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CN-121987820-A - Compound of basic fibroblast growth factor and metal organic framework, pharmaceutical composition and application

CN121987820ACN 121987820 ACN121987820 ACN 121987820ACN-121987820-A

Abstract

The invention discloses a compound of an alkaline fibroblast growth factor and a metal organic framework, a pharmaceutical composition and application thereof, and belongs to the technical field of wound healing medicines. The bFGF@ZPF-2 compound provided by the invention comprises a metal organic framework material ZPF-2 and bFGF loaded on the ZPF-2, and the bFGF@MIL-53 (Al) -FA compound provided by the invention comprises a metal organic framework material MIL-53 (Al) -FA and bFGF loaded on MIL-53 (Al) -FA. According to the invention, by constructing two compounds of bFGF@ZPF-2 and bFGF@MIL-53 (Al) -FA, the high-efficiency load and activity protection of bFGF are realized, the synergy of quick effect and continuous release can be realized in response to the wound microenvironment, the biocompatibility is good, the wound healing effect is obviously improved, and the storage and transportation cost is reduced.

Inventors

  • ZHANG WEN
  • CHEN CHAO
  • LI JIAYI
  • MENG XUAN
  • CHEN YAO
  • MENG XIN
  • LI DAWEI
  • YU XIAOTONG
  • WANG ZIXUAN
  • LIN ZHENGUANG
  • SUN YINGXIAO
  • WANG QI

Assignees

  • 山东省药学科学院
  • 南开大学
  • 天津科技大学

Dates

Publication Date
20260508
Application Date
20260130

Claims (10)

  1. 1. The bFGF@ZPF-2 compound is characterized by comprising a metal organic framework material ZPF-2 and a basic fibroblast growth factor bFGF loaded on the ZPF-2, wherein an organic ligand of the ZPF-2 is 2-hydroxy-5-fluoropyrimidine, a metal ion is Zn 2+ , and the loading amount of the bFGF is 0.2-0.8 mg/g.
  2. 2. The method for preparing bfgf@zpf-2 complex according to claim 1, comprising the steps of: Adding bFGF aqueous solution into 2-hydroxy-5-fluoropyrimidine aqueous solution, adding zinc salt aqueous solution, uniformly mixing, standing for reaction, washing a solid product obtained by the reaction, and drying to obtain the bFGF@ZPF-2 compound.
  3. 3. The preparation method of claim 2, wherein the concentration of the bFGF aqueous solution is 2-5 mug/mL, the concentration of the 2-hydroxy-5-fluoropyrimidine is 12-20 mg/mL, the concentration of the zinc salt aqueous solution is 10-25 mg/mL, the molar ratio of Zn 2+ in the 2-hydroxy-5-fluoropyrimidine and zinc salt is (2.5-3.5): 1, and the mass ratio of the bFGF to the 2-hydroxy-5-fluoropyrimidine is (0.0008-0.008): 5-8.
  4. 4. The preparation method according to claim 2, wherein the time of the standing reaction is 20 to 60 minutes, and the temperature of the standing reaction is 10 to 40 ℃.
  5. 5. The bFGF@MIL-53 (Al) -FA compound is characterized by comprising a metal organic framework material MIL-53 (Al) -FA and bFGF loaded on the MIL-53 (Al) -FA, wherein the MIL-53 (Al) -FA takes Al 3+ as a metal node and disodium fumarate as an organic ligand to form a pore structure, and the loading amount of the bFGF is 0.12-0.62 mg/g.
  6. 6. The method for preparing the bFGF@MIL-53 (Al) -FA complex according to claim 5, comprising the steps of: Adding bFGF aqueous solution into fumaric acid ligand aqueous solution, adding aluminum salt aqueous solution, uniformly mixing, standing for reaction, washing a solid product obtained by the reaction, and drying to obtain the bFGF@MIL-53 (Al) -FA compound.
  7. 7. The preparation method of claim 6, wherein the concentration of the bFGF aqueous solution is 2-5 mug/mL, the fumaric acid ligand aqueous solution is prepared by dissolving disodium fumarate in water, the concentration is 0.05-0.2 mol/L, the concentration of the aluminum salt aqueous solution is 0.05-0.2 mol/L, the molar ratio of Al 3+ in the fumaric acid ligand and aluminum salt is (0.8-1.5): 1, the standing reaction time is 20-60 min, and the standing reaction temperature is 10-40 ℃.
  8. 8. A pharmaceutical composition, which is characterized by comprising the bFGF@ZPF-2 compound according to claim 1, or the bFGF@ZPF-2 compound prepared by the preparation method according to any one of claims 2-4, or the bFGF@MIL-53 (Al) -FA compound according to claim 5, or the bFGF@MIL-53 (Al) -FA compound prepared by the preparation method according to claim 6 or 7, and pharmaceutically acceptable auxiliary materials.
  9. 9. The pharmaceutical composition of claim 8, wherein the pharmaceutically acceptable excipients comprise a poloxamer 407 gel solution, wherein the concentration of poloxamer 407 in the poloxamer 407 gel solution is 15-18 wt%, and the solvent is citrate buffer.
  10. 10. The bfgf@zpf-2 complex according to claim 1, or the bfgf@zpf-2 complex prepared by the preparation method according to any one of claims 2 to 4, or the bfgf@mils-53 (Al) -FA complex according to claim 5, or the bfgf@mils-53 (Al) -FA complex prepared by the preparation method according to claim 6 or 7, or the application of the pharmaceutical composition according to claim 8 or 9 in preparing a medicament for promoting wound healing.

