EP1567558A2 - Esters d'acide aldonique, procedes pour les preparer et procedes pour preparer des principes actifs pharmaceutiques couples a des polysaccharides ou a des derives de polysaccharides au niveau de groupes amino libres - Google Patents

Esters d'acide aldonique, procedes pour les preparer et procedes pour preparer des principes actifs pharmaceutiques couples a des polysaccharides ou a des derives de polysaccharides au niveau de groupes amino libres

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Publication number
EP1567558A2
EP1567558A2 EP03780109A EP03780109A EP1567558A2 EP 1567558 A2 EP1567558 A2 EP 1567558A2 EP 03780109 A EP03780109 A EP 03780109A EP 03780109 A EP03780109 A EP 03780109A EP 1567558 A2 EP1567558 A2 EP 1567558A2
Authority
EP
European Patent Office
Prior art keywords
aldonic acid
acid ester
aldonic
starch
acid esters
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Withdrawn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
EP03780109A
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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.)
Supramol Parenteral Colloids GmbH
Original Assignee
Supramol Parenteral Colloids 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 Supramol Parenteral Colloids GmbH filed Critical Supramol Parenteral Colloids GmbH
Publication of EP1567558A2 publication Critical patent/EP1567558A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • 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
    • 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
    • C08B31/00—Preparation of derivatives of starch
    • C08B31/18—Oxidised starch
    • C08B31/185—Derivatives of oxidised starch, e.g. crosslinked oxidised starch
    • 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
    • C08B35/00—Preparation of derivatives of amylopectin
    • C08B35/02—Esters

