CN-121971437-A - Ergothioneine lipid compound and preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to an ergothioneine lipid compound and a preparation method and application thereof. How to further improve the oral and pulmonary absorption efficiency of ergothioneine. In view of the above problems, the present invention provides a lipid complex of ergothioneine, which is a complex formed by completely coating ergothioneine with lipid through intermolecular non-covalent bonds. The invention changes the physicochemical property of the ergothioneine by forming the compound with the lipid, provides a new absorption way for the ergothioneine, particularly remarkably improves the absorption efficiency of the ergothioneine in a passive diffusion mode, effectively breaks through the limitation of the existing absorption mode, and improves the absorption capacity of the ergothioneine in vivo.

Inventors

• WANG YAJING
• XU WENYI
• LV JING
• HUANG XIANFENG
• WANG SHAN

Assignees

• 常州大学

Dates

Publication Date

20260505

Application Date

20260313

Claims (10)

1. 1. The lipid complex of ergothioneine is characterized in that the lipid complex is formed by completely coating the ergothioneine through intermolecular non-covalent bonds.
2. 2. An ergothioneine lipid complex according to claim 1, wherein the lipid comprises one or more of a phospholipid or dioleoyl trimethylammonium propane.
3. 3. An ergothioneine lipid complex according to claim 2, characterized in that the mass ratio of lipid to ergothioneine is 1 (4-8).
4. 4. A lipid ergothioneine complex according to any of claims 1-3, characterized in that the preparation method is solvent evaporation, freeze drying or melting.
5. 5. The lipid ergothioneine complex according to claim 4, wherein the solvent evaporation method is to weigh lipid and ergothioneine according to the formula, add the lipid and the ergothioneine into a reaction solvent, heat and stir the mixture to dissolve the lipid and the ergothioneine into a uniform and transparent solution, and remove the reaction solvent by reduced pressure distillation after the reaction is finished, thus obtaining the lipid ergothioneine complex.
6. 6. The lipid complex of ergothioneine according to claim 4, wherein the freeze-drying method is to weigh lipid and ergothioneine according to the formula, add the lipid and the ergothioneine into a reaction solvent, heat and stir the mixture to dissolve the mixture to form a uniform and transparent solution, remove the reaction solvent by reduced pressure distillation after the reaction, add phosphate buffer solution into the reaction system, uniformly disperse the solution by ultrasound to form a uniform solution, then centrifuge the solution at a high speed, collect solid precipitate, freeze the obtained solid precipitate at a low temperature overnight, and freeze-dry the solid precipitate for at least 24 hours to obtain the lipid complex of ergothioneine.
7. 7. The lipid ergothioneine compound according to claim 4, wherein the melting method is to heat the lipid to a temperature above the melting point to change the lipid from a solid state or a semi-solid state into a viscous liquid state, then adding the ergothioneine according to the formula amount, stirring and mixing uniformly, and cooling the mixture to room temperature for solidification and molding to obtain the lipid ergothioneine compound.
8. 8. An inhalable aerosol of ergothioneine lipid complex according to any of claims 1 to 7, wherein the ergothioneine lipid complex is heated to ultrasound hydration with physiological saline and then atomized by an air compression atomizer or a vibrating mesh atomizer to form an inhalable aerosol.
9. 9. The ergothioneine microemulsion is characterized in that the ergothioneine compound according to any one of claims 1-7 is dissolved in an oil phase, a proper amount of surfactant is added, and the mixture is stirred uniformly to obtain an organic phase, and an aqueous phase is added into the organic phase dropwise, and the mixture is stirred uniformly to obtain the ergothioneine microemulsion.
10. 10. The inhalable and atomized aerosol of the ergothioneine microemulsion according to claim 9, wherein the ergothioneine microemulsion is diluted by normal saline and atomized by an air compression atomizer or a vibrating screen mesh atomizer to form the inhalable and atomized aerosol or directly atomized by the air compression atomizer or the vibrating screen mesh atomizer to form the inhalable and atomized aerosol.

