Supramolecular ionic liquids, supramolecular fat-reducing complexes, and methods of making and using the same

Abstract

The application relates to the technical field of health-care compound, and particularly discloses a supramolecular ionic liquid, a supramolecular fat-reducing compound, a preparation method and application thereof. The supramolecular ionic liquid comprises L-carnitine molecules and hydroxyl citric acid molecules, the L-carnitine molecules and the hydroxyl citric acid molecules are self-assembled into a supramolecular structure under the interaction of non-covalent bonds, and the structure is shown in the figure. The supramolecular ionic liquid can better maintain the original effects of L-carnitine and hydroxyl citric acid, effectively improve the skin permeability and bioavailability of hydroxyl citric acid, and can be used as a delivery carrier of other active ingredients or drugs to realize the effect of drug delivery. The supramolecular fat-reducing compound constructed on the basis has the effects of significantly reducing fat and treating obesity, has high biological safety, and has great application prospects in the fields of fat-reducing drugs or weight-reducing products.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of health care compounds, in particular to a supramolecular ionic liquid, a supramolecular fat-reducing compound, and a preparation method and application thereof. BACKGROUND

[0002] Supramolecular assembly technology is a method of self-organizing molecules into ordered structures or assembly systems through non-covalent interactions between molecules. This method allows researchers to precisely design and control the interactions between molecules, thereby achieving the construction of materials with specific functions and properties. DES is part of the supramolecular assembly technology, E is composed of two or more components, usually including a combination of a hydrogen donor (such as a hydrogen bond donor) and a hydrogen acceptor (such as a hydrogen bond acceptor). It usually has the advantages of being adjustable and designable.

[0003] Hydroxycitric acid (HCA) is a natural organic acid with the chemical structure C6H8O8. It is a derivative of citric acid and has a variety of important biological activity characteristics. Hydroxycitric acid mainly exists in some plants, especially some subtropical and tropical plants belonging to the Clusiaceae family, such as Indian bitter orange (Garcinia cambogia). Hydroxycitric acid has a variety of application fields, including but not limited to medicine, food, and cosmetics. It is widely studied in the pharmaceutical field, especially its application in weight loss therapy. Hydroxycitric acid is believed to inhibit fat synthesis, promote fat metabolism in the body, and has the potential to suppress appetite. Therefore, it is used as an active ingredient in some weight loss products and drugs.

[0004] L-carnitine, also known as carnitine or methyl L-carnitine, is an amino acid derivative. The main function of L-carnitine in the human body is to promote the transport and metabolism of fatty acids. It plays an important role in transporting fatty acids into mitochondria for energy. It helps break down fatty acids into energy and plays a role in glucose metabolism. It also plays a key role in maintaining normal function of the heart, muscles, and nervous system in the body.

[0005] Although the above ingredients all have weight loss effects, their applications are usually limited to oral administration and have not yet played a role in transdermal administration for weight loss. The products currently on the market for weight loss often have side effects or are difficult to achieve the expected effect of weight loss. Therefore, it is necessary to develop a new and efficient weight loss system using the above ingredients with significant weight loss effects.

[0006] Therefore, the prior art still needs to be improved and developed. SUMMARY

[0007] In view of the above deficiencies of the prior art, the present application provides a supramolecular ionic liquid, a supramolecular fat-reducing complex, and a preparation method and application thereof, aiming at the problem of unobvious weight loss effect and side effects of existing weight loss products.

[0008] Specifically, the technical solutions of the present application are as follows:

[0009] The first aspect of the present application is to provide a supramolecular ionic liquid, which comprises L-carnitine molecules and hydroxyl citric acid molecules, and the L-carnitine molecules and the hydroxyl citric acid molecules self-assemble into a supramolecular structure under the interaction of non-covalent bonds.

[0010] The structure of the supramolecular ionic liquid is as follows:

[0011]

[0012] The second aspect of the present application is to provide a preparation method of the supramolecular ionic liquid, comprising the steps of:

[0013] S1, under an inert atmosphere, adding L-carnitine and hydroxyl citric acid into water and heating to obtain a mixed solution;

[0014] S2, performing ultrasonic and stirring treatment on the mixed solution, and after ion exchange reaction, performing crystallization, filtration and drying to obtain the supramolecular ionic liquid.

