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WO1986004240A1 - Succedane de plasma - Google Patents

Succedane de plasma Download PDF

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Publication number
WO1986004240A1
WO1986004240A1 PCT/EP1985/000589 EP8500589W WO8604240A1 WO 1986004240 A1 WO1986004240 A1 WO 1986004240A1 EP 8500589 W EP8500589 W EP 8500589W WO 8604240 A1 WO8604240 A1 WO 8604240A1
Authority
WO
WIPO (PCT)
Prior art keywords
hemoglobin
polymer
activated
inositol
phosphate
Prior art date
Application number
PCT/EP1985/000589
Other languages
German (de)
English (en)
Inventor
Jürgen GUDJONS
Peter Wiesert
Roland Reiner
Original Assignee
Battelle - Institut E.V.
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 Battelle - Institut E.V. filed Critical Battelle - Institut E.V.
Publication of WO1986004240A1 publication Critical patent/WO1986004240A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/795—Porphyrin- or corrin-ring-containing peptides
    • C07K14/805—Haemoglobins; Myoglobins
    • 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
    • A61K38/41—Porphyrin- or corrin-ring-containing peptides
    • A61K38/42—Haemoglobins; Myoglobins

Definitions

  • the invention relates to a blood substitute based on biocompatible polymers and hemoglobin.
  • Oxygen-transporting preparations with and without plasma expander effects are already known as blood substitutes. If you leave the fluorocarbons because of their fully synthetic
  • the simplest preparation to produce is the stroma-free hemoglobin solution. Since this contains neither membrane structures nor antigen determinants, the problems of typing and sensitization are eliminated.
  • the main disadvantage of the stroma-free hemoglobin solution is the too short intravascular half-life, which should be six to twelve hours for a blood or plasma substitute.
  • the average circulating half-life for batches of 6% stroma-free hemoglobin solutions is 100 to 140 minutes. 240 minutes after the exchange of 2 ml / kg of whole blood, only approx. 20% stroma-free hemoglobin solution can be detected in the bloodstream.
  • Another disadvantage of the stroma-free hemoglobin solution is the oxygen binding curve that is clearly shifted to the left in vitro compared to the oxygen dissociation curve of normal blood.
  • the stroma-free hemoglobin solution can only be accepted as a blood substitute if, on the one hand, it is possible to increase the intravascular residence time and on the other hand the release of oxygen from to facilitate the oxygen-loaded hemoglobin tetramer.
  • hemoglobin since the accessible reactive groups in hemoglobin are also responsible for their typical biological properties such as oxygen and carbon dioxide transport, a covalent bond to these groups also necessarily leads to a different biological function of the hemoglobin.
  • preparations could be made whose intravascular half-life is sufficient for twelve hours, there is usually an increase in oxygen affinity at the same time.
  • a stroma-free hemoglobin solution can be prepared by coupling pyridoxal phosphate to the terminal amino groups with a permanently reduced oxygen affinity.
  • pyridoxal phosphate to the terminal amino groups with a permanently reduced oxygen affinity.
  • the invention has for its object a hemoglobin to be developed with an increased intravascular residence time and reduced oxygen affinity.
  • the agent according to the invention is produced by activating a water-soluble polymer by introducing free OH, NH, SH and / or COOH groups and then with a compound which has the ability to bind hemoglobin absorptively and phosphate and sulfate - And / or contains sulfonate groups, is reacted and that the resulting product is then brought together with hemoglobin. Further developments of the method according to the invention are described in subclaims 6 to 10.
  • affinors which have a high affinity for hemoglobin and at the same time shift the oxygen dissociation curves to the right are covalently bound to various polymers which act as a carrier compound. It is thereby achieved that the polymer molecule is adsorbed firmly on hemoglobin via the affinity component and thus the elimination of the hemoglobin via the kidney is made more difficult by the higher molecular weight. At the same time, the oxygen affinity of the adsorptively bound hemoglobin is reduced compared to the stroma-free hemoglobin.
  • any known plasma substitute can be used as the polymer.
  • polysaccharides in particular dextran, are preferably used.
  • inositol hexaphosphate in the series 2,3-diphosphoglycerate / adenosine triphosphate / inositol tetraphosphate / inositol pentaphosphate / inositol hexasulfate / inositol hexaphosphate causes the greatest decrease in the oxygen affinity of hemoglobin.
  • the hemoglobin / inositol hexaphosphate complex has the lowest dissociation constant in the series: 2,3-diphosphoglycerate / inositol pentaphosphate / inositol hexasulfate / inositol hexaphosphate.
  • 2,3-diphosphoglycerate / inositol pentaphosphate / inositol hexasulfate / inositol hexaphosphate Apart from these suitability factors, inositol hexaphosphate occurs naturally in the human organism. In principle, there are compounds that have an even greater affinity for hemoglobin and an even smaller one
  • Dissociation constants of the corresponding complex have as inositol hexaphosphate. These are above all analogue substances which have more than six phosphoric acid or sulfate residues.
  • the water-soluble polymer is activated to produce the blood substitute according to the invention.
  • this can be carried out synthetically most simply and with the best conversion rates by catalytic reaction with epichlorohydrin.
  • a catalyst e.g. Zinc tetrafluoroborate used.
  • Zinc tetrafluoroborate used as a catalyst e.g. Zinc tetrafluoroborate used.
  • this compound (I) converts to the very reactive epoxy variant (II):
  • hemoglobin affinor for example inositol hexaphosphate (IHP)
  • IHP inositol hexaphosphate
  • R represents an inositol ring with five remaining phosphoric acid groups.
  • a product according to the invention can be prepared starting from 3-amino-2-hydroxypropyl-dextran (IV), which is obtained by reacting 3-chloro-2-hydroxypropyidextran (I) or the epoxy variant (II) in an aqueous medium with ammonia can be.
  • the unreactive amino group of 3-amino-2-hydroxypropyl-dextran (IV) has to be activated, e.g. by dicyclohexylcarbodiimide (DCC) or epichlorohydrin.
  • Polyamines e.g. Triethylenetetramine or polyethyleneimine groups can be locally enriched on the modified dextran.
  • Epichlorohydrin activated phosphate groups, the inositol hexaphosphate activated with epichlorohydrin and the alkali metal hydrogen phosphate also treated with epichlorohydrin.
  • the polymer is precipitated by pouring it dropwise into 1 liter of acetone, filtered off, washed with acetone and dried in vacuo. For further purification, the product is repeatedly dissolved in a little water and alternately precipitated by dropping it in acetone or methanol. 4 g of 3-chloro-2-hydroxypropyl-dextran are obtained as a white powder which is soluble in water. Average chlorine content: c a. 3%.
  • 3-Chloro-2-hydroxypropyl-dextran modified with triethylenetetramine is dissolved in water, mixed with an aqueous solution of the activated phosphate and stirred. The reaction solution is then concentrated in an ultrafiltration cell over a PM-10 membrane. The reaction product is precipitated by pouring it into methanol. After the precipitation has settled, the product is filtered off with suction, washed with methanol and dried. Average phosphorus content: approx. 6%
  • the inositol hexaphosphate / dextran coupling products are examined by gel chromatography for the coupling and their suitability for adsorption on hemcglobin.
  • Different mixtures of the coupling products with hemoglobin are separated by gel chromatography according to their molecular weight.
  • the chromatograms of the mixtures of hemoglobin with the coupling products always show two peaks which are more or less separate depending on the chromatography conditions (gels, eluents, etc.). This shows that, in addition to the pure hemoglobin, the fraction of a higher molecular weight, hemoglobin-containing product is present, which can be separated off by gel chromatography.
  • the coupling products cause the expected right shift of the oxygen dissociation curve of the hemoglobin.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

