EP1966239A1 - Albumine humaine a teneur reduite en octanoate - Google Patents

Albumine humaine a teneur reduite en octanoate

Info

Publication number
EP1966239A1
EP1966239A1 EP06829547A EP06829547A EP1966239A1 EP 1966239 A1 EP1966239 A1 EP 1966239A1 EP 06829547 A EP06829547 A EP 06829547A EP 06829547 A EP06829547 A EP 06829547A EP 1966239 A1 EP1966239 A1 EP 1966239A1
Authority
EP
European Patent Office
Prior art keywords
albumin
substances
octanoate
use according
preparations
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.)
Ceased
Application number
EP06829547A
Other languages
German (de)
English (en)
Inventor
Peter Kiessling
Dietrich Bosse
Johannes Zeiss
Gaston Diderrich
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.)
CSL Behring GmbH Deutschland
Original Assignee
CSL Behring GmbH Deutschland
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 CSL Behring GmbH Deutschland filed Critical CSL Behring GmbH Deutschland
Publication of EP1966239A1 publication Critical patent/EP1966239A1/fr
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/76—Albumins
    • C07K14/765—Serum albumin, e.g. HSA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/04—Chelating agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to the improvement of the transport properties of an industrially produced, for example via the Cohn process or by recombinant method albumin, which has been added in the course of its production with substances that saturate binding sites on the albumin and therefore deteriorate the binding and transport properties of the final product.
  • a specific embodiment of the invention is pasteurized and subsequently octanoate-reduced human albumin for therapeutic use, in particular in the detoxification therapy of human plasma, for example for the intravenous therapy of acute or chronic liver diseases and as dialysate for extracopinal liver dialysis with albumin in the MARS system (Molecular Adsorbent Recirculating System) or in the "single pass" dialysis.
  • MARS system Molecular Adsorbent Recirculating System
  • Albumin is the most abundant protein in blood plasma. It contributes greatly to the osmotic pressure of plasma and is therefore an important factor in the regulation of the volume of plasma and tissue fluid. The most common clinical use of albumin is therefore as a plasma volume expander.
  • albumin has also been increasingly used therapeutically as a transport protein.
  • Albumin is the major transport protein in human plasma. It binds a wide range of compounds and metabolic products such as steroids, bile acids, fatty and amino acids, heavy metals and pharmacological substances such as warfarin. Bind here the substances mainly on two subdomains of the albumin, Sudlow I (bilirubin, warfarin) and Sudlow II (tryptophan, octanoate, fatty acids), with heavy metals bind mainly at the N-terminus (Peters et al., "All About Albumin”;1996; Academic Press).
  • Detoxification therapy makes use of the transport function of albumin.
  • the main indications include the intravenous treatment of patients with chronic or acute liver disease, for detoxification (eg hyperbilirubinemia) and for the improvement of diuresis in patients with liver diseases and ascites (Gentilini et al., 1999) or in patients with nephrotic syndrome (Gines et al. , 1998), as well as in combination therapy with antibiotics in patients with bacterial peritonitis (Sort et al., 2000).
  • Used drugs e.g., phenitoin
  • albumin for detoxification in patients with acute or chronic liver disease.
  • Albumin detoxifies the patient's blood and significantly increases the survival rate of patients (Heemann et al., 1999).
  • albumin is added to substances that bind to albumin and reduce the binding ability of albumin to other substances in the final product by occupying these binding sites.
  • albumin prior to pasteurization, albumin is typically treated with a stabilizer such as octanoate (caprylate) or N-acetyl-tryptophan to prevent the denaturation or polymer formation of albumin during the pasteurization process.
  • octanoate for example, is added to prevent polymer formation during storage.
  • Pasteurization stabilizers out.
  • patients infused with albumin reduced in their binding capacity for drugs, when administered with pharmaceutical agents, have a considerably increased concentration of free, i. are not exposed to albumin-bound drug, which naturally brings an increased risk of excessive pharmacological effects and side effects for the patient. It is therefore proposed to use an albumin for which the
  • Pasteurization is replaced by the SD (solvent / detergent) method, avoiding the need for addition of a Pasteurmaschinesstabilisators also the occupation of binding sites is avoided.
  • albumin there is an increasing medical need for albumin in indications that utilize the transport function of albumin. Economically, albumin can still be produced industrially only from plasma. Here, above all, the Cohn process is used. Therapeutic plasma purified proteins must be treated with effective virus inactivation procedures before being administered to humans.
  • the present invention has therefore set itself the task of providing drugs based on albumin for certain indications, the operation of the drug in the specific indications based on the transport functions of albumin, ie on the binding of other substances to albumin, and wherein Albumin preparations that were added during their manufacturing process with substances that Occupy binding sites in the thus prepared albumin and thus block, whereby the use of such albumin in the specific indications is feasible only with reduced efficiency.
  • a stabilizer-free or stabilizer-poor albumin has in the o.g. Indications a significantly higher detoxification efficiency and binding capacity for toxins (active metabolites) than commercial albumin.
  • the invention describes the preparation of the new product and the proof of product improvement by means of novel analysis methods (analysis of the improvement in albumin transport and binding properties with ESR (Electron Spin Resonance Spectroscopy) (Matthes et al., 2000)
