A supramolecular astaxanthin liposome and its preparation method and application

Abstract

The present invention relates to the technical field of liposomes, and in particular to a supramolecular astaxanthin liposome and a preparation method and application thereof. The preparation method comprises: mixing astaxanthin with a cationic precursor in a solvent to react to obtain supramolecular astaxanthin; reacting the supramolecular astaxanthin, soybean lecithin and a surfactant to obtain the supramolecular astaxanthin liposome. The preparation method has simple synthesis steps, convenient post-treatment, high purity and high yield of the obtained product. The obtained supramolecular astaxanthin liposome has the antioxidant and repairing effects and biological activities of astaxanthin and lipids, effectively improves the solubility and skin permeability of astaxanthin and can improve its biological activity, and has potential application value in transdermal administration and delivery.

Description

Technical Field

[0001] The invention relates to the technical field of liposomes, and in particular to a supramolecular astaxanthin liposome and a preparation method and application thereof. Background Art

[0002] Astaxanthin, also known as astaxanthin, is a carotenoid with strong antioxidant properties. It has the effects of antioxidant, anti-aging, anti-tumor, and prevention of cardiovascular and cerebrovascular diseases. It has been used in the fields of health foods, high-end cosmetics, and pharmaceuticals. Astaxanthin itself is not very stable, easily oxidized, easily decomposed by light, has low solubility, and poor bioavailability. In the market, it is mostly in the form of astaxanthin gel to retain its activity.

[0003] Transdermal drug delivery has many advantages over traditional drug delivery strategies (oral, injection), such as avoiding first-pass liver clearance, improving patient dependence on drugs and reducing side effects. However, due to the insolubility or slight solubility of large molecules or poorly soluble drugs in water and most organic solvents, transdermal delivery is difficult. It is well known that large molecule drugs have never entered the clinical trial stage due to their difficulty in delivery and low bioavailability.

[0004] Therefore, the prior art still needs to be improved and developed. Summary of the invention

[0005] In view of the above-mentioned deficiencies in the prior art, the present invention provides a supramolecular astaxanthin liposome and a preparation method and application thereof, aiming to solve the problem of how to improve the skin permeability, solubility and bioavailability of astaxanthin and further provide a method for transdermal delivery.

[0006] Specifically, the technical solution of the present invention is as follows:

[0007] The present invention provides a method for preparing supramolecular astaxanthin liposomes, comprising the steps of:

[0008] Astaxanthin and a cationic precursor are mixed in a solvent to react and obtain supramolecular astaxanthin;

[0009] The supramolecular astaxanthin, soybean lecithin and a surfactant are reacted to obtain the supramolecular astaxanthin liposome.

[0010] Optionally, the step of mixing astaxanthin with a cationic precursor in a solvent to react to obtain supramolecular astaxanthin comprises:

[0011] Dissolving astaxanthin and a cationic precursor in a solvent respectively to obtain an astaxanthin solution and a cationic precursor solution;

[0012] The cationic precursor solution is added dropwise into the astaxanthin solution to mix, and heated to cause an ionization and salt-forming reaction;

[0013] The solution after the reaction is concentrated under vacuum conditions, distilled and crystallized under reduced pressure, filtered, washed and vacuum dried to obtain supramolecular astaxanthin.

[0014] Optionally, the molar ratio of astaxanthin to the cationic precursor is 1:1 to 1:10.

[0015] Optionally, the cationic precursor is selected from betaine or L-carnitine.

[0016] Optionally, the solvent is selected from one or more of ethanol, water, methanol, isopropanol, acetone, propylene glycol, butylene glycol, pentanediol, and glycerol.

[0017] Optionally, the step of reacting the supramolecular astaxanthin, soybean lecithin and a surfactant to obtain supramolecular astaxanthin liposomes comprises:

[0018] respectively preparing ethanol solutions of the supramolecular astaxanthin, soybean lecithin and surfactant;

[0019] Adding the ethanol solution of soybean lecithin and surfactant dropwise into the ethanol solution of supramolecular astaxanthin, mixing, and heating for reaction;

[0020] The solution after the reaction is concentrated under vacuum conditions, rotary evaporated, and dried to obtain the supramolecular astaxanthin liposome.

