EP1587842A1 - Diesters d'acide carbonique, procedes de production de ces diesters et procedes de production de substances actives pharmaceutiques couplees avec des polysaccharides ou des derives de polysaccharides au niveau de groupes amino libres - Google Patents

Diesters d'acide carbonique, procedes de production de ces diesters et procedes de production de substances actives pharmaceutiques couplees avec des polysaccharides ou des derives de polysaccharides au niveau de groupes amino libres

Info

Publication number
EP1587842A1
EP1587842A1 EP04704207A EP04704207A EP1587842A1 EP 1587842 A1 EP1587842 A1 EP 1587842A1 EP 04704207 A EP04704207 A EP 04704207A EP 04704207 A EP04704207 A EP 04704207A EP 1587842 A1 EP1587842 A1 EP 1587842A1
Authority
EP
European Patent Office
Prior art keywords
carbonic acid
acid diester
polysaccharide
range
starch
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Withdrawn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
EP04704207A
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.)
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 EP1587842A1 publication Critical patent/EP1587842A1/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Withdrawn legal-status Critical Current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
    • C08B35/00—Preparation of derivatives of amylopectin
    • C08B35/06—Ether-esters

Definitions

  • Carbonic acid diesters processes for their preparation and processes for
  • the present invention relates to carbonic acid diesters, 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 carbonic acid diester, 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 processes such as coupling with hydroxyethyl starch in anhydrous dimethyl sulfoxide (DMSO) can be carried out on the corresponding aldonic acid lactone of hydroxyethyl starch with free amino groups of hemoglobin or amphotericin B.
  • DMSO dimethyl sulfoxide
  • 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 selectively possible 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 changed as little as possible by the implementation. For example, intra- and intermolecular cross-linking reactions should be avoided.
  • 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 20-24 provide a solution to the underlying problem.
  • Claims 25-30 describe processes for the preparation of polysaccharide-active substance conjugates and the pharmaceutical active substances obtainable by these processes.
  • carbonic acid diesters which are derived from polysaccharides or polysaccharide derivatives, it is possible to provide compounds which solve the aforementioned tasks. They react in a watery environment with nucleophilic NH 2 groups to urethanes.
  • the carbonic acid diesters according to the invention enable an active substance to be easily bound by covalent binding to a polysaccharide or a polysaccharide derivative.
  • the carbonic acid diesters 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 carbonic acid diesters according to the invention allow a very gentle coupling to the active ingredient. Furthermore, it is possible, for example, to set a targeted stoichiometry of the desired conjugate, in particular the Production of conjugates is made possible by the use of these compounds, which comprise a high proportion of active ingredients.
  • the present invention provides simple and inexpensive processes for producing activated carbonic acid diesters and coupling products of polysaccharides or polysaccharide derivatives with active ingredients.
  • the carbonic acid diesters of the present invention are derived from polysaccharides or polysaccharide derivatives. 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 molecular weight of the polysaccharide residue can be used
  • Residence time in the body can be changed.
  • 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 amylose 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 using 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 anhydroglucose molecules bearing branch points ( ⁇ - (1-6) bonds) to the total number of anhydroglucose molecules 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 production of the carbonic acid diesters 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 a - (1-6) - bond and thus a branch point on average every 10 to 4 glucose units.
  • 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 from 2,000 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 produce the carbonic acid diesters according to the invention.
  • derivatives of polysaccharides can also be used to produce the carbonic acid diesters according to the invention.
  • 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.
  • HES hydroxyethyl starch
  • 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 theological properties and is currently used clinically as a volume substitute and for hemodilution therapy (Sommermeyer et al., Whypharmazie, Vol. 8 (8, 1987) pages 271-278 and Weidler et. Al., Drug research / 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 glue 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.
  • HES hydroxyethyl starches
  • the production of such HES is described in EP 0 402 724 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 none of the polymer molecules are substituted one after the other Anhydroglucose units occur 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.
  • the carbonic acid diesters according to the invention comprise a further group derived from an alcohol.
  • alcohol encompasses compounds which have HO groups, preferred alcohols differing from the polysaccharides or their derivatives.
