Sodium salt of vanadium oxygen cluster palmitic acid derivative, external composite gel with glucolipid metabolism regulating effect and preparation method of external composite gel

Abstract

The invention discloses a sodium salt of a vanadium oxygen cluster palmitic acid derivative, an external composite gel with a glycolipid metabolism regulating effect and a preparation method of the external composite gel. The chemical formula of the sodium salt of the vanadium oxygen cluster palmitic acid derivative is C26H48Na2O22V6, and the molecular weight of the sodium salt of the vanadium oxygen cluster palmitic acid derivative is 1064.27. The sodium salt of the vanadium oxygen cluster palmitic acid derivative can better penetrate through the cuticle of the skin to enter the body, and the vanadium oxygen cluster palmitic acid derivative can more effectively reach the fat accumulation part and play a more sufficient role in the body, so that the glycolipid metabolism of the body is improved. The invention also provides an external-use composite gel with a glycolipid metabolism regulating effect, so that the vanadium oxygen cluster palmitic acid derivative is more stably and lastingly released on the skin surface, and partial defects of the existing intervention means, such as gastrointestinal tract side effects of oral medicines, limited curative effects of traditional external-use preparations and the like, are overcome; a safe, efficient and convenient solution is provided for intervention of related diseases of glucose and lipid metabolism disorder.

Description

Technical Field

[0001] The present invention belongs to the fields of organic compounds, medicine and cosmetics, and particularly relates to a sodium salt of a vanadium-oxo cluster palmitic acid derivative, an external composite gel having the effect of regulating glycolipid metabolism, and a preparation method thereof. Background Art

[0002] With the improvement of people's living standards and the change of lifestyle, the incidence of diseases related to glycolipid metabolism disorders has shown a sharp upward trend globally. Metabolic diseases such as diabetes and obesity have become global public health problems seriously endangering human health. According to statistics, the number of global diabetes patients increases year by year, and its complications such as diabetic nephropathy and diabetic retinopathy seriously affect the quality of life and life expectancy of patients. Hyperlipidemia cannot be ignored either. This disease is an important risk factor for cardiovascular diseases such as atherosclerosis and coronary heart disease. Obesity is also closely related to diseases such as nutritional metabolism disorders, insulin resistance, and chronic inflammation, and is one of the main inducements of various chronic diseases.

[0003] Current intervention methods mainly include drug treatment and lifestyle intervention. In terms of drug treatment, for diabetes, there are insulin and various hypoglycemic drugs, such as biguanides, sulfonylureas, etc.; for hyperlipidemia, statins are commonly used to lower blood lipids; for obesity, drugs such as orlistat may be used. However, these drugs often have some limitations. Some hypoglycemic drugs may cause side effects such as hypoglycemia and gastrointestinal discomfort; statins may cause adverse reactions such as liver damage and muscle pain. Moreover, relying solely on drug treatment, the compliance of patients is poor, and it is difficult to adhere to standardized medication for a long time. Lifestyle intervention includes diet control and exercise, but in the actual implementation process, due to factors such as personal willpower and living environment, the effect is not satisfactory.

[0004] Health foods with natural plant extracts as active ingredients have problems in terms of bioavailability. For example, oral nutritional supplements may be rapidly decomposed in the gastrointestinal tract and cannot effectively play their function of regulating metabolism, so they cannot effectively play their function of regulating metabolism.

[0005] Chinese Patent Application CN112707816A discloses that vanadium oxide clusters can promote phosphorylated insulin receptor substrate (IRS) proteins. The phosphorylation of these proteins can activate downstream phosphatidylinositol 3-kinase (PI3K), which in turn activates protein kinase B (AKT). The activation of AKT can inhibit glycogen synthase kinase-3 (GSK-3), thereby promoting glycogen synthesis and glucose uptake. At the same time, the activation of AKT also has an impact on lipid metabolism. It can inhibit the expression of genes related to lipogenesis, reducing lipid synthesis; and promote the expression of genes related to lipolysis, accelerating the catabolism of fat. However, in this literature, vanadium oxide clusters are used as oral drugs. Due to problems such as the gastrointestinal side effects of oral drugs and the limited efficacy of traditional topical preparations, the bioavailability of vanadium oxide clusters remains to be improved. Summary of the Invention

[0006] To solve the drawbacks and deficiencies of the prior art, the primary object of the present invention is to provide a sodium salt of a vanadium oxide cluster palmitic acid derivative, which has the effect of regulating glucose and lipid metabolism and good water solubility, and can be prepared into a topical composite gel.

[0007] Another object of the present invention is to provide a preparation method of the above-mentioned sodium salt of a vanadium oxide cluster palmitic acid derivative.

[0008] Another object of the present invention is to provide a topical composite gel with the effect of regulating glucose and lipid metabolism, which is used to effectively regulate glucose and lipid metabolism, can overcome some defects of existing intervention means, such as the gastrointestinal side effects of oral drugs and the limited efficacy of traditional topical preparations, and provides a safe, efficient and convenient solution for the intervention of diseases related to glucose and lipid metabolism disorders.