[0021] Optionally, the surfactant is one or more of cholesterol, Tween-20, Tween-40, Tween-60, Tween-80, Span-20 and Span-80.

[0022] Optionally, the molar ratio of the supramolecular astaxanthin, soybean lecithin and surfactant is 1:1:1~1:10:10.

[0023] The invention also provides a supramolecular astaxanthin liposome, which is prepared by the preparation method of the supramolecular astaxanthin liposome.

[0024] The present invention further provides an application of the supramolecular astaxanthin liposome in cosmetics, medicine and life sciences.

[0025] The present invention provides a supramolecular astaxanthin liposome and a preparation method and application thereof. The preparation method of supramolecular astaxanthin liposome uses simple and easily available solvents such as ethanol or water as a reaction medium, and the instruments and reaction conditions used are also easy to implement. The synthesis steps are simple, the post-processing is convenient, and the obtained product has high purity and high yield. The prepared supramolecular astaxanthin liposome completely retains the main molecular skeleton of the astaxanthin monomer and the characteristics of lipids, so it has the biological activity and efficacy of the two substances at the same time, and greatly improves the solubility and transdermal permeability of astaxanthin, enhances its application effect of transdermal delivery and administration, and has potential application value in transdermal administration and transportation. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The present invention is a flow chart of the method for preparing supramolecular astaxanthin liposomes.

[0027] Figure 2 This is the H NMR spectrum of the supramolecular astaxanthin prepared in the example of the present invention.

[0028] Figure 3 2D H NMR spectrum of supramolecular astaxanthin prepared in the embodiment of the present invention.

[0029] Figure 4 TEM image of the supramolecular astaxanthin liposome prepared in the example of the present invention.

[0030] Figure 5 Graph showing the transdermal efficiency of the supramolecular astaxanthin liposomes prepared in an example of the present invention.

[0031] Figure 6 This is a graph showing the cell viability of the supramolecular astaxanthin liposomes prepared in an example of the present invention.

[0032] Figure 7 This is a solubility diagram of the supramolecular astaxanthin liposomes prepared in the examples of the present invention. DETAILED DESCRIPTION

[0033] The present invention provides a supramolecular astaxanthin liposome and a preparation method and application thereof. To make the purpose, technical scheme and effect of the present invention clearer and more specific, the present invention is further described in detail below. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the scope of protection of the present invention.

[0034] Liposome technology is used in the fields of cosmetics, medicine and life sciences. Compared with the traditional liposome preparation method, the most prominent advantage of supramolecular liposomes is that two molecules can be connected by force to double or more the effect. As a new preparation technology, supramolecular liposome technology has the advantages of penetrating the stratum corneum of the skin, increasing solubility, improving stability and bioavailability, and avoiding the first-pass effect in the liver. It is an excellent way in the fields of cosmetics, medicine and life sciences.

[0035] The present invention provides a method for preparing supramolecular astaxanthin liposomes, comprising the steps of:

[0036] Astaxanthin and a cationic precursor are mixed in a solvent to react and obtain supramolecular astaxanthin;

[0037] The supramolecular astaxanthin, soybean lecithin and a surfactant are reacted to obtain the supramolecular astaxanthin liposome.

[0038] In the embodiment, after ionization modification of betaine and / or L-carnitine using astaxanthin as an anion precursor, a pure natural supramolecular astaxanthin with excellent antioxidant properties can be obtained. The prepared supramolecular astaxanthin can not only effectively improve the solubility and skin permeability of astaxanthin, but also improve its biological activity, and has potential application value in transdermal drug delivery and transportation.

[0039] The prepared supramolecular astaxanthin liposome has a skin permeability about 31 times higher than that of single astaxanthin, and has the antioxidant and repair effects and biological activities of astaxanthin and lipids.