  • the 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 succianamide 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 that at 25 ° C certain acid dissociation constant, 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 carbonic acid diesters according to the invention can be produced by methods known per se. According to a particular aspect of the present invention, carbonic acid diesters are used to prepare the compounds according to the invention, the alcohol components of which differ from the polysaccharides or their derivatives. These compounds enable a particularly rapid and gentle reaction, with only alcohols and the desired carbonic acid diester being formed.
  • Preferred carbonic diesters include N'N-succirimidyl 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 polysaccharide and / or the polysaccharide derivative.
  • 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 ratio of carbonic diester to polysaccharide and / or polysaccharide derivative in the reaction is in the range from greater than 3: 1 to 30: 1, preferably 4: 1 to 10: 1.
  • the conversion to the carbonic acid diester according to the invention 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 conversion to carbonic acid diester 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 to 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 solutions obtained by the reaction described above can be used in the coupling reactions without isolating the carbonic acid diesters. Since the volume of the preactivated carbonic acid diester in the aprotic solvent is usually small compared to the target protein dissolved in the buffer volume, the amounts of aprotic solvent usually have no disruptive effect.
  • Preferred solutions comprise at least 10% by weight of carbonic acid diesters, preferably at least 30% by weight of carbonic acid diesters and particularly preferably at least 50% by weight of carbonic acid diesters.
  • the carbonic acid diesters can be precipitated from the solution in aprotic solvent, for example DMF, 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 carbonic acid diesters, preferably at least 30% by weight of carbonic acid diesters and particularly preferably at least 50% by weight of carbonic acid diesters.
  • Such carbonic acid diesters can then be used isolated for coupling, for example for HESylation. There are then no side reactions as described above with EDC-activated acid.
  • a solution of the activated carbonic acid diesters of polysaccharides and / or polysaccharide derivatives 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 urethane of polysaccharides and / or polysaccharide derivatives.
  • the preferred active ingredients include antibiotics, in particular amphotericin B, and 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 10 minutes to 100 hours, preferably 30 minutes to 5 hours.
  • the molar ratio of carbonic acid diester to active ingredient can be in a wide range. Depending on the intended stoichiometry, the carbonic acid diester can be used in a 1 to 5-fold molar excess, particularly preferably a 1.5 to 2-fold excess, based on the active pharmaceutical ingredient.
  • the pharmaceutical active ingredient can be used in a 2 to 20-fold molar excess, particularly preferably a 3 to 10-fold excess, based on the carbonic acid diester.
  • amphotericin B 100 mg amphotericin B are dissolved in 5 ml dry DMSO under protective gassing with argon under light protection. To this solution is added a solution of HES 10 / 0.4 - carbonic acid diester of N-hydroxy-succinimide prepared according to Example 1, prepared with twice the molar amount of N.N'-disuccinimidyl carbonate, and left for 4 hours at room temperature under argon and light protection react to completion.
  • the mixture is then diluted with 200 ml of oxygen-free water under argon and, under light protection and argon, ultrafiltered with a membrane of the cut off 1000 dalton to remove the solvents and the released N-hydroxy-succinimide.
  • the mixture is then freeze-dried to isolate the reaction product.
  • the product is characterized by gel chromatography and photometric determination of the proportion of coupled amphotericin B using photometry.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des diesters d'acide carbonique de fractions d'amidon ou de dérivés de fractions d'amidon, ainsi que des substances solides et des solutions contenant ces diesters d'acide carbonique. L'invention concerne en outre des procédés de production de ces diesters d'acide carbonique, des procédés de production de substances actives pharmaceutiques couplées avec des polysaccharides ou des dérivés de polysaccharides au niveau de fonctions amino libres, ainsi que des substances actives pharmaceutiques obtenues par ces procédés.
EP04704207A 2003-01-23 2004-01-22 Diesters d'acide carbonique, procedes de production de ces diesters et procedes de production de substances actives pharmaceutiques couplees avec des polysaccharides ou des derives de polysaccharides au niveau de groupes amino libres Withdrawn EP1587842A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10302520 2003-01-23
DE10302520A DE10302520A1 (de) 2003-01-23 2003-01-23 Kohlensäurediester von Stärkefraktionen und deren Derivate, Verfahren zu ihrer Herstellung und Verwendung zur Kopplung an pharmazeutische Wirkstoffe
PCT/EP2004/000488 WO2004065425A1 (fr) 2003-01-23 2004-01-22 Diesters d'acide carbonique, procedes de production de ces diesters et procedes de production de substances actives pharmaceutiques couplees avec des polysaccharides ou des derives de polysaccharides au niveau de groupes amino libres

