A highly permeable silymarin supramolecular preparation and its preparation method and application

Abstract

The present invention discloses a highly permeable supramolecular preparation of silymarin, its preparation method, and application. The silymarin supramolecular preparation comprises the following components by weight: 1.0 to 8.0 parts of silymarin, 0.1 to 1.0 parts of kava extract, 89.0 to 98.8 parts of a cyclodextrin derivative, and 0.1 to 2.0 parts of a hydrophilic polymer. The preparation method comprises dissolving silymarin and the kava extract in an organic solvent to obtain a yellow transparent solution A; dissolving the cyclodextrin derivative and the hydrophilic polymer in deionized water to obtain a transparent solution B; dropping the yellow transparent solution A into the transparent solution B and stirring uniformly to obtain a light yellow transparent mixed solution C; and spray drying or freeze-drying the light yellow transparent mixed solution C to obtain the silymarin supramolecular preparation. The silymarin supramolecular preparation of the present invention has the characteristics of high permeability and low irritation and can be applied to the cosmetics field to prepare skin care products.

Description

Technical Field

[0001] The present invention relates to a silymarin supramolecular preparation, in particular to a highly permeable silymarin supramolecular preparation and a preparation method and application thereof. Background Art

[0002] Silymarin is a flavonoid found in the seeds of the Asteraceae plant Silymarin. Its main medicinal benefits include: 1. Anti-free radical activity: Free radicals are primarily oxidative, causing cell aging and tissue damage. They are harmful substances produced during oxidation reactions. Silymarin reduces free radicals, slowing aging and boosting immunity. 2. Anti-lipid peroxidation: Lipid peroxidation and oxygen free radical reactions play a crucial role in the body, maintaining immunity and physiological and biochemical reactions. Normally, these two reactions are in harmony. Once imbalanced, they can cause cellular pathology, a reaction known as lipid peroxidation. Silymarin inhibits peroxide-induced lipid peroxidation, demonstrating its anti-lipid peroxidation properties. 3. Anti-lipoxygenase activity: Silymarin's anti-free radical activity inhibits lipoxygenase and cyclooxygenase, demonstrating its hepatoprotective and anti-inflammatory properties. However, due to the very low solubility of silymarin in water and oil, and its discoloration under light and high temperature, silymarin has poor stability, resulting in low bioavailability of silymarin. These characteristics limit its application.

[0003] Cyclodextrins are a series of cyclic oligosaccharides prepared from starch through enzymatic hydrolysis. They possess a unique truncated cone-shaped molecular structure, with a hydrophilic outer wall and a relatively hydrophobic inner cavity, resulting in unique amphiphilic properties. This property ensures host-guest recognition between the cyclodextrin cavity and a hydrophobic guest molecule, facilitating the embedding of the hydrophobic portion of the guest molecule within the cavity, forming a host-guest inclusion complex. Therefore, cyclodextrins can improve the solubility of silymarin to a certain extent. For example, patent application number CN200910264177.1 discloses a water-soluble silymarin and its preparation method, which uses cyclodextrin as the host molecule and silymarin as the guest molecule. The resulting water-soluble silymarin exhibits high solubility and excellent quality.

[0004] However, since cyclodextrin itself is highly hydrophilic and has a molecular weight greater than 500 Daltons, it is difficult for it to penetrate the stratum corneum composed of lipids. Therefore, simply modifying the water solubility of silymarin with cyclodextrin has a very limited effect on improving the permeability of silymarin. Since the site of action of silymarin is located in the active epidermis under the stratum corneum and deeper parts, the application of silymarin is relatively limited. Therefore, improving the permeability of silymarin is crucial for silymarin to fully exert its efficacy. At present, there is no better way to improve the permeability of silymarin, making it difficult to use silymarin in the cosmetics field. Summary of the Invention

[0005] The present invention aims to provide a highly permeable supramolecular preparation of silymarin, and its preparation method and application. The supramolecular preparation of silymarin of the present invention has the characteristics of high permeability and low irritation.

[0006] The technical solution of the present invention is a highly permeable silymarin supramolecular preparation comprising the following components in parts by weight: 1.0 to 8.0 parts of silymarin, 0.1 to 1.0 parts of kava extract, 89.0 to 98.8 parts of cyclodextrin derivatives, and 0.1 to 2.0 parts of a hydrophilic polymer.

[0007] In the aforementioned highly permeable silymarin supramolecular preparation, the mass ratio of silymarin: kava extract: hydrophilic polymer is 1:0.013-0.35:0.06-1.

[0008] In the aforementioned highly permeable silymarin supramolecular preparation, the mass content of silybin in the silymarin is not less than 98%.

[0009] In the aforementioned highly permeable silymarin supramolecular preparation, the kava extract is a kava leaf / root / stem extract or a kava root extract, and the content of capsaicin in the kava extract is not less than 90%.

[0010] In the aforementioned highly permeable silymarin supramolecular preparation, the cyclodextrin derivative includes any one of hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin.

[0011] In the aforementioned highly permeable silymarin supramolecular preparation, the glass transition temperature of the hydrophilic polymer is 70°C to 150°C.