Definitions

  • Aldonic acid esters process for their preparation and process for the preparation of active pharmaceutical ingredients coupled to polysaccharides or polysaccharide derivatives on free amino groups.
  • the present invention relates to aldonic acid esters, solids and solutions containing these esters and processes for their preparation. Furthermore, the present invention relates to processes for the preparation of active pharmaceutical ingredients coupled to free amino groups with polysaccharides or polysaccharide derivatives, which are carried out using the aldonic acid esters, and to the active pharmaceutical ingredients which can be obtained by these processes.
  • Such proteins often have a short biological half-life, which can be extended by coupling to the above-mentioned polymer compounds such as PEG or HES. Coupling can also have a positive effect on the antigenic properties of proteins. In the case of other active pharmaceutical ingredients, the water solubility can be increased considerably by the coupling.
  • DE 196 28 705 and DE 101 29 369 describe methods of coupling with hydroxyethyl starch in anhydrous dimethyl sulfoxide (DMSO) via the corresponding aldonic acid lactone of hydroxyethyl starch with free amino groups of hemoglobin or amphotericin B. Since it is often not possible to work in water-free, aprotic solvents, especially in the case of the proteins, either for reasons of solubility but also for reasons of denaturing the proteins, coupling processes with HES are also available in a water-containing environment.
  • DMSO dimethyl sulfoxide
  • the coupling of the hydroxyethyl starch oxidized selectively to the aldonic acid at the reducing chain end succeeds by mediating water-soluble carbodiimide EDC (l-ethyl-3- (3-dimethylaminopro ⁇ yl) carbodiimide) (PCT / EP 02/02928).
  • EDC l-ethyl-3- (3-dimethylaminopro ⁇ yl) carbodiimide
  • the object of the invention was to provide compounds which, while avoiding the disadvantages described above, couple polysaccharides or their derivatives to active substances containing amino groups, in particular to proteins, in purely aqueous systems or else enable specifically in solvent mixtures with water.
  • such a compound should be such that the most quantitative possible binding of an active ingredient takes place by covalent binding to a polysaccharide or a polysaccharide derivative.
  • the invention was also based on the object of creating compounds which enable a polysaccharide or a derivative thereof to be linked as gently as possible to the active ingredient.
  • the structure, the activity and the tolerance of the active ingredient should be determined by the
  • T Tm ⁇ pt.n .n ⁇ n.n ⁇ 1.r. ⁇ Jt weni ⁇ to be changed Rei ⁇ nie.l ⁇ we.se should be intra- and intermolecular crosslinking reactions are avoided. In addition, it should also be possible to link active ingredients which have phosphate groups.
  • the object of the invention was to provide a process which is as simple and inexpensive as possible for the production of such compounds and coupling products of polysaccharides or polysaccharide derivatives with active compounds.
  • claims 18-27 provide a solution to the underlying problem.
  • Claims 28-32 describe processes for the preparation of polysaccharide-active substance conjugates and the pharmaceutical active substances obtainable by these processes.
  • esters which are derived from polysaccharides or polysaccharide derivatives which are selectively oxidized to aldonic acids at the reducing chain end, it is possible to provide compounds which solve the aforementioned tasks.
  • Such esters can be regarded as activated acids. They react in a watery environment with nucleophilic NH 2 groups to (more stable) amides.
  • aldonic acid esters according to the invention enable an active substance to be easily bound by covalent binding to a polysaccharide or a polysaccharide derivative.
  • the aldonic acid esters of the present invention can be reacted with an active ingredient under mild conditions.
  • the structure, the activity and the tolerance of the active ingredient are only changed to a small extent by the implementation.
  • intermolecular and intermolecular crosslinking reactions in particular, can be avoided.
  • active pharmaceutical ingredients that have phosphate groups can be coupled without changing these groups.
  • the aldonic acid esters according to the invention allow a very selective coupling to the active substance. Furthermore, for example, a targeted stoichiometry of the desired conjugate can be set, the production of 1: 1 conjugates in particular being made possible by using these compounds.
  • the present invention provides simple and inexpensive processes for the preparation of activated aldonic acid esters and coupling products of polysaccharides or polysaccharide derivatives with active ingredients.
  • the aldonic acid esters of the present invention are of polysaccharides can be selectively oxidized. Such polysaccharides, as well as derivatives obtainable therefrom, are widely known in the art and can be obtained commercially.
  • Polysaccharides are macromolecular carbohydrates, the molecules of which have a large number (at least> 10, but usually considerably more) of monosaccharide molecules (glycose) linked to one another by glycosides.
  • the weight average molecular weight of preferred polysaccharides is preferably in the range from 1500 to 1,000,000 daltons, particularly preferably 2,000 to 300,000 daltons and very particularly preferably in the range from 2,000 to 50,000 daltons.