Publications (1)

Publication Number Publication Date
EP1587842A1 true EP1587842A1 (fr) 2005-10-26

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EP04704207A Withdrawn EP1587842A1 (fr) 2003-01-23 2004-01-22 Diesters d'acide carbonique, procedes de production de ces diesters et procedes de production de substances actives pharmaceutiques couplees avec des polysaccharides ou des derives de polysaccharides au niveau de groupes amino libres

Country Status (4)

Country Link
US (1) US20060100176A1 (fr)
EP (1) EP1587842A1 (fr)
DE (1) DE10302520A1 (fr)
WO (1) WO2004065425A1 (fr)

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DE10209821A1 (de) 2002-03-06 2003-09-25 Biotechnologie Ges Mittelhesse Kopplung von Proteinen an ein modifiziertes Polysaccharid
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
WO2005014655A2 (fr) 2003-08-08 2005-02-17 Fresenius Kabi Deutschland Gmbh Conjugues d'amidon d'hydroxyalkyle et de proteine
EP1713509A2 (fr) * 2004-02-09 2006-10-25 Noxxon Pharma AG Procede pour produire des conjugues constitues de polysaccharides et de polynucleotides
US9376648B2 (en) 2008-04-07 2016-06-28 The Procter & Gamble Company Foam manipulation compositions containing fine particles
US9296810B2 (en) 2008-05-02 2016-03-29 Novartis Ag Fibronectin-based binding molecules and uses thereof
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
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

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US2868781A (en) * 1956-04-23 1959-01-13 Monsanto Chemicals Carbohydrate esters of carboxylic acids and methods of preparing same
US4125492A (en) * 1974-05-31 1978-11-14 Pedro Cuatrecasas Affinity chromatography of vibrio cholerae enterotoxin-ganglioside polysaccharide and the biological effects of ganglioside-containing soluble polymers
US4009264A (en) * 1975-03-03 1977-02-22 Meito Sangyo Kabushiki Kaisha Complexes of polysaccharides or derivatives thereof with reduced glutathione and process for preparing said complexes
DD279486A1 (de) * 1986-03-10 1990-06-06 Akad Wissenschaften Ddr Verfahren zur aktivierung von hydroxylgruppenhaltigen polymeren verbindungen
DE3836600A1 (de) * 1988-10-27 1990-05-03 Wolff Walsrode Ag Kohlensaeureester von polysacchariden und verfahren zu ihrer herstellung
DE4130807A1 (de) * 1991-09-17 1993-03-18 Wolff Walsrode Ag Verfahren zur herstellung von polysaccharidcarbonaten
DE10126158A1 (de) * 2001-05-30 2002-12-12 Novira Chem Gmbh Eine Methode zur Synthese von Gemischen einfach aktivierter und nicht aktivierter Polyoxyalkylene zur Modifizierung von Proteinen
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WO2004065425A1 (fr) 2004-08-05
US20060100176A1 (en) 2006-05-11
DE10302520A1 (de) 2004-08-05

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