[0009] The preparation method of the above-mentioned topical composite gel with the effect of regulating glucose and lipid metabolism is simple. By physically mixing the sodium salt of a vanadium oxide cluster palmitic acid derivative with a functional gel matrix, a topical composite gel with the effect of regulating glucose and lipid metabolism can be obtained. In addition, the above-mentioned topical composite gel with the effect of regulating glucose and lipid metabolism is easy to use and can also be used to prepare beauty products.

[0010] The object of the present invention is achieved by the following technical solutions:

[0011] A sodium salt of a vanadium oxide cluster palmitic acid derivative, with the chemical formula C 26 H 48 Na 2 O 22 V 6 , and its molecular weight is 1064.27.

[0012] The sodium salt of the vanadium-oxygen cluster palmitic acid derivative of the present invention is the sodium salt of a vanadium-oxygen cluster modified with a trimethylol ligand, wherein the trihydroxy ligand is trimethylol palmitate; the vanadium-oxygen cluster is a polyoxometalate, the size of its anion is about 0.8 nm and its anion structure contains six vanadium atoms, and the vanadium atoms are bridged together by oxygen atoms.

[0013] Preferably, the sodium salt of the vanadium-oxygen cluster palmitic acid derivative is prepared by ion exchange of the tetrabutylammonium salt of the vanadium-oxygen cluster palmitic acid derivative with a sodium-type cation exchange resin.

[0014] More preferably, the tetrabutylammonium salt of the vanadium-oxygen cluster palmitic acid derivative is an ionic compound, its cation is tetrabutylammonium, and its anion is [{HOCH 2 C(CH 2 O) 3}V 6 O 13 {(OCH 2 ) 3 CCH 2 O-OC(CH 2 ) 12 CH 3}] 2- 。

[0015] More preferably, the tetrabutylammonium salt of the vanadium-oxygen cluster palmitic acid derivative is prepared by the following steps: uniformly mixing vanadium-oxygen cluster trimethylol derivative, palmitic anhydride, triethylamine, 4-dimethylaminopyridine and acetonitrile in a ratio of 2.4 - 2.6 mmol: 2.5 - 4 mmol: 2 - 3 mmol: 2 - 3 mmol: 40 - 60 mL, heating the mixed solution to 60 - 85 °C, continuously stirring for 36 - 50 h, cooling, and purifying the product to obtain the tetrabutylammonium salt of the vanadium-oxygen cluster palmitic acid derivative.

[0016] Most preferably, the vanadium-oxygen cluster trimethylol derivative, palmitic anhydride, triethylamine, 4-dimethylaminopyridine and acetonitrile are uniformly mixed in a ratio of 2.5 mmol: 3.5 mmol: 2.5 mmol: 2.5 mmol: 50 mL.

[0017] Most preferably, the mixed solution is heated to 80 °C and continuously stirred for 48 h.

[0018] The preparation method of the above-mentioned sodium salt of the vanadium-oxygen cluster palmitic acid derivative includes the following steps:

[0019] (1) Mix the vanadium-oxygen cluster trimethylol derivative, palmitic anhydride, triethylamine, 4-dimethylaminopyridine, and acetonitrile in a ratio of 2.4 - 2.6 mmol : 2.5 - 4 mmol : 2 - 3 mmol : 2 - 3 mmol : 40 - 60 mL, heat the solution to 60 - 85 °C, stir continuously for 36 - 50 h, cool, and purify the product to obtain the tetrabutylammonium salt of the vanadium-oxygen cluster palmitic acid derivative;

[0020] (2) After performing cation exchange on the tetrabutylammonium salt of the vanadium-oxygen cluster palmitic acid derivative using a sodium-type cation exchange resin, obtain the sodium salt of the vanadium-oxygen cluster palmitic acid derivative.

[0021] Preferably, the tetrabutylammonium salt of the vanadium-oxygen cluster palmitic acid derivative in step (1) is prepared by the following steps: Mix the vanadium-oxygen cluster trimethylol derivative, palmitic anhydride, triethylamine, 4-dimethylaminopyridine, and acetonitrile in a ratio of 2.5 mmol : 3.5 mmol : 2.5 mmol : 2.5 mmol : 50 mL, heat the solution to 80 °C, stir continuously for 48 h, cool, and purify the product to obtain the tetrabutylammonium salt of the vanadium-oxygen cluster palmitic acid derivative.

[0022] Preferably, the cation exchange resin in step (2) is a sodium-type cation exchange resin. The specific steps are as follows: Pack the sodium-type cation (Na + ) exchange resin into a glass tube with a piston at one end, and slowly flow the acetonitrile solution of the tetrabutylammonium salt of the vanadium-oxygen cluster palmitic acid derivative through the packed column. After eluting with pure water, the cation exchange of the vanadium-oxygen cluster palmitic acid derivative is completed.

[0023] The above-mentioned sodium salt of the vanadium-oxygen cluster palmitic acid derivative can be used to prepare external preparations for regulating glycolipid metabolism, such as gels, ointments, creams, etc.

[0024] The present invention also provides an external compound gel with the function of regulating glycolipid metabolism, which is compounded from the sodium salt of the vanadium-oxygen cluster palmitic acid derivative, a gel matrix, and a solvent according to a mass ratio of 0.4 - 0.6 : 1 - 10 : 90 - 99.5.

