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EP1819363A2 - Procedes pour produire des conjugues d'albumine au moyen d'anti-inflammatoires non steroides contre les rhumatismes (nsar) - Google Patents

Procedes pour produire des conjugues d'albumine au moyen d'anti-inflammatoires non steroides contre les rhumatismes (nsar)

Info

Publication number
EP1819363A2
EP1819363A2 EP05813969A EP05813969A EP1819363A2 EP 1819363 A2 EP1819363 A2 EP 1819363A2 EP 05813969 A EP05813969 A EP 05813969A EP 05813969 A EP05813969 A EP 05813969A EP 1819363 A2 EP1819363 A2 EP 1819363A2
Authority
EP
European Patent Office
Prior art keywords
albumin
nsaid
conjugate
protein
conjugates
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Withdrawn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
EP05813969A
Other languages
German (de)
English (en)
Inventor
Hannsjörg SINN
Marcel MÜLBAIER
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.)
SCHMIEDEBERG-SINN, CHRISTA
Original Assignee
AlbuPharm Heidelberg GmbH and Co KG
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 AlbuPharm Heidelberg GmbH and Co KG filed Critical AlbuPharm Heidelberg GmbH and Co KG
Publication of EP1819363A2 publication Critical patent/EP1819363A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to NSAIDs (non-steroidal anti-inflammatory drugs) - protein conjugates, and more particularly to NSAID-albumin conjugates, to processes for their preparation and to their use as medicaments, in particular for the treatment of inflammation.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAID-albumin conjugates to processes for their preparation and to their use as medicaments, in particular for the treatment of inflammation.
  • Non-steroidal anti-inflammatory drugs also called NSAIDs (non-steroidal anti-inflammatory drugs) have been used in their low-molecular forms for the treatment of inflammatory processes.
  • a disadvantage of the previously used therapies using NSAIDs is, in particular, the short residence time of the substances used in the circulation, so that they have only a very narrow time window for the development of their effectiveness and, moreover, only a small proportion of the administered medicament reaches the destination. This results in unwanted side effects, which lead to problems especially with longer applications.
  • side effects are, for example, complaints in the gastrointestinal tract and an inhibition of blood clotting.
  • concentration disorders or headaches were also observed.
  • acute allergic reactions favoring of asthma attacks (especially in acetylsalicylic acid) as well as the reduction of white and / or red blood cells on.
  • EP 0 630 263 describes conjugates consisting of a carboxyl group-containing active substance, a spacer and a carrier.
  • the active substance which may be a non-steroidal anti-inflammatory drug (NSAID), such as naproxen, is via an ester bond to the Spacer coupled, which in turn is linked via a covalent bond to the carrier.
  • NSAID non-steroidal anti-inflammatory drug
  • Suitable spacers for the controlled release of the active substance to the target tissue are (poly) - ⁇ -hydroxy acids and, as carriers, proteins such as isozyme, cytochrome C and aprotein.
  • a disadvantage of these conjugates is that while the active substance at the site of action is cleaved enzymatically from the spacer in the body, the carrier protein initially remains in the body, without as an energy supplier for associated with inflammatory processes cells that have a high turnover of plasma proteins to serve.
  • the additional use of a spacer to the drug and carrier is associated with a significant amount of work and thus increased costs without being of additional pharmacological benefit.
  • WO 98/00172 discloses pharmaceutical compositions intended to effect specific delivery of drugs to the target site in the body. They include microbubbles that are encased in a protein shell and that are the actual transporters for the drugs.
  • the protein shell preferably consists of human serum albumin and, as an active ingredient, naproxen may be present as an example.
  • the microbubbles are formed by means of an ultrasound.
  • WO 98/00172 does not disclose that there is a direct covalent bond between the albumin and the drug. Although it is the high specificity of the composition, but a higher residence time of the substance in the body, which is based on a direct covalent bond, not disclosed.
  • Kostiainen et al. Journal of Chromatography (1993), 647 (2), 361-365) disclose the study of naproxen-lysozyme conjugates by capillary electrophoresis and mass spectroscopy wherein the naproxen is covalently coupled via an amide bond to the lysine group in the lysozyme.
  • the document Kostiainen et al. only physical examinations of the disclosed conjugate.
  • Antirheumatics such as diclofenac, naproxen or ibuprofen and their action in the treatment of osteoarthritis or rheumatoid
  • An object of the present invention was therefore to provide NSAIDs in a form with which the difficulties arising in the prior art can be overcome and with which, in particular, targeted uptake into inflamed tissue can be achieved with simultaneously long half-life in the organism.
  • an NSAID-protein conjugate comprising an NSAID and a protein. More preferably, the NSAID-protein conjugate is an NSAID-albumin conjugate comprising a NSAID and albumin characterized in that the NSAID is directly covalently linked to the albumin and that the molar ratio of NSAID: protein is 2: 1 to 0 , 1: 1.
  • NSAIDs By directly coupling NSAIDs to proteins, particularly to carrier proteins, the low molecular weight drugs that are rapidly removed from the body are hidden from the body's excretion or trapping mechanisms, and a long half-life is achieved in the body. This makes it possible to administer small amounts of active ingredient and thus practically eliminate any possible side effects virtually completely.