[0015] In step S1, optionally, the molar ratio of the L-carnitine to the hydroxyl citric acid is 1:3-3:1.

[0016] In step S1, optionally, the inert atmosphere is any one of helium, argon and nitrogen.

[0017] In step S1, optionally, the ion exchange reaction conditions are as follows: the reaction temperature is 60-80℃, and the reaction time is 12-48h.

[0018] In step S2, optionally, the ultrasonic treatment conditions at least include one of the following a1-a4:

[0019] a1, the ultrasonic temperature is 30-70℃;

[0020] a2, the ultrasonic frequency is 10-50kHz;

[0021] a3, the ultrasonic power is 300-2000W;

[0022] a4, the ultrasonic time is 2-8h.

[0023] In step S2, optionally, the stirring rate is 20-200rad / min, and the stirring time is 8-36h.

[0024] Optionally, the drying temperature is 50-90℃, and the drying time is 12-60h.

[0025] The third aspect of the present application provides a use of the supermolecular ionic liquid in the preparation of a drug delivery carrier.

[0026] The fourth aspect of the present application provides a supermolecular fat-reducing complex, which comprises the supermolecular ionic liquid and a fat-reducing active ingredient, and the supermolecular ionic liquid encapsulates the fat-reducing active ingredient; the fat-reducing active ingredient comprises any one or more of momordicin, tripterine, lotus leaf extract and gamboge fruit extract.

[0027] The fifth aspect of the present application provides a use of the supermolecular fat-reducing complex in the preparation of a pharmaceutical preparation for treating obesity or for a weight loss group.

[0028] Beneficial effects:

[0029] The supermolecular ionic liquid is obtained by ion exchange reaction of L-carnitine and hydroxycitric acid as precursors through ultrasonic and stirring treatment. The supermolecular ionic liquid can better maintain the original efficacy of L-carnitine and hydroxycitric acid, effectively improve the skin permeability and bioavailability of hydroxycitric acid. At the same time, as a delivery carrier of other active ingredients or drugs, the supermolecular ionic liquid can realize the effect of drug delivery. The supermolecular fat-reducing complex constructed based on the supermolecular ionic liquid has significant fat-reducing and obesity-treating efficacy, and has high biological safety. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 The flowchart of the preparation method of the supermolecular ionic liquid provided in the embodiments of the present application is shown.

[0031] Figure 2 The electrostatic potential (ESP) diagram of the theoretical calculation of the supermolecular ionic liquid prepared in embodiment 1 of the present application is shown.

[0032] Figure 3 The thermogravimetric analysis curve of L-carnitine, hydroxycitric acid and the prepared supermolecular ionic liquid in embodiment 1 of the present application is shown.

[0033] Figure 4 The statistical diagram of the visceral fat intervention results of the supermolecular fat-reducing complex on obese mice in test example 4 is shown. DETAILED DESCRIPTION

[0034] The present application provides a supramolecular ionic liquid, a supramolecular fat-reducing complex, and a preparation method and application thereof. To make the purpose, technical solutions and effects of the present application clearer and more explicit, the present application is further described in detail below. It should be understood that the specific embodiments described herein are only used to explain the present application and do not limit the protection scope of the present application.

[0035] The present application provides a supramolecular ionic liquid, a supramolecular fat-reducing complex, and a preparation method and application thereof. To make the purpose, technical solutions and effects of the present application clearer and more explicit, the present application is further described in detail below. It should be understood that the specific embodiments described herein are only used to explain the present application and do not limit the protection scope of the present application.

[0036] The structure of the supramolecular ionic liquid is as follows:

[0037]

[0038] The supramolecular ionic liquid provided by the present application can better maintain the efficacy of L-carnitine and hydroxycitric acid, effectively improve the skin permeability and bioavailability of hydroxycitric acid. Moreover, it can be used as a delivery carrier for other active ingredients or drugs to achieve the effect of drug delivery.

