Multi-glycol epoxy derivative cross-linked sodium hyaluronate gel used for injection and preparation method thereof

A technology of sodium hyaluronate and alcohol epoxy, which is applied in the fields of pharmaceutical formulation, tissue regeneration, and drug delivery, and can solve problems such as good injectability, small extrusion force, and strong degradation resistance of the gel

Active Publication Date: 2018-04-06
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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  • Multi-glycol epoxy derivative cross-linked sodium hyaluronate gel used for injection and preparation method thereof
  • Multi-glycol epoxy derivative cross-linked sodium hyaluronate gel used for injection and preparation method thereof
  • Multi-glycol epoxy derivative cross-linked sodium hyaluronate gel used 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 multi-glycol epoxy derivative cross-linked sodium hyaluronate gel used for injection and a preparation method thereof. The multi-glycol epoxy derivative is preferably a compound with a single molecular weight, multiple ether bonds exist in the molecule, the compound is good in water solubility and can generate cross-linking reaction with polysaccharide more easily, and because the quantity of multi-glycol repeating units is easy to adjust and the length is relatively easy to control, the performance of sodium hyaluronate gel prepared as a cross-linking agent is relatively easy to regulate; and the cross-linked sodium hyaluronate gel is low in toxicity, less in residue, weak in extruding thrust, good in moulding property, good in enzyme resistance and long in retaining time in the body. The invention further discloses a mild cross-linking agent inactivation technology, unreacted epoxy group in the gel undergoes hydrolysis reaction in a carbonate buffer system with pH of 8-9, so as to effectively reduce the difficulty in impurity removal of cross-linked sodium hyaluronate gel and avoid the problem of toxicity of BDDE used in a cross-linking method of 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 Applications(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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