  • Direct covalent coupling of the NSAID to the carrier means that the NSAID is linked to the transport protein through a linker or spacer-free linkage.
  • the NSAID is covalently linked to the protein via an acid amide linkage formed from a carboxyl group of the NSAID and an amino group, preferably a lysine group of the protein.
  • Albumin in particular serum albumin, and most preferably human albumin or human serum albumin (HSA) are preferably used as protein in the conjugates according to the invention.
  • a protein is preferably used which is native to the patient for whom the conjugate is intended.
  • native protein is meant a protein derived from the same species as the species to which the protein is administered. This means, for example, that when administered to humans, human proteins, when administered to mice according to mouse proteins, etc. are used.
  • Human albumin is an endogenous, ubiquitously distributed and non-immunogenic protein. It has a molecular weight of about 68 kDa and is therefore not excreted via the kidney. Albumin accounts for approximately 60% of the total plasma protein level. In the healthy organism it fulfills transport functions for many substances and serves as a reserve energy source in acute emergencies, which is available everywhere in the body and at any time. Under normal conditions, it is not absorbed by healthy tissue. In contrast, cells associated with inflammatory processes have a high turnover of proteins, especially plasma proteins, predominantly albumin. As a result, the albumin in the inflamed target cells, for which the protein serves as an energy source, degraded and released the drug.
  • the biokinetic behavior of the conjugates according to the invention is determined solely by the macromolecule albumin, but not by the low-molecular weight NSAID.
  • the coupling of the NSAID to the carrier protein, for example albumin is preferably carried out without limiting its biologically active character.
  • Particularly preferred is a covalent coupling of the active ingredient to the carrier protein.
  • the covalent coupling is preferably selected so that it can be cleaved again in pathologically altered tissues, so that the biological effectiveness of the original pharmaceutical is retained and can be utilized.
  • NSAID-protein conjugates in particular NSAID-albumin conjugates, occurs without altering the biological activity of the active substance and without loss of the biologically active character of the protein used as a carrier, in particular of albumin.
  • a biologically active protein is understood to mean, in particular, an undenatured protein whose biological function is retained.
  • the protein has a biological activity of> 50%, more preferably of> 70%, more preferably of> 80%, and most preferably of> 90%, based on the activity of natural albumin.
  • the molar ratio of active ingredient to carrier protein is 2: 1 to 0.1: 1, preferably 1.5: 1 to 0.2: 1, and in particular 1, 1: 1 to 0.5: 1.
  • Albumin is still biologically active at 1: 1 loading with an NSAID.
  • conjugates can be obtained which have no or only a very small proportion of cross-linking during the loading. This further avoids rapid elimination from the circulation and unwanted side effects.
  • the proportion of dimeric albumin in the conjugates according to the invention is advantageously ⁇ 5 wt .-%, more preferably ⁇ 3 wt .-%.
  • NSAIDs which are selected in particular from acetylsalicylic acid, diclofenac, indomethacin, naproxen, flufenamic acid, mefenamic acid, tolmetin, ibuprofen, fenoprofen, ketoprofen, acemetacin or niflumic acid are used according to the invention.
  • the active substances are released only in the area of the inflammatory process, in particular by enzymatic cleavage of the protein.
  • the usual side effects that occur when using low-molecular weight NSAIDs no longer appear because in vivo healthy cells do not absorb albumin or its conjugates.
  • the biological half-life of the conjugates is determined solely by the macromolecule protein, in particular albumin. Thus, the initially available drug concentration falls after about 20 days to about 50% of the initial value.
  • the protein used according to the invention for the formation of the conjugates preferably has a molecular weight of ⁇ 18,000 Da, more preferably ⁇ 30,000 Da and even more preferably ⁇ 50,000 Da.
  • the conjugate according to the invention is active ingredient in a drug.
  • a drug has in particular low side effects and can be administered, for example, on an outpatient basis.
  • the administration is preferably intravenous.
  • a dosage unit preferably contains 0.1 to 10 mg of active ingredient NSAID per kilogram of body weight per day and in particular 0.5 to 5 mg of active ingredient per kilogram of body weight per day.
  • the dose can be chosen lower than in the conventional therapy with NSAIDs.
  • the conjugates according to the invention are particularly suitable for the treatment of inflammatory processes. All the inflammatory processes that are also treated with the NSAIDs alone can be treated with the conjugates according to the invention. Inflammatory processes which can be treated according to the invention are, for example, rheumatoid arthritis.
  • conjugates according to the invention in the combination therapy, for example together with other anti-inflammatory agents.
  • the doses of the respective components continue to reduce.
  • Another object of the present invention is a method for producing an NSAID-protein conjugate.
  • Particularly preferred within the scope of the present invention is a method of producing an NSAID-albumin conjugate comprising reacting an NSAID with albumin by direct covalent coupling, wherein the molar ratio of NSAID: albumin is 2: 1 to 0.1: 1.
  • the low molecular weight drug NSAR and the high molecular weight carrier protein are reacted with each other.
