Preparation and application of dual-sensitivity amphiphilic polysaccharide-doxorubicin conjugate and pharmaceutical composition thereof

A technology of amphiphilic polysaccharides and doxorubicin, which can be used in drug combinations, medical preparations containing active ingredients, medical preparations containing active ingredients, etc., which can solve poor oral absorption and maintain effective blood drug concentration for a short time , rapid metabolism in the body, etc.

Active Publication Date: 2016-07-06
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the clinical treatment of cancer mainly relies on medicinal chemistry, but most of the antineoplastic drugs are water-insoluble compounds, which have the following disadvantages: poor oral absorption, low bioavailability, fast metabolism in the body, and time to maintain effective blood drug concentration shorter etc.
The dual-sensitive amphiphilic polysaccharide-doxorubicin conjugate formed by introducing hydrophobic groups through linking arms containing disulfide bonds and hydrazone bonds has no literature or patent reports.

Method used

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  • Preparation and application of dual-sensitivity amphiphilic polysaccharide-doxorubicin conjugate and pharmaceutical composition thereof
  • Preparation and application of dual-sensitivity amphiphilic polysaccharide-doxorubicin conjugate and pharmaceutical composition thereof
  • Preparation and application of dual-sensitivity amphiphilic polysaccharide-doxorubicin conjugate and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: Preparation of Hyaluronic Acid-Cystamine-Adriamycin Conjugate

[0054] 0.1mmol hyaluronic acid, 1mmol cystamine, 0.2mmol EDC and 0.2mmol NHS were dissolved in formamide, and the reaction

[0055] After 24h, use excess acetone to precipitate and filter with suction. The precipitate was reconstituted by adding water, dialyzed with distilled water for 3 days (MWCO=3500), and freeze-dried to obtain a product containing disulfide bonds.

[0056] 0.1 mmol of the product from the previous step, 1 mmol of methyl acrylate and 0.2 mmol of triethylamine were dissolved in an appropriate amount of formamide and methanol mixed solvent, and after 24 hours of reaction, precipitated with excess cold acetone, and filtered with suction. Add water to redissolve the precipitate and dialyze with distilled water for 3 days (MWCO=3500), freeze-dry the obtained product and react it with an appropriate volume of hydrazine hydrate for 24 hours, spin evaporate at 50°C to remove excess ...

Embodiment 2

[0058] Example 2: Preparation of Chondroitin Sulfate-Cystamine-Adriamycin Conjugate

[0059] 0.1mmol of chondroitin sulfate, 1mmol of cystamine, 0.4mmol of EDC and 0.4mmol of NHS were dissolved in formamide, reacted for 24h, precipitated with excess acetone, and filtered with suction. The precipitate was reconstituted by adding water, dialyzed with distilled water for 3 days (MWCO=3500), and freeze-dried to obtain a product containing disulfide bonds.

[0060] 0.1 mmol of the product from the previous step, 1 mmol of methyl acrylate and 0.2 mmol of triethylamine were dissolved in an appropriate amount of formamide and methanol mixed solvent, and after 24 hours of reaction, precipitated with excess cold acetone, and filtered with suction. Add water to redissolve the precipitate and dialyze with distilled water for 3 days (MWCO=3500), freeze-dry the obtained product and react it with an appropriate volume of hydrazine hydrate for 24 hours, spin evaporate excess hydrazine hydrate...

Embodiment 3

[0062] Example 3: Preparation of Heparin-Cystamine-Adriamycin Conjugate

[0063] 0.1mmol heparin, 1mmol cystamine, 0.2mmol EDC and 0.2mmol NHS were dissolved in formamide, reacted for 24h, precipitated with excess acetone, and filtered with suction. The precipitate was reconstituted by adding water, dialyzed with distilled water for 3 days (MWCO=3500), and freeze-dried to obtain a product containing disulfide bonds.

[0064] 0.1 mmol of the product from the previous step, 1 mmol of methyl acrylate and 0.2 mmol of triethylamine were dissolved in an appropriate amount of formamide and methanol mixed solvent, and after 24 hours of reaction, precipitated with excess cold acetone, and filtered with suction. Add water to redissolve the precipitate and dialyze with distilled water for 3 days (MWCO=3500), freeze-dry the obtained product and react it with an appropriate volume of hydrazine hydrate for 24 hours, spin evaporate excess hydrazine hydrate at 50°C, dialyze with distilled wat...

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Abstract

The invention relates to a dual-sensitivity amphiphilic polysaccharide-doxorubicin conjugate.According to the conjugate, hydrophobic antitumor drug doxorubicin is introduced in a polysaccharide framework through a connecting arm containing a disulfide bond and a hydrazone bond, so that the polysaccharide-doxorubicin conjugate has an amphiphilic property, can be self-assembled into a nano-micelle in water and directly used for tumor treatment, and can also be physically loaded with an antitumor drug to be used for antitumor treatment.The conjugate is mainly characterized in that after the nano-micelle reaches a focus, the disulfide bond in the connecting arm can be degraded specifically by high-concentration reduction substances in focus cells, and meanwhile the hydrazone bond in the connecting arm can be degraded in a special pH environment of the focus, so that the micelle is degraded, the drug is quickly released, and the treatment effect is improved; the antitumor drug is loaded in two modes of chemical conjugation and physical package, and therefore the joint treatment effect is achieved.The polysaccharide conjugate and a pharmaceutical composition can be used for injection or oral administration or external administration, can remarkably improve antitumor activity, and provides a new thought for development of the antitumor drug.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a dual-sensitive amphiphilic polysaccharide-doxorubicin conjugate as a drug carrier, and also relates to a preparation method and application of the carrier. Background technique [0002] Cancer ranks among the leading causes of morbidity and mortality worldwide, and statistics from the World Health Organization show that there were approximately 14 million new cancer cases and 8.2 million cancer-related deaths in 2012. The number of new cases is expected to increase by approximately 70% over the next two decades. [0003] At present, the clinical treatment of cancer mainly relies on medicinal chemistry, but most of the antineoplastic drugs are water-insoluble compounds, which have the following disadvantages: poor oral absorption, low bioavailability, fast metabolism in the body, and time to maintain effective blood drug concentration shorter etc. At present, the solub...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K9/107A61K47/36A61K31/704A61P35/00
CPCA61K9/1075A61K31/704A61K47/36
Inventor 霍美蓉周建平汪艳艳
Owner CHINA PHARM UNIV
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