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Hyaluronic acid-adriamycin bonding medicine and preparation method thereof

A technology of hyaluronic acid and doxorubicin hydrochloride, which is used in pharmaceutical formulations, anti-infective drugs, anti-tumor drugs, etc., can solve the problems of lack of doxorubicin release, poor biocompatibility, and low drug loading, and achieve good Biological activity and biocompatibility, stable performance, enhanced efficacy

Active Publication Date: 2014-03-26
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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Problems solved by technology

[0004] The Chinese patent whose publication number is CN102406946A discloses a kind of macromolecular bonded drug, first, polyethylene glycol monomethyl ether, carboxylated doxorubicin derivatives, 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride and N-hydroxysuccinimide react in an organic solvent to obtain a reaction mixture, and then add poly (L-lysine) or chitosan to the reaction mixture to obtain Polymer doxorubicin-bonded drug; Chinese patent publication No. 101234205A discloses a polymer doxorubicin-bonded drug with targeting function, which is assembled by mixing two polyethylene glycol-polylactic acid block copolymers The polylactic acid chain end of the first polyethylene glycol-polylactic acid block copolymer is connected with doxorubicin, and the polyethylene glycol chain end of the second polyethylene glycol-polylactic acid block copolymer is connected with There is lactose, which has a sustained release function; lactose has a targeting function, which can realize the targeted delivery of doxorubicin, so the doxorubicin-bonded drug can be released slowly in tumor tissue; however, the above two bonded drugs are due to The chemical bond between the bonded polymer compound and the drug molecule is too stable, so there are problems such as low drug loading and lack of intelligence in the release of doxorubicin
Biomaterials (Vol.31, p1360-1371, 2010) disclosed a carboxyl group modified by polyethylene glycol monomethyl ether and cis-3-carboxyglutaconic anhydride on the surface amino groups of polyamide-amine dendrimers The polymer doxorubicin-bonded drug obtained by doxorubicin can be quickly released under the acidic conditions of tumor tissues and cells, thereby realizing the intelligence of drug release, but the carrier used in the bonded drug The material is a polyamide-amine dendrimer, and its preparation process is cumbersome and its biocompatibility is poor, which is not conducive to the practical application of the bonded drug.

Method used

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  • Hyaluronic acid-adriamycin bonding medicine and preparation method thereof
  • Hyaluronic acid-adriamycin bonding medicine and preparation method thereof
  • Hyaluronic acid-adriamycin bonding medicine and preparation method thereof

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preparation example Construction

[0030] The present invention also provides a preparation method of a hyaluronic acid-doxorubicin bonded drug, comprising:

[0031] mixing and reacting the buffer solution in which doxorubicin hydrochloride is dissolved with hyaluronic acid to obtain a hyaluronic acid-doxorubicin bonded drug having a structure of formula (I);

[0032] Alternatively, the buffer solution in which doxorubicin hydrochloride is dissolved is mixed with hyaluronic acid and sodium cyanoborohydride and reacted to obtain a hyaluronic acid-doxorubicin bonded drug having a structure of formula (II).

[0033] The hyaluronic acid-doxorubicin bonded drug with the structure of formula (I) is prepared according to the following method:

[0034] First, doxorubicin hydrochloride is dissolved in a buffer solution to obtain a mixed solution; the doxorubicin hydrochloride has the structure shown in formula (III):

[0035]

[0036] The buffer solution is preferably an acetate buffer solution, specifically a sodiu...

Embodiment 1～8

[0055] Prepare an acetate buffer solution with pH=5, take 5 mL of the prepared buffer solution and place them in 8 round-bottomed flasks respectively, add 0.05 g of doxorubicin hydrochloride to each flask, stir and dissolve in the dark, and then According to the dosage ratio in Table 1, add hyaluronic acid and sodium cyanoborohydride to each flask, the number average molecular weight of the hyaluronic acid is 2483g.mol -1 , then seal each reaction bottle, according to the reaction conditions in Table 1, react in the dark for 52h, after the reaction, adjust the pH of each reaction solution to 7.4 with sodium bicarbonate solution, then use a dialysis bag with a molecular weight cut-off of 7000Dalton for dialysis for 48h, filter Freeze-dried to obtain hyaluronic acid-doxorubicin bonded drug respectively, the experimental results are shown in Table 1, Table 1 is the reaction conditions and yields of the hyaluronic acid-doxorubicin bonded drug prepared in Examples 1-8 of the present...

Embodiment 9～16

[0061] Prepare an acetate buffer solution with pH=5, take 5 mL of the prepared buffer solution and place them in 8 round-bottomed flasks respectively, add doxorubicin hydrochloride to each flask according to the ratio in Table 2, and keep away from light. After stirring and dissolving, add hyaluronic acid and sodium cyanoborohydride to each flask according to the dosage ratio in Table 2, the number average molecular weight of the hyaluronic acid is 2483g.mol -1 , then seal each reaction bottle, and react in the dark at 40°C for 52h. After the reaction, adjust the pH of each reaction solution to 7.4 with sodium bicarbonate solution, then dialyze with a dialysis bag with a molecular weight cut-off of 7000Dalton for 48h, filter and freeze-dry to obtain Hyaluronic acid-doxorubicin conjugated drug, the experimental results are shown in Table 2, Table 2 is the reaction conditions and yields of the hyaluronic acid-doxorubicin conjugated drug prepared in Examples 9-16 of the present in...

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Abstract

The invention provides a hyaluronic acid-adriamycin bonding medicine which has the structure shown in formula (I) or formula (II) in the Specification, wherein n refers to the polymerization degree of hyaluronic acid, and is not less than 1 and not greater than 1290. According to the invention, hyaluronic acid, sodium cyanoborohydride and adriamycin are used as raw materials to prepare the hyaluronic acid-adriamycin bonding medicine; as the hyaluronic acid used as the raw material has excellent biological activity and biocompatibility, the prepared hyaluronic acid-adriamycin bonding medicine has excellent biological activity and biocompatibility; in addition, the hyaluronic acid and the adriamycin are connected through oxime bonds, and can be quickly released in the tumor tissue or cells with lower pH value, so that the efficacy of the hyaluronic acid-adriamycin bonding medicine is improved; the reduced hyaluronic acid-adriamycin bonding medicine which has the structure shown in the formula (II) in the Specification further has more stable performance, and the adriamycin is released more slowly, so that the ideal long-acting treatment is realized.

Description

technical field [0001] The invention relates to the technical field of chemically bonded drugs, in particular to a hyaluronic acid-doxorubicin bonded drug and a preparation method thereof. Background technique [0002] Doxorubicin, also known as 1,4-hydroxydaunorubicin, 1,4-hydroxydaunomycin, doxorubicin, hydroxyerythrobimycin, is an anthracycline antibiotic with high efficiency and broad-spectrum anti-tumor The drug is a cell cycle non-specific drug and has the strongest effect on the S phase. It mainly inserts into the DNA of the cell, thereby triggering topoisomerase II to destroy the tertiary structure of the DNA to exert its drug effect. So far, doxorubicin has been considered as a powerful clinical chemotherapy drug, mainly for the treatment of solid tumors such as liver cancer, lung cancer, gastric cancer, breast cancer, ovarian cancer, bladder cancer, and thyroid cancer. [0003] At present, clinical chemotherapy of doxorubicin mainly exerts its drug effect through ...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/704A61P35/00A61P31/00
Inventor 丁建勋许维国庄秀丽陈学思
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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