Glycosyl ionic liquid, preparation method and application thereof, and antioxidant preparation

Abstract

The invention relates to the technical field of ionic liquid and biological medicine, in particular to glycosyl ionic liquid, a preparation method and application thereof and an antioxidant preparation. The name of the glycosyl ionic liquid is [O] X, [O] represents a hydrogen bond acceptor part, and X represents a hydrogen bond donor part; the hydrogen bond receptor part is derived from furanose and analogues thereof or pyranose and analogues thereof; the hydrogen bond donor part is derived from a compound shown in the following structural formula: # imgabs0 #. The ionic liquid can be used as a solvent and a stabilizer of API (American Petroleum Institute), and can completely replace a traditional volatile organic solvent, so that dual damage to environment and health is reduced.

Description

[0001] The present invention claims priority of Chinese patent application No. 2025105137066, entitled "Glycoside Ionic Liquid, Preparation Method and Application thereof and Antioxidant Preparation", and the contents of the description and claims of the priority document are fully incorporated into the description of the present invention and are regarded as part of the original description of the present invention. Technical Field

[0002] The present invention relates to the technical field of ionic liquids and biomedicine, and in particular to sugar-based ionic liquids, preparation methods and applications thereof, and antioxidant preparations. Background Art

[0003] In the process of disease, health, and aging, the metabolism of organisms is always accompanied by the production of free radicals, which leads to oxidative stress, lipid peroxidation damage, and the production of inflammatory factors. Although many chronic inflammatory diseases are believed to be caused by oxidative stress, antioxidants such as ascorbic acid are often used for treatment. However, the use of antioxidants such as ascorbic acid to treat oxidative stress has largely failed in history, and the prognosis of the treatment group using antioxidants is often even worse than that of placebo. This is because nominal antioxidant molecules such as ascorbic acid have complex multi-electron redox chemistry and can actually be pro-oxidants (Borodina I, et al. The biology of ergothioneine, an antioxidant nutraceutical. Nutr Res Rev. 2020 Dec; 33(2): 190-217.). For example, antioxidant carotenoids may also act as pro-oxidants under certain conditions, and this has been confirmed by the ATBC trial organized by the National Cancer Institute (NIH) of the United States. In the trial, a large cohort of people supplemented with 20 mg of β-carotene daily for 5-8 years. The results showed that compared with the control group, people who took beta-carotene supplements had an 18% increased risk of lung cancer (Jomova K, et al. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging. Arch Toxicol. 2023 Oct; 97(10): 2499-2574.).

[0004] In fact, similar to ascorbic acid, many active pharmaceutical ingredients (APIs) suffer from similar instability issues, including antioxidant inactivation and biodegradation. Therefore, the solubility and stability of APIs have always been major challenges in the biopharmaceutical field.

[0005] As nonvolatile, thermally stable, nonflammable, and tunable designer green solvents, ionic liquids hold great promise as a promising alternative to volatile organic solvents in drug synthesis. Their applications in drug delivery formulations extend beyond solubilization to enhance the therapeutic efficacy of drugs when administered topically or systemically. By rationally designing the structure of ionic liquids, it is possible to manipulate drug solubility, stability, absorption, and bioavailability (Zhang Suojiang, Zhou Qing, and Lü Xingmei, eds., "Ionic Liquid Green Technology," China Railway Publishing House, 1st edition, 2024).

[0006] Therefore, the object of the present invention is to develop a bio-ionic liquid solvent and stabilizer for dissolving and stabilizing API.

[0007] In view of this, the present invention is proposed. Summary of the Invention

[0008] The present invention aims to provide a sugar-based ionic liquid, a preparation method thereof, its application, and an antioxidant preparation. Embodiments of the present invention provide a sugar-based ionic liquid for use as a solvent and stabilizer for APIs. This ionic liquid can completely replace traditional volatile organic solvents as a solvent, and when used as a stabilizer, it eliminates the need for the addition of a chelating agent, thereby reducing environmental, water, and soil pollution.