  • succinimidyl ester is first formed from the low molecular weight NSAID and this is subsequently reacted with the protein.
  • a succinimidyl ester of NSAIDs can be made by reacting low molecular weight NSAIDs with a carbodiimide.
  • Efficient covalent coupling of the active ingredient to the carrier molecule is important for the preparation of the conjugates used according to the invention.
  • the coupling must not lead to an undesired change in the carrier protein and / or the active ingredient.
  • Conventional activation of carboxyl-containing organic compounds with dicyclohexylcarbodiimide (DCC) requires at room temperature or at +4 0 C more than 12 hours (DP 41 22 210 A1; EP 0879604 A1; EP 0820308).
  • This object is achieved according to the invention by a process for the preparation of a conjugate in which NSAIDs and albumin in the presence of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC) as carbodiimide and N-hydroxysuccinimide.
  • EDC N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide
  • the activation is preferably carried out at a temperature of 10 to 100 0 C, more preferably from 20 to 90 0 C and even more preferably from 50 to 75 0 C for a reaction time of 1 minute to 10 hours, more preferably from 20 to 50 minutes.
  • the reaction of the activated active substance with the carrier protein is preferably carried out at a temperature between 10 and 50 ° C., in particular between 20 and 40 ° C.
  • the activation of the carboxyl-containing compound, in particular of methotrexate with EDC and N-hydroxysuccinimide in a 5 organic solvent, preferably in dimethyl sulfoxide (DMSO) is performed.
  • a 5 organic solvent preferably in dimethyl sulfoxide (DMSO)
  • suitable organic solvents include dimethylacetamide or dioxane.
  • the activation is preferably carried out in the absence of water, in particular in the presence of ⁇ 5% by weight of water, more preferably ⁇ 1% by weight of water and most preferably completely anhydrous.
  • An essential advantage of the preparation process according to the invention is that the activating reagents used, ie EDC and N-hydroxysuccinimide, have a high water solubility.
  • the unused coupling reagents can be removed in a simple manner from the product obtained, for example by washing with water during the reaction.
  • the coupling reagents used in the prior art for example when using di-cyclohexyl-carbodiimide (DCC), a non-resolvable residue of coupling reagent remains in the conjugate.
  • DCC di-cyclohexyl-carbodiimide
  • Another preferred aspect of the invention relates to an optimized method of producing a conjugate according to the invention comprising reacting an NSAID with albumin by direct covalent coupling, characterized in that an NSAID and albumin in the presence of N- (3-dimethylaminopropyl) -N'-ethyl -c.arbodiimid reacts as the sole activating reagent.
  • the NSAID is preferably a cytostatic or immunosuppressant, more preferably indomethacin, acetylsalicylic acid, diclofenac, ibuprofen and / or naproxen, most preferably indomethacin.
  • the protein is preferably albumin.
  • N-hydroxysuccinimide When N-hydroxysuccinimide is used, the latter also has a high UV absorption on HPLC when the UV measuring cell is set to 280 nm and disturbs or impedes by its retention time of about 11.5 minutes, during which other low molecular weight compounds appear direct determination of the coupling yield. This means that in many cases a yield determination is possible only at the end of the purification of the conjugate. Due to the optimized process without the use of N-hydroxysuccinimide this factor can now be excluded. This is also a great advantage for product safety. Another advantage of the optimized process is that the coupling yield is surprisingly on average 98-99%.
  • conjugates prepared by the processes according to the invention can be used for numerous uses and, in particular, for intravenous administration.
  • conjugates for example when using an anti-inflammatory NSAID, can be advantageously used for the preparation of medicaments for the treatment of inflammatory processes, in particular for the manufacture of a medicament for the treatment of rheumatoid arthritis.
  • the invention will be further elucidated by the following example and the attached figures.
  • FIG. 1 shows an HPLC chromatogram of indomethacin alone
  • FIG. 2 shows the chromatogram of the indomethacin-HSA conjugate prepared according to Example 1.
  • Indomethacin IMC 1 SIGMA-ALDRICH, Taufkirchen
  • N- (3-dimethylaminopropyl) -N'ethylcarbodiimide hydrochloride EDC, SIGMA-ALDRICH, Taufkirchen
  • N-hydroxysuccinimide Sigma-Aldrich, Taufmün
  • albumin Göricke, Dessau
  • the other NSAIDs acetylsalicylic acid.Diclofenac, ibuprofen, naproxen, etc. can be used for conjugation with albumin.
  • indomethacin IMC, MW 357.8
  • EDC N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
  • NHS N-hydroxysuccinimide
  • the proportion of dimeric albumin is ⁇ 3%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Rheumatology (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne des conjugués protéiniques NSAR (anti-inflammatoires non stéroïdes) et notamment des conjugués d'albumine NSAR, des procédés de réalisation associés et leur utilisation comme médicament, notamment pour traiter des inflammations.
EP05813969A 2004-11-26 2005-11-25 Procedes pour produire des conjugues d'albumine au moyen d'anti-inflammatoires non steroides contre les rhumatismes (nsar) Withdrawn EP1819363A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004057196A DE102004057196A1 (de) 2004-11-26 2004-11-26 Verfahren zur Herstellung von Albumin-Konjugaten mit Nicht-steroidalen Antirheumatika (NSAR)
PCT/EP2005/012638 WO2006056463A2 (fr) 2004-11-26 2005-11-25 Procedes pour produire des conjugues d'albumine au moyen d'anti-inflammatoires non steroides contre les rhumatismes (nsar)