[0040] In some embodiments, the step of mixing astaxanthin and a cationic precursor in a solvent and heating the mixture to obtain supramolecular astaxanthin comprises:

[0041] Dissolving astaxanthin and a cationic precursor in a solvent respectively to obtain an astaxanthin solution and a cationic precursor solution;

[0042] The cationic precursor solution is added dropwise into the astaxanthin solution to mix, and heated to cause an ionization and salt-forming reaction;

[0043] The solution after the reaction is concentrated under vacuum conditions, distilled and crystallized under reduced pressure, filtered, washed and vacuum dried to obtain supramolecular astaxanthin.

[0044] In the preparation of supramolecular astaxanthin, astaxanthin is used as an anion precursor, and a cationic precursor is used to synthesize supramolecular astaxanthin through an ionization salt-forming reaction. After the reaction, the product is separated and purified by concentration-recrystallization to obtain supramolecular astaxanthin. The interaction between supramolecular molecules can not only effectively penetrate the stratum corneum of the skin, but also improve its bioavailability as an active ingredient to exert its effect. The preparation method uses simple and easily available solvents such as ethanol or water as the reaction medium, and the instruments and reaction conditions used are also easy to implement. The synthesis steps are simple, the post-processing is convenient, and the obtained product has high purity and high yield, which can meet general research requirements.

[0045] In some embodiments, the molar ratio of astaxanthin to the cationic precursor is 1:1 to 1:10.

[0046] The astaxanthin is a chain-breaking antioxidant with strong antioxidant capacity. It can remove nitrogen dioxide, sulfide, disulfide, etc., and can also reduce lipid peroxidation, effectively inhibiting lipid peroxidation caused by free radicals. At the same time, it has many physiological effects such as inhibiting tumor occurrence, enhancing immunity, and removing free radicals in the body. It has a good therapeutic effect on skin cancer caused by ultraviolet rays, and also has a preventive and therapeutic effect on eye diseases caused by diabetes. It has broad application prospects in health products, medicines, cosmetics, food additives, and aquaculture.

[0047] In some embodiments, the cationic precursor is selected from betaine or L-carnitine.

[0048] The betaine can regulate the osmotic pressure in the body, relieve stress, and promote fat metabolism and protein synthesis; the L-carnitine has the ability to protect the stability of cell membranes, improve the body's immunity, avoid the invasion of some diseases, and play a certain preventive role in the prevention and treatment of sub-health, and is mainly used in health care, life sciences, medicine and cosmetics industries. When the astaxanthin is mixed with betaine and L-carnitine in a solvent such as ethanol or water under predetermined temperature conditions, the astaxanthin and betaine or L-carnitine undergo an ionization salt reaction to obtain supramolecular astaxanthin. The supramolecular astaxanthin liposome has the biological activity and efficacy of both astaxanthin and betaine or L-carnitine, and greatly improves the solubility and bioavailability of astaxanthin, thereby enhancing its application effect.

[0049] In some embodiments, the solvent is selected from one or more of ethanol, water, methanol, isopropanol, acetone, propylene glycol, butylene glycol, pentanediol, and glycerol.

[0050] In some embodiments, the step of reacting the supramolecular astaxanthin, soybean lecithin and a surfactant to obtain supramolecular astaxanthin liposomes comprises:

[0051] respectively preparing ethanol solutions of the supramolecular astaxanthin, soybean lecithin and surfactant;

[0052] Adding the ethanol solution of soybean lecithin and surfactant dropwise into the ethanol solution of supramolecular astaxanthin, mixing, and heating for reaction;

[0053] The solution after the reaction is concentrated under vacuum conditions, rotary evaporated, and dried to obtain the supramolecular astaxanthin liposome.

[0054] In some embodiments, the surfactant is one or more of cholesterol, Tween-20, Tween-40, Tween-60, Tween-80, Span-20 and Span-80.

[0055] In some embodiments, the molar ratio of the supramolecular astaxanthin, soybean lecithin and surfactant is 1:1:1 to 1:10:10.

