Application of cleavable polyethylene glycol (PEG) lipid derivative to preparation

A technology of lipid derivatives and derivatives, applied in the field of medicine

Inactive Publication Date: 2011-05-25
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Application of cleavable polyethylene glycol (PEG) lipid derivative to preparation
  • Application of cleavable polyethylene glycol (PEG) lipid derivative to preparation
  • Application of cleavable polyethylene glycol (PEG) lipid derivative to preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0112] Example 1-1 Changes in plasma clearance of rats with repeated injections of PEG-CHM modified liposomes

[0113] In the liposome formulation, PEG-DSPE was replaced with PEG-CHM, and the preparation of PEG-CHM modified liposome was the same as "Comparative Example 1".

[0114] Take Wista rats with a body weight of 250-300 g, divide them into 2 groups, 3 rats in each group, and administer them by tail vein injection according to Table 3, and the rest of the operations are the same as in "Example 1". see results image 3 , the results showed that the remaining amount of calcein plasma at each time point in group C was slightly higher than that in group D (P0.1), indicating that only a slight accelerated blood clearance occurred.

[0115] After the second tail vein injection of PEG-CHM modified liposomes in groups C and D, the tissue distribution at 4 h was shown in Fig. Figure 4 . Compared with group C, the amount of hepatic aggregation in group D increased (P0.1).

[...

Embodiment 1-2

[0122] Example 1-2 Changes in plasma clearance of rats with repeated injections of PEG-CHS modified liposomes

[0123] The PEG-DSPE in the liposome formulation was replaced with PEG-CHS, and the preparation of the PEG-CHS modified liposome was the same as in "Comparative Example 1".

[0124] Take Wista rats with a body weight of 250-300 g, divide them into 2 groups, 3 rats in each group, and administer them by tail vein injection according to Table 5, and the remaining operations are the same as in "Example 1". see results Figure 5 , the results showed that the clearance curves of E and F groups were almost identical. The pharmacokinetic parameters were calculated according to the non-compartment model, and the results are shown in Table 6. There was no significant difference in each pharmacokinetic parameter (P>0.1). It shows that no ABC phenomenon occurs.

[0125] After the second tail vein injection of PEG-CHS modified liposomes in groups E and F, the tissue distributi...

Embodiment 2-1

[0142] Example 2-1 Changes in plasma clearance of rats with repeated injections of PEG-CHM modified vesicles

[0143] The PEG-CHOL in the vesicle prescription was replaced with PEG-CHM, and the preparation of PEG-CHM modified CHST vesicles was the same as in "Comparative Example 2".

[0144] Take Wista rats with a body weight of 250-300 g, divide them into 2 groups, 3 rats in each group, and administer them by tail vein injection according to Table 9, and the remaining operations are the same as in "Example 1". see results Figure 9 , Table 10. The results showed that the remaining amount of calcein at several time points at the beginning of the curve of group I was slightly higher than that of group J, and by comparing the pharmacokinetic parameters, it can be seen that although the half-life is slightly reduced, there is no statistical difference between the pharmacokinetic parameters. There were no significant differences (P>0.1), indicating that only a slight ABC phenome...

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Abstract

The invention belongs to the technical field of medicaments, and provides application of a cleavable polyethylene glycol (PEG) lipid derivative to preparation of a PEGylated preparation for relieving or avoiding accelerated blood clearance. In the application, liquid microparticle preparations such as liposome, vesicles, emulsions, microemulsion, micelles, nanoparticles and the like are modified by the cleavable PEG lipid derivative such as PEG-cholesteryl hemisuccinate, PEG-cholesteryl methyl carbonate, PEG-alpha tocopheryl hemisuccinate and the like; and the measurement of variation of preparation elimination in tissues such as animal blood plasma, liver, spleen and the like after a cleavable PEG lipid derivative-modified medicinal preparation is repeatedly injected proves that repeated injection of cleavable PEG lipid derivative-modified microparticle preparations only causes light accelerated blood clearance or avoids the accelerated blood clearance, namely the accelerated blood clearance can be relieved or avoided. The invention discloses new application of the cleavable PEG lipid derivative.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to the use of cleavable PEG lipid derivatives in preparations. Background technique [0002] In clinical use, PEGylated liquid microparticle preparations often require repeated injections in order to achieve curative effect. However, at present, pharmacokinetic research data on repeated injections of PEGylated preparations in vivo is relatively scarce. Some researchers found that when PEGylated liposomes were repeatedly injected into the same animal (several days apart), it would cause abnormal changes in the pharmacokinetic behavior and liver and spleen tissue distribution of the second injection of PEGylated liposomes. The phenomenon is called Accelerated Blood Clearance (ABC) (see Dams ETM, Laverman P, Oyen WJG, et al. Accelerated Blood Clearance and Altered Biodistribution of Repeated Injections of Sterically Stabilized Liposomes [J]. J Pharmacol Exp Ther, 2000, 29...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/34A61K9/00A61K9/107A61K9/127A61K9/14C07C69/34C07C69/40C07C69/96C07D311/72C07F9/10C07J9/00C08G65/00C08G65/48A61P43/00A61K47/22A61K47/28
Inventor 邓意辉王龙徐缓邹佳宋阳张玲洪维维
Owner SHENYANG PHARMA UNIVERSITY
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