and degree of branching of the HES used.
  • the solution obtained is then passed through an H + ion exchange column (Amberlite IR 120) and then dialyzed against distilled water in a dialysis tube with an exclusion limit of 4-6 kD over a period of 20 h.
  • the dialyzed product is lyophilized and the degree of oxidation is determined using the SOMOGYI method.
  • the method of SOMOGYI was used to determine the oxidized HES (ox-HES) formed (Meth. Carbohydrate Chem., 1, 384-386, 1962). The method is based on the determination of the free aldehyde groups via the reduction of Cu 2+ to Cu + . Cu ⁇ is oxidized again to Cu 2+ with the aid of iodine formed from iodide and iodate. Excess iodine is then titrated using thiosulfate.
  • amphotericin B-HES conjugates obtained were characterized by their UV spectrum (0.5 g / 5 ml H 2 O dcst ) and showed the bands typical for polymeric or micellar interactions of amphotericin B in the range of 300-400 nm. In contrast to free amphotericin B, which is practically insoluble in water, the amphotericin-HES conjugates obtained had a water solubility of> 0.1 g / 5 ml H 2 0.
  • Weight average molecular weight M w 102,700
  • This characteristic data essentially corresponded to the characteristic data of the HES used.
  • amphotericin B from Bristol-Meyers-Squibb, batch name: A068
  • Amphotericin B from Bristol-Meyers-Squibb, batch name: A068
  • the active ingredient of which is said to be hemolytic from a concentration of 8 ⁇ g / ml
  • Stock solution for preparation according to the invention 1 1.61 g of Ampho-HES (corresponding to a weight fraction of 50 mg of amphotericin B) were dissolved in 50 ml of 5% glucose solution (batch number: 9233A4 from Braun Melsungen). The active substance content of the stock solution thus prepared was 1 mg of amphotericin B per ml. Three dilutions of this stock solution were prepared in accordance with Table 2 and also examined for their haemolytic effect.
  • amphotericin B deoxycholate formulation A 50 mg bottle was washed with 10 ml A. a. injectabilia (lot number: 0514A63 from Braun Melsungen) and diluted in 5% glucose solution to 0.12 mg / ml amphotericin B.
  • Hemolysis comparison test 5 ml each of the solutions to be tested were mixed with 1 ml of the above erythrocyte suspension, transferred to a cleaned centrifuge tube and incubated for 20 minutes in a water bath at 37 ⁇ 1 ° C. The mixture was then centrifuged for 5 minutes at a relative centrifugal acceleration of 2000.
  • the absorbance of the supernatant was measured. 5 ml of the 0.9% NaCl solution and the 5% glucose solution, which were mixed with 1 ml the erythrocyte suspension was mixed, also incubated for 20 minutes at 37 ⁇ 1 ° C and then centrifuged as above.
  • the absorbances of the respective supernatants against the negative controls were measured at a wavelength of 576 nm using a cuvette with a 10 mm layer thickness. Due to the different colorations of the solutions, the extinction was also measured for comparison of the solutions without erythrocyte suspension.
  • the tested, commercially available amphotericin B deoxycholate formulation shows a strong haemolytic effect even at a concentration of 0.1 mg / ml in the test mixture under the above test conditions.
  • the supernatant had an absorbance of 2.271 at 576 nm and was colored strongly red.
  • ampho-HES preparation according to the invention had no hemolytic effect up to a concentration of 0.2 mg amphotericin B per ml observe. Only at a concentration of 0.4 mg / ml was there a slight red color in the supernatant of the test mixture compared to the negative control, which was also noticeable in the absorbance values. At this amphotericin B concentration in the test mixture, there is a slight hemolytic activity.
  • the test preparation showed a strong hemolytic activity at a concentration of 0.83 mg / ml, where the supernatant was colored strongly red. In addition, microscopic few intact erythrocytes were found in the supernatant, which could not sediment into the pellet due to the high viscosity during the sedimentation period.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • Polymers & Plastics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Saccharide Compounds (AREA)

