Liposome, preparation method thereof, liposome assembly and carrier liposome complex

A liposome and liposome technology, which is applied in the field of liposome assemblies and liposome complexes, can solve the problems of low drug utilization, low drug concentration, and lack of selectivity.

Active Publication Date: 2019-12-06
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] (1) Targeted delivery problem: currently clinically used liposomes (represented by DPPC and DSPE liposomes) compound drugs mainly use the EPR effect of the tumor site for passive targeted enrichment
However, this passive targeting is not selective and is easily disturbed by the complex physiological environment
In addition, depending on the pure EPR effect, the drug concentration in the lesion is often low. In order to achieve effective treatment, it is necessary to increase the dosage, resulting in low drug utilization efficiency and side effects. In order to solve this problem, often Active targeting modification of common liposomes is required
[0004] (2) The problem of long circulation in the body: the liposome compound drugs currently used clinically are easily excreted out of the body by the endothelial reticulum system (RES) through the kidneys, liver, etc. during the blood circulation process, resulting in a short drug half-life, The problem of low drug utilization
Some commonly used methods for prolonging the metabolic half-life of liposome complex drugs, such as modifying polyethylene glycol (PEG) on the surface of liposomes, utilizing the anti-protein adsorption of PEG to prepare liposomes as "stealth liposomes" (stealthliposomes), although it will prolong the circulation of liposomes in the organism to a certain extent, but the repeatability is not good, and the problem of batch production needs to be solved urgently
[0005] (3) The chemical modifiability of liposomes: the liposomes currently used clinically are mainly natural soybean lecithin, egg yolk lecithin and artificially synthesized liposomes, and the main structures are long chain alkanes and phosphatidylcholine zwitterionic head group
In clinical treatment, traditional liposomes do not have environmental stimulus responsiveness (pH, oxygen partial pressure, magnetic field, ultrasound, light, enzyme, heat, etc.) due to the lack of effective chemical modification sites. Stimulus response), can only rely on the difference in drug concentration inside and outside the liposome cavity for release, and does not have controllable release

Method used

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  • Liposome, preparation method thereof, liposome assembly and carrier liposome complex
  • Liposome, preparation method thereof, liposome assembly and carrier liposome complex
  • Liposome, preparation method thereof, liposome assembly and carrier liposome complex

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preparation example Construction

[0124] According to the present invention, the first preparation method of the liposome comprises the following steps:

[0125] a) compound A 1 -COOH, Compound A 2 -COOH is reacted with 1,2-propanediol derivative X-1 to obtain compound Y-1;

[0126] b) reacting the phospholane compound X-2 with the dimethylamine compound X-3 to obtain the compound Y-2;

[0127] c) reacting the compound Y-1 with the compound Y-2 to obtain liposomes represented by formula (I);

[0128] The steps a) and b) have no order limitation;

[0129]

[0130] in,

[0131] A 1 and A 2 Independently selected from hydrocarbyl C x h 2x+y ; x is an integer from 5 to 35, and y is 1, -1, -3, -5, -7, -9 or -11;

[0132] no 1 , n 2 , L 1 and L 2 The options are as follows:

[0133] no 1 =0,n 2 =0,L 1 and L 2 Linked to form -(CH 2 ) n3 -, n 3 1 to 4. Among them, L 1 and L 2 There are no special restrictions on the type of the two reacting to form -(CH 2 ) n3 - can be, for example, L 1 f...

Embodiment 1～13

[0202] The preparation of embodiment 1~13 compound Y-1

[0203]

Embodiment 1～3

[0205] Add 56g of hexadecanoic acid (0.22mol), 12g of N,N-dimethylamino-1,2-propanediol (0.1mol) into a 500mL reaction flask, add 300mL of dichloromethane, stir well and add 27.8g of N, N'-diisopropylcarbodiimide (DIC) (0.22mol) and 0.2g 4-dimethylaminopyridine (DMAP), after fully stirring and reacting at room temperature for 24h, filtered, and the solid obtained after the filtrate rotary distillation was further recombined Through crystallization and purification, 54 g of the product was obtained with a yield of 96.8%.

[0206] According to the above preparation process, the difference is that 62 g of oleic acid and 61 g of octadecatrienoic acid (both 0.22 mol) were used to replace 56 g of hexadecanoic acid in the above preparation process. The yield and product structure of the obtained product are shown in Table 1.

[0207] The productive rate and structure of table 1 embodiment 1~3

[0208]

[0209]

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PUM

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Abstract

The invention provides a liposome, a preparation method thereof, a liposome assembly and a carrier liposome complex. The liposome provided by the invention has the structure of formula (I), the left side of the L group is the liposome part, and the right side is the choline phosphoric acid structure, and the two are connected with specific L groups to form the liposome with specific structure. Theliposome of the formula (I) provided by the invention has the properties of long circulation, stimulation response, targeting and the like, and has multiple modifiable sites, can be used for preparing biological preparations with various functions, and provides more convenient choices for diagnosis and treatment of diseases.

Description

technical field [0001] The invention relates to the technical field of drug carriers, in particular to a liposome, a preparation method thereof, a liposome assembly and a liposome complex carrying a load. Background technique [0002] At present, liposomes have been widely used as drug carriers. Adriamycin-liposomes, daunorubicin-liposomes, and paclitaxel-liposomes have been on the market for many years. For a long time, liposomes as drug carriers have faced the following four key problems: [0003] (1) Targeted delivery problem: currently clinically used liposomes (represented by DPPC and DSPE liposomes) compound drugs mainly use the EPR effect of the tumor site for passive targeted enrichment. However, this passive targeting is not selective and easily interfered by the complex physiological environment. In addition, depending on the pure EPR effect, the drug concentration in the lesion is often low. In order to achieve effective treatment, it is necessary to increase th...

Claims

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Application Information

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IPC IPC(8): C07F9/11C07F9/113C07F9/6518A61K9/127A61K47/34A61P35/00A61K31/704
CPCC07F9/11C07F9/113C07F9/6518A61K9/1271A61K47/34A61P35/00A61K31/704Y02P20/55
Inventor 于喜飞刘三荣王文靓江桑铌李晟冉
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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