[0039] The present application provides a preparation method of the supramolecular ionic liquid, comprising the following steps:

[0040] S1, under an inert atmosphere, L-carnitine and hydroxycitric acid are added to water, and heated to obtain a mixed solution;

[0041] S2, the mixed solution is subjected to ultrasonic and stirring treatment, and after ion exchange reaction, crystallization, filtration and drying, the supramolecular ionic liquid is obtained.

[0042] In the preparation method of the supramolecular ionic liquid, L-carnitine and hydroxycitric acid form a supramolecular structure through ion exchange reaction.

[0043] In step S1, in some embodiments, the molar ratio of the L-carnitine to the hydroxycitric acid is 1:3-3:1. For example, the molar ratio can be 1:3, 1:2, 1:1, 2:3, 2:1, 3:2 and 3:1, but is not limited thereto. Under the above molar ratio of L-carnitine to hydroxycitric acid, the prepared supramolecular ionic liquid has good penetration effect.

[0044] In step S1, in some embodiments, the inert atmosphere is any one of helium, argon and nitrogen.

[0045] In step S1, in some embodiments, the ion exchange reaction is carried out at a reaction temperature of 60-80℃ for 12-48h.

[0046] In step S2, in some embodiments, the conditions of the ultrasonic treatment include at least one of a1-a4 as follows:

[0047] a1, the ultrasonic temperature is 30-70℃;

[0048] a2, the ultrasonic frequency is 10-50 kHz;

[0049] a3, the ultrasonic power is 300-2000 W;

[0050] a4, the ultrasonic time is 2-8 h.

[0051] In step S2, in some embodiments, the stirring rate is 20-200 rad / min, and the stirring time is 8-36 h.

[0052] After the stirring treatment, crystallization is performed, and concentration crystallization and / or temperature reduction crystallization can be used in the crystallization process. For example, concentration crystallization or temperature reduction crystallization can be used alone, or concentration crystallization followed by temperature reduction crystallization can be used.

[0053] In some embodiments, the drying temperature is 50-90℃, for example, 50℃, 60℃, 70℃, 80℃ or 90℃, but is not limited thereto.

[0054] The drying time is 12-60 h. The drying time is determined according to the drying degree, and can be 12 h, 36 h, 48 h, 54 h or 60 h, but is not limited thereto.

[0055] The application provides an application of the supermolecular ionic liquid in preparation of a drug delivery carrier.

[0056] The application also provides a supermolecular fat-reducing compound, which comprises the supermolecular ionic liquid and a fat-reducing active ingredient, and the supermolecular ionic liquid encapsulates the fat-reducing active ingredient; the fat-reducing active ingredient comprises any one or more of momordicin, tripterine, lotus leaf extract and gamboge fruit extract.

[0057] In the process of constructing the supermolecular fat-reducing compound, the momordicin, tripterine, gamboge fruit extract or other plant extracts / active ingredients with fat-reducing efficacy are slowly added to the supermolecular ionic liquid under an inert atmosphere, and then magnetic stirring, dialysis and drying are performed to obtain the compound of the supermolecular ionic liquid encapsulating the drug active ingredient, i.e. the supermolecular fat-reducing compound.

[0058] Tripterine, momorcharin, gambir extract, and lotus leaf extract are common natural ingredients widely used in weight loss products. Tripterine promotes weight loss mainly by affecting fat cell metabolism and anti-inflammatory effects. Momorcharin extract contains various active ingredients, including momorcharin, which can promote weight loss by regulating blood sugar and suppressing appetite. Gambir extract contains hydroxyl citric acid, which can block fat synthesis and increase fat oxidation. Lotus leaf extract is often used to promote fat metabolism and has diuretic effects, which can assist in weight loss. These active ingredients all have fat-reducing effects, but they often have problems such as low solubility, poor stability, and low bioavailability, which greatly limit their application effects. The construction of a supramolecular fat-reducing complex can solve the problems of solubility, stability, and bioavailability.