[0009] The present invention is achieved in that:

[0010] In a first aspect, the present invention provides a sugar-based ionic liquid, the sugar-based ionic liquid is named [O]X, wherein [O] represents a hydrogen bond acceptor moiety and X represents a hydrogen bond donor moiety;

[0011] The hydrogen bond acceptor moiety is derived from furanose and its analogs or pyranose and its analogs;

[0012] The hydrogen bond donor portion is derived from the compound represented by the following structural formula:

[0013]

[0014] In an optional embodiment, the hydrogen bond acceptor portion is derived from any one of furan, hydrogenated furan, hydrogenated furan alcohol, carbonyl-containing furan, furanose compounds, pyran, hydrogenated pyran, hydrogenated pyranol, carbonyl-containing pyran, pyranose compounds and pyranoside compounds.

[0015] In an optional embodiment, the hydrogen bond acceptor portion is derived from any one of deoxyribose, ribose, fructose, furan, tetrahydrofuran, tetrahydrofurfuryl alcohol, furfural, ascorbic acid, and glucose, mannose, galactose, xylose, rhamnose, lactose, maltose, trehalose, sucrose, gluconolactone, maltitol, maltol, ethyl maltol, glucosamine, N-acetylglucosamine, methyl β-xylopyranoside, methyl galactopyranoside, pyran, pyranium, tetrahydropyran, 2,3-dihydropyran, tetrahydropyranol, isobutylmethyltetrahydropyranol, hydroxypropyltetrahydropyrantriol and pyrone.

[0016] In an alternative embodiment, the sugar-based ionic liquid is a hydrated sugar-based ionic liquid solvent.

[0017] In an alternative embodiment, the molar ratio of the hydrogen bond acceptor moiety to the hydrogen bond donor moiety is 5:1 to 1:5.

[0018] In a second aspect, the present invention provides a method for preparing the sugar-based ionic liquid described in the aforementioned embodiment, comprising: mixing and dissolving a raw material for forming a hydrogen bond acceptor portion [O] and a raw material for forming a hydrogen bond donor portion X.

[0019] In an optional embodiment, the preparation is carried out under non-vacuum conditions;

[0020] Preferably, the temperature of the mixed dissolution is 25-45°C and the time is 10-30 minutes;

[0021] Preferably, the raw materials for forming the hydrogen bond acceptor moiety [O] and the raw materials for forming the hydrogen bond donor moiety X are dissolved using water.

[0022] In a third aspect, the present invention provides a use of the sugar-based ionic liquid described in the aforementioned embodiment as a stabilizer for improving the stability of an antioxidant preparation;

[0023] Preferably, the antioxidant comprises ascorbic acid.

[0024] In a fourth aspect, the present invention provides a use of the sugar-based ionic liquid described in the aforementioned embodiment as a solvent and / or stabilizer for API.

[0025] In an optional embodiment, the API comprises at least one of vanillin, gallic acid, melatonin, and ascorbic acid;

[0026] Preferably, when the sugar-based ionic liquid is used as a solvent for the API, it no longer contains volatile organic solvents. That is, the sugar-based ionic liquid can completely replace traditional volatile organic solvents and be used to prepare API preparations that do not contain any organic solvents, thereby reducing the dual damage of traditional volatile organic solvents to the environment and health.

[0027] Preferably, when the sugar-based ionic liquid is used as a stabilizer for the API, no chelating agent is added. That is, the sugar-based ionic liquid can replace chelating agents such as EDTA, thereby reducing water and soil pollution caused by the chelating agent.

[0028] In a fifth aspect, the present invention provides an antioxidant preparation comprising a sugar-based ionic liquid and an antioxidant active ingredient, wherein the antioxidant active ingredient comprises ascorbic acid, wherein the antioxidant preparation does not contain any volatile organic solvent or does not contain a chelating agent.

[0029] The hydrated glycosylated ionic liquid is water-soluble, biocompatible, and can be mixed with water in any proportion to prepare pure aqueous solution preparations of the corresponding poorly soluble and unstable APIs;

[0030] The present invention has the following beneficial effects: In the embodiments of the present invention, cationic compounds and anionic compounds of specific structures are selected and combined as hydrogen bond acceptors and hydrogen bond donors to form a sugar-based hydrated ionic liquid. The ionic liquid has the dual properties of a solvent and a stabilizer for the API, can completely replace traditional volatile organic solvents, including chelating agents such as EDTA, can be mixed with water in any proportion, and can be used to prepare corresponding API pure aqueous solution preparations, thereby improving the bioavailability of the API and reducing the dual damage to the environment and health. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.

