Chitosan-carboxylated chitosan nanosphere loading insoluble antitumor drug and preparation method and application thereof

A technology for carboxylated chitosan and anti-tumor drugs, applied in the directions of anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of reduced drug entrapment rate, easy drug escape, limited preparation methods, etc., and achieves improved tumor target. Directional effect, improved bioavailability, good bioavailability effect

Inactive Publication Date: 2012-03-28
INST OF PROCESS ENG CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, chitosan and its derivatives as insoluble drug carriers have the following problems: (1) hydrophilic chitosan nanospheres cannot directly load insoluble drugs. The present invention adopts O / W / O double emulsion The loading of insoluble drugs can be achieved by using the method, and the nanospheres loaded with insoluble drugs can be prepared by further curing the double emulsion
The stability of complex emulsions, especially nano-complex emulsion droplets, is a great challenge during the preparation process.
(2) Insoluble drugs such as paclitaxel are usually easy to devitrify to form large crystal particles during the preparation process and destroy the emulsion, resulting in drug leakage or even embedding failure
(3) Pure chitosan nanospheres have a solid structure, and it is difficult for the release liquid to enter the nanospheres, resulting in a slow release rate of the drug
(4) Most of the nanospheres prepared by chitosan adopt the chemical crosslinking method. After chemical crosslinking and curing, the functional group amino groups on the surface of chitosan nanospheres are occupied during crosslinking, and cannot be further connected to PEG chains or grafted targets. To the molecule
(5) The preparation method is very limited, and the mechanical stirring method is mainly used. When using this method to prepare the emulsion, due to the uneven particle size, the small milk droplet will be absorbed by the large milk droplet, and the large milk droplet will be absorbed by the large milk droplet due to shearing. Destroyed by the effect of shear force, which leads to the very uneven particle size of the prepared chitosan nanospheres
At the same time, in the process of merging and breaking up of droplets, the internal drug can easily escape to the outside of the droplet, resulting in a decrease in the embedding rate of the drug.
The inhomogeneous particle size of nanospheres will also bring many difficulties to the practical application of chitosan and its derivative nanospheres.
(6) Most nanospheres will be recognized and cleared by the reticuloendothelial system after intravenous injection, so that the drug cannot reach the therapeutic concentration
(7) Due to the lack of targeting, the simple nanosphere carrier brings irreversible toxic and side effects to normal body tissues

Method used

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  • Chitosan-carboxylated chitosan nanosphere loading insoluble antitumor drug and preparation method and application thereof
  • Chitosan-carboxylated chitosan nanosphere loading insoluble antitumor drug and preparation method and application thereof
  • Chitosan-carboxylated chitosan nanosphere loading insoluble antitumor drug and preparation method and application thereof

Examples

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preparation example Construction

[0116] (1)O I / W / O II Preparation of double emulsion

[0117] Weigh the insoluble drug powder and dissolve it in a volatile and water-immiscible organic solvent as the internal oil phase (O I ) for subsequent use; then chitosan (CS) and its derivatives carboxylated chitosan, water phase emulsifier and other additives are added to acidic aqueous solutions such as acetic acid or citric acid, and fully dissolved under magnetic stirring conditions as the water phase (W) for subsequent use; more than one oil-soluble emulsifier is dissolved in oily liquid as the outer oil phase (O II )spare. First, the internal oil phase (O I ) and the water phase (W) are mixed, and O is prepared by homogeneous emulsification or ultrasonic method I / W type primary emulsion; the primary emulsion and the outer oil phase (O II ) to prepare a pre-emulsion by homogeneous emulsification, and then this pre-emulsion is repeatedly pressed through the microporous membrane under pressure to obtain O with...

Embodiment 1

[0121] Example 1: Preparation of chitosan-carboxylated chitosan nanospheres loaded with insoluble drugs

[0122] In this example, paclitaxel was selected as the poorly soluble drug model. Firstly, the hydrophilic membrane with a pore size of 0.5 micron is placed in a mixed oil phase of olive oil and cottonseed oil and soaked overnight or ultrasonicated for 1 hour to make the pores of the membrane fully wetted by the oil phase. Accurately weigh a certain amount of paclitaxel powder, an insoluble drug, and dissolve it in the ethyl acetate of the inner oil phase at a concentration of 40 mg / mL, and use it as the inner oil phase for later use. The mixture (mass ratio 1: 5) of taking a certain amount of chitosan and carboxylated chitosan is dissolved in 1% acetic acid aqueous solution, obtains the acetic acid aqueous solution of chitosan and carboxylated chitosan mixture, and its concentration is 1.0 wt%, while adding 8% water phase emulsifier 35. Stir magnetically at room tempe...

Embodiment 2

[0123] Example 2: Preparation of chitosan-carboxylated chitosan nanospheres of different pore sizes loaded with insoluble drugs

[0124] In this example, O-(chloroacetylcarbamoyl) fumagillin alcohol was selected as the insoluble drug model. The hydrophilic membrane with a pore size of 0.5 μm was soaked in a mixed oil phase of liquid olive oil and petroleum ether at a volume ratio of 1:4 overnight or ultrasonically for 1 hour to fully wet the membrane pores by the oil phase. Accurately weigh a certain amount of O-(chloroacetylcarbamoyl) fumagillin alcohol powder and dissolve it in dichloromethane of the inner oil phase at a concentration of 25 mg / mL, and use it as the inner oil phase for later use. Take a certain amount of chitosan and carboxylated chitosan, and dissolve them in 5 parts of 1% acetic acid aqueous solution according to the mass ratio of 1:9, 1:5, 1:1, 5:1, and 10:1 respectively, to obtain The aqueous solution of carboxylated chitosan acetic acid has a concentrat...

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Abstract

The invention relates to a chitosan-carboxylated chitosan nanosphere loading an insoluble antitumor drug. The nanosphere has a porous and aperture-controlled structure which controls rapid and stable release of the drug. Polyethylene glycol (PEG) chains and tumor-targeting specific molecules are coupled on the surface of the nanosphere, so as to effectively increase the cycle period of the drug in vivo, improve the affinity of the nanosphere to tumor cells and improve the bioavailability of the drug. Besides, the nanosphere has less toxic side effects and better antitumor effects. The invention also provides a method for preparing the chitosan-carboxylated chitosan nanosphere loading or combining the insoluble antitumor drug. The amino groups of chitosan/carboxylated chitosan are cross-linked to form a sphere, and the carboxyl groups of carboxylated chitosan are coupled with the PEG chains and then grafted with the targeting molecules, so that the drug is uniformly dispersed in the form of in-situ crystallization in chitosan and its derivative nanosphere, as a result, the drug-loading rate is greatly increased and the release rate of the drug is stabilized.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, relates to the application of nanocarriers in the field of biotechnology, and specifically discloses a chitosan-carboxylated chitosan nanosphere loaded with insoluble antitumor drugs, a preparation method and an application thereof. The chitosan-carboxylated chitosan nanospheres of the antineoplastic drug reach the lesion site after intravenous injection and exert the drug effect. The invention has potential clinical therapeutic application value. Background technique [0002] Malignant tumors have become one of the common fatal diseases that seriously endanger human health around the world, and their morbidity and mortality have shown an increasing trend in recent years. According to WHO statistics, in 2002, the number of deaths from malignant tumors in the world reached 7.106 million. In 2000, the incidence of cancer in my country was 1.8 to 2 million, and the death toll was 1.4 to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/36A61K47/42A61K9/14A61K45/00A61P35/00
Inventor 马光辉吕丕平王连艳魏炜周炜清苏志国
Owner INST OF PROCESS ENG CHINESE ACAD OF SCI
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