[0059] The present application provides a supramolecular fat-reducing complex for use in the preparation of a pharmaceutical preparation for treating obesity or for a weight loss population. The supramolecular fat-reducing complex has significant fat-reducing and obesity-treating effects, and has high biological safety.

[0060] The scheme of the present application is further described below with specific examples.

[0061] Example 1

[0062] The preparation method of the supramolecular ionic liquid as shown in Figure 1 The specific steps are as follows:

[0063] Under the protection of nitrogen atmosphere, 0.10 mol of L-carnitine and 0.10 mol of hydroxyl citric acid were added to deionized water, heated to a temperature of 60℃, and reacted for 48 h. Ultrasonic treatment was carried out at 50℃, with an ultrasonic frequency of 50 kHz, an ultrasonic power of 2000 W, and an ultrasonic time of 12 h, with an intermittent time of 5 s of ultrasonic treatment every 3 s. During stirring, the stirring time was 48 h and the stirring rate was 200 rad / min. The obtained solution was concentrated and crystallized under vacuum conditions; dried in a vacuum drying oven for 24 h at a drying temperature of 60℃ to obtain the supramolecular ionic liquid.

[0064] As shown in Figure 2 , the electrostatic potential (ESP) map shows that L-carnitine and hydroxyl citric acid attract each other during the formation of the supramolecular structure.

[0065] As shown in Figure 3 , the supramolecular ionic liquid formed by L-carnitine and hydroxyl citric acid in this embodiment has good thermal stability.

[0066] Example 2

[0067] Under the protection of nitrogen atmosphere, 0.10 mol of L-carnitine and 0.20 mol of hydroxyl citric acid were added into deionized water, heated to a temperature of 60°C, and reacted for 24 h. Ultrasonic treatment was performed at 90°C, with an ultrasonic frequency of 50 kHz, an ultrasonic power of 4000 W, an ultrasonic time of 12 h, and an intermittent time of 5 s of ultrasonic treatment every 3 s of interval. During stirring, the stirring time was 24 h, and the stirring rate was 100 rad / min. The obtained solution was concentrated and crystallized under vacuum, and dried in a vacuum drying oven for 48 h at a drying temperature of 90°C to obtain a supramolecular ionic liquid.

[0068] Example 3

[0069] Under the protection of nitrogen atmosphere, 0.10 mol of L-carnitine and 0.20 mol of hydroxyl citric acid were added into deionized water, heated to a temperature of 60°C, and reacted for 24 h. Ultrasonic treatment was performed at 90°C, with an ultrasonic frequency of 50 kHz, an ultrasonic power of 4000 W, an ultrasonic time of 12 h, and an intermittent time of 5 s of ultrasonic treatment every 3 s of interval. During stirring, the stirring time was 24 h, and the stirring rate was 100 rad / min. The obtained solution was concentrated and crystallized under vacuum, and dried in a vacuum drying oven for 48 h at a drying temperature of 90°C to obtain a supramolecular ionic liquid.

[0070] Under the protection of nitrogen atmosphere, 0.10 mol of L-carnitine and 0.20 mol of hydroxyl citric acid were added into deionized water, heated to a temperature of 60°C, and reacted for 24 h. Ultrasonic treatment was performed at 90°C, with an ultrasonic frequency of 50 kHz, an ultrasonic power of 4000 W, an ultrasonic time of 12 h, and an intermittent time of 5 s of ultrasonic treatment every 3 s of interval. During stirring, the stirring time was 24 h, and the stirring rate was 100 rad / min. The obtained solution was concentrated and crystallized under vacuum, and dried in a vacuum drying oven for 48 h at a drying temperature of 90°C to obtain a supramolecular ionic liquid.

