CN114010522B - Lipoic acid mixed micelle and preparation method and application thereof - Google Patents
Lipoic acid mixed micelle and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a lipoic acid mixed micelle, which is prepared from lipoic acid, phospholipid and sodium lipoic acid, has simple components and high drug loading capacity, and the obtained mixed micelle has stronger stability and can still keep the properties of the micelle after different dilution factors and long-term storage. The invention also discloses a preparation method of the mixed micelle, which has simple process and high repeatability and is suitable for industrial production. The mixed micelle does not need ethanol, propylene glycol and other organic solvents which are greatly stimulated to solubilize, and the obtained mixed micelle has no side effect in use, is safe and reliable, and has wide raw material sources and low cost. The invention also discloses application of the mixed micelle, the mixed micelle can be used for preparing cosmetics and pharmaceutical compositions prepared from the mixed micelle and pharmaceutically acceptable pharmaceutical excipients, and the lipoic acid mixed micelle can be prepared into injections, oral preparations and skin coatings, can be diluted to different degrees and is used, so that clinical administration is greatly facilitated.
Description
Technical Field
The invention relates to a lipoic acid mixed micelle, in particular to a lipoic acid mixed micelle, a preparation method and application thereof.
Background
Alpha-lipoic acid (ALA) is a natural antioxidant with very strong antioxidant capacity, and is widely distributed in animal liver tissues and plants such as spinach, tomatoes and the like. Lipoic acid belongs to the vitamin B class of compounds and acts as a coenzyme in the multienzyme complexes of pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, aminocaproate decarboxylase, and the like. In recent years, the oxidation resistance of lipoic acid is receiving more and more attention, and is becoming a hot spot of research in the scientific community. Alpha-lipoic acid (ALA, oxidized form) can be converted into dihydrolipoic acid (DHLA, reduced form) in vivo, and both ALA and DHLA have strong oxidation resistance, and the ALA and the DHLA have synergistic effects in vivo, are one of the most effective known natural antioxidants, and have oxidation resistance which is 400 times of the combined capacity of vitamin C and vitamin E, and are known as universal antioxidants. They play an important role in the prevention and treatment of diseases associated with free radicals, such as cancer, aging, diabetes, atherosclerosis, degeneration of brain and nerve tissues, etc.
In the cosmetic field, alpha-lipoic acid is considered as a general antioxidant, which can increase the level of glutathione in all cells and has the effects of whitening, removing freckles and resisting aging. Internationally, alpha-lipoic acid has been applied as a cosmetic raw material in some well-known anti-aging and whitening and freckle-removing products, such as Pei Likang, reviva Labs, paula's Choice, hada-Labo (myo-research) and the like, and good market feedback is obtained. However, the application of lipoic acid still has a certain limitation, which is mainly related to the special physical and chemical properties, and is characterized by the solubility in water and weak solubility, wherein the mass fraction of the solution is only 0.08% at normal temperature, which brings inconvenience to the processing and preparation of subsequent products. And lipoic acid is easy to decompose under oxygen and light, has low bioavailability and poor stability, and has certain irritation. In order to fully exert the application of the lipoic acid in the cosmetic field, the lipoic acid in different dissolution states is needed, which is mainly caused by more dust on the skin surface due to the problems of air pollution and the like, and more metal ions are contained in sweat, at the moment, the water-soluble lipoic acid is needed to be quickly dissolved on the skin surface such as sweat and the like to chelate and remove the lipoic acid with metal ions such as iron, copper, cadmium, lead, mercury and the like, so that the peroxidation reaction of macromolecules such as lipid and the like caused by the metal ions is reduced; the lipoic acid with fat solubility is required to be capable of directly playing a role in scavenging free radicals such as hydroxyl free radicals and singlet oxygen after entering cells rapidly, and recovering the capacity of endogenous antioxidants such as vitamin E, glutathione and the like, so that the overall antioxidant capacity of an organism is improved. Therefore, it is important to find a method for solving the problems of water solubility and fat solubility of lipoic acid, improving the stability of lipoic acid and reducing the irritation.
Disclosure of Invention
In order to overcome the defects of the prior art, one of the purposes of the invention is to provide the lipoic acid mixed micelle, which greatly improves the water solubility and stability of lipoic acid and has good clinical value.