Description

Compound of basic fibroblast growth factor and metal organic framework, pharmaceutical composition and application Technical Field The invention relates to the technical field of wound healing medicines, in particular to a compound of an alkaline fibroblast growth factor and a metal organic framework, a pharmaceutical composition and application thereof. Background The information disclosed in the background of the invention is only for enhancement of understanding of the general background of the invention and is not necessarily to be taken as an admission or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art. Normal skin tissue has impaired barrier function due to surgery, burns, trauma, skin disease, microbial infection or metabolic dysfunction, and thus initiates wound formation. Wound healing is a key biological process for recovering tissue integrity, repairing skin barrier function and reconstructing skin homeostasis, and basic fibroblast growth factor (bFGF) is used as an important healing promoting factor, and can effectively promote capillary regeneration, improve local blood circulation and accelerate wound healing. However, bFGF has poor stability itself, is sensitive to external environmental factors such as temperature, pH, protease, etc., and is susceptible to polymerization, oxidation, cleavage or deamidation, etc., resulting in a decrease or even loss of its biological activity. The existing bFGF preparation needs low-temperature storage and transportation, has harsh conditions and has higher cost. Meanwhile, the existing bFGF preparation comprises an external solution and external gel, wherein the solution prescription does not contain a controlled release component, the gel prescription is formed by taking carbomer as a gel matrix, and bFGF is diffused and released in the gel prescription, so that a large amount of bFGF is easily released in a short time after clinical application, and an abrupt release effect is formed. The burst release can cause the problems of non-persistent efficacy, frequent dressing change, easy adverse reaction caused by a large amount of high-activity bFGF in a short time, degradation and failure of a large amount of bFGF due to factors such as pH value, protease, oxidative stress, exudate flushing and the like in the wound environment, and poor drug availability. As a novel porous material, the Metal Organic Framework (MOF) has high specific surface area, adjustable pore channel structure and good structural diversity, and has potential application value in the field of drug delivery. In the prior art, when the bFGF-like bioactive proteins with complex structures and low stability are loaded on most MOF materials, a plurality of technical problems exist that the pore canal size or chemical environment of part of MOFs is not matched with bFGF, so that the encapsulation efficiency is low or bFGF activity is lost in the loading process, the biocompatibility of part of MOFs is insufficient and the MOFs are difficult to directly apply to the field of medicines, the existing MOFs loaded bFGF release system is designed for small molecular medicines, the responsiveness to the wound microenvironment is poor, the rapid onset and sustained release synergy of bFGF are difficult to realize, and the activity of bFGF in the wound environment cannot be effectively protected. Therefore, there is a need to provide a bFGF-MOF complex system that can efficiently load bFGF, effectively protect its bioactivity, respond to wound microenvironment, and achieve rapid onset and sustained release synergy, and has good biocompatibility, so as to solve the above-mentioned problems in the prior art. Disclosure of Invention In view of the above, the invention provides a compound of basic fibroblast growth factor and metal organic framework, a pharmaceutical composition and application thereof, and the invention realizes high-efficiency load and activity protection of bFGF by constructing two compounds of bFGF@ZPF-2 and bFGF@MIL-53 (Al) -FA, can respond to wound microenvironment to realize rapid onset and sustained release synergy, has good biocompatibility, remarkably improves wound healing effect and reduces storage and transportation cost. In a first aspect, the invention provides a bFGF@ZPF-2 compound which comprises a metal organic framework material ZPF-2 and a basic fibroblast growth factor bFGF loaded on the ZPF-2, wherein an organic ligand of the ZPF-2 is 2-hydroxy-5-fluoropyrimidine, a metal ion is Zn 2+, and the loading capacity of the bFGF is 0.2-0.8 mg/g. In a second aspect, the invention provides a preparation method of the bFGF@ZPF-2 complex, which comprises the following steps: Adding bFGF aqueous solution into 2-hydroxy-5-fluoropyrimidine aqueous solution, adding zinc salt aqueous solution, uniformly mixing, standing for reaction, washing a solid product obtained by the reaction, and drying to obtain the bFGF@