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Low-concentration polyethylene glycol-lipid (PEG-lipid) derivative and application thereof

A lipid derivative, low-concentration technology, used in the field of medicine

Inactive Publication Date: 2012-12-12
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, lipid exchange may cause defects in the liposome bilayer membrane, resulting in rapid leakage of the loaded drug.
[0014]In addition, recently we used the property that the ester bond can be gradually broken / degraded under the action of esterase in plasma / tissue, and proposed for the first time to modify Effects of cleavable PEG-cholesterol derivatives on the accelerated blood clearance of PEGylated liposomes. Biomaterials, 2010;31(17):4757-63 .), but the research on non-cholesterol PEG derivatives is not detailed. Under the support of the National Natural Science Foundation of China (No81072602), we conducted a comprehensive study on the ABC phenomenon induced by different concentrations of PEG lipid derivatives such as MPEG-DSPE, especially Eliminate or weaken the ABC phenomenon of PEGylated preparations by using low-concentration PEG-lipid derivatives alone / or in combination with other substances, and its formulation composition and application in drug delivery systems
So far, the concentration of MPEG-DSPE used in the study of ABC phenomenon accounts for more than 5%moL of the total lipid concentration, and there is no study on ABC of low-concentration MPEG-DSPE preparations.

Method used

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  • Low-concentration polyethylene glycol-lipid (PEG-lipid) derivative and application thereof
  • Low-concentration polyethylene glycol-lipid (PEG-lipid) derivative and application thereof
  • Low-concentration polyethylene glycol-lipid (PEG-lipid) derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Embodiment 1 PEG density (mPEG 2000 -DSPE dosage) on ABC

[0105] Table 1 Composition of formulations with different PEG densities

[0106] Ingredients / Prescription 1 2 3 4 5 6 7 8 9 TN (mg) 20 20 20 20 20 20 20 20 20 MCT (mg) 100 100 100 100 100 100 100 100 100 S75 (mg) 26.0 26.0 26.0 26.0 26.0 26.0 26.0 26.0 26.0 mPEG-DSPE (mg) - 0.5 1.0 1.5 2.0 5.0 10.0 20.0 30.0 5% glucose injection was added to 5mL 5mL 5mL 5mL 5mL 5mL 5mL 5mL 5mL

[0107] [The mass percent concentration of mPEG-DSPE in the preparation is 0.00%, 0.01%, 0.02%, 0.03% (approximately equivalent to 0.11mM), 0.04% (approximately equivalent to 0.15mM), 0.1%, 0.2%, 0.4%, 0.6% % (g / ml). (Based on the mass percentage of mPEG-DSPE and oil (MCT) (mPEG-DSPE / MCT), they are 0.0%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0%, 10.0%, 20.0%, 30.0%, respectively. )]

[0108] The emulsion was prepared according to the prescriptio...

Embodiment 2

[0131] Embodiment 2 adopts LCT (preparation concentration 10%)

[0132] Table 2 Emulsion formulations with 10% LCT

[0133] Ingredients / Prescription 1 2 3 TN (mg) 100 100 100 LCT (mg) 500 500 500 E80 (mg) 130 130 130 mPEG-DSPE (mg) 2.5 5.0 7.5 5% xylitol injection was added to 5mL 5mL 5mL

[0134] The preparation and measurement methods are the same as in "Example 1", and the average particle size is about 100 nm.

[0135] Results All three preparations did not produce ABC phenomenon.

[0136] Shaking stability: put the above-mentioned preparation containing low concentration of mPEG-DSPE and the preparation without mPEG-DSPE (except for mPEG-DSPE in Table 2, the others are identical) in a shaker at the same time, shake back and forth for 10 days, The results showed that the control conventional emulsion without mPEG-DSPE showed oil floating, while the remaining three formulations containing low concentration of mPE...

Embodiment 3

[0137] Example 3 Different mPEG molecular weights

[0138] For mPEG-DSPE derivatives with different mPEG molecular weights, according to the mPEG in "Example 1" 2000 -DSPE molar (0.546mM) ratio is calculated, i.e.

[0139] Table 3 Using 10% LCT / MCT (1:1) as the oil phase

[0140] Ingredients / Prescription 1 2 3 TN (mg) 100 100 100 LCT / MCT (mg) 500 500 500 E80 (mg) 130 130 130 mPEG 750 -DSPE (mg) 4.1 - - mPEG 5000 -DSPE (mg) - 15.7 - mPEG 20000 -DSPE (mg) - - 56.6 5% glucose injection was added to 5mL 5mL 5mL

[0141] Note: mPEG 750 - The molecular weight of DSPE is 750+748.1=1498.1; mPEG 5000 -DSPE molecular weight 5748.1; mPEG 20000 -DSPE molecular weight 20748.1

[0142] The preparation and measurement methods are the same as in "Example 1", and the average particle size is about 120 nm.

[0143] As a result, the ABC phenomenon did not occur. That is, adding 0.546 mM PEG lipid derivatives to...

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Abstract

The invention belongs to the technical field of medicine, relates to a low-concentration PEG-lipid derivative and an application thereof, particularly to a prescription composition and an application thereof which can relieving or avoiding accelerated blood clearance (ABC) of PEGylation preparations. According to the low-concentration PEG-lipid derivative and the application thereof, the low-content PEG-lipid derivative is used for modifying liquid particle preparations such as emulsions, liposome, vesicles, micro emulsions, micelles and nano-particles, PEG and lipid chain segments are connected through ester bonds, amido bonds or ether bonds in the PEG-lipid derivative, and the molecular weight of the PEG is 200-20000 Dalton. Preparations prepared by the PEG-lipid derivative can only cause slight or cannot cause the ABC, namely, can reduce or avoid the ABC after repeated injection. The low-concentration PEG does not reduce in vitro anti-tumor activity of preparations, and stability of the preparation can be improved if the low-concentration PEG-lipid derivative is added, particularly shaking instability of antagonistic emulsions.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and in particular relates to a formula composition for eliminating or weakening the phenomenon of accelerated blood clearance of PEGylated preparations by using low-concentration PEG-lipid derivatives / or in combination with other substances and its application in a drug delivery system. Background technique: [0002] Conventional ordinary (classic / traditional) intravenous drug delivery systems, such as ordinary liposomes, are easily phagocytized by the mononuclear macrophage system (MPS), and quickly distributed to liver, spleen and other organs after intravenous injection, resulting in blood circulation of liposomes Short time and poor targeting. In order to solve such problems, researchers use polyethylene glycol (PEG) lipid derivatives to modify the surface of liposomes, and use PEG to have both hydrophilic and flexible characteristics to prolong the circulation time of liposomes. Reduce ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/34A61K47/48
Inventor 邓意辉王龙赵永雪严米娜王春玲马艳玲佘振南
Owner SHENYANG PHARMA UNIVERSITY
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