The second object of the present invention is to provide a method for preparing the lipoic acid mixed micelle.
It is a further object of the present invention to provide the use of the lipoic acid mixed micelles.
One of the purposes of the invention is realized by adopting the following technical scheme:
a lipoic acid mixed micelle consists of lipoic acid, phospholipid, sodium lipoic acid and solvent;
the solvent is selected from purified water, aqueous sodium chloride solution, and phosphate solution with pH of 7.4-8.2.
Further, the addition ratio of the phospholipid to the lipoic acid, the sodium lipoic acid and the solvent is (2-4) mg:1mg: (1-2) mg: (0.1-0.5) mL.
Further, the phospholipid is selected from one of soybean lecithin, egg yolk lecithin, hydrogenated soybean lecithin, cephalin, inositol phospholipid, serine phospholipid, and polyene phosphatidylcholine.
The second purpose of the invention is realized by adopting the following technical scheme:
the preparation method of the lipoic acid mixed micelle comprises the following steps: dissolving lipoic acid and phospholipid in an organic solvent, uniformly dispersing by ultrasonic, and removing the organic solvent to obtain a lipoic acid micelle coprecipitate film; and dissolving sodium lipoic acid in a solvent to obtain a mixed solution, adding the mixed solution into the lipoic acid micelle coprecipitate film for hydration, and carrying out ultrasonic treatment and filtration to obtain the lipoic acid mixed micelle.
Further, the organic solvent is selected from one or more of ethyl acetate, acetone, chloroform, methanol, ethanol and diethyl ether.
Further, the addition ratio of the phospholipid to the organic solvent is 1mg:0.01-0.5mL.
Further, the pore size of the filtering membrane is 0.22-0.8 μm.
The third purpose of the invention is realized by adopting the following technical scheme:
the lipoic acid mixed micelle can be used in cosmetics or can be prepared into a pharmaceutical composition with pharmaceutically acceptable pharmaceutical excipients.
Furthermore, the lipoic acid mixed micelle is used in cosmetics for whitening, removing freckles and resisting aging or is prepared into a pharmaceutical composition with the functions of resisting oxidization, treating cardiovascular diseases, treating acute and chronic inflammations, treating gout and protecting liver with pharmaceutically acceptable pharmaceutical auxiliary materials.
Further, the final dosage form of the mixture micelle is one of ointment, gel, emulsion, nano preparation, tablet, capsule, granule, suspension and powder injection.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a lipoic acid mixed micelle, which is prepared from lipoic acid, phospholipid and sodium lipoic acid, has simple components, and has stronger stability, and can still keep the properties of the micelle after different dilution factors and long-term storage. The invention also provides a preparation method of the lipoic acid mixed micelle, which has simple process and high repeatability, and the used organic solvent can be recycled and is suitable for industrial production. And the phospholipid and the sodium lipoic acid in the mixed micelle have good biocompatibility, do not need ethanol, propylene glycol and other organic solvents which are greatly stimulated to solubilize, and the obtained mixed micelle has no side effect when in use, is safe and reliable, and has wide raw material sources and low cost. The mixed micelle contains lipoic acid in different dissolution states, which is mainly caused by more dust on the skin surface and more metal ions in sweat due to the problems of air pollution and the like, and at the moment, water-soluble sodium lipoic acid needs to be used for rapidly dissolving on the skin surface such as sweat and the like, and chelating and removing the water-soluble sodium lipoic acid with metal ions such as iron, copper, cadmium, lead, mercury and the like, so that peroxidation of macromolecules such as lipid and the like caused by the metal ions is reduced; it is also required that the liposoluble protolipoic acid can directly play a role in scavenging free radicals such as hydroxyl free radicals and singlet oxygen after entering cells rapidly, and recover the capacity of endogenous antioxidants such as vitamin E, glutathione and the like, thereby improving the overall antioxidant capacity of the organism. The invention also provides application of the lipoic acid mixed micelle, the mixed micelle can be used for preparing cosmetics and pharmaceutical compositions prepared from the lipoic acid mixed micelle and pharmaceutically acceptable pharmaceutical excipients, and the lipoic acid mixed micelle can be used for preparing oral preparations and skin coatings and can be diluted to different degrees for use, so that clinical administration is greatly facilitated.
