Sodium hyaluronate gel cross-linked with polyglycol epoxy derivatives for injection and preparation method thereof

A sodium hyaluronate, alcohol epoxy technology, applied in drug delivery, tissue regeneration, pharmaceutical formulations, etc., can solve the problems of small pushing force, long retention time in the body, and good injectability.

Active Publication Date: 2020-09-29
JENKEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to overcome the problem that the sodium hyaluronate gel prepared in the prior art cannot have the advantages of strong gel degradation resistance, low cross-linking agent toxicity, and good injectability, the present invention firstly designed and synthesized a new , low toxicity, high reactivity, water-soluble cross-linking agent, and then use the cross-linking agent to prepare a low toxicity, less residue, small extrusion thrust, good plasticity, good enzyme resistance, long retention time in vivo Modified Sodium Hyaluronate Gel for Injection

Method used

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  • Sodium hyaluronate gel cross-linked with polyglycol epoxy derivatives for injection and preparation method thereof
  • Sodium hyaluronate gel cross-linked with polyglycol epoxy derivatives for injection and preparation method thereof
  • Sodium hyaluronate gel cross-linked with polyglycol epoxy derivatives for injection and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Embodiment 1: synthetic tetraethylene glycol diglycidyl ether (Ia)

[0099] Synthesize tetraethylene glycol diglycidyl ether of following structure:

[0100]

[0101] Add tetraethylene glycol (0.1mol), tetrahydrofuran (100mL) and potassium hydroxide (0.4mol) into the three-necked flask, stir in a water bath, then add epichlorohydrin (0.6mol) dropwise to the reaction system, and control the reaction temperature not to exceed React overnight at room temperature at 35°C. After the reaction, the reaction solution was filtered, and the filter residue was washed with dichloromethane, then the filtrate was collected, and the dichloromethane was removed by rotary evaporation to obtain a crude product. The crude product was molecularly distilled to obtain pure tetraethylene glycol diglycidyl ether.

[0102] 1 H-NMR (DMSO-d6): 2.52-2.55 (m, 2H), 2.70-2.73 (m, 2H), 3.07-3.11 (m, 2H), 3.22-3.28 (m, 2H), 3.52-3.56 (m , 16H), 3.68-3.73(m, 2H);

[0103] HPLC detection: the pro...

Embodiment 2

[0105] Embodiment 2: Synthesis of dodecaethylene glycol diglycidyl ether (Ib)

[0106] Synthesize dodecaethylene glycol diglycidyl ether of following structure:

[0107]

[0108] Add dodecaethylene glycol (0.1mol), tetrahydrofuran (100mL) and potassium hydroxide (0.4 mol) in the there-necked flask, stir in a water bath, then drop epichlorohydrin (0.6mol) in the reaction system, control the reaction temperature Over 35°C, react overnight at room temperature. After the reaction, the reaction solution was filtered, and the filter residue was washed with dichloromethane, then the filtrate was collected, and the dichloromethane was removed by rotary evaporation to obtain a crude product. The crude product was molecularly distilled to obtain pure dodecaethylene glycol diglycidyl ether.

[0109] 1 H-NMR (DMSO-d6): 2.51-2.55 (m, 2H), 2.70-2.73 (m, 2H), 3.07-3.11 (m, 2H), 3.22-3.29 (m, 2H), 3.51-3.57 (m , 48H), 3.68-3.73(m, 2H);

[0110] HPLC detection: the product purity is 99...

Embodiment 3

[0112] Embodiment 3: synthesizing Tetracethylene glycol diglycidyl ether (Ic)

[0113] Synthesize four tetraethylene glycol diglycidyl ethers of the following structure:

[0114]

[0115] Add tetracosanethylene glycol (0.1mol), tetrahydrofuran (100mL) and potassium hydroxide (0.4mol) into the three-necked flask, stir in a water bath, then add epichlorohydrin (0.6mol) dropwise to the reaction system, and control the reaction temperature Do not exceed 35°C, and react overnight at room temperature. After the reaction, the reaction solution was filtered, and the filter residue was washed with dichloromethane, then the filtrate was collected, and the dichloromethane was removed by rotary evaporation to obtain a crude product. The crude product was separated by a column to obtain pure tetracosanthyl glycol diglycidyl ether.

[0116] 1 H-NMR (DMSO-d6): 2.51-2.55 (m, 2H), 2.70-2.73 (m, 2H), 3.07-3.11 (m, 2H), 3.22-3.28 (m, 2H), 3.51-3.56 (m , 96H), 3.68-3.73(m, 2H);

[0117] H...

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Abstract

The invention discloses a sodium hyaluronate gel cross-linked with polyglycol epoxy derivatives for injection and a preparation method thereof. The polyglycol epoxy derivatives are preferably compounds with a single molecular weight. There are multiple ether bonds in the polyglycol, which has good water solubility and is more likely to undergo cross-linking reactions with polysaccharides. At the same time, because the number of polyglycol repeating units is easier to adjust and the length is easier to control, the performance of the sodium hyaluronate gel prepared by it as a cross-linking agent It is easier to control; the cross-linked sodium hyaluronate gel has low toxicity, less residue, small pushing force, good plasticity, good enzyme resistance, and long retention time in vivo. The invention also discloses a mild cross-linking agent inactivation technology, which hydrolyzes unreacted epoxy groups in the gel in a carbonate buffer system with pH=8-9, which can effectively reduce cross-linked hyaluronic acid It is difficult to remove impurities from the sodium phosphate gel, and avoids the toxicity problem of using BDDE in the cross-linking method in the prior art.

Description

technical field [0001] The invention relates to the technical field of sodium hyaluronate gel, in particular to a sodium hyaluronate gel cross-linked with polyglycol epoxy derivatives and a preparation method thereof. Background technique [0002] Hyaluronic acid (HA) is a linear polymer viscous polysaccharide composed of repeating disaccharide units of glucuronic acid and acetylglucosamine. Hyaluronic acid is an endogenous substance in the human body and has good biocompatibility; it has high viscoelasticity and non-Newtonian rheological properties; it is non-toxic, non-immunogenic, non-irritating, and has a high It is widely used as a soft tissue filler in cosmetology because of its safety and its ability to be degraded and eliminated by injecting hyaluronidase. That is to inject hyaluronic acid into the skin to increase the volume of soft tissue, which can achieve the purpose of wrinkle removal or shaping. However, because hyaluronic acid itself exists in liquid form, i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08J3/075C08J3/24C08G59/04C07D303/30C07D301/00A61L27/20A61L27/50C08L5/08
CPCA61L27/20A61L27/50A61L2430/34C07D301/00C07D303/30C08G59/04C08J3/075C08J3/24C08J3/246C08J2305/08C08L5/08A61L27/52A61L27/54A61L2400/06C07D303/28C08G65/10C08J2471/02
Inventor 魏真林美娜赵宣
Owner JENKEM TECH
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