Patent EP0091183A2 successfully refreshed from Google Patents.
EP0091183A2
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Functional oxygen transport system
Assignee: University of California Berkeley
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Filing: 1983-02-15
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Granted: —
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Expires: 2003-02-15
Abstract
Abstract Functional oxygen transport systems (OTS) have been devised which may serve as temporary blood substitutes in the circulatory system. The OTS comprises pure crystalline hemoglobin dissolved in an aqueous solution and encapsulated within a complex lipid and carbohydrate modified lipid phase. The hemoglobin encapsulated inner aqueous phase and the encapsulating lipid phase are dispensed in an outer isotonic aqueous phase to form a suspension of the multiple water-in-oil-in water emulsion type. The emulsion is suitable to transfusion into the circulatory system to assist in oxygen transport. The carbohydrate modified lipids are included in the lipid phase to "mask" the OTS from the tissue binding and take up by the reticuloendothelial system. The OTS are also suitable for use as calibrating fluids in gas analysis apparatus.
Inventors
- 👤 Carver Anthony Hunt
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-24 02:09
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/0012; A61K9/0019; A61K9/0026; A61K38/00; A61K38/16; A61K38/41; A61K38/42; A61P; A61P7/00; A61P7/08; G; G01; G01N; G01N33/00; G01N33/0004; G01N33/0006; Y; Y10; Y10T; Y10T436/00; Y10T436/10; Y10T436/106664
Claims Analysis
Total Claims: 39
Claim 1
Independent Claim
38 words
An oxygen transport system comprising an emulsion including an inner aqueous phase having crystalline hemoglobin dissolved therein, a lipid oil phase enclosing said aqueous phase and a nonreducing carbohydrate bound to a lipid included in said oil phase.
Claim 2
Dependent Claim
38 words
An oxygen transport system comprising an emulsion including an inner aqueous phase having crystalline hemoglobin dissolved therein, a lipid oil phase enclosing said aqueous phase and a nonreducing carbohydrate bound to a lipid included in said oil phase.
Claim 3
Dependent Claim
33 words
The oxygen transport system according to Claim 1, wherein an outer aqueous phase entrains said oil phase and the enclosed inner aqueous phase, said outer-aqueous phase being physiologically acceptable and isotonic with blood.
Claim 4
Dependent Claim
21 words
The oxygen transport system of Claim 2, wherein said outer aqueous phase is a saline solution buffered to about pH 7.4.
Claim 5
Dependent Claim
25 words
The oxygen transport system according to Claim 1, Claim 2 or Claim 3, wherein the hemoglobin in said inner_aqueous phase is essentially pure recrystallized hemoglobin.
Claim 6
Dependent Claim
31 words
The oxygen transport system according to Claim 4, wherein the oxygen transport action of said pure .hemoglobin is stabilized by the inclusion of a glycerate or phosphate in the inner phase.
Claim 7
Dependent Claim
22 words
The oxygen transport system according to Claim 4 or Claim 5, wherein said pure hemoglobin is stabilized by inclusion of an antioxidant.
Claim 8
Dependent Claim
37 words
The oxygen transport system according to any one of the preceding Claims, wherein the inner aqueous phase is buffered to a pH of about 7.4 and is rendered isoosmolar with blood plasma by the inclusion of carbohydrate.
Claim 9
Dependent Claim
30 words
The oxygen transport system according to any one of the preceding Claims, wherein said oil phase is a membrane separating the inner aqueous hemoglobin phase from the outer aqueous phase.
Claim 10
Dependent Claim
22 words
The oxygen transport system according to any one of the preceding Claims, wherein the lipids oil phase includes a mixture of lipids.
Claim 11
Dependent Claim
17 words
The oxygen transport system according to Claim 9, wherein an anti-oxidant is included in the lipid mixture.
Claim 12
Dependent Claim
16 words
A composition consisting of a lipid covalently bound to a carbohydrate to form a non-reducing carbohydrate.
Claim 13
Dependent Claim
16 words
A composition consisting of a lipid covalently bound to a carbohydrate to form a non-reducing carbohydrate.
Claim 14
Dependent Claim
23 words
The composition according to Claim 11 or the system according to any one of Claims 1 to 10, wherein the lipid-is-a phosphatidyl alkanolamine.
Claim 15
Dependent Claim
25 words
The composition according to Claim 11 or the system according to any one of Claims 1 to 10, wherein the lipid is a phosphatidyl ethanolamine.
Claim 16
Dependent Claim
24 words
The composition according to Claim 11 or the system according to any one of Claims 1 to 10, wherein the lipid contains phosphatidic acid.
Claim 17
Dependent Claim
40 words
The composition according to Claim 11 or the system according to any one of Claims 1 to 10, wherein the lipid is cholesterol, sucrose, insulin, malabiose, raffinose or dextran. of the carbohydrate with lipids already present in the formed OTS.
Claim 18
Dependent Claim
8 words
Example A-1 The preparation of raffinose- phosphatidylethanolamine (PE).
Claim 19
Dependent Claim
8 words
Example A-1 The preparation of raffinose- phosphatidylethanolamine (PE).
Claim 20
Dependent Claim
19 words
This procedure is based on the procedure of J. Van Zile et al. (J. Bio. Chem., 254(9), 3547-3553, 1979).
Claim 21
Dependent Claim
19 words
This procedure is based on the procedure of J. Van Zile et al. (J. Bio. Chem., 254(9), 3547-3553, 1979).
Claim 22
Dependent Claim
11 words
Raffinaldehyde is generated from raffinose (a galactose-sucrose trisaccharide) using galactose oxidase.