Detailed Description
The present invention will be further described with reference to the following specific embodiments, and it should be noted that, on the premise of no conflict, new embodiments may be formed by any combination of the embodiments or technical features described below.
Example 1
The preparation method of the lipoic acid mixed micelle comprises the following steps:
150mg of soybean lecithin and 50mg of lipoic acid are weighed and placed in a 50mL round-bottom flask, 10mL of methanol is added into the flask for dissolution, and ultrasonic dispersion is uniform. Removing methanol by rotary evaporation at the water bath temperature of 40 ℃ to form a layer of transparent lipoic acid micelle coprecipitate film, dissolving 50mg of sodium lipoic acid in 10mL of purified water to obtain a mixed solution, adding the mixed solution into the transparent film to hydrate the film to obtain a dispersion solution containing medicine mixed micelles, performing ultrasonic treatment (50W, interval 2s,2 min) on the probe, filtering with a 0.22 mu m microporous filter membrane, taking filtrate, and sub-packaging to obtain the lipoic acid mixed micelles.
Example 2
The preparation method of the lipoic acid mixed micelle comprises the following steps:
150mg of soybean lecithin and 50mg of lipoic acid are weighed and placed in a 50mL round bottom flask, 10mL of dichloromethane is added into the mixture to dissolve the mixture, and the mixture is uniformly dispersed by ultrasonic waves. Removing dichloromethane by rotary evaporation at the water bath temperature of 35 ℃ to form a layer of transparent lipoic acid micelle coprecipitate film, dissolving 50mg of sodium lipoic acid in 10mL of purified water to obtain a mixed solution, adding the mixed solution into the transparent film to hydrate the film to obtain a dispersion solution containing medicine mixed micelles, performing ultrasonic treatment (50W, interval 2s,2 min) on the probe, filtering with a 0.22 mu m microporous filter membrane, taking filtrate, and sub-packaging to obtain the lipoic acid mixed micelles.
Example 3
The preparation method of the lipoic acid mixed micelle comprises the following steps:
150mg of soybean lecithin and 50mg of lipoic acid are weighed and placed in a 50mL round-bottom flask, 10mL of ethanol is added into the flask for dissolution, and ultrasonic dispersion is uniform. Removing ethanol by rotary evaporation at the water bath temperature of 45 ℃ to form a layer of transparent lipoic acid micelle coprecipitate film, dissolving 100mg of sodium lipoic acid in 10mL of purified water to obtain a mixed solution, adding the mixed solution into the transparent film to hydrate the film to obtain a dispersion solution containing medicine mixed micelles, performing ultrasonic treatment (50W, interval 2s,2 min) on the probe, filtering with a 0.22 mu m microporous filter membrane, taking filtrate, and sub-packaging to obtain the lipoic acid mixed micelles.
Example 4
The preparation method of the lipoic acid mixed micelle comprises the following steps:
150mg of egg yolk lecithin and 50mg of lipoic acid are weighed and placed in a 50mL round-bottom flask, 10mL of methanol is added into the flask for dissolution, and the mixture is uniformly dispersed by ultrasound. Removing methanol by rotary evaporation at the water bath temperature of 45 ℃ to form a layer of transparent lipoic acid micelle coprecipitate film, dissolving 100mg of sodium lipoic acid in 10mL of purified water to obtain a mixed solution, adding the mixed solution into the transparent film to hydrate the film to obtain a dispersion solution containing medicine mixed micelles, performing ultrasonic treatment (50W, interval 2s,2 min) on the probe, filtering with a 0.22 mu m microporous filter membrane, taking filtrate, and sub-packaging to obtain the lipoic acid mixed micelles.
Example 5
The preparation method of the lipoic acid mixed micelle comprises the following steps:
150mg of egg yolk lecithin and 50mg of lipoic acid are weighed and placed in a 50mL round-bottom flask, 10mL of ethanol is added into the flask for dissolution, and ultrasonic dispersion is uniform. Removing ethanol by rotary evaporation at the water bath temperature of 45 ℃ until no ethanol smell exists, forming a layer of transparent lipoic acid micelle coprecipitation film, dissolving 50mg of sodium lipoic acid in 10mL of purified water to obtain a mixed solution, adding the mixed solution into the transparent film to hydrate the film to obtain a dispersion solution containing medicine mixed micelles, performing ultrasonic treatment (50W, interval 2s,2 min) on the probe, filtering with a 0.22 mu m microporous filter membrane, taking filtrate, and sub-packaging to obtain the lipoic acid mixed micelles.