[0012] In the aforementioned highly permeable silymarin supramolecular preparation, the hydrophilic polymer comprises one or both of sodium polystyrene sulfonate and polyvinyl pyrrolidone.

[0013] The preparation method of the above-mentioned silymarin supramolecular preparation comprises the following steps:

[0014] A. Dissolve silymarin and kava extract in an organic solvent, wherein the mass ratio of silymarin to organic solvent is 1:8-40, to obtain a yellow transparent solution A;

[0015] B. dissolving a cyclodextrin derivative and a hydrophilic polymer in deionized water at a mass ratio of 1:4 to obtain a transparent solution B;

[0016] C. Add the yellow transparent solution A dropwise into the transparent solution B and stir evenly to obtain a light yellow transparent mixed solution C;

[0017] D. Spray-dry or freeze-dry the light yellow transparent mixed solution C to obtain a silymarin supramolecular preparation.

[0018] In the aforementioned method for preparing the silymarin supramolecular preparation, in step A, the organic solvent is selected from one or two of anhydrous ethanol, isopropyl alcohol, 1,3-propylene glycol, ethoxydiglycol, and 1,3-butylene glycol.

[0019] In the aforementioned method for preparing the supramolecular preparation of silymarin, in step D, the spray drying conditions are: under the protection of nitrogen, controlling the inlet air temperature at 120-130° C. and the feed rate at 10-20 ml / min.

[0020] The present invention also provides application of the silymarin supramolecular preparation in the preparation of skin care products.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] First, the present invention adopts a cyclodextrin derivative inclusion process to form an inclusion complex with the cyclodextrin derivative as the main molecule and silymarin as the guest molecule, thereby increasing the water solubility of silymarin by about 900 times. Moreover, since the silymarin molecules are protected in the cavity of the cyclodextrin derivative, the light and heat stability of silymarin is also increased.

[0023] Secondly, the present invention adds a specific proportion of kava extract and a hydrophilic polymer with a glass transition temperature of 70°C to 150°C, and combines them with a cyclodextrin derivative to prepare a silymarin supramolecular preparation. When the cosmetic is applied to the skin, the preparation can form a skin-friendly soft film on the skin surface. The closed structure formed by the skin-friendly soft film enables silymarin to continuously penetrate into the active epidermis and deeper parts to exert its efficacy, significantly increasing the permeability of silymarin and greatly improving the utilization rate of silymarin. In addition, the hydrophilic groups contained in the hydrophilic polymer can associate with the hydroxyl groups in the outer cavity of the cyclodextrin derivative through intermolecular forces, while the kava extract and the silymarin cyclodextrin derivative associate in the cavity, thereby forming a stable supramolecular structure as a whole.

[0024] Finally, the silymarin supramolecular preparation prepared by the present invention can ensure that silymarin penetrates into the active epidermis and deeper parts while having low skin irritation, thereby achieving simultaneous improvement in the solubility, stability, permeability and irritation of silymarin, and is suitable for application in the cosmetics field. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Differential scanning calorimetry spectra confirming the supramolecular structure.

[0026] Figure 2The permeability results of Examples 2 and 3 and Comparative Examples 1, 2 and 3 are shown in FIG.

[0027] Figure 3 The figure is a comparison chart of the permeability significance analysis of Examples 2 and 3 and Comparative Examples 1, 2 and 3. DETAILED DESCRIPTION

[0028] The present invention will be further described below with reference to the examples, but they are not intended to limit the present invention.

[0029] A highly permeable silymarin supramolecular preparation comprises the following components in parts by mass: 1.0 to 8.0 parts of silymarin, 0.1 to 1.0 parts of kava extract, 89.0 to 98.8 parts of cyclodextrin derivatives, and 0.1 to 2.0 parts of a hydrophilic polymer, wherein the mass ratio of silymarin to kava extract to hydrophilic polymer is 1:0.013 to 0.35:0.06 to 1.

[0030] The preparation method of silymarin supramolecular preparation comprises the following steps:

[0031] A. Weigh silymarin and kava extract, dissolve them in an organic solvent at 50-60°C, wherein the mass ratio of silymarin to organic solvent is 1:8-40, to obtain a yellow transparent solution A;

[0032] B. Dissolve the cyclodextrin derivative and the hydrophilic polymer in deionized water at 20° C., with the mass ratio of the cyclodextrin derivative to deionized water being 1:4, and stir with a stirrer at 500-800 rpm until completely dissolved to obtain a transparent solution B;

[0033] C. Add the yellow transparent solution A dropwise into the transparent solution B at a rate of 5-20 ml per minute, and continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C;

[0034] D. The light yellow transparent mixed solution C was spray-dried in a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 120-130° C. and the feed rate at 10-20 ml / min to obtain a spray-dried product, which was a supramolecular preparation of silymarin.

[0035] The agitator used in the present invention is the HSJ water bath thermostatic agitator produced by Yuhua Instrument Co., Ltd.; the spray dryer used in the present invention is produced by BUCHI Company of Switzerland, model B-290, with a B-295 organic solvent recovery device.