  • the transport function and binding capacity of the albumin for fatty acids can be measured by loading albumin with a spin probe (eg 16-doxylpalmitic acid) as a fatty acid in the presence of ethanol
  • DTE DTE
  • the method is particularly suitable for the use of industrially produced albumin preparations, which were added during their production process with substances that occupy binding sites in albumin thus produced block and thus, by as far as possible removal of these substances, the binding ability of these albumin preparations was improved or restored for the manufacture of a medicament whose pharmacological mode of action depends on the binding of other substances to the albumin used. For example,> 50%, or for example> 75%, or for example> 95% of the substance initially bound to albumin is removed.
  • albumins prepared in this way are suitable for the preparation of a medicament for the detoxification of human plasma.
  • a preferred embodiment of the invention are albumin preparations whose binding capacity is above that of plasmatic albumin.
  • Albumin preparations are not only the stabilizers optionally added during the manufacturing process, but also the plasma albumin-binding substances in the plasma have been reduced or completely removed.
  • One embodiment of the invention is the use of large scale albumin preparations after removal of albumin bound pasteurization stabilizers.
  • Preferred pasteurization stabilizers are octanoate and / or N-acetyl-tryptophan.
  • Another embodiment of the invention is the use of industrially produced albumin preparations after removal of albumin-bound substances which prevent the polymer formation of albumin, in particular the removal of octanoate.
  • the invention relates equally to liquid as well as freeze-dried albumin preparations.
  • Albumin preparations according to the invention are administered, for example, parenterally, for example intravenously.
  • One embodiment of the invention is the use of an albumin prepared according to the invention in extracorporeal plasma dialysis, such as, for example, MARS dialysis or single-pass dialysis.
  • the albumin preparations prepared according to the invention are particularly suitable for the preparation of a medicament for the treatment of chronic or acute liver diseases (eg chronic liver cirrhosis with ascites, acute liver poisoning with encephalopathy (hepatic coma)), for the detoxification of medicaments (eg warfarin overdose) or metabolic products ( eg hyperbilirubinemia) and to improve diuresis in patients with liver diseases and ascites (Gentilini et al., 1999) or in patients with nephrotic syndrome (Gines et al., 1998), as well as for combination therapy with antibiotics in patients with bacterial peritonitis (Sort et al., 2000).
  • chronic or acute liver diseases eg chronic liver cirrhosis with ascites, acute liver poisoning with encephalopathy (hepatic coma)
  • medicaments eg warfarin overdose
  • metabolic products eg hyperbilirubinemia
  • Fig. 1 Detoxification efficiency (DTE) of 8 different commercially available albumin preparations
  • Fig. 2 Modification of the detoxification efficiency (DTE) of intermediates in the production process of a commercially available albumin preparation
  • Fig.3 Experimental dialysis device Mini-MARS
  • the dialysate is passed, in which the albumin used for detoxification is contained.
  • Fig.4 Detoxification efficiency (DTE) of HSA in the dialysate cycle
  • the DTE increases with decreasing octanoate content
  • Fig.5 Detoxification efficiency (DTE) of HSA in the plasma cycle
  • Example 4 Analysis of binding and transport properties of octanoate-free albumin with ESR and AbiC.
  • the octanoate-free albumin and octanoate-containing products according to Example 3 were investigated with ESR and AbiC (determination of the albumin binding capacity with dansylsarcosine at the albumin binding site Sudlow II (Klammt S, 2000)) in an experimental dialysis plant (Mini Mars see FIG. 3).
  • HSA preparations were used at 6.4 mM, 3.2 mM, 1.6 mM and without octanoate. The more octanoate removed from the HSA, the higher the binding capacity determined with AbiC. Capacitance measurements with AbiC confirmed the results of DTE measurement by ESR qualitatively (data not shown). Furthermore, these HSA preparations were dialyzed against plasma loaded with the following toxins:
  • the stability of the octanoate-free albumin preparation according to Example 3 was investigated after lyophilization or freeze-drying with respect to aggregate formation according to the requirements of the European Pharmacopoeia (4.0 Edition 2002), using exclusion chromatography using a Toso Haas TSK 300 SWXL column. The aggregate formation was then calculated according to the specifications of the European Pharmacopoeia.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Urology & Nephrology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne l'amélioration des propriétés de transport d'une albumine produite à l'échelon industriel, par exemple par le procédé de Cohn ou par des procédés de recombinaison, qui, lors de sa production, a été mise en réaction avec des substances qui saturent les sites de liaison sur l'albumine et, partant, détériorent les propriétés de liaison et de transport du produit final. Dans un mode de réalisation spécial de la présente invention, de l'albumine humaine pasteurisée dont la teneur en octanoate a ensuite été réduite est utilisée à des fins thérapeutiques, en particulier pour la thérapie de détoxication de plasma humain, par exemple pour la thérapie intraveineuse de maladies hépatiques aiguës ou chroniques et en tant que dialysat pour la dialyse hépatique extracorporelle à l'albumine dans le système MARS (Molecular Adsorbent Recirculating System) ou dans la dialyse sans recirculation (SPAD).
EP06829547A 2005-12-22 2006-12-13 Albumine humaine a teneur reduite en octanoate Ceased EP1966239A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005062043 2005-12-22
PCT/EP2006/011970 WO2007079886A1 (fr) 2005-12-22 2006-12-13 Albumine humaine a teneur reduite en octanoate

