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Method for the preparation of a heat stable oxygen carrier-containing composition facilating beta-beta cross-linking

a technology of oxygen carrier and composition, which is applied in the field of preparation of heat stable oxygen carrier-containing pharmaceutical composition, can solve the problems of affecting the sustainability of functional hemoglobin in circulation, affecting the stability of plasma hemoglobin, and substantial renal injury

Inactive Publication Date: 2013-02-28
BILLION KING INT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a process for creating a stable and crosslinked hemoglobin molecule that can be used as an oxygen carrier for various applications. The process involves using a specific chemical called bis-3,5-dibromosalicyl fumarate to crosslink the hemoglobin molecule. This results in a tetrameric hemoglobin molecule with a controlled oxygen affinity and no formation of polymeric hemoglobin. The crosslinked hemoglobin is then heat-treated to remove any non-crosslinked hemoglobin and impurities, and stabilized with the addition of N-acetyl cysteine. The resulting stabilized hemoglobin is formulated and packaged to prevent oxygen contamination. The technical effects of this patent are the creation of a stable and highly effective oxygen carrier that can be tailored for specific applications.

Problems solved by technology

However, when naturally-occurring hemoglobin is removed from red blood cells, it becomes unstable in plasma and splits into two α-β dimers.
These dimers may cause substantial renal injury when filtered through the kidneys and excreted.
The breakdown of the tetramer linkage also negatively impacts the sustainability of the functional hemoglobin in circulation.
Met-hemoglobin cannot bind oxygen and therefore cannot oxygenate tissue.
Therefore, the cross-linking taught by the prior art that causes the formation of polymeric hemoglobin is a problem.
Further problems with the prior art attempts to stabilize hemoglobin include production of tetrameric hemoglobin that includes an unacceptably high percentage of dimer units (or non-crosslinked tetrameric hemoglobin that quickly dissociates to dimeric hemoglobin if administered to a patient); the presence of dimers makes the hemoglobin composition unsatisfactory for administration to mammals.
The dimeric form of the hemoglobin can cause severe renal injury in a mammalian body; this renal injury can be severe enough to cause death.
Another problem with prior art hemoglobin products is a sudden increase in blood pressure following administration.
Further problems with prior art attempts to create stable hemoglobin include the presence of protein impurities such as immunoglobin G that can cause allergic effects in mammals.

Method used

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  • Method for the preparation of a heat stable oxygen carrier-containing composition facilating beta-beta cross-linking
  • Method for the preparation of a heat stable oxygen carrier-containing composition facilating beta-beta cross-linking
  • Method for the preparation of a heat stable oxygen carrier-containing composition facilating beta-beta cross-linking

Examples

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Effect test

example 1

[0061]Process Overview

[0062]A schematic flow diagram of the process of the present invention is illustrated in FIG. 1. Bovine whole blood is collected into an enclosed sterile container / bag containing 3.8% (w / v) tri-sodium citrate solution as anti-coagulant. Blood is then immediately mixed well with tri-sodium citrate solution to inhibit blood clotting. Red blood cells (RBC) are isolated and collected from plasma and other smaller blood cells by an apheresis mechanism. A “cell washer” is used for this procedure with gamma sterilized disposable centrifuge bowl. RBC are washed with an equal volume of 0.9% (w / v sodium chloride) saline.

[0063]Washed RBC are lysed to release hemoglobin content by manipulating hypotonic shock to the RBC cell membrane. A specialized instant cytolysis apparatus for RBC lysis device depicted in FIG. 2 is used for this purpose. Following RBC lysis, hemoglobin molecules are isolated from other proteins by tangential-flow ultrafiltration using a 100 kDa membrane...

example 2

[0065]Time & Controlled Hypotonic Lysis and Filtration

[0066]Bovine whole blood is freshly collected and transported under a cool condition (2 to 10° C.). The red blood cells are separated from the plasma via a cell washer and subsequently with a 0.65 μm filtration. After washing the red blood cells (RBC) filtrate with 0.9% saline, the filtrate is disrupted by hypotonic lysis. The hypotonic lysis is performed by using the instant cytolysis apparatus depicted in FIG. 2. The instant cytolysis apparatus includes a static mixer to assist in cell lysis. A RBC suspension with controlled hemoglobin concentration (12-14 g / dL) is mixed with 4 volumes of purified water to generate a hypotonic shock to RBC cell membranes. The period of hypotonic shock is controlled to avoid unwanted lysis of white blood cells and platelets. The hypotonic solution passes through the static mixer portion of the instant cytolysis apparatus for 2 to 30 seconds or otherwise a time sufficient to lyse the red blood ce...

example 3

[0068]Viral Clearance Study on Stroma-Free Hemoglobin Solution

[0069]In order to demonstrate the safety of the product from this invention, the virus removal abilities of (1) 0.65 μm diafiltration step and (2) 100 kDa ultrafiltration step are demonstrated by virus validation study. This is done by the deliberate spiking of a down-scaled version of these two processes with different model viruses (encephalomyocarditis virus, pseudorabies virus, bovine viral diarrhea virus and bovine parvovirus). In this study, four types of viruses (see Table 3) are used. These viruses vary in their biophysical and structural features and they display a variation in resistance to physical and chemical agents or treatments.

TABLE 3TargetSizeVirusModel VirusTaxonomyGenomeStructure[nm]Stability*HepatitisBovine viral diarrheaFlaviviridaessRNAenveloped40-60lowC virusvirus (BVDV)—EncephalomyocarditisPicornavirusssRNAnon-25-30mediumvirus (EMCV)envelopedParvovirusBovine parvovirusParvoviridaessDNAnon-18-26very...

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Abstract

Methods for preparation of a heat stable hemoglobin based oxygen-carrier-containing pharmaceutical composition such that beta-beta cross-linking is favored are provided. Using the methods of the present invention, the oxygen affinity of the resultant molecule can be controlled so that hemoglobin based oxygen carriers tailored for specific applications can be produced. Lower oxygen affinity crosslinked hemoglobin is useful for applications requiring rapid tissue oxygenation (e.g. hemorrhagic shock) while higher oxygen affinity cross-linked hemoglobin is useful for applications requiring a slower rate of oxygenation (e.g. cancer adjunct therapy). A highly purified and heat stable crosslinked non-polymeric tetrameric hemoglobin having beta-beta cross-linking of greater than 40-60% and suitable for use in mammals without causing renal injury and vasoconstriction is produced. A high temperature and short time (HTST) heat processing step is performed to effectively remove any undesired dimeric hemoglobin, non-crosslinked tetrameric hemoglobin, and plasma protein impurities.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims priority to provisional U.S. Patent Application No. 61 / 529,279 filed Aug. 31, 2011, the disclosure of which is incorporated by reference herein.COPYRIGHT NOTICE / PERMISSION[0002]A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever. The following notice applies to the processes, experiments, and data as described below and in the drawings attached hereto: Copyright © 2011, Billion King International Limited, All Rights Reserved.TECHNICAL FIELD[0003]The present invention relates to methods for the preparation of a heat stable oxygen-carrier-containing pharmaceutical composition such that beta-beta cross-l...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/00C12N5/071A61P9/00A61K38/42
CPCA61K38/42A61P17/00A61P43/00A61P7/00A61P7/08A61P9/00A61K47/50A61K9/08A61K35/14A61K47/08
Inventor WONG, BING LOUKWOK, SUI YIBUTT, KWOK CHU
Owner BILLION KING INT
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