[0025] Preferably, the solvent is water.

[0026] Preferably, the gel matrix is at least one of sodium carboxymethylcellulose, sodium alginate, chitosan, Carbomer, and polyvinyl alcohol (PVA).

[0027] The preparation method of the above-mentioned external compound gel with the function of regulating glycolipid metabolism includes the following steps:

[0028] (1) Add the gel matrix to the solvent to prepare a solution;

[0029] (2) Dissolve the sodium salt of the vanadium-oxygen cluster palmitic acid derivative fully in water to prepare an aqueous solution of the sodium salt of the vanadium-oxygen cluster palmitic acid derivative, and mix this aqueous solution evenly with the gel matrix solution to obtain the external composite gel with the function of regulating glycolipid metabolism.

[0030] Preferably, the mass concentration of the gel matrix solution in step (1) is 0.5-20%.

[0031] Preferably, when the gel matrix in step (2) is sodium carboxymethylcellulose, the preparation steps of the gel matrix solution are as follows: slowly add sodium carboxymethylcellulose to an appropriate amount of deionized water, with the mass fraction of sodium carboxymethylcellulose being 1%-5%, stir while adding, and continuously stir at room temperature for several hours until a uniform and transparent gel is formed.

[0032] Preferably, when the gel matrix in step (1) is sodium alginate, the preparation steps of the gel matrix solution are as follows: first weigh sodium alginate with a mass fraction accounting for 1%-3% of the mass of the gel matrix, add an appropriate amount of deionized water, and completely dissolve it under heating and stirring conditions. Then, add a calcium ion solution (such as CaCl 2 solution) dropwise to this solution until a gel is formed.

[0033] Preferably, when the gel matrix in step (1) is chitosan, the preparation steps of the gel matrix solution are as follows: weigh chitosan powder with a mass fraction accounting for 1%-5% of the mass of the gel matrix, add it to an aqueous solution of acetic acid with a mass fraction of 1%-3%, dissolve it under stirring, and then gradually increase the pH value of the chitosan solution. When the pH value reaches about 6, the solution will gradually gel. Glutaraldehyde can also be used as a cross-linking agent. An appropriate amount of glutaraldehyde solution (with a mass fraction of glutaraldehyde being 0.1%-0.5%) can be added to the chitosan solution, and a gel is formed after reacting at a certain temperature for a period of time.

[0034] Preferably, when the gel matrix in step (1) is carbomer, the preparation steps of the gel matrix solution are as follows: first slowly add carbomer powder to water, with the mass fraction of carbomer accounting for 0.5%-2% of the mass of the gel matrix, stir while adding, and let it fully swell to form a uniform dispersion. Then, use an alkaline solution such as sodium hydroxide solution or triethanolamine for neutralization, stir while dropping the alkaline solution until the pH value of the carbomer solution reaches above 6, and at this time the solution will rapidly gel.

[0035] Preferably, when the gel matrix in step (1) is polyvinyl alcohol, the preparation steps of the gel matrix solution are as follows: Dissolve polyvinyl alcohol in hot water (80 - 90 °C), and completely dissolve it under stirring to form a solution with a certain concentration (the mass fraction of polyvinyl alcohol is 10% - 20%). Then, freeze the solution at a low temperature (-20 °C) for a certain period of time (12 - 24 hours), and then thaw it. After multiple repeated freeze-thaw cycles, a gel is formed.

[0036] Preferably, the mass concentration of the aqueous sodium salt solution of the vanadium-oxygen cluster palmitic acid derivative in step (2) is 4.5% - 6%, and more preferably 5%.

[0037] The present invention also provides the application of the above-mentioned external composite gel with the function of regulating glycolipid metabolism in beauty products and beauty instrument supporting products.

[0038] Preferably, it is applied in body care gels, and more preferably in body firming gels and skin care creams.

[0039] The technical principle of the present invention: After the vanadium-oxygen cluster is modified by palmitic acid, palmitic acid, as a long hydrocarbon chain, is similar to the fatty acid chain in phospholipids and has non-polar characteristics, while the hexavanadic acid part can be regarded as a head with a certain polarity, thus forming a combined structure similar to the polar head and non-polar tail of phospholipids, improving the liposolubility of the vanadium-oxygen cluster and making it easier to penetrate the stratum corneum of the skin, thereby enhancing the ability of the vanadium-oxygen cluster to penetrate the skin. The gel preparation can increase the residence time of the vanadium-oxygen cluster palmitic acid derivative on the skin surface. The gel matrix can fix the vanadium-oxygen cluster palmitic acid derivative in its three-dimensional network structure, and the vanadium-oxygen cluster palmitic acid derivative slowly releases from the gel to the skin surface and then penetrates into the skin, prolonging the contact time between the vanadium-oxygen cluster palmitic acid derivative and the skin, thereby providing a more lasting driving force for the penetration of the vanadium-oxygen cluster palmitic acid derivative. The adhesiveness of the gel can make the vanadium-oxygen cluster palmitic acid derivative closely contact with the skin, providing sufficient time and concentration gradient for the penetration of the vanadium-oxygen cluster palmitic acid derivative, which is beneficial to improving the transdermal penetration efficiency and bioavailability of the vanadium-oxygen cluster palmitic acid derivative.