Abstract

L'invention concerne de nouvelles formes galéniques pour les antibiotiques à base de sucre aminé, Amphotéricine B, Daunorubicine et Doxorubicine, dans lesquelles les effets secondaires connus sont réduits et qui s'utilisent de manière simple. L'antibiotique Amphotéricine B est néphrotoxique. Les cytostatiques que sont la Daunorubicine et la Doxorubicine sont fortement cardiotoxiques. Les nouvelles formes galéniques sont des conjugués antibiotiques-amidon, l'antibiotique étant combiné au polysaccharide à son extrémité réductrice par l'intermédiaire d'une liaison peptidique. Selon l'invention, cette liaison s'effectue par oxydation J2 du dérivé amidon à son extrémité réductrice en solution alcaline aqueuse, puis par couplage du dérivé amidon ainsi oxydé avec l'antibiotique en solution organique. Les conjugués obtenus sont moins toxiques. La part de polysaccharide peut être décomposée par sérum- alpha -amylase et la liaison peptidique est accessible à un agent enzymatique.
EP02762293A 2001-06-21 2002-06-19 Antibiotique soluble dans l'eau comportant un sucre amine, sous forme de conjugue polysaccharide Withdrawn EP1397162A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10129369A DE10129369C1 (de) 2001-06-21 2001-06-21 Wasserlösliches, einen Aminozucker aufweisendes Antibiotikum in Form eines Pol ysaccharid-Konjugats
DE10129369 2001-06-21
PCT/EP2002/006764 WO2003000738A2 (fr) 2001-06-21 2002-06-19 Antibiotique soluble dans l'eau comportant un sucre amine, sous forme de conjugue polysaccharide

Publications (1)

Publication Number Publication Date
EP1397162A2 true EP1397162A2 (fr) 2004-03-17

Family

ID=7688583

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02762293A Withdrawn EP1397162A2 (fr) 2001-06-21 2002-06-19 Antibiotique soluble dans l'eau comportant un sucre amine, sous forme de conjugue polysaccharide

Country Status (9)

Country Link
US (1) US7115576B2 (fr)
EP (1) EP1397162A2 (fr)
JP (1) JP2004534086A (fr)
CN (1) CN1596129A (fr)
AU (1) AU2002328294A1 (fr)
CA (1) CA2446205A1 (fr)
DE (1) DE10129369C1 (fr)
PL (1) PL366438A1 (fr)
WO (1) WO2003000738A2 (fr)