[0032] Figure 1 A comparison diagram of the thermodynamic energies of ascorbic acid in aqueous solution, gas phase, and sugar-based ionic liquid aqueous solution provided by an embodiment of the present invention;

[0033] Figure 2 The figure is a comparison of the color changes of an aqueous solution of ascorbic acid glycoside ionic liquid, an aqueous solution of ascorbic acid, and an existing commercially available ascorbic acid solution when stored at room temperature in the dark for more than 3 months. DETAILED DESCRIPTION

[0034] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be purchased commercially.

[0035] In a first aspect, the present invention provides a sugar-based ionic liquid, which is named [O]X, wherein [O] represents a hydrogen bond acceptor portion, that is, a cationic portion, and X represents a hydrogen bond donor portion, that is, an anionic portion.

[0036] The hydrogen bond acceptor moiety is derived from furanose and its analogs or pyranose and its analogs;

[0037] The hydrogen bond donor portion is derived from the compound represented by the following structural formula:

[0038]

[0039] Specifically, carbohydrates are the primary source of energy required to sustain life in all organisms. They are important components of biological tissues and cells, and serve as crucial raw materials for the synthesis of fats, proteins, and nucleic acids in the human body. Carbohydrates can be used to modify other drugs, resulting in hybrid molecules with enhanced activity and reduced side effects compared to the parent drug. Therefore, naturally derived carbohydrates are ideal building blocks for biofunctionalized ionic liquids. Carbohydrates are also the primary low-molecular-weight compatible solutes in organisms, playing a crucial role in protecting cells from various external stresses, such as high temperature, high osmotic pressure, desiccation, and radiation.

[0040] From a molecular perspective, carbohydrates are polyhydroxy aldehydes or polyhydroxy ketones and their dehydration condensation products. These structures are polyhydroxy aldehydes or polyhydroxy ketones, and therefore exhibit varying degrees of reducing and antioxidant properties. Naturally derived carbohydrate compounds, including six-membered heterocyclic pyranose and five-membered heterocyclic furanose, contain multiple chiral centers. These multifunctional compounds are susceptible to chemical reactions, acting as cationic moieties or hydrogen bond acceptors to combine with appropriate anionic moieties or hydrogen bond donors via hydrogen bonding forces, thereby self-assembling to form task-specific, cationic chiral, functional carbohydrate-based ionic liquid solvents and stabilizers.

[0041] Therefore, in the embodiments of the present invention, the hydrogen bond acceptor moiety is derived from furanose and its analogs or pyranose and its analogs. Specifically, the cation or hydrogen bond acceptor moiety is derived from any one of furan, hydrogenated furan, hydrogenated furanol, carbonyl-containing furan, furanose compounds, pyran, hydrogenated pyran, hydrogenated pyranol, carbonyl-containing pyran, pyranose compounds, and pyranoside compounds. For example, it includes but is not limited to deoxyribose, ribose, fructose, furan, tetrahydrofuran, tetrahydrofurfuryl alcohol, furfural, ascorbic acid, and any one of glucose, mannose, galactose, xylose, rhamnose, lactose, maltose, trehalose, sucrose, gluconolactone, maltitol, maltol, ethyl maltol, glucosamine, N-acetylglucosamine, methyl β-xylopyranoside, methyl galactopyranoside, pyran, pyranium, tetrahydropyran, 2,3-dihydropyran, tetrahydropyranol, isobutylmethyltetrahydropyranol, hydroxypropyltetrahydropyrantriol and pyrone.

[0042] The hydrogen bond donor portion of the sugar-based biological ionic liquid is derived from 2-mercapto-histidine-trimethyl inner salt, and its structural formula is shown below:

[0043] 2-Mercapto-histidine-trimethyl inner salt is a natural product synthesized by many bacteria and most fungi and is non-toxic to humans. The hydrogen at the 2-position of the ring of 2-Mercapto-histidine-trimethyl inner salt is replaced by a thiol group, and it exists as both thiol and thiol tautomers. The thiol isomer predominates at physiological pH.