Example 6
The lipoic acid mixed micelle comprises the following steps:
150mg of soybean lecithin and 50mg of lipoic acid are weighed and placed in a 50mL round bottom flask, 10mL of dichloromethane is added into the mixture to dissolve the mixture, and the mixture is uniformly dispersed by ultrasonic waves. Removing dichloromethane by rotary evaporation at the water bath temperature of 35 ℃ to form a layer of transparent lipoic acid micelle coprecipitate film, dissolving 50mg of sodium lipoic acid in 10mL of purified water to obtain a mixed solution, adding the mixed solution into the transparent film to hydrate the film to obtain a dispersion solution containing medicine mixed micelles, performing ultrasonic treatment (50W, interval 2s,2 min) on the probe, filtering with a 0.22 mu m microporous filter membrane, taking filtrate, and sub-packaging to obtain the lipoic acid mixed micelles.
Example 7
The preparation method of the lipoic acid mixed micelle comprises the following steps:
150mg of polyene phosphatidyl choline and 50mg of lipoic acid are weighed into a 50mL round bottom flask, and then 10mL of diethyl ether is added into the flask for dissolution, and ultrasonic dispersion is uniform. Removing diethyl ether by rotary evaporation at the water bath temperature of 35 ℃ to form a layer of transparent lipoic acid micelle coprecipitate film, dissolving 50mg of sodium lipoic acid in 10mL of pH7.4 phosphate aqueous solution to obtain a mixed solution, adding the mixed solution into the transparent film to hydrate the film to obtain a dispersion solution containing medicine mixed micelles, performing ultrasonic treatment (50W, interval 2s,2 min) on the probe, filtering with a 0.22 mu m microporous filter membrane, taking the filtrate, and sub-packaging to obtain the lipoic acid mixed micelles.
Example 8
The preparation method of the lipoic acid mixed micelle comprises the following steps:
150mg of hydrogenated soybean phospholipid and 50mg of lipoic acid are weighed into a 50mL round bottom flask, and then 10mL of ethanol is added into the flask for dissolution, and ultrasonic dispersion is uniform. Removing ethanol by rotary evaporation at the water bath temperature of 45 ℃ to form a layer of transparent lipoic acid micelle coprecipitate film, dissolving 50mg of sodium lipoic acid in 10mL of purified water to obtain a mixed solution, adding the mixed solution into the transparent film to hydrate the film to obtain a dispersion solution containing medicine mixed micelles, performing ultrasonic treatment (50W, interval 2s,2 min) on the probe, filtering with a 0.22 mu m microporous filter membrane, taking filtrate, and sub-packaging to obtain the lipoic acid mixed micelles.
Comparative example 1
Comparative example 1 differs from example 3 in that: the sodium lipoic acid was omitted, and the rest was the same as in example 3, to obtain lipoic acid mixed micelles.
Experimental example 1
The lipoic acid mixed micelles obtained in examples 1 to 8 and comparative example 1 were examined for particle size, zeta potential, and distribution coefficient (PDI) using a malvern ZS-90 nano-particle sizer, and the results are shown in table 1:
TABLE 1
As is clear from Table 1, the particle size of the lipoic acid mixed micelles obtained in examples 1 to 8 of the present invention is in the range of 61.1-101.7nm, zeta potential is-17.3 to-28.1 mV, PDI is 0.162-0.231, so that the lipoic acid mixed micelles are suitable for preparing suspension or powder injection. Compared with the comparative example 1 and the example 3, the sodium lipoic acid is omitted, the particle size of the obtained lipoic acid mixed micelle is smaller, the zeta potential is lower, the PDI is larger, and the preparation of a plurality of later medicament forms is not facilitated.
Experimental example 2
Stability test
2.1 dilution stability experiment
The lipoic acid mixed micelles obtained in examples 1 to 8 and comparative example 1 of the present invention were diluted with 1-fold, 3-fold and 5-fold purified water, respectively, and their stability after dilution at different fold was observed, and the results are shown in table 2. The results show that the lipoic acid mixed micelle obtained by the invention has the appearance characteristics of light yellow transparent solution after being diluted by different multiples, has opalescence, has no precipitation and has good stability. The lipoic acid mixed micelle obtained in comparative example 1 was not significantly different from that obtained in example 3 when diluted 1 time, but the diluted micelle was not stably present when diluted 3 times and 5 times, and the unstable micelle phenomenon such as flocculation and delamination gradually occurred.
