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High-temperature stable oxygen-carrier-containing pharmaceutical composition

A technology of high temperature stability and composition, applied in the directions of drug combination, pharmaceutical formulation, chemical instrument and method, etc., can solve the problem of unacceptable high percentage of dimer units, vasoconstriction, and unsatisfactory administration of hemoglobin composition to breastfeeding animals, etc.

Active Publication Date: 2012-04-04
FIRST GAIN INT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Further problems with prior art attempts to stabilize hemoglobin include: tetrameric hemoglobin produced contains an unacceptably high percentage of dimer units; the presence of dimers makes the hemoglobin composition unsatisfactory administered to mammals
[0008] Further problems with prior art attempts to form stable hemoglobin include: the presence of protein impurities such as immunoglobulin G can lead to allergic effects in mammals
[0009] Other problems with prior art hemoglobin preparations include: Vasoconstriction after infusion in mammals

Method used

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  • High-temperature stable oxygen-carrier-containing pharmaceutical composition
  • High-temperature stable oxygen-carrier-containing pharmaceutical composition
  • High-temperature stable oxygen-carrier-containing pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] total process

[0068] A schematic flow diagram of the method of the present invention is shown in figure 2 middle. Bovine whole blood was collected in closed sterile containers / bags containing 3.8% (w / v) sodium citrate solution as anticoagulant. The blood is then immediately mixed well with a sodium citrate solution to inhibit clots. Red blood cells (RBCs) are separated and collected from plasma and other smaller blood cells by an apheresis mechanism. A "cell washer" was used with a gamma sterilized disposable centrifuge bowl for this step. RBCs were washed with an equal volume of 0.9% (w / v sodium chloride) saline.

[0069] Hypotonic shock to the cell membrane of red blood cells to lyse washed red blood cells to release the hemoglobin contents. image 3 An RBC-specific rapid cell lysis device was drawn for this purpose. After RBC lysis, hemoglobin molecules were separated from other proteins by tangential flow ultrafiltration using a 100 kDa membrane. Hemoglobi...

Embodiment 2

[0072] Timed & Controlled Hypotonic Lysis and Filtration

[0073] Whole bovine blood is collected fresh and shipped refrigerated. Red blood cells were separated from plasma by a cell washer followed by 0.65 μm filtration. After washing the red blood cell (RBC) filtrate with 0.9% saline, the filtrate was disrupted by hypotonic lysis. by using image 3 The rapid cell lysis device drawn in the paper for hypotonic lysis. The rapid cell lysis device includes a static mixer to aid in cell lysis. An RBC suspension containing a controlled concentration of hemoglobin (in the range of 12-14 g / dL) was mixed with 4 volumes of purified water to hypotonically impact the RBC cell membrane. The timing of the hypotonic shock is controlled to avoid undesired lysis of leukocytes and platelets. The hypotonic solution was passed through the static mixer section of the rapid cell lysis device for about 30 seconds. The shock was terminated after 30 seconds as the lysate exited the static mixer...

Embodiment 3

[0076] Virus clearance studies on stroma-free hemoglobin solutions

[0077] In order to demonstrate the safety of the product described in the present invention, we demonstrated the virus clearance capacity of (1) 0.65 μm diafiltration step and (2) 100 kDa ultrafiltration step through virus validation studies. We implemented both methods with scaled-down small-scale reaction systems to which different model viruses were artificially added, such as encephalomyocarditis virus, pseudorabies virus, bovine viral diarrhea virus (bovine viral diarrhea virus) and bovine parvovirus (bovine parvovirus). Four types of viruses were used in this study, see Table 2 below. These viruses differ in their biophysical and structural characteristics and in their resistance to physical and chemical agents or treatments.

[0078] Table 2

[0079]

[0080] The virus validation scheme is briefly shown in Table 3 below.

[0081] table 3

[0082]

[0083] Table 4 below summarizes the logarit...

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Abstract

A high temperature-stable and highly purified cross-linked (optionally > 70% ss-ss linked) tetrameric hemoglobin with high efficiency of oxygen delivery suitable for use in mammals without causing renal injury and vasoconstriction is provided. The dimeric form of hemoglobin is degenerated and purification processes are performed on red blood cells from whole blood. Controlled hypotonic lysis in an instant cytolysis apparatus prevents lysis of white blood cells. Nucleic acids from white blood cells and phospholipids impurities are not detected. Blocking of reactive sulfhydryl groups by a sulfhydryl reagent is performed in an oxygenated environment. Flowthrough column chromatography removes different plasma protein impurities. N-acetyl cysteine is added to the cross-linked tetrameric hemoglobin to maintain a low level of met-hemoglobin. The stabilized hemoglobin is preserved in an infusion bag with aluminum overwrap to prevent formation of inactive met-hemoglobin from oxygen intrusion. The product finds use in tissue oxygenation and cancer treatment.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Patent Application Serial No. 61 / 348,764, filed May 27, 2010, and U.S. Patent Application Serial No. 13 / 013,847, filed January 26, 2011 and U.S. Parts filed April 11, 2011 Continuing on the priority of patent application serial number 13 / 083,639, the disclosure of which application is incorporated by reference. technical field [0003] The present invention relates to a method for preparing a high-temperature stable oxygen carrier-containing pharmaceutical composition and the composition prepared by the method. The present invention also relates to the use of said high temperature stable oxygen carrier pharmaceutical composition in cancer treatment, oxygen-deprivation disorder and organ preservation in humans and other animals. Background technique [0004] Hemoglobin plays an important role in the vasculature and gas exchange between tissues in most vertebrates. It is respons...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/14
CPCC07K14/805A61P35/00A61P35/02A61P39/00A61P7/00A61P7/06A61P7/08A61P9/10A61K38/42A61K47/08A61K35/12
Inventor 黄炳镠郭瑞仪
Owner FIRST GAIN INT
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