Un succédané volhémique de plasma se compose d'un polymère hydrosoluble biocompatible avec des groupes de phosphate, sulfate et/ou sulfonate. Ces produits sont obtenus par couplage du polymère avec des combinaisons contenant des groupes de phosphate, sulfate et sulfonate, lesquelles peuvent fixer l'hémoglobine par adsorption. On utilise de préférence de la dextrane comme constituant polymère et de l'inositolhexaphosphate comme combinaison affine d'hémoglobine.
PCT/EP1985/000589 1985-01-17 1985-11-04 Succedane de plasma WO1986004240A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP3501349.4 1985-01-17
DE19853501349 DE3501349A1 (de) 1985-01-17 1985-01-17 Blutersatz

Publications (1)

Publication Number Publication Date
WO1986004240A1 true WO1986004240A1 (fr) 1986-07-31

Family

ID=6260024

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1985/000589 WO1986004240A1 (fr) 1985-01-17 1985-11-04 Succedane de plasma

Country Status (3)

Country Link
EP (1) EP0208697A1 (fr)
DE (1) DE3501349A1 (fr)
WO (1) WO1986004240A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0265865A2 (fr) * 1986-10-28 1988-05-04 B. Braun Melsungen AG Substitut du sang
WO1998012171A1 (fr) * 1996-09-18 1998-03-26 Daiso Co., Ltd. Procede de preparation d'ethers 3-amino-2-hydroxy-1-propyliques

