EP0208697A1 - Succedane de plasma - Google Patents
Succedane de plasmaInfo
- Publication number
- EP0208697A1 EP0208697A1 EP19850905515 EP85905515A EP0208697A1 EP 0208697 A1 EP0208697 A1 EP 0208697A1 EP 19850905515 EP19850905515 EP 19850905515 EP 85905515 A EP85905515 A EP 85905515A EP 0208697 A1 EP0208697 A1 EP 0208697A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hemoglobin
- polymer
- activated
- inositol
- phosphate
- 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- Withdrawn
Links
- 239000003058 plasma substitute Substances 0.000 title claims description 6
- 108010054147 Hemoglobins Proteins 0.000 claims abstract description 36
- 102000001554 Hemoglobins Human genes 0.000 claims abstract description 36
- 229920002307 Dextran Polymers 0.000 claims abstract description 19
- IMQLKJBTEOYOSI-GPIVLXJGSA-N Inositol-hexakisphosphate Chemical compound OP(O)(=O)O[C@H]1[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@@H]1OP(O)(O)=O IMQLKJBTEOYOSI-GPIVLXJGSA-N 0.000 claims abstract description 15
- IMQLKJBTEOYOSI-UHFFFAOYSA-N Phytic acid Natural products OP(O)(=O)OC1C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C1OP(O)(O)=O IMQLKJBTEOYOSI-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229940068041 phytic acid Drugs 0.000 claims abstract description 14
- 229920000642 polymer Polymers 0.000 claims abstract description 14
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract description 8
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 7
- 239000010452 phosphate Substances 0.000 claims abstract description 7
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims abstract description 7
- 229920003169 water-soluble polymer Polymers 0.000 claims abstract description 6
- 238000001179 sorption measurement Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 14
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 11
- 239000003633 blood substitute Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 claims description 6
- NBTMNFYXJYCQHQ-UHFFFAOYSA-N (2,3,4,5,6-pentasulfooxycyclohexyl) hydrogen sulfate Chemical compound OS(=O)(=O)OC1C(OS(O)(=O)=O)C(OS(O)(=O)=O)C(OS(O)(=O)=O)C(OS(O)(=O)=O)C1OS(O)(=O)=O NBTMNFYXJYCQHQ-UHFFFAOYSA-N 0.000 claims description 5
- CTPQAXVNYGZUAJ-UHFFFAOYSA-N Inositol pentaphosphate Natural products OC1C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C1OP(O)(O)=O CTPQAXVNYGZUAJ-UHFFFAOYSA-N 0.000 claims description 5
- CTPQAXVNYGZUAJ-UYSNGIAKSA-N [(1s,2r,4s,5r)-3-hydroxy-2,4,5,6-tetraphosphonooxycyclohexyl] dihydrogen phosphate Chemical compound OC1[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)C(OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@@H]1OP(O)(O)=O CTPQAXVNYGZUAJ-UYSNGIAKSA-N 0.000 claims description 5
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims description 5
- XOHUEYCVLUUEJJ-UHFFFAOYSA-I 2,3-Diphosphoglycerate Chemical compound [O-]P(=O)([O-])OC(C(=O)[O-])COP([O-])([O-])=O XOHUEYCVLUUEJJ-UHFFFAOYSA-I 0.000 claims description 4
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 claims description 4
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims description 4
- YDHWWBZFRZWVHO-UHFFFAOYSA-H [oxido-[oxido(phosphonatooxy)phosphoryl]oxyphosphoryl] phosphate Chemical compound [O-]P([O-])(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O YDHWWBZFRZWVHO-UHFFFAOYSA-H 0.000 claims description 4
- 210000004369 blood Anatomy 0.000 claims description 4
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims description 4
- 229960000367 inositol Drugs 0.000 claims description 4
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 claims description 4
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 claims description 4
- 229960001327 pyridoxal phosphate Drugs 0.000 claims description 4
- UFSQFZYUGSALND-UHFFFAOYSA-N 5-[(2,4-diphosphonooxyphenyl)methylamino]naphthalene-1-sulfonic acid Chemical compound OP(=O)(O)OC1=CC(OP(O)(=O)O)=CC=C1CNC1=CC=CC2=C(S(O)(=O)=O)C=CC=C12 UFSQFZYUGSALND-UHFFFAOYSA-N 0.000 claims description 3
- OBJOZRVSMLPASY-UHFFFAOYSA-N 8-hydroxypyrene-1,3,6-trisulfonic acid Chemical compound C1=C2C(O)=CC(S(O)(=O)=O)=C(C=C3)C2=C2C3=C(S(O)(=O)=O)C=C(S(O)(=O)=O)C2=C1 OBJOZRVSMLPASY-UHFFFAOYSA-N 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229920002873 Polyethylenimine Polymers 0.000 claims description 2