[0056] The present invention also provides a supramolecular astaxanthin liposome, which is prepared by the supramolecular astaxanthin liposome preparation method.

[0057] The solubility and transdermal effect of single astaxanthin are poor, which limits its application effect and scope. Compared with single astaxanthin, supramolecular astaxanthin liposomes have better biocompatibility and significantly improve their transdermal absorption, thus enhancing their application effect. Supramolecular astaxanthin liposomes completely retain the main molecular skeleton and lipid properties of astaxanthin monomers, thus having the biological activity and efficacy of both substances, and greatly improving the solubility and transdermal permeability of astaxanthin, thus enhancing its application effect of transdermal delivery.

[0058] The scheme of the present invention is further described below with specific embodiments.

[0059] Example 1

[0060] Under nitrogen atmosphere, 0.01 mol of astaxanthin was dissolved in 10 mL of water and ethanol in a reactor, and 0.01 mol of betaine was dissolved in 10 mL of water and added dropwise to the reactor containing astaxanthin, and heated to 60°C for 12 hours for ionization and salt formation reaction;

[0061] After the reaction is completed, the solution is concentrated to 1 / 10 of the reaction solution under vacuum conditions, and then distilled and crystallized under reduced pressure. The supramolecular astaxanthin is obtained by filtration, washing and separation. The supramolecular astaxanthin with a purity of more than 99% is obtained by drying in a vacuum drying oven for 48 hours. The yield is 90.74%, and supramolecular astaxanthin is obtained.

[0062] At room temperature, 0.01 mol of supramolecular astaxanthin was dissolved in 10 mL of ethanol in a reactor, 0.01 mol of soybean lecithin and cholesterol were dissolved in 10 mL of ethanol and added dropwise to the reactor in which supramolecular astaxanthin was dissolved, heated to 40°C, mixed evenly and reacted for 12 hours;

[0063] After the reaction is completed, the solution is concentrated to 1 / 10 of the reaction solution under vacuum conditions, and the supermolecular astaxanthin liposomes are obtained by reduced pressure distillation and crystallization. The supermolecular astaxanthin liposomes are dried in a vacuum drying oven for 48 hours to obtain supramolecular astaxanthin liposomes with a purity of more than 90%, with a yield of 92.48%, to obtain supramolecular astaxanthin liposomes.

[0064] At room temperature, supramolecular astaxanthin, soybean lecithin and cholesterol were mixed in a molar ratio of 1:1:1, and fully mixed with a magnetic stirrer to obtain a mixed solution. The system was observed to be completely dissolved to a clear state, and then rotary evaporation was performed to finally obtain supramolecular astaxanthin liposomes.

[0065] Figure 1 Flow chart of the preparation method of supramolecular astaxanthin liposomes.

[0066] like Figure 2 As shown, the H NMR data of the supramolecular astaxanthin (supramolecular astaxanthin-betaine) prepared in this embodiment are: 1H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 6.54-6.28 (m, 3H), 5.34-5.17 (m,6H), 4.28 (m, 4H), 4.15 (s,1H), 3.99 (s, 1H) 3.59-3.16 (t, 6H), 2.78-2.57 (t,5H), 2.04-1.78 (t, 6H); 1.56-0.83 (m, 4H); the C NMR data are: 13C NMR (400 MHz,DMSO) δ 164.09 (s), 142.47 (s), 133.51 (s), 130.96 (s), 128.63 (s), 126.20 (s), 125.82 (s), 119.96 (s), 79.45 (s), 66.18 (s), 61.14 (s), 51.99 (s),51.95 (s), 31.59 (s), 28.65 (s), 27.45 (s), 26.33 (s), 25.48 (s), 24.16 (s),23.90 (s), 21.94 (s), 19.01 (s). The melting point of the supramolecular astaxanthin prepared in this embodiment is 198°C.

[0067] Depend on Figure 3 It can be seen that there is an interaction force between astaxanthin and betaine, which indicates that a supramolecular structure is formed between astaxanthin and betaine.