[0040] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0041] (1) For the sodium salt of the vanadium-oxygen cluster palmitic acid derivative of the present invention, by utilizing the liposolubility characteristics of palmitic acid, the interaction between the vanadium-oxygen cluster palmitic acid derivative and the skin lipid layer is enhanced, enabling it to better penetrate the stratum corneum of the skin and enter the body. The vanadium-oxygen cluster palmitic acid derivative can more effectively reach the fat accumulation site, play a more sufficient role in the body, and improve the glycolipid metabolism of the body.

[0042] (2) The external composite gel with the function of regulating glycolipid metabolism according to the present invention has a gel texture that gives good adhesiveness. After application, it can adhere to the skin surface for a long time, enabling the more stable and persistent release of vanadium oxo cluster palmitic acid derivatives on the skin surface. Compared with oral drugs, the composite gel provided by the present invention avoids the first-pass effect of the gastrointestinal tract, reduces the degradation and absorption differences of active ingredients in the gastrointestinal tract, improves the bioavailability of active ingredients, and can act on local skin or subcutaneous tissues more precisely, achieving targeted treatment for skin diseases related to glycolipid metabolism or local fat accumulation problems.

[0043] (3) In the external composite gel with the function of regulating glycolipid metabolism according to the present invention, vanadium oxo cluster palmitic acid derivatives can penetrate the skin more efficiently and be released in a stable manner, continuously exerting the function of regulating glycolipid metabolism, reducing the trouble of frequent drug administration, and improving the convenience of use and patient compliance.

[0044] (4) During the transdermal drug delivery process, skin irritation is an important factor to be considered. The present invention modifies and combines with a hydrogel matrix through palmitic acid, changes the interaction mode between vanadium oxo clusters and the skin, effectively reduces the irritation of vanadium oxo clusters to the skin, and avoids possible adverse reactions such as skin redness and itching. Description of the Drawings

[0045] Figure 1 Structural diagrams of vanadium oxo cluster palmitic acid derivative anion, vanadium oxo cluster trimethylol derivative anion, and dipalmitoyl phosphatidylglycerol (from top to bottom: vanadium oxo cluster palmitic acid derivative anion, vanadium oxo cluster trimethylol derivative anion, and dipalmitoyl phosphatidylglycerol).

[0046] Figure 2 ESI-MS mass spectrum of vanadium oxo cluster palmitic acid derivative anion (anion mode).

[0047] Figure 3 Physical pictures of the external composite gels of Examples 1-5 and Comparative Example 1 (from left to right: Example 1, Example 2, Example 3, Example 4, Example 5, and Comparative Example 1).

[0048] Figure 4 Graph showing the change of cumulative penetration amount of the external composite gels of Examples 1-5 and the corresponding gel matrix (blank group) and the composite gel of Comparative Example 1 through the skin over time.

[0049] Figure 5 Graph showing the change of skin penetration rate of the external composite gels of Examples 1-5 and the corresponding gel matrix and the composite gel of Comparative Example 1 over time.

[0050] Figure 6Retention amount in the epidermis 24 h after application of the topical composite gels of Examples 1-5, the corresponding gel matrices (blank groups), and the composite gel of Comparative Example 1.

[0051] Figure 7 Retention amount in the dermis 24 h after application of the topical composite gels of Examples 1-5, the corresponding gel matrices (blank groups), and the composite gel of Comparative Example 1.

[0052] Figure 8 Comparison chart of the body weights of obese mice before and after the topical composite gels of Examples 1-5, the corresponding gel matrices (blank groups), and the composite gel of Comparative Example 1 were continuously applied to the skin surface of obese mice twice a day for 8 weeks.

[0053] Figure 9 Comparison chart of the blood glucose levels of obese mice before and after the topical composite gels of Examples 1-5, the corresponding gel matrices (blank groups), and the composite gel of Comparative Example 1 were continuously applied to the skin surface of obese mice twice a day for 8 weeks.

[0054] Figure 10 Comparison chart of the triglyceride levels of obese mice before and after the topical composite gels of Examples 1-5, the corresponding gel matrices (blank groups), and the composite gel of Comparative Example 1 were continuously applied to the skin surface of obese mice twice a day for 8 weeks.

[0055] Figure 11 Comparison chart of the cholesterol levels of obese mice before and after the topical composite gels of Examples 1-5, the corresponding gel matrices (blank groups), and the composite gel of Comparative Example 1 were continuously applied to the skin surface of obese mice twice a day for 8 weeks.

[0056] Figure 12 Comparison chart of the changes in subcutaneous adipose tissue of obese mice before and after the topical composite gels of Examples 1-5, the corresponding gel matrices (blank groups), and the composite gel of Comparative Example 1 were continuously applied to the skin surface of obese mice twice a day for 8 weeks (a, b, c, d, e, f, g are: Example 1, Example 2, Example 3, Example 4, Example 5, gel matrix, Comparative Example 1 in sequence).

