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Cisplatin complex and preparation method thereof

A complex, cisplatin technology, applied in pharmaceutical formulations, medical preparations with non-active ingredients, and medical preparations containing active ingredients, etc. It can avoid the sudden release of cisplatin, promote the release and improve the stability.

Active Publication Date: 2013-01-09
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For example, the micelles (NC-6004) prepared by Kataoka et al. using polyethylene glycol-b-polyglutamic acid complexed with cisplatin have entered the second phase of clinical research, but the micelles obtained are cross-linked between polyamino acid side chains. Formed, the lyophilized powder of the complex obtained by this method will be difficult to redissolve
Stenzel et al. used the "mercapto-alkynyl" and "mercapto-alkenyl" Click reactions to introduce thioglycolic acid and mercaptosuccinic acid into the polymer side chain to obtain a cisplatin complex (Biomacromolecules 12(5):1738-1751), The complex has good solubility, but the polymer used as the carrier has poor biocompatibility and cannot be degraded, thus limiting its further application

Method used

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  • Cisplatin complex and preparation method thereof
  • Cisplatin complex and preparation method thereof
  • Cisplatin complex and preparation method thereof

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preparation example Construction

[0068] The present invention also provides a preparation method of a cisplatin complex, which comprises the following steps: a complex reaction occurs between cisplatin and a polymer having the structure of formula (I) in an aqueous medium to generate a cisplatin complex;

[0069]

[0070] In formula (I), R 1 Independently selected from C2~C10 straight chain alkyl, C3~C10 branched chain alkyl, phenyl or R'-CO-, R' independently selected from C2~C10 straight chain alkyl, C3~C10 branched alkyl or phenyl, R 1 Preferably C3-C8 straight-chain alkyl, C4-C8 branched-chain alkyl, phenyl, more preferably C6 alkyl;

[0071] R 2 Independently selected from H atom, C1~C20 alkyl or substituted C1~C20 alkyl, preferably H atom, C1~C10 alkyl or substituted C1~C10 alkyl, the substituted alkyl The substituents are selected from one or more of ketal, aldol, hydroxyl, aldehyde, amino, sulfhydryl and sugar residues;

[0072] R 3 independently selected from H atoms or cations, preferably H ...

Embodiment 1

[0096] 10g of γ-benzyl-L-glutamic acid was added to 100ml of anhydrous tetrahydrofuran under the condition of dry inert gas, fully reacted under the action of 6.5g of triphosgene, then petroleum ether was added to settle to obtain a solid, weighing After crystallization and drying, 7.85g of γ-benzyl-L-glutamic acid-N-carboxylic anhydride (BLG-NCA) monomer was finally obtained; under the condition of inert gas, the dimethylformamide (DMF) of n-hexylamine Add the solution to the DMF solution of BLG-NCA, the ratio of n-hexylamine to γ-benzyl-L-glutamic acid-N-carboxylic acid anhydride (BLG-NCA) is 1:160, add ether to settle after reaction, and filter Obtain a solid, and after drying, obtain a glutamic acid copolymer with a benzyl protecting group with a degree of polymerization of 160; after deprotection, obtain a glutamic acid copolymer with a structure of formula (II) with a degree of polymerization of 160, denoted as P(Glu) 160 .

[0097] Add 1.010g of P(Glu) prepared above t...

Embodiment 2

[0100] 10g of γ-benzyl-L-glutamic acid was added to 100ml of anhydrous tetrahydrofuran under the condition of dry inert gas, fully reacted under the action of 6.5g of triphosgene, then petroleum ether was added to settle to obtain a solid, weighing After crystallization and drying, 7.34g of γ-benzyl-L-glutamic acid-N-carboxylic anhydride (BLG-NCA) monomer was finally obtained; under the condition of inert gas, the dimethylformamide (DMF) solution of n-hexylamine Added to the DMF solution of BLG-NCA, the mass ratio of n-hexylamine and γ-benzyl-L-glutamic acid-N-carboxylic acid anhydride (BLG-NCA) was 1:160, after the reaction, adding ether to settle, and filtered to obtain Solid, after drying, obtain a glutamic acid copolymer with a benzyl protecting group with a degree of polymerization of 160; after deprotection, obtain a glutamic acid copolymer with a structure of formula (II) with a degree of polymerization of 160, denoted as P(Glu) 160 .

[0101] Add the 1.012g P(Glu) pre...

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Abstract

The invention provides a cisplatin complex which is formed by complexing cisplatin with polymer with a structure as a formula (I), and further provides a preparation method of the cisplatin complex. The cisplatin and the polymer with the structure as the formula (I) are in complex reaction in aqueous media to generate the cisplatin complex. The cisplatin complex has fine biocompatibility and is degradable, and polyethylene glycol is grafted on a side chain of the polymer, so that the prepared cisplatin complex has fine dissolvability. When the cisplatin complex is dissolved in the aqueous media, the cisplatin is protected by a hydrophilic polyethylene glycol chain segment and a hydrophobic amino acid chain segment, and accordingly sudden release of cisplatin caused by influences of a blood circulation system after intravenous injection can be effectively avoided, and stability of the cisplatin complex is improved. In addition, carboxyl contained in the cisplatin complex has pH sensitivity and deprotonation tendency in a low-pH environment, medicine release is facilitated, and medicine curative effect can be improved.

Description

technical field [0001] The invention relates to the field of polymer medicine, in particular to a cisplatin complex and a preparation method thereof. Background technique [0002] Cisplatinum (cis-diamminedichloroplatinum, referred to as CDDP) is a metal complex with anticancer activity, which was first discovered by B. Rosenborg et al. in 1965. Cisplatin has the characteristics of broad anticancer spectrum, strong effect, synergistic effect with many antitumor drugs, and no cross-resistance. Therefore, cisplatin is one of the most commonly used drugs in combination chemotherapy. At present, cisplatin has a good effect on the treatment of reproductive system tumors, malignant lymphoma, head and neck cancer, bladder cancer, and lung cancer. Oral administration of cisplatin is ineffective, and the clinical application method is mostly in the form of intravenous infusion. After intravenous injection, cisplatin disappears rapidly in the plasma and quickly distributes throughout...

Claims

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Application Information

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IPC IPC(8): C08G81/00C08G69/48A61K47/48A61K33/24A61P35/00A61K33/243
CPCC08G69/10A61K47/48C08G69/40A61K47/48246C08L77/04A61K47/48215A61K33/24C08G81/00A61K47/60A61K47/64A61K47/645A61P35/00A61K33/243
Inventor 汤朝晖于海洋宋万通李明强庄秀丽陈学思
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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