[0044]

[0045] It is understood that the hydrogen bond donor moiety provided in the embodiments of the present invention also includes tautomers in the form of thiol and thiol.

[0046] Therefore, the widespread presence of phenolic hydroxyl, ketone, thiol, and thioketone functional groups in the sugar-based ionic liquids provided by the present invention, as well as the strong hydrogen bonding between ions, endow the sugar-based ionic liquids with the dual properties of solvent and stabilizer. They not only serve as good solvents for poorly soluble APIs, especially antioxidants, but also as stabilizers for API antioxidants.

[0047] Based on the electronegativity theory, the structural formula The 2-mercapto-histidine-trimethyl inner salt molecule represented by the above formula has a large electronegativity of the central atom O and a partial negative charge, which enhances the stability and acidity of the carboxylate anion and is more conducive to the dissociation into R-COO - The negative ion can therefore serve as an anionic portion or hydrogen bond donor in the [O]X structure in the sugar-based ionic liquid;

[0048] Saccharide compounds have furan and pyran heterocyclic structures containing O. Under acidic conditions, the O atoms on the ring are protonated to form typical oxonium ions. Or it can be protonated to form a stable cation under the induction of polar molecules, such as furanose cation In the examples, all products have an acidic pH (pH <7.4), tending to accept protons to form oxygen cations. Only under alkaline conditions can sugar hydroxyl groups be deprotonated to form oxygen anions. Therefore, sugar compounds can act as cationic moieties or hydrogen bond acceptors in the [O]X structure in the sugar-based ionic liquids.

[0049] The following embodiments of the present invention are specifically described using ascorbic acid as an example.

[0050] Ascorbic acid is a water-soluble antioxidant whose antioxidant activity is primarily achieved through free radical scavenging. It converts to semi-dehydroascorbic acid through the gradual electron donation process. Ascorbic acid is extremely unstable and easily oxidizes in aqueous solution to form dehydroascorbic acid, resulting in browning and pro-oxidative properties. Structurally, ascorbic acid is an oxide of trihydroxyfuran and exists as a tautomer of an unsaturated lactone.

[0051]

[0052] Ascorbic acid exhibits significant thermochromic and photochromic properties, leading to browning. The thermochromic mechanism may be related to the delocalized π bond on the furan ring of the ascorbic acid molecule, which causes changes in the crystal or molecular structure. Photochromism may be accompanied by a number of photochemical reactions, leading to changes in the molecular structure. These reactions primarily involve valence isomerization and oxidation. Ascorbic acid is not only sensitive to heat but also to other external stimuli, such as acidochromism and solvatochromism.

[0053] The mechanism by which sugar-based ionic liquids, as provided in the present invention, mitigate the color-induced changes in ascorbic acid may be related to the interaction of delocalized electrons on the furan and pyran rings. This electrostatic interaction, combined with interionic hydrogen bonding, helps stabilize the large π bond, thereby further stabilizing the molecular configuration of ascorbic acid. When ionic liquids can replace organic solvents, the solvatochromic changes in ascorbic acid can be further mitigated.

[0054] Ascorbic acid, as a five-membered heterocyclic furanose derivative, can also self-assemble with 2-mercapto-histidine-trimethylol anion through hydrogen bonding to form the sugar-based ionic liquid of the present invention, just like other sugar derivatives, and also has a certain stabilizer effect.

[0055] Molecular simulation experimental data show that the molecular conformation of ascorbic acid molecules in the glycosylated ionic liquid aqueous solution is more stable and has lower thermodynamic energy than that in aqueous solution and gas phase (see Figure 1 The molecular simulation experimental data are consistent with the experimental results of Application Examples 6-13.

[0056] According to experimental verification, the sugar-based ionic liquid provided by the embodiment of the present invention also has the same effect of improving the solubility and stability of other API model compounds.