- 229920000249 biocompatible polymer Polymers 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 229920000768 polyamine Polymers 0.000 claims description 2
- 230000000274 adsorptive effect Effects 0.000 claims 1
- 229960001124 trientine Drugs 0.000 claims 1
- 230000008878 coupling Effects 0.000 abstract description 7
- 238000010168 coupling process Methods 0.000 abstract description 7
- 238000005859 coupling reaction Methods 0.000 abstract description 7
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 14
- 239000001301 oxygen Substances 0.000 description 14
- 229910052760 oxygen Inorganic materials 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 108010001708 stroma free hemoglobin Proteins 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- 239000011574 phosphorus Substances 0.000 description 6
- 238000010494 dissociation reaction Methods 0.000 description 5
- 230000005593 dissociations Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- -1 Zinc tetrafluoroborate Chemical compound 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000004593 Epoxy Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- FENRSEGZMITUEF-ATTCVCFYSA-E [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].OP(=O)([O-])O[C@@H]1[C@@H](OP(=O)([O-])[O-])[C@H](OP(=O)(O)[O-])[C@H](OP(=O)([O-])[O-])[C@H](OP(=O)(O)[O-])[C@H]1OP(=O)([O-])[O-] Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].OP(=O)([O-])O[C@@H]1[C@@H](OP(=O)([O-])[O-])[C@H](OP(=O)(O)[O-])[C@H](OP(=O)([O-])[O-])[C@H](OP(=O)(O)[O-])[C@H]1OP(=O)([O-])[O-] FENRSEGZMITUEF-ATTCVCFYSA-E 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000005227 gel permeation chromatography Methods 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 229940083982 sodium phytate Drugs 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000004001 inositols Chemical class 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853501349 DE3501349A1 (de) | 1985-01-17 | 1985-01-17 | Blutersatz |
| DE3501349 | 1985-01-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0208697A1 true EP0208697A1 (fr) | 1987-01-21 |
Family
ID=6260024
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19850905515 Withdrawn EP0208697A1 (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) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3636590A1 (de) * | 1986-10-28 | 1988-05-26 | Braun Melsungen Ag | Blutersatzmittel |
| 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 |
| ATE222231T1 (de) * | 1996-09-18 | 2002-08-15 | Daiso Co Ltd | Verfahren zur herstellung von 3-amino-2-hydroxy-1-propylethern |
| BR9917605A (pt) * | 1999-08-12 | 2003-03-05 | Alexandr V Asafov | Composição substituta de plasma |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1055932A (fr) * | 1975-10-22 | 1979-06-05 | Hematech Inc. | Succedane du sang comparable a l'hemoglobine |
| DE2617822C3 (de) * | 1976-04-23 | 1981-01-08 | Biotest-Serum-Institut Gmbh, 6000 Frankfurt | Verfahren zur Herstellung eines für die intravenöse Injektion geeigneten Hämoglobinpräparates mit erhöhter Sauerstoffabgabe gegenüber Erythrozyten |
| JPS5716815A (en) * | 1980-07-02 | 1982-01-28 | Ajinomoto Co Inc | Oxygen transporting agent for artificial blood |
| DE3144705C2 (de) * | 1981-11-11 | 1983-12-08 | Biotest-Serum-Institut Gmbh, 6000 Frankfurt | Verfahren zur Herstellung eines lagerstabilen, vernetzten Hämoglobinpräparates mit hoher Sauerstoff-Transportkapazität, sowie das nach diesem Verfahren hergestellte Hämoglobinpräparat |
| US4529719A (en) * | 1983-05-04 | 1985-07-16 | Tye Ross W | Modified crosslinked stroma-free tetrameric hemoglobin |
| DE3340592A1 (de) * | 1983-11-10 | 1985-05-23 | B. Braun Melsungen Ag, 3508 Melsungen | Konjugate makromolekularer verbindungen an haemoglobine, verfahren zu ihrer herstellung und sie enthaltende arzneimittel |
-
1985
- 1985-01-17 DE DE19853501349 patent/DE3501349A1/de not_active Ceased
- 1985-11-04 EP EP19850905515 patent/EP0208697A1/fr not_active Withdrawn
- 1985-11-04 WO PCT/EP1985/000589 patent/WO1986004240A1/fr not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO8604240A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3501349A1 (de) | 1986-07-17 |
| WO1986004240A1 (fr) | 1986-07-31 |
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