Publications (1)

Publication Number Publication Date
EP1819363A2 true EP1819363A2 (fr) 2007-08-22

Family

ID=35907990

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05813969A Withdrawn EP1819363A2 (fr) 2004-11-26 2005-11-25 Procedes pour produire des conjugues d'albumine au moyen d'anti-inflammatoires non steroides contre les rhumatismes (nsar)

Country Status (5)

Country Link
US (1) US20080306245A1 (fr)
EP (1) EP1819363A2 (fr)
CA (1) CA2589455A1 (fr)
DE (1) DE102004057196A1 (fr)
WO (1) WO2006056463A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9629920B2 (en) 2009-12-18 2017-04-25 Exodos Life Sciences Limited Partnership Methods and compositions for stable liquid drug formulations

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0282057A3 (fr) * 1987-03-11 1990-03-07 The Board Of Regents Of The University Of Michigan Produits associés chémo-radio-immunologiques
NL9200481A (nl) * 1992-03-13 1993-10-01 Univ Groningen Farmaceutisch preparaat met plaatsgerichte afgifte.
US5849727A (en) * 1996-06-28 1998-12-15 Board Of Regents Of The University Of Nebraska Compositions and methods for altering the biodistribution of biological agents
EP0879604B1 (fr) * 1997-05-09 2003-04-09 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Conjugué comprenant un antagoniste de l'acide folique et un porteur

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006056463A2 *

Also Published As

Publication number Publication date
WO2006056463A2 (fr) 2006-06-01
CA2589455A1 (fr) 2006-06-01
US20080306245A1 (en) 2008-12-11
DE102004057196A1 (de) 2006-06-01
WO2006056463A3 (fr) 2006-07-27

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