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2630329B1 (fr) * 1988-04-20 1991-07-05 Merieux Inst Conjugues macromoleculaires d'hemoglobine, leur procede de preparation et leurs applications
US5055259A (en) * 1988-07-29 1991-10-08 Sanraku Incorporated Bloodless blood typing training kit
FR2640141B1 (fr) * 1988-12-14 1993-04-16 Merieux Inst Conjugues macromoleculaires d'hemoglobine, leur procede de preparation et leurs applications
CA2380908A1 (fr) * 1999-08-12 2001-02-22 Alexandr Vilenovich Asafov Composition d'un substitut de plasma

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2328478A1 (fr) * 1975-10-22 1977-05-20 Wong Jeffrey Substitut du sang a base d'hemoglobine
FR2348703A1 (fr) * 1976-04-23 1977-11-18 Biotest Serum Institut Gmbh Preparation d'hemoglobine appropriee pour l'injection intraveineuse et son procede d'obtention
EP0043675A1 (fr) * 1980-07-02 1982-01-13 Ajinomoto Co., Inc. Hémoglobines modifiées utilisables comme véhicules d'oxygène pour succédanés du sang
EP0078961A2 (fr) * 1981-11-11 1983-05-18 Biotest-Serum-Institut GmbH Procédé de fabrication d'une préparation stable d'hémoglobine réticulée à capacité élevée de transport d'oxygène et préparation d'hémoglobine ainsi obtenue
WO1984004248A1 (fr) * 1983-05-04 1984-11-08 Ross W Tye Hemoglobine tetramere exempte de stroma reticulee modifiee
EP0142125A2 (fr) * 1983-11-10 1985-05-22 Intermedicat GmbH Conjugués de composés macromoléculaires et d'hémoglobine, leur procédé de préparation et médicament les contenant

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2328478A1 (fr) * 1975-10-22 1977-05-20 Wong Jeffrey Substitut du sang a base d'hemoglobine
FR2348703A1 (fr) * 1976-04-23 1977-11-18 Biotest Serum Institut Gmbh Preparation d'hemoglobine appropriee pour l'injection intraveineuse et son procede d'obtention
EP0043675A1 (fr) * 1980-07-02 1982-01-13 Ajinomoto Co., Inc. Hémoglobines modifiées utilisables comme véhicules d'oxygène pour succédanés du sang
EP0078961A2 (fr) * 1981-11-11 1983-05-18 Biotest-Serum-Institut GmbH Procédé de fabrication d'une préparation stable d'hémoglobine réticulée à capacité élevée de transport d'oxygène et préparation d'hémoglobine ainsi obtenue
WO1984004248A1 (fr) * 1983-05-04 1984-11-08 Ross W Tye Hemoglobine tetramere exempte de stroma reticulee modifiee
EP0142125A2 (fr) * 1983-11-10 1985-05-22 Intermedicat GmbH Conjugués de composés macromoléculaires et d'hémoglobine, leur procédé de préparation et médicament les contenant

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Biological Abstracts, Volume 64, No. 5959, 01 December 1977, Philadelphia, (US) G. AMICONI et al.: "The Effect of Macromolecular Polyanions on the Functional Properties of Human Hemoglobin", see Abstract 60857 & Eur. J. Biochem. 76 (2); 339-344, 1977 *
CHEMICAL ABSTRACTS, Volume 103, No. 19, 11 November 1985, Columbus, Ohio, (US) P. MENU et al.: "Effects of four Polyanionic Dextrans on the Dissociation Curve and Transfusional Capacity of Oxyhemogolbin", see page 60, Abstract 153669v & Bull. Soc. Pharm. Bordeaux 1984, 123 (1-2-3-4 ) 161-70 (FR) *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0265865A2 (fr) * 1986-10-28 1988-05-04 B. Braun Melsungen AG Substitut du sang
EP0265865A3 (en) * 1986-10-28 1989-01-04 B. Braun Melsungen Ag Blood substitute
WO1998012171A1 (fr) * 1996-09-18 1998-03-26 Daiso Co., Ltd. Procede de preparation d'ethers 3-amino-2-hydroxy-1-propyliques
US6057476A (en) * 1996-09-18 2000-05-02 Daiso Co., Ltd. Process for the preparation of 3-amino-2-hydroxy-1-propyl ethers

Also Published As

Publication number Publication date
EP0208697A1 (fr) 1987-01-21
DE3501349A1 (de) 1986-07-17

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