  • the molecular weight Mw can be determined using conventional methods. These include, for example, aqueous GPC, HPLC, light scattering and the like.
  • the residence time in the body can be changed via the molecular weight of the polysaccharide residue.
  • the preferred polysaccharides include starch and the starch fractions obtainable by hydrolysis, which can be regarded as starch degradation products.
  • Starch is usually divided into atylose and amylopectin, which differ in the degree of branching. According to the invention, amylopectin is particularly preferred.
  • Amylopectins are initially understood to mean very generally branched starches or starch products with - (1-4) and ⁇ - (1-6) bonds between the glucose molecules.
  • the branches of the chain are made via the ⁇ - (1-6) bonds. These are present irregularly about every 15-30 glucose segments in naturally occurring amylopectins.
  • the molecular weight of natural amylopectin is very high in the range from 10 7 to 2x10 S daltons. It is believed that amylopectin also forms helices within certain limits.
  • a degree of branching can be defined for amylopectins.
  • the measure of branching is the ratio of the number of molecules of anhydroglucose, the branch points ( ⁇ - (1-6) bonds) contribute to the total number of molecules of the anhydroglucose of amylopectin, this ratio being expressed in mol%.
  • Amylopectin occurring in nature has degrees of branching of approximately 4 mol%.
  • Amylopectins used preferably for the preparation of the aldonic acid esters have an average branching in the range from 5 to 10 mol%.
  • hyperbranched amylopectins can be used which have a degree of branching which goes significantly beyond the degree of branching known from nature for amylopectins.
  • the degree of branching is in any case an average (mean degree of branching), since amylopectins are polydisperse substances.
  • hyperbranched amylopectins have significantly higher degrees of branching, expressed as mol% of the branching anhydroglucoses, compared to unchanged amylopectin or hydroxyethyl starch and are therefore more similar in structure to glycogen.
  • the average degree of branching of the hyperbranched amylopectins is usually in the range between> 10 and 25 mol%. This means that these amylopectins have on average approximately every 10 to 4 glucose units an ⁇ - (1-6) bond and thus a branch point.
  • An amylopectin type which can preferably be used in the medical field is characterized by a degree of branching between 11 and 16 mol%.
  • hyperbranched amylopectins have a degree of branching in the range between 13 and 16 mol%.
  • amylopectins which can be used in the invention preferably have a value for the weight average molecular weight Mw in the range of 2,000 up to 800,000 daltons, in particular 2,000 to 300,000 and particularly preferably 2,000 to 50,000 daltons.
  • starch can be obtained from potatoes, tapioca, cassava, rice, wheat or corn.
  • the starches obtained from these plants are often first subjected to a hydrolytic degradation reaction.
  • the molecular weight is reduced from about 20,000,000 daltons to several million daltons, and a further reduction in the molecular weight to the values mentioned above is also known.
  • waxy maize starch degradation fractions can particularly preferably be used to prepare the aldonic acid esters according to the invention.
  • Derivatives of polysaccharides can also be used to prepare the aldonic acid esters according to the invention.
  • These include in particular hydroxyalkyl starches, for example hydroxyethyl starch and hydroxypropyl starch, which can be obtained by hydroxyalkylation from the starches set out above, in particular from amylopectin.
  • hydroxyethyl starch HES is preferred.
  • HES hydroxethylated derivative of the amylopectin glucose polymer which is present in waxy maize starch to an extent of over 95%.
  • Amylopectin consists of glucose units which are present in ⁇ -1,4-glycosidic bonds and have ⁇ -1,6-glycosidic branches.
  • HES has advantageous rheological properties and is currently used clinically as a volume substitute and for hemodilution therapy (Sommermeyer et al., I rankenhauspharmazie, Vol. 8 (8, 1987) pages 271-278 and Weidler et. Al., Arzneistoffforschung / Drug Res., 41, (1991) pages 494-498).
  • HES is essentially characterized by the weight average molecular weight Mw, the number average molecular weight Mn, the molecular weight distribution and the degree of substitution. Substitution with hydroxyethyl groups in ether linkage is possible at the carbon atoms 2, 3 and 6 of the anhydroglucose units.
  • the degree of substitution can be described as DS ("degree of substitution"), which refers to the proportion of substituted glucose molecules of all glucose units, or as MS (“molar substitution”), which denotes the average number of hydroxyethyl groups per glucose unit.
  • the degree of substitution MS (molar substitution) is defined as the average number of hydroxyethyl groups per anhydroglucose unit. It is determined from the total number of hydroxyethyl groups in a sample, for example according to Morgan, by ether cleavage and subsequent quantitative determination of ethyl iodide and ethylene, which are formed here.
  • a hydroxyethyl starch residue preferably has a degree of substitution MS of 0.1 to 0.8.
  • the hydroxyethyl starch residue particularly preferably has a degree of substitution MS of 0.4 to 0.7.
  • the reactivity of the individual hydroxy groups in the unsubstituted anhydroglucose unit with respect to hydroxyethylation differs depending on the reaction conditions.