Claim 23
Dependent Claim
11 words
Raffinaldehyde is generated from raffinose (a galactose-sucrose trisaccharide) using galactose oxidase.
Claim 24
Dependent Claim
136 words
To a pH 7 solution of raffinose, 5 mol/ml, add 20 units/ml of galactose oxidase, 130 units of catalase and incubate at 37° for 4 hours. Then separate the raffinaldehyde and unreacted raffinose from the enzymes on a Sephadex column using distilled water as the eluant. The triose peak, collected from the column, is then freeze dried, and dissolved in tetrahydrofuran. For each mol of original raffinose, 0.3 mol of P E is added along with 0.3 mg of NaBH 3 CN (dilute and heat if precipitation occurs). Reaction is continued at 50° for 8 hours, and the reaction mixture is then reduced to dryness under vacuum (if unreacted PE 5%, repeat). The residue is then dissolved in minimum amount of warm methanol. The above reaction is a classical Shiff's base formation and reduction to give:
Claim 25
Dependent Claim
136 words
To a pH 7 solution of raffinose, 5 mol/ml, add 20 units/ml of galactose oxidase, 130 units of catalase and incubate at 37° for 4 hours. Then separate the raffinaldehyde and unreacted raffinose from the enzymes on a Sephadex column using distilled water as the eluant. The triose peak, collected from the column, is then freeze dried, and dissolved in tetrahydrofuran. For each mol of original raffinose, 0.3 mol of P E is added along with 0.3 mg of NaBH 3 CN (dilute and heat if precipitation occurs). Reaction is continued at 50° for 8 hours, and the reaction mixture is then reduced to dryness under vacuum (if unreacted PE 5%, repeat). The residue is then dissolved in minimum amount of warm methanol. The above reaction is a classical Shiff's base formation and reduction to give:
Claim 26
Dependent Claim
22 words
The PE-raffinose lipid is then available to mix with the other oil phase lipids to form the OTS membrane as previously described.
Claim 27
Dependent Claim
22 words
The PE-raffinose lipid is then available to mix with the other oil phase lipids to form the OTS membrane as previously described.
Claim 28
Dependent Claim
25 words
PE-malabiose may be obtained in essentially the,same way by simply substituting glucose oxidase for galactose oxidase in the above procedure. Malabiose is a glucose-sucrose trisaccharide.
Claim 29
Dependent Claim
25 words
PE-malabiose may be obtained in essentially the,same way by simply substituting glucose oxidase for galactose oxidase in the above procedure. Malabiose is a glucose-sucrose trisaccharide.
Claim 30
Dependent Claim
9 words
Example A2 - The preparation of sucrose - PE.
Claim 31
Dependent Claim
9 words
Example A2 - The preparation of sucrose - PE.
Claim 32
Dependent Claim
16 words
This synthesis is based en standard synthetic procedures and is outlined below: to prepare compound (II):
Claim 33
Dependent Claim
16 words
This synthesis is based en standard synthetic procedures and is outlined below: to prepare compound (II):
Claim 34
Dependent Claim
19 words
The PE-sucrose reaction product is then incorporated into the OTS along with the other lipid components as noted above.
Claim 35
Dependent Claim
19 words
The PE-sucrose reaction product is then incorporated into the OTS along with the other lipid components as noted above.
Claim 36
Dependent Claim
14 words
Example Bl - The preparation of PE-inulin in situ in the OTS oil phase.
Claim 37
Dependent Claim
14 words
Example Bl - The preparation of PE-inulin in situ in the OTS oil phase.
Claim 38
Dependent Claim
182 words
A saturated solution of insulin is prepared at pH 5.0, 0.15M acetate buffer. 10 ml of a 0.1M NaIO 4 (pH 5.0) solution is added to each 100 ml of inulin solution and allowed to react for one hour in the dark. The mixture is then dialyzed for two hours against, or against an excess of, the reducing solution, which consists of 20 mM H 3 BO 3 , 20 mM Na 2 B 4 O 7 and 100 mM NaCl adjusted to pH 8.5. After dialysis this solution is mixed, ml for ml, with the preformed OTS solution, where the OTS membrane contains a specific amount of phosphatidyl ethanolamine as the substrate for subsequent carbohydrate reaction, and where the lipid concentration has been adjusted to 10 m mol/L in pH=8.5 borate buffer. After 12 hrs. at 20° NaBH 3 is added to produce final concentration of 0.3g/L. After 1 hr. the OTS is separated by centrifugation and washed twice with isotonic phosphate (pH 7.4) buffer. This procedure attaches partially oxidized inulin to 10 to 50% of the oil phase surface PE.
Claim 39
Dependent Claim
182 words
A saturated solution of insulin is prepared at pH 5.0, 0.15M acetate buffer. 10 ml of a 0.1M NaIO 4 (pH 5.0) solution is added to each 100 ml of inulin solution and allowed to react for one hour in the dark. The mixture is then dialyzed for two hours against, or against an excess of, the reducing solution, which consists of 20 mM H 3 BO 3 , 20 mM Na 2 B 4 O 7 and 100 mM NaCl adjusted to pH 8.5. After dialysis this solution is mixed, ml for ml, with the preformed OTS solution, where the OTS membrane contains a specific amount of phosphatidyl ethanolamine as the substrate for subsequent carbohydrate reaction, and where the lipid concentration has been adjusted to 10 m mol/L in pH=8.5 borate buffer. After 12 hrs. at 20° NaBH 3 is added to produce final concentration of 0.3g/L. After 1 hr. the OTS is separated by centrifugation and washed twice with isotonic phosphate (pH 7.4) buffer. This procedure attaches partially oxidized inulin to 10 to 50% of the oil phase surface PE.
References Cited (Backward Citations)
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