[0057] Furthermore, the sugar-based ionic liquid is a sugar-based hydrated ionic liquid solvent, and the molar ratio of the hydrogen bond acceptor part to the hydrogen bond donor part is 5:1 to 1:5, that is, the molar ratio of [O] to X is (5:1) to (1:5); for example, it is any value between (5:1)-(1:5) such as 2:1, 3:1, 4:1, 5:1, 1:1, 1:2, 1:3 and 1:4.

[0058] In a second aspect, the present invention provides a method for preparing the sugar-based ionic liquid described in the aforementioned embodiment, comprising: mixing and dissolving a raw material for forming a hydrogen bond acceptor portion [O] and a raw material for forming a hydrogen bond donor portion X.

[0059] The entire preparation process is carried out under non-vacuum conditions (e.g., room temperature and pressure). The raw materials for forming the hydrogen bond acceptor [O] and the raw materials for forming the hydrogen bond donor X are dissolved in water. The mixed dissolution temperature is 25-45°C, and the time is 10-30 minutes. Alternatively, no solvent is added during the preparation of the sugar-based ionic liquid, and the two raw materials are directly mixed to form the desired ionic liquid.

[0060] In a third aspect, the present invention provides a use of the sugar-based ionic liquid described in the aforementioned embodiment as a stabilizer for improving the stability of an antioxidant preparation; wherein the antioxidant comprises ascorbic acid.

[0061] In a fourth aspect, the present invention provides a use of the sugar-based ionic liquid described in the aforementioned embodiment as a solvent and / or stabilizer for API.

[0062] In an alternative embodiment, the API model compound includes at least one of vanillin, gallic acid, melatonin, and ascorbic acid.

[0063] The sugar-based ionic liquid is used as a solvent, wherein the solvent contains only the sugar-based ionic liquid and does not contain other solvents or organic solvents, and can completely replace traditional volatile organic solvents to prepare API preparations that do not contain any organic solvents, thereby reducing the dual damage of traditional volatile organic solvents to the environment and health.

[0064] The hydrated glycosylated ionic liquid is water-soluble, biocompatible, and can be mixed with water in any proportion to prepare pure aqueous solutions of the corresponding API. It can replace chelating agents such as EDTA, mitigating water and soil pollution.

[0065] In a fifth aspect, the present invention provides an antioxidant preparation comprising a sugar-based ionic liquid and an antioxidant active ingredient, wherein the antioxidant active ingredient comprises ascorbic acid, wherein the antioxidant preparation does not contain any volatile organic solvent or the antioxidant preparation does not contain a chelating agent.

[0066] The features and performance of the present invention are further described in detail below with reference to the embodiments.

[0067] Method for determining the physical properties of the sugar-based ionic liquid:

[0068] pH test method: pH is measured using a pH meter. The actual test temperature is 25-30°C.

[0069] Thermal stability test method: (1) Cold resistance: Pre-adjust the refrigerator to 0℃ (temperature control accuracy ±1℃) or (0℃±1℃), and place a bottle of sample in the refrigerator. Take it out after 24 hours, return it to room temperature and observe visually. If there is no obvious difference in properties from before the test, it is considered stable. (2) Heat resistance: Pre-adjust the constant temperature incubator to 40℃ (temperature control accuracy ±1℃), and place a bottle of sample in the constant temperature incubator. Take it out after 24 hours, return it to room temperature and observe visually. If there is no obvious difference in properties from before the test, it is considered stable.

[0070] Photochromic change determination method: (1) Photochromic change: at room temperature 18-20℃, 10m 2 In a dark room, place a bottle of sample under a 100W UV lamp. After 24 hours, remove the sample and observe visually. No obvious color difference is found compared to before the test. (2) Thermochromic change: Pre-adjust the constant temperature incubator to 40℃ (temperature control accuracy ±1℃) and place a bottle of sample in the constant temperature incubator. After 24 hours, remove the sample and return it to room temperature and observe visually. No obvious difference is found compared to before the test.