[0036] The silymarin (SILYBIN) described in the present invention is its standard INCI name in the "Catalogue of Used Cosmetic Raw Materials (2021 Edition)" in China, with the number 06270 in the Catalogue of Used Cosmetic Raw Materials (2021 Edition), and the CAS number is: 65666-07-1. The mass content of silybin in the silymarin used in the present invention is not less than 98%.

[0037] The kava extract of the present invention is any one of a Piper methysticum leaf / root / stem extract and a Piper methysticum root extract. The content of capsaicin in the kava extract is not less than 90%, and the extract has a certain penetration-promoting effect.

[0038] The cyclodextrin derivative described in the present invention is any one of hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin, wherein hydroxypropyl-β-cyclodextrin (HYDROXYPROPYL-β-CYCLODEXTRIN) has a CAS number of 128446-35-5, an INCI name of hydroxypropyl cyclodextrin, and is numbered 05228 in the Directory of Used Cosmetic Ingredients (2021 Edition). Methyl-β-cyclodextrin has a CAS number of 128446-36-6, an INCI name of methylcyclodextrin, and is numbered 03310 in the Directory of Used Cosmetic Ingredients (2021 Edition).

[0039] The hydrophilic polymer described herein has a glass transition temperature between 70°C and 150°C and comprises one or both of sodium polystyrene sulfonate and polyvinyl pyrrolidone. The combination of the hydrophilic polymer and the cyclodextrin derivative forms a thin, soft film on the skin surface during application. This closed structure prolongs the penetration of the active ingredient, silymarin. Furthermore, the hydrophilic groups of the hydrophilic polymer associate with the hydroxyl groups in the outer cavity of the cyclodextrin derivative through intermolecular forces, forming a stable supramolecular structure.

[0040] The deionized water used in the present invention has an electrical conductivity of less than 10 micromhos.

[0041] The organic solvent used in the present invention has a cosmetic grade purity; the organic solvent is selected from one or two of anhydrous ethanol, isopropyl alcohol, 1,3-propylene glycol, ethoxydiglycol, and 1,3-butylene glycol.

[0042] Example 1: A method for preparing a highly permeable silymarin supramolecular formulation, comprising the following steps:

[0043] A. Weigh, by mass percentage, 3.0% silymarin, 94.0% hydroxypropyl-β-cyclodextrin, 1.0% Piper methysticum leaf / root / stem extract, 1.0% polyvinylpyrrolidone, and 1.0% sodium polystyrene sulfonate;

[0044] B. Weigh appropriate amounts of ethanol and 1,3-propylene glycol as organic solvents, wherein the mass ratio of ethanol to 1,3-propylene glycol is 1:1. Dissolve silymarin in the organic solvent at a mass ratio of 1:40. Add the Piper methysticum leaf / root / stem extract, heat to 50°C in a water bath, and stir evenly to obtain a yellow transparent solution A.

[0045] C. Weigh an appropriate amount of deionized water, mix the hydroxypropyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., add polyvinylpyrrolidone and sodium polystyrene sulfonate after mixing evenly, and stir at 500-800 rpm with a stirrer until completely dissolved to obtain a transparent solution B;

[0046] D. Add the yellow transparent solution A to the transparent solution B dropwise at a rate of 5 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0047] E. The light yellow transparent mixed solution C was spray-dried in a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 120° C. and the feed rate at 10 ml / min. The spray-dried product was collected to obtain the silymarin supramolecular preparation.

[0048] Example 2: A method for preparing a highly permeable silymarin supramolecular formulation, comprising the following steps:

[0049] A. Weigh, by mass percentage, 7.7% silymarin, 91.3% hydroxypropyl-β-cyclodextrin, 0.5% Piper methysticum leaf / root / stem extract, and 0.5% polyvinylpyrrolidone;

[0050] B. Weigh appropriate amounts of ethanol and ethoxydiglycol as organic solvents, wherein the mass ratio of ethanol to ethoxydiglycol is 1:1. Dissolve silymarin in the organic solvent at a mass ratio of 1:30. Add the Piper methysticum leaf / root / stem extract, heat to 60°C in a water bath, and stir evenly to obtain a yellow transparent solution A.

[0051] C. Weigh an appropriate amount of deionized water, mix the hydroxypropyl β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., add polyvinyl pyrrolidone after mixing evenly, and stir at 500-800 rpm with a stirrer until completely dissolved to obtain a transparent solution B;

[0052] D. Add the yellow transparent solution A to the transparent solution B dropwise at a rate of 10 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0053] E. The light yellow transparent mixed solution C was spray dried using a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 130° C. and the feed rate at 15 ml / min. The spray dried product was collected to obtain the silymarin supramolecular preparation.

[0054] Example 3: A method for preparing a highly permeable silymarin supramolecular formulation, comprising the following steps:

[0055] A. Weigh, by mass percentage, 7.7% silymarin, 91.3% hydroxypropyl-β-cyclodextrin, 0.5% Piper methysticum leaf / root / stem extract, and 0.5% sodium polystyrene sulfonate;

[0056] B. Weigh appropriate amounts of ethoxydiglycol and ethanol as organic solvents, wherein the mass ratio of ethoxydiglycol to ethanol is 2:1. Dissolve silymarin in the organic solvent at a mass ratio of 1:8. Add the Piper methysticum leaf / root / stem extract, heat to 60°C in a water bath, and stir evenly to obtain a yellow transparent solution A.