Publications (1)

Publication Number Publication Date
EP1966239A1 true EP1966239A1 (fr) 2008-09-10

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ID=37908302

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06829547A Ceased EP1966239A1 (fr) 2005-12-22 2006-12-13 Albumine humaine a teneur reduite en octanoate

Country Status (7)

Country Link
US (2) US20100168000A1 (fr)
EP (1) EP1966239A1 (fr)
JP (2) JP2009520714A (fr)
KR (1) KR20080078010A (fr)
AU (1) AU2006334795B2 (fr)
CA (1) CA2634329A1 (fr)
WO (1) WO2007079886A1 (fr)

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WO2010049010A1 (fr) 2008-10-28 2010-05-06 Murauski Uladzimir A Procédés et kits pour la détection de la toxémie
EP2729492B1 (fr) 2011-07-05 2019-01-02 Albumedix Ltd Formulation d'albumine et utilisation
US8497124B2 (en) 2011-12-05 2013-07-30 Factor Bioscience Inc. Methods and products for reprogramming cells to a less differentiated state
RU2691027C2 (ru) 2011-12-05 2019-06-07 Фэктор Байосайенс Инк. Способы и препараты для трансфекции клеток
WO2013124325A1 (fr) 2012-02-20 2013-08-29 Murauski Uladzimir A Procédés et trousses pour la détection de tumeur maligne active
KR102596302B1 (ko) 2012-11-01 2023-11-01 팩터 바이오사이언스 인크. 세포에서 단백질을 발현시키는 방법들과 생성물들
WO2014091002A1 (fr) 2012-12-14 2014-06-19 Gambro Lundia Ab Nettoyage de fluide biologique
ES2787198T3 (es) 2014-01-31 2020-10-15 Factor Bioscience Inc ARN sintético para su uso en el tratamiento de la epidermólisis ampollosa distrófica
WO2016131052A1 (fr) 2015-02-13 2016-08-18 Factor Bioscience Inc. Produits d'acides nucléiques et leurs procédés d'administration
CA3033788A1 (fr) 2016-08-17 2018-02-22 Factor Bioscience Inc. Produits d'acides nucleiques et leurs procedes d'administration
KR20190102011A (ko) 2016-12-21 2019-09-02 프로메틱 파마 에스엠티 리미티드 상피-중간엽 전이를 예방 또는 최소화하는 방법 및 조성물
CN107033236B (zh) * 2017-05-05 2021-03-23 浙江大学 一种从酵母发酵液中分离人血白蛋白的混合模式层析方法
US10501404B1 (en) 2019-07-30 2019-12-10 Factor Bioscience Inc. Cationic lipids and transfection methods
CA3231611A1 (fr) * 2021-09-17 2023-03-23 Nenad SESTAN Procedes, systemes et compositions permettant la restauration et la conservation d'organes intacts chez un mammifere

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FR2630115B1 (fr) 1988-04-14 1994-10-28 Merieux Inst Procede de stabilisation des solutions d'albumine humaine et solution obtenue
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See also references of WO2007079886A1 *

Also Published As

Publication number Publication date
WO2007079886A1 (fr) 2007-07-19
US20100168000A1 (en) 2010-07-01
AU2006334795B2 (en) 2012-02-16
JP2012233007A (ja) 2012-11-29
US8877711B2 (en) 2014-11-04
JP2009520714A (ja) 2009-05-28
US20120238998A1 (en) 2012-09-20
AU2006334795A1 (en) 2007-07-19
KR20080078010A (ko) 2008-08-26
CA2634329A1 (fr) 2007-07-19

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