[0057] Figure 13 Comparison chart of the gene expression of lipoprotein lipase (LPL) in adipose tissue of obese mice before and after the topical composite gels of Examples 1-5, the corresponding gel matrices (blank groups), and the composite gel of Comparative Example 1 were continuously applied to the skin surface of obese mice twice a day for 8 weeks.

[0058] Figure 14The external composite gel of Examples 1-5, the corresponding gel matrix (blank group), and the composite gel of Comparative Example 1 were continuously applied to the skin surface of obese mice twice a day for 8 weeks. The following is a comparison chart of the expression of fatty acid synthase (FAS) gene in the adipose tissue of mice before and after the experiment.

[0059] Figure 15 The following is a physical picture of the powder of Comparative Example 1 after being added to the gel matrix.

[0060] Figure 16 The following are the detection results of the cytotoxicity of the tetrabutylammonium salt of vanadium oxo cluster palmitic acid derivative and the sodium salt of vanadium oxo cluster palmitic acid derivative to HaCaT cells. Detailed implementation manners

[0061] The present invention will be further described in detail below in conjunction with examples and drawings, but the implementation manners of the present invention are not limited thereto.

[0062] In the examples of the present invention, those not specified in specific conditions are carried out according to conventional conditions or the conditions recommended by the manufacturer. The raw materials, reagents, etc. not specified in the manufacturer are all conventional products that can be obtained by purchasing in the market.

[0063] Example 1

[0064] (1) Prepare the tetrabutylammonium salt of vanadium oxo cluster palmitic acid derivative as follows. Mix the vanadium oxo cluster trimethylol derivative (for its synthesis reference: DMAP-catalyzed Esterification of Pentaerythritol-derivatized POMs: a New Route for the Functionalization of Polyoxometalates. Chem Commun, 2011, 47: 5557-5559), palmitic anhydride, triethylamine, 4-dimethylaminopyridine, and acetonitrile in a round-bottom flask in a ratio of 2.5 mmol: 3.5 mmol: 2.5 mmol: 2.5 mmol: 50 mL. Heat the solution to 80 °C, continuously stir magnetically for 48 h, cool, purify the product to obtain the vanadium oxo cluster palmitic acid derivative (attached Figure 1 and 2 ) tetrabutylammonium salt. Pack the sodium-type cation (Na + ) exchange resin into a glass tube with a piston at the end. Redissolve the tetrabutylammonium salt of vanadium oxo cluster palmitic acid derivative in acetonitrile, slowly flow the acetonitrile solution through the packed column, and complete the cation exchange of the vanadium oxo cluster palmitic acid derivative after eluting with pure water, and then freeze-dry to obtain the sodium salt of vanadium oxo cluster palmitic acid derivative.

[0065] (2) Redissolve 1 g of the sodium salt of the vanadium-oxygen cluster palmitic acid derivative in 19 mL of deionized water to prepare a 5% aqueous solution of the vanadium-oxygen cluster palmitic acid derivative. Slowly add 3 g of sodium carboxymethylcellulose to 97 mL of deionized water. The mass fraction of sodium carboxymethylcellulose is 3%. Stir while adding, and continuously stir at room temperature for several hours until a uniform and transparent gel is formed. Take 10 mL of the aqueous solution of the vanadium-oxygen cluster palmitic acid derivative and add it to 90 mL of the sodium carboxymethylcellulose gel. Stir slowly with a mechanical stirrer until evenly mixed to obtain a golden-yellow topical composite gel with the effect of regulating glycolipid metabolism (attached Figure 3 ).

[0066] Example 2

[0067] Prepare the sodium salt of the vanadium-oxygen cluster palmitic acid derivative according to the method of Example 1. Redissolve 0.9 g of the sodium salt of the vanadium-oxygen cluster palmitic acid derivative in 19.1 mL of deionized water to prepare a 4.5% aqueous solution of the vanadium-oxygen cluster palmitic acid derivative. Add 2 g of sodium alginate to 95 mL of deionized water and completely dissolve it under the conditions of heating and stirring at 50 °C. Then, add 5 mL of CaCl 2 solution until a uniform gel is formed. Take 10 mL of the aqueous solution of the vanadium-oxygen cluster palmitic acid derivative and add it to 90 mL of the sodium alginate gel. Stir slowly with a mechanical stirrer until evenly mixed to obtain a golden-yellow topical composite gel with the effect of regulating glycolipid metabolism (attached Figure 3 ).

[0068] Example 3

[0069] Prepare the sodium salt of the vanadium-oxygen cluster palmitic acid derivative according to the method of Example 1. Redissolve 1.2 g of the sodium salt of the vanadium-oxygen cluster palmitic acid derivative in 18.8 mL of deionized water to prepare a 6% aqueous solution of the vanadium-oxygen cluster palmitic acid derivative. Add 3 g of chitosan powder to 95 mL of a 3% aqueous acetic acid solution and dissolve it with stirring. Then, add 2 mL of NaOH solution to this solution and gradually increase the pH value of the chitosan solution. When the pH value reaches about 6, the solution gradually gels. Continuously stir until a uniform gel is formed. Take 10 mL of the aqueous solution of the vanadium-oxygen cluster palmitic acid derivative and add it to 90 mL of the chitosan gel. Stir slowly with a mechanical stirrer until evenly mixed to obtain a golden-yellow topical composite gel with the effect of regulating glycolipid metabolism (attached Figure 3 ).