[0057] C. Weigh an appropriate amount of deionized water, mix the hydroxypropyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., add sodium polystyrene sulfonate after mixing evenly, and stir at 500-800 rpm with a stirrer until completely dissolved to obtain a transparent solution B;

[0058] D. Add the yellow transparent solution A to the transparent solution B dropwise at a rate of 20 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0059] E. The light yellow transparent mixed solution C was spray dried using a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 130° C. and the feed rate at 20 ml / min. The spray dried product was collected to obtain the silymarin supramolecular preparation.

[0060] Example 4: A method for preparing a highly permeable silymarin supramolecular formulation, comprising the following steps:

[0061] A. Weigh, by mass percentage, 7.7% silymarin, 90.8% hydroxypropyl-β-cyclodextrin, 0.5% kava root extract, 0.5% polyvinylpyrrolidone, and 0.5% sodium polystyrene sulfonate;

[0062] B. Weigh an appropriate amount of isopropyl alcohol as an organic solvent, dissolve silymarin in the organic solvent at a mass ratio of 1:40, add kava root extract, heat to 60°C in a water bath, and stir evenly to obtain a yellow transparent solution A;

[0063] C. Weigh an appropriate amount of deionized water, mix the hydroxypropyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., add polyvinylpyrrolidone and sodium polystyrene sulfonate after mixing evenly, and stir at 500-800 rpm with a stirrer until completely dissolved to obtain a transparent solution B;

[0064] D. Add the yellow transparent solution A dropwise into the transparent solution B at a rate of 20 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0065] E. The light yellow transparent mixed solution C was spray dried using a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 130° C. and the feed rate at 20 ml / min. The spray dried product was collected to obtain the silymarin supramolecular preparation.

[0066] Example 5: A method for preparing a highly permeable silymarin supramolecular formulation, comprising the following steps:

[0067] A. Weigh 8.0% silymarin, 91.4% methyl-β-cyclodextrin, 0.1% kava root extract, and 0.5% sodium polystyrene sulfonate by mass;

[0068] B. Weigh appropriate amounts of 1,3-butanediol and ethanol as organic solvents, wherein the mass ratio of 1,3-butanediol to ethanol is 2:8. Dissolve silymarin in the organic solvent at a mass ratio of 1:20. Add kava root extract and heat to 60°C in a water bath, stirring evenly to obtain a yellow transparent solution A.

[0069] C. Weigh an appropriate amount of deionized water, mix the methyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., add sodium polystyrene sulfonate after mixing evenly, and stir at 500-800 rpm using a stirrer until completely dissolved to obtain a transparent solution B;

[0070] D. Add the yellow transparent solution A to the transparent solution B dropwise at a rate of 15 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0071] E. The light yellow transparent mixed solution C was spray dried using a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 120° C. and the feed rate at 12 ml / min. The spray dried product was collected to obtain the silymarin supramolecular preparation.

[0072] Example 6: A method for preparing a highly permeable silymarin supramolecular formulation, comprising the following steps:

[0073] A. Weigh, by mass percentage, 1.0% silymarin, 98.8% methyl-β-cyclodextrin, 0.1% Piper methysten leaf / root / stem extract, and 0.1% sodium polystyrene sulfonate;

[0074] B. Weigh appropriate amounts of ethoxydiglycol and isopropyl alcohol as organic solvents, wherein the mass ratio of ethoxydiglycol to isopropyl alcohol is 1:9. Dissolve silymarin in the organic solvent at a mass ratio of 1:28. Add the Piper methysticum leaf / root / stem extract, heat to 50°C in a water bath, and stir evenly to obtain a yellow transparent solution A.

[0075] C. Weigh an appropriate amount of deionized water, mix the methyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., add sodium polystyrene sulfonate after mixing evenly, and stir at 500-800 rpm using a stirrer until completely dissolved to obtain a transparent solution B;

[0076] D. Add the yellow transparent solution A to the transparent solution B dropwise at a rate of 20 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0077] E. The light yellow transparent mixed solution C was spray dried using a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 130° C. and the feed rate at 12 ml / min. The spray dried product was collected to obtain the silymarin supramolecular preparation.

[0078] Example 7: A method for preparing a highly permeable silymarin supramolecular formulation, comprising the following steps:

[0079] A. Weigh, by mass percentage, 5.0% silymarin, 93.2% hydroxypropyl-β-cyclodextrin, 0.3% Piper mesenteriae leaf / root / stem extract, 0.5% sodium polystyrene sulfonate, and 1.0% polyvinylpyrrolidone;

[0080] B. Weigh appropriate amounts of ethoxydiglycol and ethanol as organic solvents, wherein the mass ratio of ethoxydiglycol to ethanol is 1:2. Dissolve silymarin in the organic solvent at a mass ratio of 1:30. Add the Piper methysticum leaf / root / stem extract, heat to 60°C in a water bath, and stir evenly to obtain a yellow transparent solution A.