[0071] The sources and abbreviations of the raw materials provided in the embodiments of the present invention are as follows:

[0072] 2-Mercapto-histidine-trimethylol salt (99%, Nanjing Letao), histidine, deoxyribose, ribose, maltol, ethyl maltol, glucosamine, gallic acid (95-99%, Aladdin), fructose, mannose, galactose, xylose, maltose (BR, Sinopharm), N-acetylglucosamine, hydroxypropyl tetrahydropyrantriol (98%, Huaxi), tetrahydrofuran (AR, 97%, McLean), tetrahydrofurfuryl alcohol (AR, Lin's), ascorbic acid, glucose (AR, 99.5%, Xiyu), rhamnose (100%, Taidong), trehalose (100%, Linyuan), gluconolactone (99%, Xinhuanghai), melatonin (99%, Leibu).

[0073] deo (deoxyribose), rib (ribose), fructose, fur (furan), thf (tetrahydrofuran), thk (tetrahydrofurfuryl alcohol), fal (furfural), lvc (ascorbic acid), glu (glucose), man (mannose), gal (galactose), xyl (xylose), rha (rhamnose), gdl (gluconolactone), lac (lactose), maltose, tre (trehalose), suc (sucrose), mat (maltitol), m et (maltol), ema (ethyl maltol), gla (glucosamine), nag (N-acetylglucosamine), xym (methyl β-xylopyranoside), mga (methyl galactopyranoside), pyr (pyran), pyl (pyranium), thp (tetrahydropyran), dhp (2,3-dihydropyran), thl (tetrahydropyranol), imt (isobutylmethyltetrahydropyranol), pro (hydroxypropyltetrahydropyrantriol), apy (pyrone), H (histidine).

[0074] Examples 1-19

[0075] Examples 1-19 each provide a sugar-based ionic liquid, the composition of which is shown in Table 1 below.

[0076] Examples 1-19 all provide a method for preparing a saccharide ionic liquid, comprising: adding a saccharide raw material for forming a hydrogen bond acceptor [O] and a raw material 2-mercapto-histidine-trimethyl inner salt for forming a hydrogen bond donor X in sequence according to the composition molar ratio in Table 1, stirring at 25-45° C. for 10-30 minutes until completely dissolved, and adding water to a total amount of 100%, thereby obtaining the saccharide ionic liquid [O]X of Examples 1-19.

[0077] Among them, the sugar-based ionic liquid provided in Example 1 is a slightly yellow transparent solution due to the color of the deoxyribose raw material itself, and the other sugar-based ionic liquids are all colorless transparent solutions.

[0078] Table 1 Composition and physicochemical properties of sugar-based ionic liquids

[0079]

[0080]

[0081] Note: The molar ratio is rounded to the nearest integer.

[0082] As shown in Table 1, the sugar-based hydrated ionic liquid provided in this example exhibited good thermal stability. No separation, crystallization, precipitation, or pH shift was observed after standing at room temperature for more than three months.

[0083] Application Examples 1-5

[0084] The sugar-based ionic liquids of Example 1 were used to dissolve API model compounds, such as vanillin, gallic acid, and melatonin, to verify the solubility and stability of the sugar-based ionic liquids for poorly soluble and unstable API model compounds. Specific results are shown in Table 2.

[0085] Specifically, the preparation method includes: mixing the sugar-based ionic liquid of the example with the API. The specific amount of each substance is shown in Table 2.

[0086] Table 2 Composition and physicochemical properties of application examples 1-5

[0087]

[0088]

[0089] Note: The molar ratio is rounded to the nearest integer.

[0090] As can be seen from Table 2, the sugar-based ionic liquids provided in the embodiments of the present invention can dissolve and stabilize poorly soluble and unstable API model compounds, such as vanillin, gallic acid, and melatonin, and the obtained API solution is a colorless and transparent aqueous solution.

[0091] Furthermore, the sugar-based ionic liquids provided in the embodiments of the present invention can dissolve poorly soluble API compounds even without the addition of any organic solvents. For example, they can dissolve 0.1-1.0 wt% vanillin, 1 wt% gallic acid, and 1 wt% melatonin. This shows that the sugar-based ionic liquids provided in the embodiments of the present invention can effectively dissolve and stabilize poorly soluble and unstable API model compounds and can be used as solvents and stabilizers for poorly soluble and unstable APIs.

[0092] Application Example 6-13

[0093] Application Examples 6-13 verified the stabilizer effect of the sugar-based ionic liquid on the unstable API model compound ascorbic acid, see Table 3.