[0070] Example 4

[0071] Prepare the sodium salt of the vanadium-oxygen cluster palmitic acid derivative according to the method of Example 1. Redissolve 1.0 g of the sodium salt of the vanadium-oxygen cluster palmitic acid derivative in 19 mL of deionized water to prepare a 5% aqueous solution of the vanadium-oxygen cluster palmitic acid derivative. Slowly add 1.2 g of chitosan powder to 96.8 mL of deionized water, stirring while adding to allow it to swell fully to form a uniform dispersion, and then add 2 mL of an alkaline solution such as sodium hydroxide solution or triethanolamine for neutralization, stirring while adding the alkaline solution until the pH value of the carbomer solution reaches above 6, at which point the solution will rapidly gel. Take 10 mL of the aqueous solution of the vanadium-oxygen cluster palmitic acid derivative and add it to 90 mL of the chitosan gel, stirring slowly mechanically until evenly mixed to obtain a golden-yellow external-use composite gel with the function of regulating glycolipid metabolism (attached Figure 3 ).

[0072] Example 5

[0073] Prepare the sodium salt of the vanadium-oxygen cluster palmitic acid derivative according to the method of Example 1. Redissolve 1.0 g of the sodium salt of the vanadium-oxygen cluster palmitic acid derivative in 19 mL of deionized water to prepare a 5% aqueous solution of the vanadium-oxygen cluster palmitic acid derivative. Slowly add 10 g of polyvinyl alcohol to 90 mL of deionized water, heat to 80 - 90 °C, stirring while adding, and stir to completely dissolve it under stirring to form a polyvinyl alcohol solution with a certain concentration of 10% by mass fraction. Then freeze the solution at a low temperature (-20 °C) for 12 hours first, and then thaw it, repeating the freeze-thaw cycle multiple times until a gel is formed. Take 10 mL of the aqueous solution of the vanadium-oxygen cluster palmitic acid derivative and add it to 90 mL of the chitosan gel, stirring slowly mechanically until evenly mixed to obtain a golden-yellow external-use composite gel with the function of regulating glycolipid metabolism (attached Figure 3 ).

[0074] Comparative Example 1

[0075] Redissolve 1 g of the sodium salt of the vanadium-oxygen cluster trimethylol derivative (attached Figure 1 ) according to the method of Example 1 in 19 mL of deionized water to prepare a 5% aqueous solution of the vanadium-oxygen cluster trimethylol derivative. Slowly add 3 g of sodium carboxymethylcellulose to 97 mL of deionized water, with the mass fraction of sodium carboxymethylcellulose being 3%, stirring while adding, and continuously stir at room temperature for several hours until a uniform and transparent gel is formed. Take 10 mL of the aqueous solution of the vanadium-oxygen cluster trimethylol derivative and add it to 90 mL of the sodium carboxymethylcellulose gel, stirring slowly mechanically until evenly mixed to obtain the external-use composite gel of Comparative Example 1 (attached Figure 3 ).

[0076] Example 6

[0077] Purchase food industry waste pig ears. Select healthy pig ears, shave the hair on the skin to ensure that the skin is intact without inflammation or other abnormalities, and trim the skin to a thickness of about 750 μm. Randomly divide the skin samples into an experimental group and a control group, with at least 6 pieces in each group. Fix the processed skin with the stratum corneum facing up between the donor chamber and the receptor chamber of the Franz diffusion cell, and screen the skin with qualified transepidermal water loss for the experiment. Uniformly coat the external composite gel prepared in Examples 1-5 in the diffusion cell of the experimental group, add the composite gel containing an equal amount of vanadium oxo cluster trihydroxymethyl derivative in Comparative Example 1 in the diffusion cell of the control group, and add the corresponding gel matrix without vanadium oxo cluster palmitic acid derivative in an equal amount in the diffusion cell of the blank group. During the experiment, the temperature in the diffusion cell is maintained at 32 ± 1 °C. At predetermined time points, collect 200 μL of the receiving solution from the receiving solution in the diffusion cell, detect the concentration of vanadium element in it using the receiving solution in the diffusion cell, draw the percutaneous penetration concentration-time curve, and compare the penetration amount differences between the two groups at different time points. After the experiment, remove the diffusion cell, collect skin tissue samples, wash and peel off the stratum corneum, collect the epidermis and dermis, digest the tissue and then determine the content of vanadium element in the skin tissue, and compare the retention amount differences between the two groups in the skin and the distribution of vanadium in the skin. The vanadium concentration in the receiving solution of the experimental groups of Examples 1-5 was significantly higher than that of the control group (attached Figure 4 and 5 ), and the retention amount in the skin was relatively high (attached Figure 6 and 7 ), indicating that the lipophilicity of palmitic acid promoted the percutaneous penetration of vanadium oxo cluster palmitic acid derivative and its function in the skin. Judging from the process of percutaneous penetration of the drug shown in attached Figure 5 , it maintained a relatively high rate level from 5 to 18 hours, indicating that components such as the lipid bilayer and keratin in the stratum corneum may not have changed significantly during this period, enabling the drug to pass through the skin barrier at a relatively constant rate, suggesting that the release mechanism of the drug is relatively stable during this time period.