[0081] C. Weigh an appropriate amount of deionized water, mix the hydroxypropyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., add sodium polystyrene sulfonate and polyvinylpyrrolidone after mixing evenly, and stir at 500-800 rpm with a stirrer until completely dissolved to obtain a transparent solution B;

[0082] D. Add the yellow transparent solution A to the transparent solution B dropwise at a rate of 20 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0083] E. The light yellow transparent mixed solution C was spray dried using a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 130° C. and the feed rate at 15 ml / min. The spray dried product was collected to obtain the silymarin supramolecular preparation.

[0084] Example 8: A method for preparing a highly permeable silymarin supramolecular formulation, comprising the following steps:

[0085] A. Weigh, by mass percentage, 2.0% silymarin, 95.5% hydroxypropyl-β-cyclodextrin, 0.5% Piper methysticum leaf / root / stem extract, and 2.0% polyvinylpyrrolidone;

[0086] B. Weigh appropriate amounts of isopropyl alcohol and ethanol as organic solvents, wherein the mass ratio of isopropyl alcohol to ethanol is 2:1. Dissolve silymarin in the organic solvent at a mass ratio of 1:18. Add the Piper methysticum leaf / root / stem extract, heat to 50°C in a water bath, and stir evenly to obtain a yellow transparent solution A.

[0087] C. Weigh an appropriate amount of deionized water, mix the hydroxypropyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., add polyvinyl pyrrolidone after mixing evenly, and stir at 500-800 rpm with a stirrer until completely dissolved to obtain a transparent solution B;

[0088] D. Add the yellow transparent solution A to the transparent solution B dropwise at a rate of 20 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0089] E. The light yellow transparent mixed solution C was spray-dried in a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 120° C. and the feed rate at 10 ml / min. The spray-dried product was collected to obtain the silymarin supramolecular preparation.

[0090] Example 9: A method for preparing a highly permeable silymarin supramolecular formulation, comprising the following steps:

[0091] A. Weigh, by mass percentage, 7.0% silymarin, 92.3% hydroxypropyl-β-cyclodextrin, 0.2% Piper methysticum leaf / root / stem extract, and 0.5% sodium polystyrene sulfonate;

[0092] B. Weigh appropriate amounts of isopropyl alcohol and ethoxydiglycol as organic solvents, wherein the mass ratio of isopropyl alcohol to ethoxydiglycol is 2:1. Dissolve silymarin in the organic solvent at a mass ratio of 1:18. Add the Piper methysticum leaf / root / stem extract, heat to 50°C in a water bath, and stir evenly to obtain a yellow transparent solution A.

[0093] C. Weigh an appropriate amount of deionized water, mix the hydroxypropyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., add sodium polystyrene sulfonate after mixing evenly, and stir at 500-800 rpm with a stirrer until completely dissolved to obtain a transparent solution B;

[0094] D. Add the yellow transparent solution A to the transparent solution B dropwise at a rate of 20 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0095] E. The light yellow transparent mixed solution C was spray dried using a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 130° C. and the feed rate at 10 ml / min. The spray dried product was collected to obtain the silymarin supramolecular preparation.

[0096] Example 10: A method for preparing a highly permeable silymarin supramolecular formulation, comprising the following steps:

[0097] A. Weigh, by mass percentage, 6.0% silymarin, 91.7% hydroxypropyl-β-cyclodextrin, 1.0% Piper methysticum leaf / root / stem extract, 0.3% polyvinylpyrrolidone, and 1.0% sodium polystyrene sulfonate;

[0098] B. Weigh appropriate amounts of ethoxydiglycol and 1,3-propylene glycol as organic solvents, wherein the mass ratio of ethoxydiglycol to 1,3-propylene glycol is 4:6. Dissolve silymarin in the organic solvent at a mass ratio of 1:30. Add the Piper methysticum leaf / root / stem extract, heat to 60°C in a water bath, and stir evenly to obtain a yellow transparent solution A.

[0099] C. Weigh an appropriate amount of deionized water, mix the hydroxypropyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., add polyvinylpyrrolidone and sodium polystyrene sulfonate after mixing evenly, and stir at 500-800 rpm with a stirrer until completely dissolved to obtain a transparent solution B;

[0100] D. Add the yellow transparent solution A to the transparent solution B dropwise at a rate of 20 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0101] E. The light yellow transparent mixed solution C was spray dried using a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 130° C. and the feed rate at 20 ml / min. The spray dried product was collected to obtain the silymarin supramolecular preparation.

[0102] Comparative Example 1:

[0103] A. Weigh 7.7% silymarin and 92.3% hydroxypropyl β-cyclodextrin by mass;

[0104] B. Weigh appropriate amounts of ethoxydiglycol and ethanol as organic solvents, wherein the mass ratio of ethoxydiglycol to ethanol is 2:1. Dissolve silymarin in the organic solvent at a mass ratio of 1:30. Heat to 60°C in a water bath and stir evenly to obtain a yellow transparent solution A.