[0094] Table 3 Composition and physicochemical properties of application examples 6-13

[0095]

[0096]

[0097] Note: The molar ratio is rounded to the nearest integer.

[0098] The results show that ascorbic acid exhibits good stability in the sugar-based ionic liquid aqueous solution, that is, the sugar-based ionic liquid provided in the embodiment of the present invention can be used as a stabilizer to improve the stability of antioxidant preparations.

[0099] Specifically, according to Table 3, the color change test results show that: (1) Photochromic change test results: The ascorbic acid glycoside ionic liquid aqueous solution obtained in Application Examples 6-13 did not undergo any color change visible to the naked eye under direct UV100W for 24 hours; (2) Thermochromic change test results: The ascorbic acid glycoside ionic liquid aqueous solution obtained in Application Examples 6-13 did not undergo any color change visible to the naked eye when continuously heated in a constant temperature incubator at 40°C for 24 hours.

[0100] Furthermore, the API solutions obtained in Example 6-13 were subjected to cold and heat resistance tests, which showed good thermal stability. No separation, crystallization, precipitation or pH shift was observed after standing at room temperature for more than 3 months.

[0101] Furthermore, the ascorbic acid glycoside ionic liquid aqueous solution obtained in Example 6-13 was left to stand for more than 3 months at room temperature and under non-dark conditions, and the color change of the solution was observed visually. Figure 2 .

[0102] according to Figure 2 It can be seen that Example 6 (10% ascorbic acid glycoside ionic liquid aqueous solution) is light yellow (I); Example 10 (20% ascorbic acid glycoside ionic liquid aqueous solution) is light yellow (II); the control group (10% ascorbic acid aqueous solution) is obvious yellow (III); the control group (20% ascorbic acid aqueous solution) is brown (IV); the control group (15% ascorbic acid CE commercial skin care product, packaged in a brown light-proof glass bottle) is brown (V).

[0103] It can be seen that the sugar-based ionic liquid aqueous solution has a significant stabilizing effect on API model compounds that are unstable when exposed to heat and light, such as ascorbic acid, and still exhibits good stabilizing effects even at high concentrations of up to 20%, making the stability of ascorbic acid in aqueous solution significantly better than the stability of APIs under existing technical conditions.

[0104] Furthermore, when the sugar-based ionic liquid is used to prepare an API preparation or an antioxidant preparation, the sugar-based ionic liquid can be selected from any one or a combination of two or more of Examples 1-19 as a solvent or stabilizer for the antioxidant.

[0105] Furthermore, when the ascorbic acid glycoside ionic liquid aqueous solution is directly used as an API preparation or antioxidant preparation, other pharmaceutical excipients, such as cellulose, sodium hyaluronate, sodium alginate, carrageenan, xanthan gum, agar, carbomer and other gelling agents, can be conveniently added to prepare a transparent gel, an emulsion or a cream gel or a spray and other external skin dosage forms.

[0106] Molecular simulation experiments

[0107] Molecular simulations employed density functional theory (DFT) at the B3LYP / 6-31G(d,p) level for molecular structure optimization and frequency calculations. The thermodynamic energy of ascorbic acid in a hydrated sugar-based ionic liquid was further calculated using the SCRF method. The reaction conditions were set at 298.150 Kelvin and 1 atm.

[0108] Among the sugar compounds tested, most reactions had Gibbs free energies (ΔG ≤ 0) and formed stable hydrogen bonds, predicting that the reactions would proceed toward the product and form stable ionic liquids. This is consistent with laboratory testing results. Molecular simulation experimental data are shown in Table 4.

[0109] Furthermore, the solvation simulation experimental data showed that the thermodynamic energy of ascorbic acid in aqueous solution of sugar-based ionic liquids is lower and more stable than that in gas phase, and is far lower than that in aqueous solution, which is consistent with the laboratory test results. Among them, the thermodynamic energy of ascorbic acid in aqueous solution of tetrahydrofurfuryl alcohol and furfural ionic liquids is the lowest, followed by deoxyribose, galactose, trehalose, fructose, glucose, rhamnose, lactose and other sugar-based ionic liquids (not all shown in the figure) Figure 1 ). The thermodynamic energy of ascorbic acid molecules is as follows Figure 1 shown.

