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Preparation method of protein nanoparticles coating insoluble drug

A technology of insoluble drugs and nanoparticles, which is applied in the field of protein nanoparticle preparation, can solve the problems of loss of curative effect, unfavorable tumor targeting, easy drug failure, etc., to improve the convenience and safety of medication, and to achieve good internal and external stability Sexuality, the effect of good pharmacodynamic properties

Active Publication Date: 2014-06-11
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0015] However, through the direct chemical coupling of HSA and drugs, there are the following problems: 1) The range of drug selection is narrow: the drug needs to have a certain reactive group, and the drug is prone to failure during the chemical coupling process; 2) The curative effect is uncertain Performance: The ease of breaking the chemical bond between the drug and HSA determines the efficacy of the drug. If it breaks too fast, HSA will lose its advantage as a carrier material. If it breaks too slowly, the drug will not be able to exert its curative effect; 3) High cost and low drug loading : In the coupling process, the drug dosage is much larger than HSA, and the coupling drug amount is limited, resulting in high preparation costs (especially the high price of anti-tumor drug raw materials) and low drug loading in the system.
Because HSA is highly water-soluble, the prepared nanoparticles need to be cured, that is, add a chemical cross-linking agent to cross-link albumin or heat to denature the protein. The former is more toxic, and it is easy for the drug to cross-link at the same time and lose its efficacy , the latter is not suitable for the loading of temperature-sensitive drugs; in addition, some people think that the method of cross-linking or heat curing will reduce the hydrophilicity of the surface of HSA nanoparticles, thereby reducing the circulation time in the blood, which is not conducive to tumor targeting;
[0020] 3) The post-processing process is complex
Due to the use of toxic additives such as surfactants, oils, and chemical cross-linking agents in the process, a large amount of organic solvents are required to clean and purify, but a small amount of residue will still bring hidden dangers to drug safety; high-speed centrifugation (16000-20000g) is used to collect nano Particles, not only have high requirements for instruments, but also have poor redispersibility in water;
[0021] 4) The scope of applicable drugs is small
But the precipitation of nanoparticle occurs very soon, it is more difficult when carrying out described microporous membrane filtration (1.2um, 0.8um, 0.45um and 0.22um), and the situation of clogging occurs easily in filter membrane, and its freeze-dried product is in The nanosuspension formed after reconstitution in physiological solution is unstable, with macroscopic precipitation appearing within about 8 hours, which is completely different from the results claimed in the patent that the stability is greater than 24 hours

Method used

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  • Preparation method of protein nanoparticles coating insoluble drug
  • Preparation method of protein nanoparticles coating insoluble drug
  • Preparation method of protein nanoparticles coating insoluble drug

Examples

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Effect test

Embodiment 1

[0134] Example 1 Preparation of Paclitaxel Albumin Nanoparticles by Melting Method

[0135] Dissolve 500 mg of paclitaxel in 9.0 mL of ethanol. After 1200 mg of polyethylene glycol was heated and completely melted in an oil bath at 60°C, the paclitaxel solution was added thereto, and stirred by magnetic force until it was completely mixed evenly. After the ethanol was removed by rotary evaporation, it was rapidly cooled under vigorous stirring conditions. After vacuum drying overnight, the solid dispersion was added to 85 ml of human serum albumin aqueous solution (4.5% w / v, g / ml, the same below). The mixture was premixed by a high-speed disperser (XHF-1, Shanghai Jinda Biochemical Instrument Factory) for 1 minute to form a coarse milk, and then transferred to a high-pressure homogenizer (EmulsiFlex-05, Avestin, Canada). High pressure homogenization at 5000-30,000 psi 2 Under certain conditions, the emulsion is repeatedly circulated at least 5 times to obtain a suspension of...

Embodiment 2

[0137] Example 2 Preparation of paclitaxel albumin nanoparticles by melting-solvent evaporation method

[0138] Dissolve 300 mg of paclitaxel in 6.0 mL of ethanol. Dissolve 900 mg of polyethylene glycol in 1.5 ml of absolute ethanol, heat and completely melt in an oil bath at 45°C, add the paclitaxel solution into it, stir magnetically until it is completely mixed, and remove the ethanol by rotary evaporation, quickly under vigorous stirring conditions cool down. After drying under vacuum overnight, the solid dispersion was added to 65 ml of aqueous human serum albumin (4.5% w / v). The mixture was premixed by a high-speed disperser (XHF-1, Shanghai Jinda Biochemical Instrument Factory) for 1 minute to form a coarse milk, and then transferred to a high-pressure homogenizer (EmulsiFlex-05, Avestin, Canada). Emulsified at 5000-30,000 lbs / in 2 Carried out under the conditions of the above conditions, the emulsion was repeatedly circulated at least 6 times to obtain a protein nan...

Embodiment 3

[0140] Example 3 Preparation of Paclitaxel Albumin Nanoparticles Sterile Filterable Less than 200 Nanometers

[0141] Dissolve 500 mg of paclitaxel in 9.0 mL of ethanol. Dissolve 800 mg of polyethylene glycol in 1.5 ml of absolute ethanol, heat and completely melt in an oil bath at 45°C, add paclitaxel solution into it, stir magnetically until it is completely mixed evenly, and remove ethanol by rotary evaporation, rapidly under vigorous stirring conditions cool down. After drying under vacuum overnight, the solid dispersion was added to 97 ml of aqueous human serum albumin (4.5% w / v). The mixture was premixed by a high-speed disperser (XHF-1, Shanghai Jinda Biochemical Instrument Factory) for 1 minute to form a coarse milk, and then transferred to a high-pressure homogenizer (EmulsiFlex-05, Avestin, Canada). Emulsified at 10,000-40,000 lbs / in 2 Carried out under the conditions of the above conditions, the emulsion was repeatedly circulated at least 6 times to obtain a prot...

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Abstract

The invention belongs to the field of pharmacy, and discloses a preparation method of protein nanoparticles coating an insoluble drug, which comprises the following steps: preparing an insoluble drug and a water-soluble carrier material into a water-soluble carrier solid dispersion containing the insoluble drug; adding the solid dispersion into a water-based medium containing protein substances, evenly mixing, and processing the mixture under high shear conditions to obtain the protein nanoparticle suspension coating the insoluble drug; and preparing the required preparation formulation. The method does not need to introduce any other organic solvent except ethanol, and even does not need to introduce any organic solvent, thereby preventing organic solvent residues in the preparation, and greatly enhancing the safety of clinical application. The method has the advantages of simple technique, low cost and strong operability.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to a preparation method of protein nanoparticle encapsulating insoluble drugs. Background technique [0002] The poorly soluble drugs involved in the present invention are taxane drugs as examples. Taxane drugs (such as paclitaxel, docetaxel, etc.) are one of the most effective anti-tumor drugs currently used clinically. Paclitaxel is a natural product isolated from the bark or needles of Taxus or its species discovered in the 1970s. Docetaxel is a semi-synthetic product, which was later discovered to be a class of anti-tumor agents with a special anti-tumor mechanism of action . [0003] The anti-tumor mechanism of taxane drugs is to promote microtubule polymerization and reduce the depolymerization speed of microtubules, so that the microtubules are in a stable non-functional state, thereby achieving the purpose of preventing tumor cell mitosis and proliferation. And preclinical studies h...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/14A61K47/42A61K47/34A61K47/32A61K47/14A61K47/26A61K47/18A61K47/36
Inventor 周建平霍美蓉崔蓓
Owner CHINA PHARM UNIV
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