TABLE 2
2.2 Long term stability detection
The lipoic acid mixed micelles obtained in examples 1 to 8 and comparative example 1 were allowed to stand in a refrigerator at 4℃for 0 to 3 months to examine their long-term stability, and the results are shown in Table 3. The appearance of the micelle prepared by each example is light yellow transparent solution, has opalescence, and has no precipitation after standing for 3 months, thus showing good stability. The appearance properties of the freshly prepared lipoic acid mixed micelles obtained in comparative example 1 are not significantly different from those of the lipoic acid mixed micelles obtained in example 3, but the lipoic acid mixed micelles in comparative example 1 gradually undergo flocculation and layering phenomena when the lipoic acid mixed micelles are respectively stood for 1 month and 3 months under the same test conditions, and it is known that the elimination of sodium lipoic acid reduces the stability of the lipoic acid mixed micelles.
TABLE 3 Table 3
Experimental example 3
Detection of DPPH free radical scavenging ability of lipoic acid mixed micelle
The lipoic acid mixed micelles obtained in examples 1 to 8 and comparative example 1 of the present invention were diluted 10 times to obtain test solutions, respectively. 20mg of DPPH is dissolved in 250mL of ethanol and stored at 0-4 ℃ in a dark place. 3mL of DPPH ethanol solution is added to each tube, equal volume of water (A1) is added to the control tube, equal volume of the example test solution (A2) is added to the sample tube, and 3mL of water and equal volume of the example test solution (A3) are added to the blank control tube. After 30min of reaction, the absorbance of each tube was measured at 517nm wavelength and DPPH radical scavenging was calculated. The DPPH radical scavenging rate was calculated as follows and the results are shown in Table 4.
TABLE 4 Table 4
As can be seen from Table 4, the clearance of the lipoic acid mixed micelles obtained in examples 1 to 8 of the present invention to DPPH free radicals is 21.11% -44.18%. It is known that the lipoic acid mixed micelle prepared by the method does not negatively influence the free radical scavenging capability of lipoic acid. In contrast, in comparative example 1, the DPPH radical scavenging rate was only 17.18% compared with example 3, and it was found that the elimination of sodium lipoic acid did not allow lipoic acid in lipoic acid mixed micelles to fully and effectively exert its own radical scavenging function.
Experimental example 4
Detection of effects on inflammatory factor release levels
Taking logarithmic growth phase HaCat cells (human immortalized epidermal cells) at 2×10 6 The cell turbid liquid is inoculated on a 6-hole cell culture plate at the density of each mL, 1mL of cell suspension is added into each hole, the incubator is used for culturing for 24 hours, and the supernatant is carefully sucked; the blank group and the model group are respectively added with 1mL of DMEM solution; example 3 the test solution was diluted 1000 times with the lipoic acid mixed micelle prepared in example 3, and the lipoic acid mixed micelle prepared in comparative example 1 was added in the comparative example 1 in the same ratio as in exampleThe 3 groups are identical. After addition, the culture was continued for 6 hours, and the model group and the example 3 group and the comparative example 1 group were irradiated with ultraviolet light at an irradiation power of 9J/cm 2 The irradiation time is 1.5h, and the blank group is not irradiated. Incubation was continued for 24h after illumination, 3 replicates were performed for each group, and each replicate was tested 3 times. Treating cells, collecting cell lysate, centrifuging at 10000r/min for 10min to obtain cell lysate supernatant, and taking 20 μL to detect total protein content in sample with BCA kit. The release levels of IL-1α inflammatory factor in the blank group, model group, example 3 group and comparative example 1 group were measured, respectively, and after experimental operation was performed according to ELISA kit instructions, OD values were measured at 450nm, and the release levels of IL-1α inflammatory factor were calculated from the OD values, and the results are shown in Table 5:
TABLE 5
As can be seen from the table, the lipoic acid mixed micelles added in the example 3 group showed a stronger inhibitory effect on the release of IL-1α -factor level, and the expression level thereof was only 0.87ng/L, compared with the model group, the blank group and the comparative example 1 group. Therefore, the property of the lipoic acid mixed micelle prepared by the method does not influence the property of lipoic acid.