[0105] C. Weigh an appropriate amount of deionized water, mix the hydroxypropyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., and stir with a stirrer at 500-800 rpm until completely dissolved to obtain a transparent solution B;

[0106] D. Add the yellow transparent solution A to the transparent solution B dropwise at a rate of 20 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0107] E. The light yellow transparent mixed solution C was spray dried using a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 130° C. and the feed rate at 15 mL / min. The spray dried product was collected to obtain the silymarin supramolecular preparation.

[0108] Comparative Example 2:

[0109] A. Weigh 7.7% silymarin, 91.8% hydroxypropyl-β-cyclodextrin, and 0.5% Piper methysticum leaf / root / stem extract by mass;

[0110] B. Weigh appropriate amounts of ethoxydiglycol and ethanol as organic solvents, wherein the mass ratio of ethoxydiglycol to ethanol is 3:7, dissolve silymarin in the organic solvent at a mass ratio of 1:30, and add the Piper methysticum leaf / root / stem extract. Heat to 60° C. in a water bath and stir evenly to obtain a yellow transparent solution A.

[0111] C. Weigh an appropriate amount of deionized water, mix the hydroxypropyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., and stir with a stirrer at 500-800 rpm until completely dissolved to obtain a transparent solution B;

[0112] D. Add the yellow transparent solution A to the transparent solution B dropwise at a rate of 20 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0113] E. The light yellow transparent mixed solution C was spray dried using a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 130° C. and the feed rate at 15 mL / min. The spray dried product was collected to obtain the silymarin supramolecular preparation.

[0114] Comparative Example 3:

[0115] A. Weigh 7.7% silymarin, 91.8% hydroxypropyl-β-cyclodextrin, and 0.5% polyvinylpyrrolidone by mass;

[0116] B. Weigh appropriate amounts of ethoxydiglycol and ethanol as organic solvents, wherein the mass ratio of ethoxydiglycol to ethanol is 3:7, dissolve silymarin in the organic solvent at a mass ratio of 1:30, heat to 60° C. in a water bath, and stir evenly to obtain a yellow transparent solution A;

[0117] C. Weigh an appropriate amount of deionized water and mix the hydroxypropyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C. After mixing evenly, add polyvinyl pyrrolidone and stir at 500-800 rpm using a stirrer until completely dissolved to obtain a transparent solution B.

[0118] D. Add the yellow transparent solution A to the transparent solution B dropwise at a rate of 20 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0119] E. The light yellow transparent mixed solution C was spray dried using a spray dryer under the protection of nitrogen, with the inlet air temperature controlled at 130° C. and the feed rate at 15 ml / min. The spray dried product was collected to obtain the silymarin supramolecular preparation.

[0120] Comparative Example 4:

[0121] A. Weigh, by mass percentage, 7.7% silymarin, 91.3% hydroxypropyl-β-cyclodextrin, 0.5% Piper methysticum leaf / root / stem extract, and 0.5% microcrystalline cellulose;

[0122] B. Weigh appropriate amounts of ethoxydiglycol and ethanol as organic solvents, wherein the mass ratio of ethoxydiglycol to ethanol is 3:7, dissolve silymarin in the organic solvent at a mass ratio of 1:30, and add the Piper methysticum leaf / root / stem extract. Heat to 60° C. in a water bath and stir evenly to obtain a yellow transparent solution A.

[0123] C. Weigh an appropriate amount of deionized water, mix the hydroxypropyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., add microcrystalline cellulose after mixing evenly, and stir evenly at 500-800 rpm using a stirrer to obtain solution B;

[0124] D. Add the yellow transparent solution A to solution B dropwise at a rate of 20 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow mixed solution C.

[0125] E. The light yellow mixed solution C was spray-dried under nitrogen protection, with the inlet air temperature controlled at 130° C. and the feed rate at 15 ml / min. The spray-dried product was collected to obtain a silymarin supramolecular preparation.

[0126] Comparative Example 5:

[0127] A. Weigh, by mass percentage, 4.0% silymarin, 90.5% hydroxypropyl-β-cyclodextrin, 0.5% Piper mesenteriae leaf / root / stem extract, and 5.0% polyvinylpyrrolidone;

[0128] B. Weigh appropriate amounts of ethoxydiglycol and ethanol as organic solvents, wherein the mass ratio of ethoxydiglycol to ethanol is 3:7, dissolve silymarin in the organic solvent at a mass ratio of 1:30, and add the Piper methysticum leaf / root / stem extract. Heat to 60° C. in a water bath and stir evenly to obtain a yellow transparent solution A.

[0129] C. Weigh an appropriate amount of deionized water, mix the hydroxypropyl-β-cyclodextrin and deionized water at a mass ratio of 1:4 at 20° C., add polyvinylpyrrolidone after mixing evenly, and stir evenly at 500-800 rpm using a stirrer to obtain solution B;

[0130] D. Add the yellow transparent solution A to solution B dropwise at a rate of 20 ml per minute. Continue stirring at 500-800 rpm at 20°C for 1 hour to obtain a light yellow transparent mixed solution C.

[0131] E. The light yellow transparent mixed solution C was spray-dried under nitrogen protection, with the inlet air temperature controlled at 130° C. and the feed rate at 15 ml / min. The spray-dried product was collected to obtain a silymarin supramolecular preparation.