[0071] Example 4

[0072] Under the protection of nitrogen atmosphere, 0.10 mol of L-carnitine and 0.20 mol of hydroxyl citric acid were added into deionized water, heated to a temperature of 60°C, and reacted for 24 h. Ultrasonic treatment was performed at 90°C, with an ultrasonic frequency of 50 kHz, an ultrasonic power of 4000 W, an ultrasonic time of 12 h, and an intermittent time of 5 s of ultrasonic treatment every 3 s of interval. During stirring, the stirring time was 24 h, and the stirring rate was 100 rad / min. The obtained solution was concentrated and crystallized under vacuum, and dried in a vacuum drying oven for 48 h at a drying temperature of 90°C to obtain a supramolecular ionic liquid.

[0073] Under the protection of nitrogen atmosphere, 0.10 mol of L-carnitine and 0.20 mol of hydroxyl citric acid were added into deionized water, heated to a temperature of 60°C, and reacted for 24 h. Ultrasonic treatment was performed at 90°C, with an ultrasonic frequency of 50 kHz, an ultrasonic power of 4000 W, an ultrasonic time of 12 h, and an intermittent time of 5 s of ultrasonic treatment every 3 s of interval. During stirring, the stirring time was 24 h, and the stirring rate was 100 rad / min. The obtained solution was concentrated and crystallized under vacuum, and dried in a vacuum drying oven for 48 h at a drying temperature of 90°C to obtain a supramolecular ionic liquid.

[0074] Example 5

[0075] Under the protection of nitrogen atmosphere, 0.10 mol of L-carnitine and 0.20 mol of hydroxycitric acid were added into deionized water for 48 h. Ultrasonic treatment was carried out at 50℃, with an ultrasonic frequency of 50 kHz, an ultrasonic power of 2000 W, an ultrasonic time of 12 h, and an intermittent time of 5 s for every 3 s. During stirring, the stirring time was 48 h, and the stirring rate was 200 rad / min. The obtained solution was concentrated and crystallized under vacuum. After drying in a vacuum drying oven for 24 h at 60℃, a supramolecular ionic liquid was obtained.

[0076] Under a nitrogen atmosphere, 0.01 mg of gamboge fruit extract was slowly added into the supramolecular ionic liquid, stirred at 25℃ for 5 h under magnetic stirring, dialyzed for 2 h, and dried for 6 h to obtain a supramolecular fat-reducing complex.

[0077] Example 6

[0078] The difference from Example 1 is only that the molar ratio of L-carnitine and hydroxycitric acid is 3:1.

[0079] Example 7

[0080] The difference from Example 1 is only that the molar ratio of L-carnitine and hydroxycitric acid is 1:3.

[0081] Comparative Example 1

[0082] L-carnitine and hydroxycitric acid were mixed in water at a molar ratio of 1:2 to obtain a physical mixture containing L-carnitine and hydroxycitric acid.

[0083] Comparative Example 2

[0084] L-carnitine, hydroxycitric acid, and momordicin were mixed in water at a molar ratio of 1:2:0.2 to obtain a physical mixture containing L-carnitine, hydroxycitric acid, and momordicin.

[0085] Test Example 1

[0086] Safety test:

[0087] The effects of Examples 1-6 on the survival rate of L929 fibroblast cell lines were investigated, and the specific method was as follows:

[0088] The CCK-8 kit of Biyun Tian Biological Company was used to detect the toxicity of the supramolecular ionic liquid and the supramolecular fat-reducing complex on L929 fibroblasts. The test results are shown in Table 1:

[0089] Table 1

[0090]

[0091]

[0092] From the data in Table 1, it can be seen that the supermolecular ionic liquid and the supermolecular fat-reducing complex prepared in the embodiments have good biological safety.

[0093] Test Example 2

[0094] Transdermal absorption test:

[0095] The samples prepared in Example 3 and Comparative Example 2 were subjected to transdermal absorption test. Specifically, a Franz diffusion cell was used to perform in vitro skin penetration experiment at 32℃ and 350 r / min, with mini-pig skin as a model, to detect the cumulative transdermal amount (μg / cm 2 ) of momordin at each time point, so as to evaluate the skin penetration performance of the supermolecular fat-reducing complex. The test results are shown in Table 2.

