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In-situ hydrogel composition taking nano-micelles as cross-linking agent and application of in-situ hydrogel composition

A technology of hydrogel and composition, applied in the field of in-situ hydrogel composition, can solve the problems of low drug loading, difficult administration, limited number of active groups, etc., so as to reduce the toxic and side effects of drugs and reduce drug administration frequency, the effect of improving the photothermal efficiency

Active Publication Date: 2020-09-22
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the above-mentioned carriers show certain kidney-targeting properties after systemic administration, there are the following problems in application: the structure of drug-carrier conjugates is not clear, and there is unknown difficulty in developing them into new drugs; the carrier has a large molecular weight , limited number of active groups, low drug loading; complex preparation process, poor reproducibility, not suitable for large-scale industrial production; immunogenicity, poor biocompatibility, high toxicity
[0008] Two-drug combination or multi-drug combination strategies usually show better curative effect. However, biomacromolecular drugs and insoluble small molecule drugs are usually delivered by different drug delivery systems due to the large difference in physical and chemical properties, making drug administration difficult. And it is difficult to ensure the drug concentration in the lesion at the same time

Method used

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  • In-situ hydrogel composition taking nano-micelles as cross-linking agent and application of in-situ hydrogel composition
  • In-situ hydrogel composition taking nano-micelles as cross-linking agent and application of in-situ hydrogel composition
  • In-situ hydrogel composition taking nano-micelles as cross-linking agent and application of in-situ hydrogel composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1: Preparation of base-catalyzed F127-HA micellar hydrogel composition and characterization of its physical and chemical properties

[0059] Schematic diagram of the structure of the micellar hydrogel figure 1 shown.

[0060] First, synthesize F127 methacrylate (bis-F127-MA), the structural formula and NMR spectrum are as follows figure 2 shown. Weigh 5 g (0.4 mmol) of Pluronic F127 (F127), dissolve it in 100 mL of anhydrous dichloromethane, add 2 mL of triethylamine and 4 mL of methacrylic anhydride ( 0.026 mol), and reacted at room temperature for 24 hours. After the reaction, the reaction solution was concentrated under reduced pressure to 20 mL, precipitated and crystallized with glacial ether with 5 times the volume of the reaction solution, filtered by suction, and dried in vacuum to obtain double bond-modified F127 (bis- F127-MA, 4.2 g, 80% yield). 1 HNMR (400 MHz, CDCl3, δ): 6.13 (s, 2H), 5.58 (s, 2H), 3.57 (bs, PEG), 1.13 (bs, 6H) ( figure 2 ). ...

Embodiment 2

[0063] Example 2: Preparation of alkali-catalyzed F127-HA micellar hydrogel composition loaded with tripterine

[0064] Weigh 10 mg of tripterine (CLT) and dissolve in 10 mL of acetonitrile to prepare a 1 mg / mL stock solution. Weigh 50 mg of bis-F127-MA, dissolve it in 5 mL of acetonitrile, add 3 mL of CLT stock solution, mix well, then rotate and evaporate to form a drug-containing polymer film, and then disperse in 2 mL of HEPES (pH8.0, 0.1M) buffer CLT-loaded F127-MA micelles were obtained. The micelles prepared by the above method were spherical and uniform in size, with an average particle diameter of 35.6 ± 0.6 nm, a PDI of 0.168 ± 0.02, a zeta potential of -0.13 ± 0.011mV, and an encapsulation efficiency of (95.4 ± 2.0)%. The dose was (1.62 ± 0.1)%. F127-MA micelles TEM image and particle size image as shown Figure 5 shown.

[0065] Prepare drug-loaded micelles (5% - 10%) with 1M, pH8.0 HEPES as solvent, and prepare 1% - 10% solution by dissolving thiol-modified hy...

Embodiment 3

[0066] Example 3: Preparation of the base-catalyzed F127-HA micellar hydrogel composition loaded with prednisolone

[0067] Weigh 10 mg of prednisolone (PRE) and dissolve in 10 mL of acetonitrile to prepare a 1 mg / mL stock solution. Weigh 50 mg of bis-F127-MA, dissolve it in 5 mL of acetonitrile, add 3 mL of PRE stock solution, mix well, then rotatively evaporate to form a drug-containing polymer film, and then disperse in 2 mL of HEPES (pH8.0, 0.1M) buffer Preloaded F127-MA micelles. The micelles are spherical in shape, uniform in particle size distribution, and the encapsulation efficiency is greater than 90%. In the same way, 10% HASH solution was prepared with pure water as solvent, and 2 mL of HASH solution was mixed with 2 mL of PRE-loaded micellar solution in equal volume. The glue is uniform and transparent.

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Abstract

The invention discloses an in-situ hydrogel composition taking nano-micelles as a cross-linking agent and application of the in-situ hydrogel composition. The invention discloses an in-situ hydrogel composition suitable for local co-delivery of macromolecular drugs and / or micromolecular drugs and application. Functionalized micelles are used as indissolvable micromolecular solubilizing carriers and are crosslinked with a hydrophilic polymer hydrogel framework material to construct a reticular three-dimensional hydrogel structure, so that local controllable delivery and release of micromolecular drugs and biomacromolecular drugs is realized. According to the in-situ hydrogel composition, micelles with functionalized end groups are used as solubilizing carriers of indissolvable drugs to realize local controllable delivery and release of micromolecular drugs, and the functionalized end groups are used as the cross-linking agent of hydrogel to be cross-linked with a side chain functionalized modified chain hydrophilic polymer material to construct a hydrophilic reticular three-dimensional gel structure. Micromolecules for local photothermal therapy can improve the photothermal efficiency of the photothermal agent and the photothermal stability after repeated illumination effectively, and can be applied to adjuvant therapy after tumor surgery.

Description

technical field [0001] The invention belongs to the technical field of medicines, and mainly relates to an in-situ hydrogel composition which uses nano-sized micelles as a cross-linking agent and is suitable for local co-delivery of macromolecular drugs and small molecular drugs and its anti-renal fibrosis, anti- Applications in tumor therapy. Background technique [0002] The incidence of chronic kidney disease (CKD) is increasing year by year worldwide. Among them, interstitial renal fibrosis (interstitial renal fibrosis) is a common pathological pathway leading to end-stage renal failure (ESRF) in chronic kidney disease, and can also cause progressive renal failure, complications of renal function damage, and Induce cardiovascular disease, seriously endanger human health and quality of life. Renal interstitial fibrosis is the inevitable result of excessive accumulation of extracellular matrix (ECM), and is the wound healing process of renal tissue after chronic persiste...

Claims

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Application Information

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IPC IPC(8): A61K9/107A61K9/06A61K47/36A61K47/10A61K47/40A61P13/12A61P35/00
CPCA61K9/06A61K9/1075A61K47/10A61K47/36A61K47/40A61P13/12A61P35/00
Inventor 符垚邓黎张志荣
Owner SICHUAN UNIV
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