[0132] In order to confirm the beneficial effects of the highly permeable silymarin supramolecular preparation prepared in the present invention, the following experiments were conducted.

[0133] 1. Supramolecular structure confirmation—DSC test:

[0134] The silymarin supramolecular preparation prepared in Example 2 was taken as test sample 1, and pure silymarin was taken as test sample 2. The mass content of silybin in the silymarin in test sample 1 was consistent with that in the silymarin in test sample 2.

[0135] Differential scanning calorimetry was used to scan the test sample 1 and the test sample 2 at a temperature range of 10 to 200 °C at a rate of 10 °C / min. The scanning results are shown in the figure below. Figure 1 The results show that test sample 2 has characteristic peaks near 160°C and 190°C, which are related to the melting temperature and decomposition temperature of silymarin. The curve of test sample 1 is smooth, and the characteristic peaks of silymarin disappear, indicating that test sample 1 has a new stable structure, which can be used to characterize the formation of its supramolecular structure.

[0136] Therefore, the silymarin supramolecular preparation prepared by the present invention can form a supramolecular structure after the silymarin is subjected to supramolecular treatment using specific materials, proportions and processes.

[0137] 2. Solubility and stability test:

[0138] Pure silymarin, as well as supramolecular silymarin formulations prepared in Examples 2 and 4, and Comparative Examples 1, 2, 4, and 5, were tested for their solubility and stability in water. The solubility test conditions were 50°C and light exposure for 7 days. The results of the solubility and stability in water are shown in Table 1 below.

[0139] Table 1: Solubility and stability

[0140]

[0141] As shown in Table 1, pure silymarin has very low solubility in water, which greatly limits its application in the cosmetics industry. However, the supramolecular formulation obtained by inclusion of cyclodextrin derivatives can increase the solubility of silymarin by approximately 900 times. Furthermore, Examples 2 and 4 and Comparative Examples 1 and 2 showed no precipitation even after 7 days at 50°C under light conditions. However, due to the addition of the non-hydrophilic polymer microcrystalline cellulose, the aqueous solution of the supramolecular formulation prepared in Comparative Example 4 exhibited precipitation at 50°C under light conditions. Furthermore, due to the addition of an excessive amount of hydrophilic polymer, the resulting supramolecular structure in Comparative Example 5 was unstable, resulting in precipitation after 7 days.

[0142] The above solubility and stability results indicate that the supramolecular preparation prepared by the present invention can greatly improve the solubility of silymarin in water and has good stability at 50° C. under light conditions.

[0143] The silymarin supramolecular preparations prepared in Example 2 and Example 4 were selected as test samples and placed at room temperature in the dark, 50°C, light, and -10°C for stability experiments. At the end of the third week, the supramolecular preparation samples were removed and the silymarin content was measured using HPLC after returning to room temperature. The specific chromatographic conditions were: liquid chromatography column reverse phase C18 (5 μm, 4.6 mm × 150 mm); mobile phase: methanol: water: glacial acetic acid (48:52:1); column temperature: 25°C; detection wavelength: 287 mm; flow rate: 1.0 ml / min; injection volume: 10 μl. The silymarin content was calculated based on the established standard curve and the measurement results. The results are shown in Table 2.

[0144]

[0145] Table 2: Results of 3-week stability test of silymarin supramolecular formulation

[0146]

[0147] As shown in Table 2, after three weeks of stability testing, the retention rates of the two test samples under the four stability conditions were all between 100 ± 1%. This demonstrates that the silymarin supramolecular formulation prepared in the present invention has a stable protective effect on silymarin under photothermal conditions and can effectively preserve silymarin in the cavity structure of cyclodextrin.

[0148] 3. Permeability test:

[0149] The penetration-enhancing property of the silymarin supramolecular preparation was tested by human Raman spectroscopy. The specific steps were as follows: a comparative test was performed on the front end of the human forearm. The samples used for the test were the silymarin supramolecular preparations prepared in Examples 2 and 3 and Comparative Examples 1, 2, and 3. They were added to the prepared paste at a concentration of 0.3% silymarin. The specific formula of the paste is shown in Table 3.

[0150] Table 3: Cream formulations used in penetration and irritation tests

[0151]

[0152]

[0153] Select 1×1cm 2 The test skin area was tested at 0.5h, 1h, 2h, 4h, 8h, and 12h. The test number was 2 people and the test area was 3 pieces of 1×1cm 2The relative permeability of silymarin in Examples 2 and 3, both containing 7.7% silymarin in the supramolecular formulations, was compared with that in Comparative Examples 1, 2, and 3. Relative permeability (%) = normalized (change in Raman characteristic peak after use of the test product) * 100%.

[0154] The experiment was conducted using a LabRAM Odyssey high-speed, high-resolution confocal Raman microscope (HORIBA). Data were tested for normal distribution using the Shapiro-Wilk test using ORIGIN software. Before-and-after comparisons were performed, a paired t-test was used if the data showed a normal distribution; otherwise, a two-sample rank sum test was used. Graphpad Prism software was used for significance analysis and plotting.