Description

Ergothioneine lipid compound and preparation method and application thereof Technical Field The invention relates to the technical field of medicines, in particular to an ergothioneine lipid compound and a preparation method and application thereof. Background Ergothioneine (Ergothenine, EGT) is a natural chiral amino acid, has colorless, odorless and water-soluble properties, and is widely distributed in foods of plant and animal kingdom, such as mushrooms, black beans, red meats, oats, etc. EGT is concentrated in the human body in cells and tissues frequently exposed to oxidative stress, such as erythrocytes, ocular lens and cornea, liver, brain and bone marrow, where it is the highest in content, up to millimole range, and plays a key role as an antioxidant. Research shows that ergothioneine can be used as an adaptive antioxidant to protect damaged tissues, and has great development and utilization value and market potential in the fields of medicines, foods, beverages and cosmetics by virtue of a special thioketone structure, a higher oxidation-reduction potential (-60 mV) and the effects of safety, non-toxicity, strong in-vitro oxidation resistance, potential cytoprotection, anti-inflammation and neuroprotection. The trans-membrane transport mode of the substance mainly comprises passive diffusion, active transport and membrane bubble transport. Lipinski penta, proposed by the company of Buddha in 1997, suggested that molecules with poor water solubility were generally poorly fat-soluble, and that it was difficult to effectively cross the lipid barrier of the cell membrane by passive diffusion, resulting in lower bioavailability. Ergothioneine is thought to enter cells by active transport through OCTN-1 (organic cation transporter-1), but is not absorbed efficiently and has variability due to differences in the level of expression and site of expression of the transporter. Meanwhile, the ergothioneine raw material is expensive, so that the absorption way of the ergothioneine is increased, and particularly the absorption efficiency of the ergothioneine in a passive diffusion mode is improved, and the method has important practical significance. Currently, there are several common strategies for improving the absorption efficiency of water-soluble drugs. First, lipid prodrugs or lipid drug conjugates are prepared by structural modification. The chemical modification of the medicine with medium chain fatty acid, lysophospholipid and surfactant can improve the permeability of the molecule. For example, the anti-tumor drug gemcitabine is esterified to obtain CP-4126, the half-life period is prolonged to 3 times of that of the original drug, the tumor inhibition effect is more obvious, the cetyloxy modification of tenofovir to obtain CMX157 can improve the activity of NRTI resistant strain by thousands of times, and the cell permeability of caco-2 is improved by 3-5 times after the esterification of ginsenoside K. And secondly, is used in combination with an absorption enhancer or an enzyme inhibitor. The permeation promoter can transiently and reversibly improve the permeability of epithelial cells, for example, can open the tight connection among cells by adopting modes of combining sodium caproate, spermine and sodium taurine and the like, improves the oral absorption of BCS IV and the pulmonary absorption of interferon-alpha, can inhibit metabolic enzymes or efflux transport proteins in intestinal tracts and livers by using typical powerful cytochrome P450A 4 and P-glycoprotein (P-GP) inhibitors such as ketoconazole, itraconazole and the like, reduces the loss of medicines in the absorption process and before entering the systemic circulation, and is one of delivery strategies for improving the absorption widely applied clinically at present. Thirdly, nanotechnology is applied. The drug carrying systems such as liposome, nanoemulsion, polymer nanoparticle and the like are prepared, so that the physicochemical properties (such as lipophilicity, particle size distribution, crystal form and the like) of the drug are changed or the release behavior of the drug in the gastrointestinal tract is regulated, thereby improving the membrane permeability of the drug, reducing enzymolysis and first pass effect, and finally improving the bioavailability. In earlier studies, structural analysis of ergothioneine found that it has specific chirality, easy racemization, and high dependence of biological activity on structure, chemical modification of EGT was difficult, and not practical. The method further comprises the steps of 1) combining absorption promoters such as 8- (2-hydroxybenzoylamino) sodium octoate (SNAC), sodium octoate, sodium caprate and sodium cholate, finding that the interaction between EGT and molecules is very weak and the absorption promoting efficiency is limited, 2) regarding a lipid nano carrier, lipid represented by phospholipid has good biocompatibility, is a typical membrane material for prepar