Fatty-acid-binding alhumin-drug nanoparticle lyophilized preparation and preparation method thereof

A fatty acid combination and nanoparticle technology, which is applied in pharmaceutical formulations, drug combinations, freeze-dried delivery, etc., can solve the problems of inability to effectively avoid PE38 antigenicity and reduce PE38 toxin antigenicity

Active Publication Date: 2014-11-05
TIANJIN PAIGE BIOTECHNOLOGY CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Specific antibody fusion to PE38 can significantly improve the anti-tumor targeting, but it cannot effectively avoid the antigenicity of PE38 toxin and its damage to vascular endothelial cells, resulting in severe toxicity, especially vascular leak syndrome ⑨
Therefore, for PE toxins and other molecules and drugs that can cause severe toxic side effects in the blood circulation, it is not enough to improve the affinity of antibodies and/or reduce the antigenicity of PE38 toxins only through the optimization of amino acid sequences
The

Method used

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  • Fatty-acid-binding alhumin-drug nanoparticle lyophilized preparation and preparation method thereof
  • Fatty-acid-binding alhumin-drug nanoparticle lyophilized preparation and preparation method thereof
  • Fatty-acid-binding alhumin-drug nanoparticle lyophilized preparation and preparation method thereof

Examples

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preparation example Construction

[0131] Preparation of fatty acid-binding albumin (Fatty-acid Binding Albumin, FBA)-"water-insoluble" drug (Insoluble Drug, ID) nanoparticle / solution (Solution, So) freeze-dried preparation (Nanoparticle, NP) of the present invention The method, referred to as the FBA-ID / So method, includes:

[0132] 1. "Extraction" treatment of albumin ----- preparation of liquid A and liquid C

[0133] Under sterile conditions, take human serum albumin (HSA), add water for injection, and prepare 10-200 mg / ml, preferably 20 mg-80 mg / ml HSA solution; use an organic solvent immiscible with water such as chloroform (chloroform) , dichloromethane, ethyl acetate or their mixed solution with ethanol (10~5:5~1, v / v) is liquid A, "treat" fatty acid bound to albumin molecules, organic solvent or its mixture and HSA The volume ratio of the solution is 0.3% to 15%, preferably 0.5% to 5.0%; the specific method is to slowly drop liquid A into the continuously stirred HSA solution at 5,000 to 15,000 rpm, p...

Embodiment 1

[0307] Preparation method of fatty acid-binding albumin (Fatty-acid Binding Albumin, FBA) "water-insoluble" drug (Insoluble Drug, ID) nanoparticle / solution type (Solution, So) lyophilized preparation (referred to as FBA-ID / So method)

[0308] -------FBA-ID / So method to prepare curcumin (Curcumin, C) nanoparticles freeze-dried preparation (FBA-ID / So-C)

[0309] Under sterile conditions, take 1000mg of Sigma human serum albumin (HSA), add water for injection, and prepare 10mg / ml HSA100ml; slowly drop 300ul of chloroform and absolute ethanol mixture (10:1, v / v), that is, liquid A In the 10 mg / ml HSA solution at 10,000 rpm (10,000 rpm), continue stirring for 10 minutes to obtain liquid C (reserve sample S1).

[0310] Co-dissolve 1ug of oleic acid for intravenous injection and 10mg of curcumin (Curcumin, C) in 100ul chloroform-ethanol mixed solution (9:1, v / v) (liquid D), which contains solution B, namely 1ug of oleic acid for intravenous injection / 100ul chloroform-ethanol mixed ...

Embodiment 2

[0312] Example 2: Preparation of rapamycin (Rapamycin, R) nanoparticle lyophilized formulation (FBA-ID / So-R) by FBA-ID / So method

[0313] Under sterile conditions, take 1800 mg of Sigma HSA, add water for injection, and prepare 100 mg / ml HSA 18 ml; slowly drop 500 ul of dichloromethane (liquid A) into 100 mg / ml HSA solution at 8,000 rpm for 5 minutes, and obtain liquid C ( Reserve sample S2). Dissolve 90ug of linoleic acid for intravenous injection and 20mg of rapamycin (Rapamycin, R) in 1300ul of dichloromethane solution (liquid D), and then add this solution containing linoleic acid, rapamycin and dichloromethane The mixed solution of liquid D is slowly dropped into the 100mg / ml HSA solution treated with dichloromethane under high-speed stirring, the stirring speed is 12,000rpm, and the duration is 20 minutes; this suspension is quickly put into the vacuum rotary evaporator In 35° C. under reduced pressure (20 mmHg) rotary evaporation for 30 minutes to remove all organic so...

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Abstract

The invention discloses a fatty-acid-binding alhumin-drug nanoparticle lyophilized preparation and a preparation method thereof; by use of high affinity and stable binding characteristics of fatty acids and albumin specific sites, nanoparticles using the fatty acids as the core are prepared under the effects of high shearing forces, one or a plurality of ''water-insoluble'' or ''water-soluble '' drug in the form of ''solution'' or ''ultrafine nanoparticles'' is/are ''packaged'' or ''bound'' to obtain various types of nanoparticles suspensions, and the lyophilized preparation is obtained by removal of organic solvent, sterilization and drying. The fatty-acid-binding alhumin-drug nanoparticle lyophilized preparation is composed only by albumin, the drugs and the fatty acids, does not contain any accessories, and has the biological properties of high nanoparticles integrity and stability in a in vitro solution and in vivo blood circulation, , significant increase of drug content in gp60-rich receptor cells or tumor tissues, significant improvement of the LD50 (half lethal dose) and MTD (maximum tolerated dose) of load drugs, close of antigen sites of ''packaged'' or ''bound'' proteins, and the like.

Description

technical field [0001] The invention relates to a nanoparticle freeze-dried preparation and a preparation method, in particular to a fatty acid-binding albumin-drug nanoparticle freeze-dried preparation and a preparation method, belonging to the technical field of medicine preparation. Background technique [0002] Human serum albumin (Human Serum Albumin, referred to as HSA) is the main protein in human plasma, is a non-glycosylated protein, consists of 585 amino acids, and has a molecular weight of 66kD. The concentration of HSA in the plasma of healthy people is 35-55g / L, and the half-life is about 19 days. HSA plays an important role in maintaining blood colloid osmotic pressure, amino acid and energy metabolism of tissue cells, and transport of fat-soluble substances such as bilirubin, fatty acids and drugs. HSA has sufficient sources, can be extracted from human blood, and can also be produced by genetic recombination technology. HSA is non-toxic, non-immunogenic, and...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K9/19A61K45/00A61P35/00
CPCA61K9/19A61K47/50
Inventor 张旋王洁银
Owner TIANJIN PAIGE BIOTECHNOLOGY CO LTD
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