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Method for extending in vivo half life of protein medicine by making red cell as carrier

A protein and red blood cell technology, applied in peptide/protein components, drug combinations, pharmaceutical formulations, etc., can solve problems such as re-embolization and bleeding, and achieve the effects of preventing side effects, reducing side effects, and prolonging the action time

Inactive Publication Date: 2005-06-22
SHANGHAI FUCHUN ZHONGNAN BIOTECH
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  • Summary
  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

However, reactions such as bleeding and re-embolization often occur after thrombolysis

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 Preparation of hirudin and erythrocyte complex

[0038] 1.1 Biotin labeling of red blood cells

[0039] Whole blood was drawn, anticoagulated with heparin, and then centrifuged to collect red blood cells, washed three times with pH 7.4 phosphate buffer (PBS, 125mM NaCl+20mM PB), and suspended in PBS-G (PBS+5mMglucose) according to 10% red blood cell volume. Dissolve NHS-biotin at 200mg / ml in 90% DMSO, then add 0.055mg of NHS-biotin per milliliter of red blood cells, mix well, keep warm at 37°C for 1 hour, and then wash three times with PBS to obtain labeled red blood cells.

[0040] 1.2 Biotin labeling of hirudin

[0041] Make NHS-Biotin into a 1mg / ml solution with DMF, and then use 0.1M, pH 9.0NaHCO 3 Dilute the hirudin to 1 mg / ml. Mix NHS-Biotin and hirudin at a weight ratio of about 1:7, react for 4 hours under stirring at room temperature, put into a dialysis bag, and dialyze against 0.05M pH 7.2 PBS overnight at 4°C to remove unreacted NHS-biotin.

[...

Embodiment 2

[0047] Example 2 Preparation of hirudin and erythrocyte complex

[0048] 2.1 Biotin labeling of red blood cells

[0049] Same as step 1.1 of Example 1.

[0050] 2.2 Streptavidin labeling of hirudin

[0051] Dissolve the frozen hirudin in 0.1M pH 6.8 PB buffer solution containing 1.25% glutaraldehyde, the final concentration is 10 mg / ml, and react overnight at room temperature; put it into a dialysis bag, and dialyze against 0.05M pH 7.2 PBS at 4°C 12 hours; remove dialysate, add 15 mg streptavidin and 0.5 ml 1M pH 9.5 Na per ml hirudin solution 2 CO 3 , combined at 4°C for 24 hours; 50ul 0.2M lysine was added for 2 hours at room temperature to terminate the reaction; put into a dialysis bag, and dialyze against 0.05M pH 7.2 PBS overnight at 4°C. Macromolecular polymers were removed by centrifugation to obtain streptavidin-labeled hirudin.

[0052] 2.3 Formation of hirudin-erythrocyte complex

[0053] Mix biotinylated erythrocytes with streptavidin-labeled hirudin (calcul...

Embodiment 3

[0056] Example 3 Comparison of half-life in vivo between hirudin-erythrocyte complexes and individual hirudin

[0057] Take 30 New Zealand rabbits, divide them into six groups, inject hirudin or hirudin-erythrocyte complex intravenously, and the dosage (calculated according to the protein weight of hirudin) is divided into high (0.4 mg / kg), medium (0.2 mg / kg) , low (0.1 mg / kg) three groups, and then 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours after injection Blood was collected, and then the concentration of hirudin was detected by sandwich ELISA. The obtained data was calculated with P87 software for T1 / 2 (the α phase was not calculated, only the β phase was calculated). The results showed that the half-life of hirudin was greatly extended after fusion with red blood cells.

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Abstract

The invention provides a method for extending in vivo half life of protein medicine by making red cell as carrier, which can not only extend the half life of protein medicine, but also reduce medicament consumption, prevent medicament from diffusing to outside the blood vessel, thus reduce the side effects of the medicine. The invention also relates to a protein medicament-erythrocyte compound, the protein medicine employs erythrocyte as carrier to be transferred in vivo.

Description

technical field [0001] The invention relates to a method for prolonging the half-life of protein medicine by using red blood cells as carriers. Background technique [0002] In recent years, due to the popularization and application of genetic engineering, the clinical application of protein drugs (including the treatment of cardiovascular diseases) has become more and more extensive. However, due to their physical and chemical properties, most protein drugs are not stable, and their half-life in the body is very short. Many drugs need to be administered every day. At the same time, due to the presence of proteases in the digestive tract, protein drugs are difficult to be administered orally, and continuous infusion or continuous injection will bring mental and physical torture to patients. Therefore, more and more research institutions are concentrating on the formulation research of protein drugs, mainly long-acting drugs and oral and spray ad...

Claims

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Application Information

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IPC IPC(8): A61K38/43A61K38/58A61K47/54A61P9/00
Inventor 倪健杨子义杨武剑
Owner SHANGHAI FUCHUN ZHONGNAN BIOTECH
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