[0110] Furthermore, molecular simulation results show that when the anion or hydrogen bond donor component of the sugar-based ionic liquid is replaced with histidine, the Gibbs free energy of most reactions (ΔG ≥ 0) predicts that ionic liquids will not form. Even when the Gibbs free energy of the reaction (ΔG ≤ 0) is high, the hydrogen bond energy is low, making it difficult to form a stable ionic liquid. Molecular simulation data are shown in Table 5.

[0111] Table 4 Molecular simulation experimental data of sugar-based ionic liquids

[0112]

[0113]

[0114]

[0115]

[0116] Table 5 Histidine glycoside ionic liquid molecular simulation experimental data

[0117]

[0118]

[0119]

[0120]

[0121] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A sugar-based ionic liquid, characterized in that The name of the sugar-based ionic liquid is [O]X, wherein [O] represents a hydrogen bond acceptor moiety and X represents a hydrogen bond donor moiety; The hydrogen bond acceptor moiety is derived from furanose and its analogs or pyranose and its analogs; The hydrogen bond donor portion is derived from the compound represented by the following structural formula:

2. The sugar-based ionic liquid according to claim 1, characterized in that The hydrogen bond acceptor moiety is derived from any one of furan, hydrogenated furan, hydrogenated furan alcohol, carbonyl-containing furan, furanose compounds, pyran, hydrogenated pyran, hydrogenated pyranol, carbonyl-containing pyran, pyranose compounds and pyranoside compounds.

3. The sugar-based ionic liquid according to claim 1, characterized in that The hydrogen bond acceptor portion is derived from any one of deoxyribose, ribose, fructose, furan, tetrahydrofuran, tetrahydrofurfuryl alcohol, furfural, ascorbic acid, and glucose, mannose, galactose, xylose, rhamnose, lactose, maltose, trehalose, sucrose, gluconolactone, maltitol, maltol, ethyl maltol, glucosamine, N-acetylglucosamine, methyl β-xylopyranoside, methyl galactopyranoside, pyran, pyranium, tetrahydropyran, 2,3-dihydropyran, tetrahydropyranol, isobutylmethyltetrahydropyranol, hydroxypropyltetrahydropyrantriol and pyrone.

4. The sugar-based ionic liquid according to claim 1, characterized in that The sugar-based ionic liquid is a hydrated sugar-based ionic liquid solvent.

5. The sugar-based ionic liquid according to claim 1, characterized in that The molar ratio of the hydrogen bond acceptor moiety to the hydrogen bond donor moiety is 5:1 to 1:

5.

6. A method for preparing the sugar-based ionic liquid according to claim 1, characterized in that: include: The raw material for forming the hydrogen bond acceptor portion [O] and the raw material for forming the hydrogen bond donor portion X are mixed and dissolved.

7. The preparation method according to claim 6, characterized in that Preparation was performed under non-vacuum conditions; Preferably, the temperature of the mixed dissolution is 25-45°C and the time is 10-30 minutes; Preferably, the raw materials for forming the hydrogen bond acceptor moiety [O] and the raw materials for forming the hydrogen bond donor moiety X are dissolved using water.

8. Use of the sugar-based ionic liquid according to claim 1 as a stabilizer for improving the stability of an antioxidant preparation; Preferably, the antioxidant formulation comprises ascorbic acid.

9. Use of the sugar-based ionic liquid according to claim 1 as a solvent and / or stabilizer for API; The API comprises at least one of vanillin, gallic acid, melatonin, and ascorbic acid; Preferably, the sugar-based ionic liquid no longer contains volatile organic solvents when used as a solvent for the API; Preferably, when the sugar-based ionic liquid is used as a stabilizer for the API, no chelating agent is added.

10. An antioxidant preparation, characterized in that It comprises the sugar-based ionic liquid according to claim 1 and an antioxidant active ingredient, wherein the antioxidant active ingredient comprises ascorbic acid; Preferably, the antioxidant formulation does not contain any volatile organic solvents or the antioxidant formulation does not contain a chelating agent.

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