[0068] Depend on Figure 4 It can be seen that the particle size of the supramolecular astaxanthin liposome is about 4 nm and is evenly dispersed.

[0069] Depend on Figure 5 It can be seen that the permeability of supramolecular astaxanthin liposomes is 2.65 times that of supramolecular astaxanthin and 30.65 times that of astaxanthin.

[0070] Depend on Figure 6 It can be seen that the cell viability of supramolecular astaxanthin liposomes is higher than 96%, indicating that supramolecular astaxanthin liposomes have good safety and biocompatibility.

[0071] Depend on Figure 7 It can be seen that compared with supramolecular astaxanthin, supramolecular astaxanthin liposomes can increase the solubility of astaxanthin by about 1.17 times, which is 376.17 times and 1.71 times in aqueous solution and ethanol respectively.

[0072] Therefore, these results indicate that supramolecular astaxanthin liposomes have good biocompatibility, high bioavailability, and improved solubility of astaxanthin.

[0073] In summary, the present invention provides a supramolecular astaxanthin liposome and a preparation method and application thereof. In the preparation method, betaine or L-carnitine is used as a cationic precursor and astaxanthin is used as an anionic precursor to synthesize supramolecular astaxanthin through an ionization salt-forming reaction, and then the supramolecular astaxanthin and lipid are injected into the supramolecular astaxanthin liposome by an ethanol injection method. The supramolecular astaxanthin liposome has a skin permeability that is about 31 times higher than that of single astaxanthin, and simultaneously has the antioxidant and repairing effects and biological activities of single astaxanthin and lipid, effectively improving the solubility and skin permeability of astaxanthin and can improve its biological activity, and has potential application value in transdermal administration and delivery.

[0074] It should be understood that the application of the present invention is not limited to the above examples. For ordinary technicians in this field, improvements or changes can be made based on the above description. All these improvements and changes should fall within the scope of protection of the claims attached to the present invention.

Claims

1. A method for preparing supramolecular astaxanthin liposomes, characterized in that: Includes steps: The astaxanthin is dissolved in ethanol to obtain an astaxanthin solution, and the cationic precursor aqueous solution is added dropwise to the astaxanthin solution for mixing, and heated to cause an ionization and salt-forming reaction; the solution after the reaction is concentrated under vacuum conditions, and is subjected to reduced pressure distillation and crystallization, and then filtered, washed, and vacuum dried to obtain supramolecular astaxanthin; The supramolecular astaxanthin, soybean lecithin and a surfactant are reacted to obtain the supramolecular astaxanthin liposome; The cationic precursor is selected from betaine; The molar ratio of astaxanthin to cationic precursor is 1:

1.

2. The method for preparing supramolecular astaxanthin liposomes according to claim 1, characterized in that: The step of reacting the supramolecular astaxanthin, soybean lecithin and a surfactant to obtain supramolecular astaxanthin liposomes comprises: respectively preparing ethanol solutions of the supramolecular astaxanthin, soybean lecithin and surfactant; Adding the ethanol solution of soybean lecithin and surfactant dropwise into the ethanol solution of supramolecular astaxanthin, mixing, and heating for reaction; The solution after the reaction is concentrated under vacuum conditions, rotary evaporated, and dried to obtain the supramolecular astaxanthin liposome.

3. The method for preparing supramolecular astaxanthin liposomes according to claim 2, characterized in that: The surfactant is one or more of cholesterol, Tween-20, Tween-40, Tween-60, Tween-80, Span-20 and Span-80.

4. The method for preparing supramolecular astaxanthin liposomes according to claim 3, characterized in that: The molar ratio of the supramolecular astaxanthin, soybean lecithin and surfactant is 1:1:1-1:10:

10.

5. A supramolecular astaxanthin liposome, characterized in that: The supramolecular astaxanthin liposome is prepared by the preparation method of any one of claims 1 to 4.

6. Use of the supramolecular astaxanthin liposome as claimed in claim 5 in the preparation of cosmetics.

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