[0078] Example 7

[0079] A C57BL / 6J obese mouse model was established by high-fat diet induction. The obese mice were randomly divided into groups of 10 each. In the experimental group, the abdominal skin of the obese mice was smeared with the external composite gel containing vanadyl cluster palmitic acid derivatives of Examples 1-5. In the control group, the abdominal skin of the obese mice was smeared with the composite gel containing an equal amount of vanadyl cluster trimethylol derivatives of Comparative Example 1. In the blank group, the corresponding blank gel without vanadyl cluster palmitic acid derivatives was smeared on the abdominal skin of the obese mice. 0.1 mL of the external composite gel was evenly smeared on the abdominal skin of the mice, and the drug was administered twice at a fixed time every day. The body weight of the mice was regularly monitored for 8 weeks. Before the start of the experiment, once every 2 weeks during the experiment, and after the end of the experiment, blood samples of the mice were collected respectively. The blood glucose was detected by the glucose oxidase method, and the lipid metabolism-related indicators such as blood lipids (including triglycerides and cholesterol) were detected by the corresponding biochemical detection kits. After the end of the experiment, the mice were sacrificed, and adipose tissues (including subcutaneous fat and visceral fat) were dissected and obtained. The morphological changes of the adipose tissues were observed by tissue section and hematoxylin-eosin staining (HE staining), the size and distribution of adipocytes were observed, and the expression levels of genes related to glycolipid metabolism such as fatty acid synthase (FAS) and lipoprotein lipase (LPL) in the adipose tissues were detected by real-time fluorescence quantitative PCR. After 8 weeks of the experiment, the glucose tolerance of the experimental group mice using Examples 1-5 gradually increased, and the blood lipid levels and body weight gradually decreased during the experiment, and the degree of decrease was significantly lower than that of the control group, indicating that the external composite gels of Examples 1-5 can effectively regulate glycolipid metabolism (attached Figures 8 - 11 ). The size and distribution of adipocytes were observed by tissue section. The adipocytes of the experimental group mice of Examples 1-5 became smaller and were more evenly distributed, while there were no obvious changes in the adipocytes of the control group (attached Figure 12 ), indicating that the external composite gel has a positive effect on adipose tissue. In the experimental group mice of Examples 1-5, the gene expression of LPL that promotes fat decomposition was up-regulated (attached Figure 13 ), and the gene expression of FAS for fat synthesis was down-regulated (attached Figure 14 ), which was significantly different from that of the negative control group, indicating that the external composite gels of Examples 1-5 are beneficial to improving glycolipid metabolism, indicating that the external composite gel can play a role in regulating glycolipid metabolism in vivo, and it may be due to the more effective arrival of vanadyl cluster palmitic acid derivatives at the fat accumulation site to play a role. In addition, throughout the experimental period, the behavior of the mice was normal, there was no scratching behavior, and there were no redness, erythema, papules, blisters, erosions, etc. on the coated skin surface, and there was no significant difference from the blank control group, indicating that the external composite gels of Examples 1-5 have very weak irritation to the skin.

[0080] Comparative Example 2

[0081] Collect the tetrabutylammonium salt powder of the vanadium oxo cluster palmitic acid derivative according to the method of Example 1. Since the tetrabutylammonium salt of the vanadium oxo cluster palmitic acid derivative has poor water solubility, it cannot be effectively dispersed when the tetrabutylammonium salt powder of the vanadium oxo cluster palmitic acid derivative is directly added to the gel matrix (attached Figure 15 ). Since tetrabutylammonium salt is a quaternary ammonium salt and has the characteristics of a cationic surfactant, the positively charged part of it can interact with the negatively charged phospholipid bilayer on the cell membrane surface, destroying the integrity and permeability of the cell membrane, causing substances inside the cell such as enzymes and ions to leak outside the cell, and affecting the normal physiological functions of the cell. Human epidermal cells (HaCaT) were selected to study the toxicity to skin cells, and the MTT (thiazolyl blue) colorimetric method was used to detect cell viability. The tetrabutylammonium salt of the vanadium oxo cluster palmitic acid derivative or the sodium salt of the vanadium oxo cluster palmitic acid derivative was dissolved in dimethyl sulfoxide and pure water respectively, and then a series of solutions with different concentrations were prepared by diluting with pure water respectively. HaCaT cells in the logarithmic growth phase were inoculated into 96-well plates, with about 8000 cells per well. After culturing for 24 hours, different concentrations of the tetrabutylammonium salt solution of the vanadium oxo cluster palmitic acid derivative or the sodium salt solution of the vanadium oxo cluster palmitic acid derivative were added, and the culture was continued for 24 hours. Then, MTT solution (concentration: 5 mg / mL) was added to each well, and the incubation was continued for 4 hours. MTT will be reduced by mitochondrial succinate dehydrogenase in living cells to insoluble blue-violet formazan crystals. The supernatant was carefully aspirated, and dimethyl sulfoxide was added to dissolve the formazan crystals. The absorbance of the supernatant was measured using an enzyme-linked immunosorbent assay (ELISA) reader at a specific wavelength (570 nm). The absorbance value is proportional to the number of living cells. By comparing with untreated control cells, the survival rate of cells treated with different concentrations of the tetrabutylammonium salt of the vanadium oxo cluster palmitic acid derivative or the sodium salt of the vanadium oxo cluster palmitic acid derivative can be calculated, so as to evaluate its cytotoxicity. The cytotoxicity experiment on HaCaT cells at the same concentration shows that due to the characteristics of the quaternary ammonium salt, the tetrabutylammonium salt of the vanadium oxo cluster palmitic acid derivative exhibits certain cytotoxicity (attached Figure 16 ).