  • the substitution pattern ie the individual, differently substituted anhydroglucoses, which are statistically distributed among the individual polymer molecules, can be influenced within certain limits.
  • the C 2 and C 6 positions are advantageously hydroxyethylated, the C 6 position being substituted more frequently because of its easier accessibility.
  • Hydroxyethyl starches which are substituted in the C 2 position and are substituted as homogeneously as possible are preferably used in the context of this invention.
  • HES Hydroxyethyl starches
  • the production of such HES is described in EP 0402 724 B2. They are completely biodegradable within a physiologically reasonable time and still have controllable elimination behavior on the other hand.
  • the predominant C 2 substitution makes the hydroxyethyl starch relatively difficult to break down for ⁇ -amylase. It is advantageous that, as far as possible, there are no anhydroglucose units which are substituted one after the other within the polymer molecules, in order to ensure complete degradability.
  • such hydroxyethyl starches have a sufficiently high solubility in an aqueous medium so that the solutions are stable even over long periods of time and no agglomerates or gels form.
  • a hydroxyethyl starch residue preferably has a ratio of C 2 : C 6 substitution in the range from 2 to 15.
  • the ratio of C 2 : C 6 substitution is particularly preferably 3 to 11.
  • aldonic acid The selective oxidation of the aldehyde group of the polysaccharides or polysaccharide derivatives described above to form aldonic acid is known per se. This can be done by mild oxidizing agents, for example iodine / potassium hydroxide according to DE 196 28 705 AI, or by enzymes.
  • the free aldonic acid can be used for the reaction.
  • Salts can also be used. These include, in particular, the alkali salts, such as the sodium and / or the potassium salt of the aldonic acids.
  • Alcohols are used to prepare the aldonic acid esters according to the invention.
  • the term alcohol includes compounds that have HO groups. These HO groups can be bound, inter alia, to a nitrogen atom or to a phenyl radical.
  • Acidic alcohols which are known in the technical field are preferably used. These include, inter alia, N-hydroxy imides, for example N-hydroxy succinimide and sulfo-N-hydroxysuccinimide, substituted phenols and hydroxy azoles, for example hydroxy-benzotriazole, N-hydroxy succinimides and sulfo-N-hydroxysuccinimide being particularly preferred ,
  • alcohols are used whose HO group has a pk s value in the range from 6 to 12, preferably in the range from 7 to 11. This value refers to the acid dissociation constant determined at 25 ° C, and this value is often listed in the literature.
  • the molecular weight of the alcohol is preferably in the range from 80 to 500 g / mol, in particular 100 to 200 g / mol.
  • the alcohol can be added as the free one to a reaction mixture. Furthermore, it is also possible to use compounds for the reaction which release alcohol when water is added, if appropriate with acid catalysis.
  • carbonic acid diesters are used for the reaction with the aldonic acid or an aldonic acid salt. These compounds enable a particularly rapid and gentle reaction, with only carbonic acid or carbonates, alcohols and the desired aldonic acid ester being formed.
  • Preferred carbonic diesters include N'N-succinimidyl carbonate and sulfo-N'N-succinimidyl carbonate.
  • carbonic acid diesters can be used in relatively small amounts.
  • the carbonic acid diester can be used in a 1 to 3 molar excess, preferably 1 to 1.5 molar excess, based on the aldonic acid and / or the aldonic acid salt.
  • the reaction time when using carbonic acid diesters is relatively short. The reaction can often be terminated after 2 hours, preferably after 1 hour.
  • the conversion to the aldonic ester preferably takes place in an anhydrous aprotic solvent.
  • the water content should preferably be at most 0.5% by weight, particularly preferably at most 0.1% by weight.
  • Suitable solvents include dimethyl sulfoxide (DMSO), N-methylpyrrolidone, dimethylacetamide (DMA) and / or dimethylformamide (DMF).
  • the esterification reaction is known per se, and any method can be used.
  • the conversion to the aldonic acid ester can be carried out, inter alia, using activating compounds.
  • activating compounds include in particular carbodiimide, for example Dicyclohexylcarbodiimide (DCC) and l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC).
  • DCC Dicyclohexylcarbodiimide
  • EDC l-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • the free alcohol can be used in a molar excess.
  • the alcohol component is preferably in a 5 to 50-fold molar excess, particularly preferably an 8 to 20-fold excess based on the aldonic acid and / or the aldonic acid derivative. used.
  • the conversion to the aldonic acid ester succeeds under mild conditions.
  • the reactions described above can thus be carried out at temperatures preferably in the range from 0 ° C. to 40 ° C., particularly preferably 10 ° C. to 30 ° C.
  • the implementation takes place with a low base activity.
  • the low base activity can be measured by adding the reaction mixture in a 10-fold excess of water.
  • the water has a pH of 7.0 at 25 ° C. before addition, the water containing essentially no buffer.
  • the base activity of the reaction mixture is obtained by measuring the pH at 25 ° C. after adding the reaction mixture.
  • this mixture preferably has a pH of at most 9.0, particularly preferably of at most 8.0 and particularly preferably of at most 7.5.