Families Citing this family (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10112825A1 (de) 2001-03-16 2002-10-02 Fresenius Kabi De Gmbh HESylierung von Wirkstoffen in wässriger Lösung
DE10209821A1 (de) 2002-03-06 2003-09-25 Biotechnologie Ges Mittelhesse Kopplung von Proteinen an ein modifiziertes Polysaccharid
DE10209822A1 (de) * 2002-03-06 2003-09-25 Biotechnologie Ges Mittelhesse Kopplung niedermolekularer Substanzen an ein modifiziertes Polysaccharid
DE10242076A1 (de) * 2002-09-11 2004-03-25 Fresenius Kabi Deutschland Gmbh HAS-Allergen-Konjugate
MXPA05002594A (es) 2002-09-11 2005-05-27 Fresenius Kabi Gmbh Derivados de polipeptidos con hidroxialquilalmidon, especialmente derivados de eritropoyetina con hidroxialquilalmidon.
AU2003273413A1 (en) 2002-10-08 2004-05-04 Fresenius Kabi Deutschland Gmbh Pharmaceutically active oligosaccharide conjugates
DE10256558A1 (de) * 2002-12-04 2004-09-16 Supramol Parenteral Colloids Gmbh Ester von Polysaccharid Aldonsäuren, Verfahren zu ihrer Herstellung und Verwendung zur Kopplung an pharmazeutische Wirkstoffe
DE10302520A1 (de) * 2003-01-23 2004-08-05 Supramol Parenteral Colloids Gmbh Kohlensäurediester von Stärkefraktionen und deren Derivate, Verfahren zu ihrer Herstellung und Verwendung zur Kopplung an pharmazeutische Wirkstoffe
DE10324710A1 (de) * 2003-05-30 2004-12-16 Supramol Parenteral Colloids Gmbh Stärkederivatkomplexe
HRP20110056T1 (hr) * 2003-08-08 2011-02-28 Fresenius Kabi Deutschland Gmbh Konjugati hidroksialkil škroba i g-csf
BRPI0412671A (pt) * 2003-08-08 2006-10-03 Fresenius Kabi De Gmbh conjugados de um polìmero e uma proteìna ligados por um grupo de ligação de oxima
WO2005014655A2 (fr) 2003-08-08 2005-02-17 Fresenius Kabi Deutschland Gmbh Conjugues d'amidon d'hydroxyalkyle et de proteine
AR048918A1 (es) * 2004-03-11 2006-06-14 Fresenius Kabi De Gmbh Conjugados de almidon de hidroxietilo y eritropoyetina
CN101659704A (zh) 2004-03-11 2010-03-03 弗雷泽纽斯卡比德国有限公司 通过还原氨基化制备的羟烷基淀粉和蛋白质的偶联物
WO2005092391A2 (fr) * 2004-03-11 2005-10-06 Fresenius Kabi Deutschland Gmbh Conjugues d'amidon hydroxyalkyle et de proteine, par ligature chimique naturelle
WO2006094810A2 (fr) * 2005-03-11 2006-09-14 Fresenius Kabi Deutschland Gmbh Production de glycoproteines bioactives a partir d'un materiau de depart inactif
EP1762250A1 (fr) * 2005-09-12 2007-03-14 Fresenius Kabi Deutschland GmbH Conjugués d' amidon hydroxyalkyle et une substance active obtenue par ligation chimique via thiazolidine
CN101045163B (zh) * 2006-03-29 2011-03-30 重庆莱美药业股份有限公司 一种高分子抗癌前药及其制备方法和用途
DE102006020035A1 (de) * 2006-04-26 2007-10-31 B. Braun Melsungen Ag Herstellung und Verwendung von Poly(hydroxyethylstärke)chitin- und Poly(Carboxymethylstärke)chitin-Verbindungen
CN1973902B (zh) * 2006-12-12 2010-11-10 东北师范大学 以人参多糖为载体的抗肿瘤药物阿霉素复合物及制备方法
CN100569296C (zh) * 2007-09-17 2009-12-16 重庆莱美药业股份有限公司 一种抗癌前药及其制备方法和用途
EP2070951A1 (fr) * 2007-12-14 2009-06-17 Fresenius Kabi Deutschland GmbH Procédé de production d'un dérivé hydroxyalkyle de l'amidon avec deux liens
EP2070950A1 (fr) 2007-12-14 2009-06-17 Fresenius Kabi Deutschland GmbH Dérivés hydroxyalkylés de l'amidon et leur procédé de préparation
WO2009133208A1 (fr) 2008-05-02 2009-11-05 Novartis Ag Molécules de liaison à base de fibronectine améliorées et leurs utilisations
WO2011051327A2 (fr) 2009-10-30 2011-05-05 Novartis Ag Petites protéines à chaîne unique de type anticorps
WO2011051466A1 (fr) 2009-11-02 2011-05-05 Novartis Ag Molécules de liaison anti-idiotypiques à base de fibronectine et leurs utilisations
WO2011061747A1 (fr) 2009-11-23 2011-05-26 Conjugate Ltd. Conjugués antifongiques et antiparasitaires dérivés d'amphotéricine b
WO2011092233A1 (fr) 2010-01-29 2011-08-04 Novartis Ag Conjugaison de levures pour produire des combinaisons de liants à base de fibronectine à haute affinité
US20130178437A1 (en) * 2010-07-09 2013-07-11 Fresenius Kabi Deutschland Gmbh Conjugates comprising hydroxyalkyl starch and a cytotoxic agent and process for their preparation
EP2742064B1 (fr) 2011-08-09 2016-07-27 UAB Profarma Dérivés de protéines recombinantes, homomultimères du facteur de stimulation de colonie de granulocytes et leur procédé de préparation
PL221351B1 (pl) 2012-03-14 2016-03-31 Politechnika Warszawska Sposób otrzymywania nanocząstek polisacharydowych
CN104055787B (zh) * 2013-07-25 2017-04-26 北京蓝贝望生物医药科技股份有限公司 药用水溶性抗真菌大分子化合物
KR102869384B1 (ko) 2017-07-07 2025-10-15 에피센트알엑스, 인코포레이티드 치료제의 비경구 투여를 위한 조성물
CN110669087B (zh) * 2018-07-02 2023-03-31 上海医药工业研究院 两性霉素b肽衍生物及其制备方法
US11028113B2 (en) * 2018-10-26 2021-06-08 Wisconsin Alumni Research Foundation Cyphomycin, compositions and uses thereof
CN113166188B (zh) * 2018-12-13 2023-06-20 正大天晴药业集团股份有限公司 两性霉素b肽衍生物

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6045163B2 (ja) * 1977-07-01 1985-10-08 協和醗酵工業株式会社 新規組成物
ATE111746T1 (de) * 1989-11-15 1994-10-15 Sandoz Ag Polymyxinkonjugate.
GB2270920B (en) * 1992-09-25 1997-04-02 Univ Keele Alginate-bioactive agent conjugates
DE19628705A1 (de) * 1996-07-08 1998-01-15 Fresenius Ag Neue Sauerstoff-Transport-Mittel, diese enthaltende Hämoglobin-Hydroxyethylstärke-Konjugate, Verfahren zu deren Herstellung, sowie deren Verwendung als Blutersatzstoffe
US5939016A (en) 1996-08-22 1999-08-17 Quantum Catalytics, L.L.C. Apparatus and method for tapping a molten metal bath
US6011008A (en) * 1997-01-08 2000-01-04 Yissum Research Developement Company Of The Hebrew University Of Jerusalem Conjugates of biologically active substances
US6338843B1 (en) * 1997-06-12 2002-01-15 Ml Laboratories Biologically active materials
AU783886B2 (en) 1999-06-18 2005-12-22 Innovata Plc Biologically active materials
EP1296719A2 (fr) * 2000-07-01 2003-04-02 ML Laboratories Plc Medicaments
DE10112825A1 (de) * 2001-03-16 2002-10-02 Fresenius Kabi De Gmbh HESylierung von Wirkstoffen in wässriger Lösung
EP1401875A4 (fr) 2001-05-04 2005-01-26 Univ Utah Res Found Acide hyaluronique contenant des bioconjugues: administration ciblee de medicaments anticancereux dans des cellules cancereuses