[0155] The permeability results are shown in Table 4. The permeability comparison of Examples 2, 3 and Comparative Examples 1, 2, and 3 in the active epidermis is shown in the Appendix. Figure 2 、 Figure 3 .

[0156] Table 4: Human Raman spectroscopy test results

[0157]

[0158]

[0159] According to Table 4, Figure 2 and Figure 3 As can be seen, compared to Comparative Example 1, Examples 2 and 3, which added specific ratios of kava extract and hydrophilic polymer, significantly improved the permeability of silymarin in the human active epidermis, with improvement rates of 123% and 87%, respectively. The permeability data of Comparative Example 2, which added kava extract alone, and Comparative Example 3, which added hydrophilic polymer alone, were both lower than those of Examples 2 and 3, and the data results were significantly different.

[0160] The above permeability results indicate that the kava extract, hydrophilic polymer, and cyclodextrin derivative added in the present invention have a synergistic permeation-enhancing effect. The prepared silymarin supramolecular preparation can significantly improve the permeability of silymarin in the skin, thereby increasing the utilization rate of silymarin.

[0161] 4. Irritation test:

[0162] 32 volunteers aged 18-60 were selected, and an irritation test was conducted with reference to the "Technical Specifications for Safety of Cosmetics 2015 Edition" - human skin patch test.

[0163] The silymarin supramolecular formulations prepared in Examples 2, 3, and 4 (wherein the silymarin content was 7.7%) were added to the cream to form patch test samples, with the added silymarin content being 0.3% by mass. The cream formulation compositions are shown in Table 3.

[0164] Add the test sample to the patch tester. Apply the patch to the subject's back using non-irritating tape. Use your palm to gently press the patch evenly onto the skin. Allow the test sample to remain on the skin for 24 hours. Afterward, remove the patch tester and gently wipe any remaining test sample from the test area with a moistened cotton ball. After 0.5 hours, wait for the indentation to disappear before observing the skin for a reaction. If the result is negative, observe again 24 hours after removing the patch. If there are no Grade 2-4 adverse reactions, or if fewer than five subjects experience Grade 1 adverse reactions, the test is considered to be negative. Record the reaction results according to the grading criteria. Valid results are shown in Table 5.

[0165] Table 5: Irritation test results

[0166]

[0167]

[0168] Description: 2 (9,26) The number of adverse reactions is 2, and the corresponding subject numbers are 9, 26; 1 (23) Indicates that the number of adverse reactions is 1, and the corresponding subject number is 23

[0169] As shown in Table 5, when the mass percentage of silymarin added to the cream was 0.3%, the supramolecular formulation prepared by the present invention had no adverse skin reactions on humans. This indicates that the supramolecular formulation prepared by the present invention has a high penetration rate and low skin irritation.

[0170] In summary, the supramolecular preparation prepared by the present invention can significantly improve the water solubility of silymarin and has good light and heat stability. The specific proportion of kava extract and hydrophilic polymer added has a synergistic penetration-enhancing effect, which can help silymarin penetrate into the active epidermis, while also having good mildness.

Claims

1. A highly permeable supramolecular preparation of silymarin, characterized by: The invention comprises the following components in parts by weight: 1.0-8.0 parts of silymarin, 0.1-1.0 parts of kava extract, 89.0-98.8 parts of cyclodextrin derivatives, and 0.1-2.0 parts of a hydrophilic polymer; the mass content of silybin in the silymarin is not less than 98%; the kava extract is selected from any one of a kava leaf / root / stem extract and a kava root extract, and the content of capsaicin in the kava extract is not less than 90%; the cyclodextrin derivative is selected from any one of hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin; and the hydrophilic polymer is selected from one or both of sodium polystyrene sulfonate and polyvinyl pyrrolidone.

2. The highly permeable supramolecular preparation of silymarin according to claim 1, characterized in that: The mass ratio of silymarin: kava extract: hydrophilic polymer is 1:0.013-0.35:0.06-1.

3. The method for preparing the silymarin supramolecular preparation according to any one of claims 1 to 2, characterized in that: The following steps are involved: A. Dissolving silymarin and kava extract in an organic solvent, wherein the mass ratio of silymarin to organic solvent is 1:8-40, to obtain a yellow transparent solution A; the organic solvent is one or two of anhydrous ethanol, isopropyl alcohol, 1,3-propylene glycol, ethoxydiglycol, and 1,3-butylene glycol; B. dissolving a cyclodextrin derivative and a hydrophilic polymer in deionized water at a mass ratio of 1:4 to obtain a transparent solution B; C. Add the yellow transparent solution A dropwise into the transparent solution B and stir evenly to obtain a light yellow transparent mixed solution C; D. Spray-dry or freeze-dry the light yellow transparent mixed solution C to obtain a silymarin supramolecular preparation.

4. The preparation method according to claim 3, wherein: In step D, the spray drying conditions are: under the protection of nitrogen, the inlet air temperature is controlled at 120-130° C., and the feed rate is 10-20 ml / min.

5. Use of the silymarin supramolecular preparation according to any one of claims 1 to 2 in the preparation of skin care products.

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