Biologically related substances modified by multifunctional H-type polyethylene glycol derivative

A bio-related substance, polyethylene glycol technology, applied in the field of polymer synthesis, can solve problems such as failure to meet biological safety requirements, decreased drug activity, limited application range, etc., to improve pharmacokinetics or tissue distribution, Weaken the effect, reduce the effect of immunogenicity

Active Publication Date: 2015-04-22
XIAMEN SINOPEG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Branched polyethylene glycol with two polyethylene glycol arms represented by this traditional V-shaped structure has only a single active group that can react with drug molecules, and the drug loading is low, so the application range is very limited
In addition, since the active group is located in the center of the two polyethylene glycol arms, the active group is embedded by the polyethylene glycol chain, resulting in low modification efficiency when modifying the drug molecule
[0005] In addition, for drug molecules modified by PEGylated derivatives, since the binding site may be connected to the active site or near the active site of the drug, or the steric effect is introduced, the activity of the drug after PEGylation will often result. decline or even disappear
Moreover, in conventional administration methods, such as injection, oral administration, etc., besides acting on the lesion, drug molecules usually also accumulate in normal tissues, causing certain or even serious side effects.
Although the toxicity and side effects can be greatly reduced through PEGylation modification, for some drugs, especially anticancer drugs, the existing PEGylation modification still cannot meet the biological safety requirements

Method used

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  • Biologically related substances modified by multifunctional H-type polyethylene glycol derivative
  • Biologically related substances modified by multifunctional H-type polyethylene glycol derivative
  • Biologically related substances modified by multifunctional H-type polyethylene glycol derivative

Examples

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preparation example Construction

[0118] In the preparation method part of the present invention, dotted lines are used in the structural formulas of some skeleton groups to indicate that the skeletons will be directly connected to the groups shown in the structural formulas in the specified compounds.

[0119] In the present invention, the ring structure is represented by a circle, and different labels are given according to the difference of the ring structure. For example,

[0120] represents any ring structure;

[0121] Represents an aliphatic ring structure without any aromatic or heteroaromatic rings, also known as aliphatic rings;

[0122] Represents an aromatic ring structure, containing at least one aromatic ring or heteroaromatic ring, also known as an aromatic ring;

[0123] Indicates the skeleton of sugars or sugar derivatives containing cyclic monosaccharide skeletons, also known as sugar rings;

[0124] Indicates a ring containing amide bonds, ester bonds, imides, acid anhydrides and...

Embodiment 1

[1148] Example 1: Preparation of interferon α-2a modified by polyfunctional H-type polyethylene glycol succinimide active ester derivative (amide bond connection)

[1149] Add 645 mg (about 2 times the molar ratio) of polyfunctional H-type polyethylene glycol succinimide active ester derivative (A1-1, molecular weight about 26 kDa) into a dry and clean 50 mL round bottom flask, nitrogen protection, add PBS The pH value of the buffer was adjusted to pH=8.0, and 7.5 mL of interferon α-2a (NH 2 - IFN) in PBS buffered saline solution, shake and react at 25°C for 4 hours, shake and react at 4°C for 12 hours, add 1.5ml of glycine solution to terminate the reaction. The concentration of interferon α-2a was diluted to 0.5 mg / mL with PBS buffered saline solution with pH=8.0, and then purified by agarose gel exchange resin, and the single-modified and double-modified components were collected respectively, and concentrated by ultrafiltration. MALDI-TOF-MS test showed that the molecular...

Embodiment 2

[1156] Example 2: Preparation of recombinant human granulocyte colony-stimulating factor (rhG-CSF) modified by multifunctional H-type polyethylene glycol aldehyde derivatives (secondary amine linkage)

[1157] Add 600mg (about 1.5 times the molar ratio) of multifunctional H-type polyethylene glycol aldehyde derivatives (D5-1, molecular weight about 20kDa) into a dry and clean 50mL round bottom flask, nitrogen protection, add PBS buffer solution to adjust the pH Adjust pH value to 5.0, add 7.6mL rhG-CSF PBS buffered saline solution, react at room temperature for 4 hours, add sodium cyanoborohydride, react at room temperature for about 24 hours, add saturated ammonium chloride solution to quench, dilute with water to protein The concentration is about 0.1mg / mL. Use dilute hydrochloric acid to adjust the pH value to about 5.0, and use Resource S ion-exchange column chromatography to elute with a gradient of 0-0.5mol / L NaCl solution (containing 20mmol / L NaAc, pH5.0) to collect sin...

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Abstract

The invention discloses biologically related substances modified by a multifunctional H-type polyethylene glycol derivative. The derivative comprises a linear main axis LPEG and four PEG branched chains, and n1, n2, n3 and n4 are polymerization degrees of the branched chains, respectively; U1 and U2 are trivalent branching groups connecting the main axis LPEG with two PEG branched chains; F1 and F2 contain functional groups or their protected forms R01, and the number of R01 is one or more than one. Any linking group in the molecule or linking groups formed with adjacent heteroatom groups are stable or degradable; any PEG chain segment in the molecule independently shows polydispersity or monodispersity. One H-type molecule can modify multiple types of or multiple biologically related substances; the modified product has a flexible branching structure, a high drug loading capacity, optimized pharmacokinetics and tissue distribution, and can also carry two biologically related substances with different functions, so as to generate fluorescence property or targeting function.

Description

technical field [0001] The invention relates to the fields of polymer synthesis and biochemical modification, in particular to a bio-related substance modified by multifunctional H-type polyethylene glycol derivatives. Background technique [0002] PEGylation is one of the important means of drug modification. Among them, functionalized polyethylene glycol (PEG) can use its active groups to interact with drug molecules (including protein drugs and organic small molecule drugs), peptides, sugars, lipids, oligonucleotides, affinity ligands, etc. Polymers, cofactors, liposomes, and biological materials are coupled through covalent bonds to achieve polyethylene glycol modification of drugs and other biologically related substances. The modified drug molecule will have many excellent properties of polyethylene glycol (such as hydrophilicity, flexibility, anticoagulation, etc.). At the same time, due to the steric repulsion effect, the PEG-modified drug avoids glomerular filteri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/32C08G65/331C08G65/333C08G65/334C08G65/00C08G65/336A61K47/48
Inventor 翁文桂刘超闫策周纯
Owner XIAMEN SINOPEG BIOTECH
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