  • the reaction with HES-aldonic acids succeeds in dry DMA with exclusion of water with EDC in a smooth reaction at room temperature to the HES-acid-N-hydroxy-succinimide ester. It is particularly surprising that no side reaction of the HES molecules occurs via the reaction of the OH groups of the anhydroglucoses in extreme excess with EDC and the rearrangement reaction of the primarily formed O-acyl isourea from EDC and the aldonic acid to give the corresponding N-acyl Urea is suppressed.
  • the solutions obtained by the reaction described above can be used in the coupling reactions without isolating the aldonic acid esters.
  • Preferred solutions comprise at least 10% by weight of aldonic acid esters, preferably at least 30% by weight of aldonic acid esters and particularly preferably at least 50% by weight of aldonic acid esters.
  • the aldonic acid esters can be precipitated from the solution in aprotic solvent, for example DMA, using known precipitants, such as, for example, dry ethanol, isopropanol or acetone, and can be purified by repeating the process several times.
  • Preferred solids comprise at least 10% by weight of aldonic acid esters, preferably at least 30% by weight of aldonic acid esters and particularly preferably at least 50% by weight of aldonic acid esters.
  • aldonic acid esters can then be used in bulk for coupling, for example for HESylation. There are then no side reactions as described above with EDC-activated acid.
  • a solution of the activated aldonic acid can be added to an aqueous solution of the active pharmaceutical ingredient, which is preferably buffered, at a suitable pH for coupling.
  • the active pharmaceutical ingredients comprise at least one amino group which can be converted to the aldonic acid amide.
  • the preferred active ingredients include proteins and peptides.
  • the pH of the reaction depends on the properties of the active ingredient. Preferably, if this is possible, the pH is in the range from 7 to 9, particularly preferably 7.5 to 8.5.
  • the coupling generally takes place at temperatures in the range from 0 ° C. to 40 ° C., preferably from 10 ° C. to 30 ° C., without any intention that this should impose a restriction.
  • the reaction time can easily be determined by suitable methods. In general, the reaction time is in the range of 1 hour to 100 hours, preferably 20 hours to 48 hours.
  • the aldonic acid ester can be used in excess with respect to the active pharmaceutical ingredient.
  • the aldonic acid ester is preferably used in a 1 to 5-fold molar excess, particularly preferably a 1.5 to 2-fold excess based on the active pharmaceutical ingredient.
  • Fig. 1 MALLS-GPC chromatogram of the unreacted bovine albumin (BSA). Monomeric and dimeric albumin are clearly separated.
  • bovine serum albumin (BSA corresponding to 0.7 ⁇ mol) are dissolved in 6 mL of a 0.3 molar bicarbonate solution with pH 8.4. The solution according to Example 3 is added to the solution and the mixture is left to react for 2 hours with stirring at room temperature.
  • Figures 1 to 4 show the chromatograms of the unreacted HES 10 / 0.4 succinimidyl esters, the starting product BSA and the reaction mixture.
  • the successful reaction results from a significant decrease in the BSA peak and the appearance of a higher molecular weight peak, which is detected at 280 nm.
  • bovine serum albumin BSA 50 mg bovine serum albumin BSA (0.7 ⁇ mol) are dissolved in 6 ml of a 0.3 molar bicarbonate solution with pH 8.4. The solution of the activated HES 50 / 0.7 acid according to Example 5 is added to the solution and allowed to react for 2 hours with stirring at room temperature.
  • the analytical control of the reaction mixture is carried out using low-pressure HPGPC with triple detection as described in Example 4.
  • the successful reaction results from a decrease in the signal at 280 nm of the unreacted BSA and the corresponding occurrence of the signal for the coupling product which has been shifted to higher molecular weights.
  • the shift is increased in accordance with the higher molecular weight of the HES acid compared to Example 4.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne des esters d'acide aldonique de fractions d'amidon, ou de dérivés de fractions d'amidon, oxydés de manière sélective à l'extrémité réduite de la chaîne pour donner de l'acide aldonique, des substances solides et des solutions qui contiennent ces esters d'acide aldonique. L'invention a également pour objet des procédés pour préparer ces esters d'acide aldonique, des procédés pour préparer des principes actifs pharmaceutiques couplés à des polysaccharides ou à des dérivés de polysaccharides au niveau de groupes amino libres, et les principes actifs pharmaceutiques ainsi obtenus.
EP03780109A 2002-12-04 2003-12-03 Esters d'acide aldonique, procedes pour les preparer et procedes pour preparer des principes actifs pharmaceutiques couples a des polysaccharides ou a des derives de polysaccharides au niveau de groupes amino libres Withdrawn EP1567558A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10256558A DE10256558A1 (de) 2002-12-04 2002-12-04 Ester von Polysaccharid Aldonsäuren, Verfahren zu ihrer Herstellung und Verwendung zur Kopplung an pharmazeutische Wirkstoffe
DE10256558 2002-12-04
PCT/EP2003/013622 WO2004050710A2 (fr) 2002-12-04 2003-12-03 Esters d'acide aldonique, procedes pour les preparer et procedes pour preparer des principes actifs pharmaceutiques couples a des polysaccharides ou a des derives de polysaccharides au niveau de groupes amino libres