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03000738A2 *

Also Published As

Publication number Publication date
JP2004534086A (ja) 2004-11-11
US20040180858A1 (en) 2004-09-16
AU2002328294A1 (en) 2003-01-08
WO2003000738A2 (fr) 2003-01-03
WO2003000738A3 (fr) 2003-08-28
PL366438A1 (en) 2005-02-07
CA2446205A1 (fr) 2003-01-03
US7115576B2 (en) 2006-10-03
DE10129369C1 (de) 2003-03-06
CN1596129A (zh) 2005-03-16

Similar Documents

Publication Publication Date Title
DE10129369C1 (de) Wasserlösliches, einen Aminozucker aufweisendes Antibiotikum in Form eines Pol ysaccharid-Konjugats
DE69430126T2 (de) Cyclodextrine zur reduzierung des durch zytotoxische substanzen verursachten gefässaustritts
EP0149197B2 (fr) Compositions pharmaceutiques contenant des médicaments peu solubles dans l'eau ou instables et procédés de leur préparation
EP1480681B1 (fr) Couplage de substances a faible poids moleculaire avec un polysaccharide modifie
DE69331900T2 (de) Cyclodextrinderivate mit erhöhter wasserlösichkeit und deren verwendung
DE69029006T2 (de) Wasserlösliche hochmolekulare polymere Arzneistoffzubereitung
DE69130165T2 (de) Cyclodextrinderivate mit erhöhter wasserlöslichkeit sowie deren verwendung
DE2845326C2 (de) Verwendung einer spezifischen mikrodispersen, amorphen, porösen Kieselsäure zur Herstellung von Digoxin enthaltenden Tabletten mit stark beschleunigter Wirkstoff-Freisetzung
EP1429789B1 (fr) Glucides anti-infectieux
DE69625326T2 (de) Anthracyclinderivate und sie enthaldende medizinische zubereitungen
DE2701405C2 (de) Triferridoxorubicin, Verfahren zu dessen Herstellung und diese Verbindung enthaltendes pharmazeutisches Mittel
DE60307249T2 (de) Eisen-dextrin verbindung zur behandlung von anämien durch eisenmangel
DE60024601T2 (de) Dispergierbare zusammensetzungen von macroliden und verfahren zu deren herstellung
DE69412760T2 (de) Neue inklusionskomplexe von salzen von nimesulide mit cyclodextrinen
DE69425948T2 (de) Zusammensetzung mit verbesserter Wasserlöslichkeit, enthaltend eine Wasserunlösliche oder an Wasser schwerunlösliche Verbindung
DE69730902T2 (de) Verfahren zur Selektion eines Salzes zur Herstellung eines Inklusionskomplexes
DE69128760T2 (de) Antidiarrhoeika
DE69833487T2 (de) Polymer-wirkstoff-konjugate zur behandlung von krebs
DE69423683T2 (de) Cyclodextrin Einschluskomplexe mit Taxol, ein Verfahren zu ihrer Herstellung und ihre Anwendung
DE69103869T2 (de) Arzneizubereitung mit verzögerter Wirkstoffabgabe auf Basis von Platin enthaltenden Antikrebsmitteln.
DE10155098A1 (de) Mittel zur Prävention von mykotischen Kontaminationen bei der Zell- und Gewebekultur bakteriellen, pflanzlichen, animalischen und humanen Ursprungs, bestehend aus Polyen-Makrolid-Konjugaten mit Polysacchariden
DE2926463C2 (fr)
DE4207922A1 (de) Wasserloesliche einschlussverbindungen und verfahren zu deren herstellung
EP0147851B1 (fr) Formes hydrosolubles d'antibiotiques du type polyène et procédé de leur préparation
DE69727507T2 (de) Therapeutische und kosmetische mittel, ihre verwendung und herstellungsverfahren

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20031016

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17Q First examination report despatched

Effective date: 20070807

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20110319