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Heparin-modified adriamycin liposome preparation and preparation method thereof

A technology of liposome preparation and doxorubicin lipid, which is applied in the field of pharmaceutical preparations, can solve the problems of clinical application limitations of toxic side effects, dose-dependent cardiotoxicity, and damage to myocardial cells, so as to improve bioavailability, prolong half-life in vivo, The effect of improving compliance

Inactive Publication Date: 2014-04-16
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, while doxorubicin plays a therapeutic role, it also produces many side effects such as vomiting, nausea, hair loss, bone marrow suppression and gastrointestinal toxicity.
In addition, because the affinity of doxorubicin compounds to the myocardium is significantly higher than that of other tissues, and can produce semiquinone metabolites to damage cardiomyocytes, resulting in severe dose-dependent cardiotoxicity, manifested as various arrhythmias, and even Irreversible myocardial damage and congestive heart failure
These toxic and side effects have greatly limited its clinical application.

Method used

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  • Heparin-modified adriamycin liposome preparation and preparation method thereof
  • Heparin-modified adriamycin liposome preparation and preparation method thereof
  • Heparin-modified adriamycin liposome preparation and preparation method thereof

Examples

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Embodiment 1

[0058] Weigh 10 mg of soybean lecithin, 1 mg of cholesterol, and 0.5 mg of dioctadecyldimethylammonium bromide respectively in prescription quantities and place them in an eggplant-shaped bottle, add an appropriate amount of dichloromethane, and ultrasonically dissolve them completely; rotary vacuum evaporation The organic solvent was removed to form a dry and uniform lipid film on the bottle wall. Add 1 mL of 300 mmol / L ammonium sulfate solution to wash the membrane, and hydrate at 37°C for 1 hour to form a liposome primary emulsion. Probe ultrasound (200W, 100 times) to obtain blank liposomes. The above blank liposomes were dialyzed in 10% sucrose solution for 3 hours (change the dialysate every 1 hour), then add adriamycin solution (1 mg / mL), and incubate in a water bath at 60°C for 30 minutes to obtain DOX-Lip. Take the DOX-Lip solution and incubate with an equal volume of enoxaparin solution (4mg / mL) for 30min at 25°C. Remove free heparin by ultrafiltration to obtain He...

Embodiment 2

[0065] Weigh 15 mg of soybean lecithin, 2 mg of cholesterol, and 0.5 mg of stearylamine in prescription quantities and place them in an eggplant-shaped bottle, add an appropriate amount of chloroform, and ultrasonically dissolve them completely; rotary vacuum evaporation removes the organic solvent, and forms a dry Uniform lipid film. Add 1 mL of 300 mmol / L ammonium sulfate solution to wash the membrane, and hydrate at 37°C for 1 hour to form a liposome primary emulsion. Probe ultrasound (200W, 100 times) to obtain blank liposomes. The above blank liposomes were dialyzed in 10% glucose solution for 3 hours (change the dialysate every 1 hour), then add adriamycin solution (1 mg / mL), and incubate in a water bath at 60°C for 30 minutes to obtain DOX-Lip. Take the DOX-Lip solution and incubate with an equal volume of unfractionated heparin solution (4mg / mL) for 30min at 25°C. Remove free heparin by ultrafiltration to obtain Hep-DOX-Lip suspension. Then add an appropriate amount...

Embodiment 3

[0068] Weigh 20 mg of soybean lecithin, 1.5 mg of cholesterol, and 0.5 mg of trimethylhexadecyl ammonium bromide respectively in prescription quantities and place them in an eggplant-shaped bottle, add an appropriate amount of methanol, and ultrasonically dissolve them completely; Solvent, forming a dry and uniform lipid film on the bottle wall. Add 1 mL of 300 mmol / L ammonium sulfate solution to wash the membrane, and hydrate at 37°C for 1 hour to form a liposome primary emulsion. Probe ultrasound (200W, 100 times) to obtain blank liposomes. The above blank liposomes were dialyzed in 10% lactose solution for 3 hours (change the dialysate every 1 hour), then add adriamycin solution (1 mg / mL), and incubate in a water bath at 60°C for 30 minutes to obtain DOX-Lip. Take the DOX-Lip solution and incubate with an equal volume of dalteparin sodium solution (4mg / mL) for 30min at 25°C. Remove free heparin by ultrafiltration to obtain Hep-DOX-Lip suspension. Then add an appropriate ...

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Abstract

The invention relates to the field of medicinal preparations, and in particular relates to a heparin-modified adriamycin liposome (Hep-DOX-Lip) preparation. The preparation is characterized by consisting of 1 part of adriamycin, 1-4 parts of heparin, 5-30 parts of soybean lecithin, 0.5-4 parts of cholesterol and 0.5 part of a cationic material. The invention further discloses a preparation method of the heparin-modified adriamycin liposome preparation. The heparin-modified adriamycin liposome preparation has an effect similar to pegylation, and can remarkably enhance the stability of an adriamycin liposome, prolong the in-vivo half-life period of a medicament, and enhance the bioavailability of the medicament. Meanwhile, the heparin-modified adriamycin liposome preparation can remarkably lower the toxic and side effects of chemotherapeutic drugs and enhance the compliance of patients.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to a heparin-modified doxorubicin liposome (Hep-DOX-Lip) preparation, and also discloses a preparation method of the Hep-DOX-Lip preparation. Background technique [0002] Heparin (Hep) is an acidic mucopolysaccharide, which has been proved to be safe, extensive and effective in preventing venous thrombosis complicated by cancer. The researchers were also excited to discover that adjuvant treatment with heparin can significantly prolong the lifespan of patients with malignant tumors. Therefore, heparin is not only a clinically available antithrombotic drug, but other biological activities of heparin make it have wider application value. For example: A large number of animal experiments have confirmed that heparin can inhibit the metastasis of tumor cells by inhibiting the intercellular adhesion mediated by selectin. Heparin can also promote the release of tissue factor p...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K9/19A61K47/28A61K47/24A61K47/36A61K31/704A61P35/00A61P35/02
Inventor 柯学陈艺韩苗苗胡丹蓉鞠明珠
Owner CHINA PHARM UNIV
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