Publications (1)

Publication Number Publication Date
EP1567558A2 true EP1567558A2 (fr) 2005-08-31

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EP03780109A Withdrawn EP1567558A2 (fr) 2002-12-04 2003-12-03 Esters d'acide aldonique, procedes pour les preparer et procedes pour preparer des principes actifs pharmaceutiques couples a des polysaccharides ou a des derives de polysaccharides au niveau de groupes amino libres

Country Status (15)

Country Link
US (1) US20060052342A1 (fr)
EP (1) EP1567558A2 (fr)
JP (1) JP4749720B2 (fr)
KR (1) KR101170033B1 (fr)
CN (1) CN100535015C (fr)
AU (1) AU2003288218B2 (fr)
BR (1) BR0316493A (fr)
CA (1) CA2504799A1 (fr)
DE (1) DE10256558A1 (fr)
MX (1) MXPA05005572A (fr)
NO (1) NO20053179L (fr)
PL (1) PL210453B1 (fr)
RU (1) RU2330046C2 (fr)
WO (1) WO2004050710A2 (fr)
ZA (1) ZA200503135B (fr)

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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
JP2006516534A (ja) 2002-09-11 2006-07-06 フレセニウス・カビ・ドイッチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Ｈａｓ化ポリペプチド、特にｈａｓ化エリスロポエチン
AU2003273413A1 (en) 2002-10-08 2004-05-04 Fresenius Kabi Deutschland Gmbh Pharmaceutically active oligosaccharide conjugates
WO2005014655A2 (fr) 2003-08-08 2005-02-17 Fresenius Kabi Deutschland Gmbh Conjugues d'amidon d'hydroxyalkyle et de proteine
US20090281296A1 (en) * 2004-02-09 2009-11-12 Supramol Parenteral Colloid Gmbh Process for the production of conjugates from polysaccharides and polynucelotides
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NO20053179D0 (no) 2005-06-28
US20060052342A1 (en) 2006-03-09
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JP4749720B2 (ja) 2011-08-17
KR20050072832A (ko) 2005-07-12
AU2003288218A1 (en) 2004-06-23
PL375693A1 (en) 2005-12-12
PL210453B1 (pl) 2012-01-31
WO2004050710A3 (fr) 2004-09-02
AU2003288218B2 (en) 2010-05-20
WO2004050710A2 (fr) 2004-06-17
CN100535015C (zh) 2009-09-02
CA2504799A1 (fr) 2004-06-17
NO20053179L (no) 2005-08-15
JP2006509849A (ja) 2006-03-23
ZA200503135B (en) 2006-07-26
RU2005120736A (ru) 2006-01-20
CN1720264A (zh) 2006-01-11
MXPA05005572A (es) 2005-11-23
BR0316493A (pt) 2005-10-11
RU2330046C2 (ru) 2008-07-27

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