In conclusion, the invention provides the lipoic acid mixed micelle which is prepared from lipoic acid, phospholipid and sodium lipoic acid, and has simple components and high drug loading. The obtained lipoic acid mixed micelle has strong stability, can still keep good stability after being diluted 5 times and stored for a long time, and has no crystals and other precipitates. And the phospholipid and the sodium lipoic acid in the mixed micelle have good biocompatibility, do not need ethanol, propylene glycol and other organic solvents with great stimulation for solubilization, reduce the toxicity of medicines and cosmetics prepared in the later stage, have small irritation to blood vessels and skin, and are beneficial to reducing adverse reactions of users on medicines or cosmetics. The lipoic acid mixed micelle prepared by the invention has no influence on the scavenging effect of free radicals and the release level of inflammatory factors, and has no limit or other negative influence on the property of lipoic acid. When the lipoic acid mixed micelle is used for preparing a pharmaceutical composition, the lipoic acid mixed micelle can be used in modes of preparing oral preparations, coating skin and the like, can be diluted to different degrees and is used, and clinical administration is greatly facilitated.
The above embodiments are only preferred embodiments of the present invention, and the scope of the present invention is not limited thereto, but any insubstantial changes and substitutions made by those skilled in the art on the basis of the present invention are intended to be within the scope of the present invention as claimed.
Claims (8)
1. The lipoic acid mixed micelle is characterized by comprising lipoic acid, phospholipid, sodium lipoic acid and a solvent;
the solvent is selected from one of purified water, sodium chloride water solution and phosphate solution with pH of 7.4-8.2; the addition ratio of the phospholipid to the lipoic acid, the sodium lipoic acid and the solvent is (0.1-4) mg:1mg: (0.5-2) mg: (0.1-0.5) mL;
the preparation method of the lipoic acid mixed micelle comprises the following steps: dissolving lipoic acid and phospholipid in an organic solvent, uniformly dispersing by ultrasonic, and removing the organic solvent to obtain a lipoic acid micelle coprecipitate film; and dissolving sodium lipoic acid in a solvent to obtain a mixed solution, adding the mixed solution into the lipoic acid micelle coprecipitate film for hydration, and carrying out ultrasonic treatment and filtration to obtain the lipoic acid mixed micelle.
2. The lipoic acid mixed micelle of claim 1, wherein the phospholipid is selected from one of soybean lecithin, egg yolk lecithin, hydrogenated soybean lecithin, cephalin, inositol phospholipid, serine phospholipid, and polyene phosphatidylcholine.
3. The lipoic acid mixed micelle of claim 1, wherein the organic solvent is selected from one or more of ethyl acetate, acetone, chloroform, methanol, ethanol, diethyl ether.
4. The lipoic acid mixed micelle according to claim 3, wherein the phospholipid and the organic solvent are added in a ratio of 1mg:0.01-0.5mL.
5. The lipoic acid mixed micelle of claim 4, wherein the filter membrane pore size of the filtration is 0.22-0.8 μm.
6. The use of the lipoic acid mixed micelle according to any one of claims 1 to 5, characterized in that the lipoic acid mixed micelle is used in the preparation of cosmetics or the lipoic acid mixed micelle is used with pharmaceutically acceptable pharmaceutical excipients in the preparation of pharmaceutical compositions.
7. The use of the lipoic acid mixed micelle according to claim 6, wherein the lipoic acid mixed micelle is used for preparing cosmetics for whitening, removing freckles and resisting aging, or the lipoic acid mixed micelle and pharmaceutically acceptable pharmaceutical excipients are used for preparing a pharmaceutical composition with antioxidant and liver protecting functions.
8. The use of the lipoic acid mixed micelle as in claim 7, wherein the mixed micelle is in one of an ointment, a gel, an emulsion, a nano preparation, a tablet, a capsule, a granule, a suspension and a powder injection.
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CN115429758B (en) * | 2022-09-06 | 2024-05-14 | 厦门金达威生物科技有限公司 | Coenzyme Q10-lipoic acid type phospholipid nano-composite micelle and preparation method and application thereof |
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