[0096] Table 2

[0097] Cumulative transdermal amount 0h 2h 6h 12h 24h Example 3 0 6.8 12.3 24.2 37.9 Comparative Example 2 0 2.6 4.5 6.2 7.5

[0098] From the data in Table 2, it can be seen that the supermolecular fat-reducing complex has better skin penetration performance than the physical mixture of L-carnitine, hydroxycitric acid and momordin.

[0099] Test Example 3

[0100] Fat-reducing effect test:

[0101] The samples prepared in Example 3 and Comparative Example 2 were subjected to mouse fat-reducing effect evaluation. Specifically, an obese mouse model was constructed by using high-fat diet, and the effects of the products in each group were evaluated. Linotbal was used as a positive control group, and was administered once a day for 30 days in the form of oral administration or smearing administration. The statistical results of the body weight of the mice before and after administration are shown in Table 3.

[0102] Table 3

[0103] Body weight (g) 0 days 30 days Control group 25.8 28.6 Model group 30.5 35.4 Experimental group 30.7 25.2

[0104] As can be seen from the body weight change in Table 3, the fat-reducing effect of the supermolecular fat-reducing complex is significantly better than that of the other groups. Among them, the smearing administration effect and the oral administration effect of the supermolecular fat-reducing complex are not much different, and the smearing administration effect is slightly better than the oral administration effect.

[0105] Test Example 4

[0106] Intervention test of supermolecular complex on visceral fat:

[0107] The sample prepared in Example 3 and Comparative Example 2 was evaluated for visceral fat reduction in mice, by the following method: the mice which had completed the test in Test Example 3 were dissected, and epididymal fat was removed and compared.

[0108] The test results are shown in Table 1. Figure 4 As shown in Table 1, the supermolecular fat reduction complex prepared in Example 3 had a significant effect on visceral fat reduction.

[0109] It should be understood that the application is not limited to the above examples, and that modifications and variations can be made by those skilled in the art in light of the above teachings, all of which are intended to fall within the scope of the following claims.

Claims

1. A supramolecular ionic liquid characterized in that, The supramolecular ionic liquid comprises L-carnitine molecules and hydroxyl citric acid molecules, and the L-carnitine molecules and the hydroxyl citric acid molecules are self-assembled into a supramolecular structure under non-covalent interaction; The structure of the supramolecular ionic liquid is as follows: ； The preparation method of the supramolecular ionic liquid comprises the following steps: S1. Under an inert atmosphere, L-carnitine and hydroxyl citric acid are added to water, and heated to obtain a mixed solution; S2. The mixed solution is subjected to ultrasonic and stirring treatment, and after ion exchange reaction, the supramolecular ionic liquid is obtained by crystallization, filtration and drying; In step S1, the molar ratio of the L-carnitine to the hydroxyl citric acid is 1:3-3:1; In step S1, the inert atmosphere is any one of helium, argon and nitrogen; In step S1, the ion exchange reaction conditions are as follows: the reaction temperature is 60-80℃, and the reaction time is 12-48h; In step S2, the ultrasonic treatment conditions at least include one of the following a1-a4: a1. The ultrasonic temperature is 30-70℃; a2. The ultrasonic frequency is 10-50kHz; a3. The ultrasonic power is 300-2000W; a4. The ultrasonic time is 2-8h; In step S2, the stirring rate is 20-200rad / min, and the stirring time is 8-36h; The drying temperature is 50-90℃, and the drying time is 12-60h.

2. Use of the supramolecular ionic liquid of claim 1 in the preparation of a drug delivery carrier.

3. A supramolecular fat reduction complex, characterized in that, The supramolecular fat-reducing complex comprises the supramolecular ionic liquid of claim 1 and a fat-reducing active ingredient, and the supramolecular ionic liquid encapsulates the fat-reducing active ingredient; The fat-reducing active ingredient comprises any one or more of momordica charantia glycosides, tripterine, lotus leaf extract and gamboge fruit extract.

4. Use of the supramolecular fat-reducing complex according to claim 3, characterized in that, Use of the supramolecular fat-reducing complex in the preparation of a pharmaceutical preparation for treating obesity or for a weight loss group.

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