[0082] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A sodium salt of a vanadium oxocarbyl palmitic acid derivative, characterized in that: The chemical formula of the sodium salt of the vanadium oxocarbyl palmitic acid derivative is C 26 H 48 Na2O 22 V6, its molecular weight is 1064.

27.

2. The sodium salt of a vanadium oxocarbyl palmitic acid derivative according to claim 1, characterized in that: The sodium salt of the palmitic acid derivative of the vanadyl group is prepared by ion exchange between the tetrabutylammonium salt of the palmitic acid derivative of the vanadyl group and a sodium type cation exchange resin; the tetrabutylammonium salt of the palmitic acid derivative of the vanadyl group is an ionic compound, wherein the cation is tetrabutylammonium and the anion is [{HOCH2C(CH2O)3}V6O 13 {(OCH2)3CCH2O-OC(CH2) 12 CH3}] 2- .

3. The sodium salt of a vanadium oxocarbyl palmitic acid derivative according to claim 2, characterized in that: The tetrabutylammonium salt of the palmitic acid derivative of the vanadium oxycarbon cluster is prepared by the following steps: uniformly mixing the trihydroxymethyl derivative of the vanadium oxycarbon cluster, palmitic anhydride, triethylamine, 4-dimethylaminopyridine and acetonitrile according to 2.4-2.6mmol:2.5-4mmol:2-3mmol:2-3mmol:40-60mL, heating the mixed solution to 60-85°C, stirring continuously for 36-50h, cooling, purifying the product, and obtaining the tetrabutylammonium salt of the palmitic acid derivative of the vanadium oxycarbon cluster.

4. The sodium salt of a vanadium oxocarbyl palmitic acid derivative according to claim 3, characterized in that: The vanadium oxycarbon trishydroxymethyl derivative, palmitic anhydride, triethylamine, 4-dimethylaminopyridine and acetonitrile are uniformly mixed in the ratio of 2.5 mmol: 3.5 mmol: 2.5 mmol: 2.5 mmol: 50 mL.

5. The sodium salt of a vanadium oxocarbyl palmitic acid derivative according to claim 3, characterized in that: The mixed solution was heated to 80° C. and stirred for 48 h.

6. The method for preparing the sodium salt of the vanadium oxocarbyl palmitic acid derivative according to any one of claims 1 to 5, characterized in that: The following steps are involved: (1) mixing a trimethylol derivative of a vanadium oxo cluster, palmitic anhydride, triethylamine, 4-dimethylaminopyridine and acetonitrile in the ratio of 2.4-2.6 mmol: 2.5-4 mmol: 2-3 mmol: 2-3 mmol: 40-60 mL, heating the solution to 60-85° C., stirring continuously for 36-50 h, cooling, purifying the product, and obtaining a tetrabutylammonium salt of a palmitic acid derivative of a vanadium oxo cluster; (2) The tetrabutylammonium salt of the vanadyl palmitic acid derivative is subjected to cation exchange using a sodium type cation exchange resin to obtain the sodium salt of the vanadyl palmitic acid derivative.

7. The preparation method according to claim 6, characterized in that: The tetrabutylammonium salt of the palmitic acid derivative of the vanadium oxycarbon cluster described in step (1) is prepared by the following steps: the trihydroxymethyl derivative of the vanadium oxycarbon cluster, palmitic anhydride, triethylamine, 4-dimethylaminopyridine and acetonitrile are mixed uniformly according to 2.5mmol:3.5mmol:2.5mmol:2.5mmol:50mL, the mixed solution is heated to 80°C, stirred continuously for 48h, cooled, and the product is purified to obtain the tetrabutylammonium salt of the palmitic acid derivative of the vanadium oxycarbon cluster.

8. Use of the sodium salt of the vanadium oxocarbyl palmitic acid derivative according to any one of claims 1 to 5 in the preparation of an external preparation for regulating glucose and lipid metabolism.

9. An external composite gel having the function of regulating glucose and lipid metabolism, characterized in that: The invention is prepared by mixing the sodium salt of the palmitic acid derivative of the vanadyl cluster as claimed in any one of claims 1 to 5, a gel matrix and a solvent in a mass ratio of 0.4 to 0.6: 1 to 10: 90 to 99.

5.

10. The external composite gel having the function of regulating sugar and lipid metabolism according to claim 9, characterized in that: The solvent is water; The gel matrix is ​​at least one of sodium carboxymethyl cellulose, sodium alginate, chitosan, carbomer and polyvinyl alcohol.

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