CN113244224A - Ellagic acid sustained-release gel and preparation method and application thereof - Google Patents
Ellagic acid sustained-release gel and preparation method and application thereof Download PDFInfo
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- CN113244224A CN113244224A CN202110585783.4A CN202110585783A CN113244224A CN 113244224 A CN113244224 A CN 113244224A CN 202110585783 A CN202110585783 A CN 202110585783A CN 113244224 A CN113244224 A CN 113244224A
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- ellagic acid
- gel
- release
- water
- 30min
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Abstract
本发明公开了一种鞣花酸缓释凝胶及其制备方法和应用。包括：0.1wt％～0.6wt％鞣花酸、不超过3.0wt％的凝胶基质，凝胶基质为卡拉胶，或者卡拉胶与刺槐豆胶的混合物。通过控制凝胶基质种类及复合比例与总浓度，所制备的凝胶具有软硬适中、弹性好且透明度高的特点。本发明通过使用低浓度的复合凝胶基质体系，并通过分散等手段，提高了鞣花酸在凝胶体系中的浓度，有助于解决由于鞣花酸在水中溶解度很小从而不利于其在医药、食品和化妆品等产品领域的应用困境。制备的鞣花酸凝胶，包装、运输、携带方便，且使用方便，将进一步促进鞣花酸的生物性应用。The invention discloses an ellagic acid sustained-release gel and a preparation method and application thereof. Including: 0.1wt% to 0.6wt% of ellagic acid, no more than 3.0wt% of gel matrix, the gel matrix is carrageenan, or a mixture of carrageenan and locust bean gum. By controlling the type of the gel matrix, the composite ratio and the total concentration, the prepared gel has the characteristics of moderate hardness, good elasticity and high transparency. The present invention increases the concentration of ellagic acid in the gel system by using a low-concentration composite gel matrix system and dispersing and other means, which helps to solve the problem that the solubility of ellagic acid in water is very small, which is not conducive to its Application dilemmas in the fields of medicine, food and cosmetics. The prepared ellagic acid gel is convenient to package, transport, carry and use, and will further promote the biological application of ellagic acid.
Description
Technical Field
The invention belongs to the technical field of medicine health care, food and cosmetics, and particularly relates to an ellagic acid gel and a preparation method and application thereof.
Background
1. Structure and properties of ellagic acid
Ellagic acid is a natural polyphenol active substance. Ellagic acid is a dimethyl derivative of gallic acid, a polyphenol dilactone. It may be present not only in the free form but also in the condensed form (e.g. ellagitannins, glycosides, etc.). Ellagic acid is present in large amounts in a variety of soft fruits, nuts and other plant tissues, including blackberries, raspberries, strawberries, cranberries, chestnuts, pomegranates, and other plants. Ellagic acid is substantially non-toxic. Ellagic acid has good effects of resisting mutation and cancer, and especially has good inhibitory effect on colon cancer, esophageal cancer, hepatocarcinoma, lung cancer, etc. At the same time, the study of the cytotoxic and antioxidant properties of ellagic acid also stimulated the potential of ellagic acid, a certain ellagic acid was beneficial in alleviating nephrotoxic symptoms, and some ellagitannins and ellagic acids may also inhibit immunodeficiency virus (HIV) and avian cytoma (AMV) viruses. Ellagic acid has been developed and studied in recent years because of its natural components with multiple efficacies.
The pure ellagic acid is yellow, is needle-like crystal, is yellow when encountering sulfuric acid, is blue when encountering ferric trichloride, and is easily mixed with metal cation (such as Ca)2+、Mg2+) And (4) reacting. The pure ellagic acid is insoluble in water and conventional organic solvents such as alcohols, soluble in alkali, pyridine and dimethyl sulfoxide, and insoluble in diethyl ether. The melting point is higher than 360 ℃ and the boiling point is 420 ℃.
2. Functional application of ellagic acid
2.1 Oxidation resistance
Ellagic acid has strong ability to scavenge free radicals and resist oxidation, and has effect in scavenging oxygen free radicals and hydroxyl free radicals. Ellagic acid can be used not only as an internal oxidant to protect protected materials from oxidation, but also as an external antioxidant, making ellagic acid useful for protecting foods such as edible oils, soybean oil, lard, methyl oleate, and oxidized fats. Ellagic acid is considered to be the most effective inhibitor of the microsomal NADPH-dependent lipid peroxidation initiation phase in inhibiting lipid peroxidation, and ellagic acid can also strongly inhibit lipid peroxidation induced by doxorubicin. Ellagic acid inhibits the ferrimyoglobin/hydrogen peroxide dependent lipid peroxidation. Ellagic acid can prevent Lipid Peroxide (LPO) induced by exogenous substances in T cells, inhibit Reactive Oxygen Species (ROS) generation, and improve cell death caused by cytotoxin.
Ellagic acid can also reduce cellular damage caused by radiation, hydrogen peroxide and mitomycin C in mouse bone marrow cells. Ellagic acid effectively inhibits the oxidation of DCDHF induced by peroxynitrite as well as the oxidation of peroxynitrite itself. At the same time, ellagic acid prevents single strand breaks in pTZ 18U plasmid DNA induced by peroxynitrite and the nitration of tyrosyl groups in calf serum proteins. Thus, in vitro, ellagic acid protects biomolecules from oxidative and nitration damage caused by peroxynitrite.
2.2 anticancer Activity
It has been shown that, when pomegranate rind extract is orally administered to a human body, it can be directly absorbed by the human body and only ellagic acid is utilized. Ellagic acid shows obvious inhibiting effect on canceration induced by chemical substances and other multiple canceration, and especially has good inhibiting effect on colon cancer, esophageal cancer, liver cancer, lung cancer, tongue and skin tumor, etc. Scientists at home and abroad have conducted a great deal of experiments to reach several conclusions: (1) ellagic acid can effectively inhibit the metabolic activity of pathogens; (2) ellagic acid can combine with the active metabolic form of carcinogens into a harmless compound, so that it cannot combine with cellular DNA, and functions as a carcinogen scavenger; (3) ellagic acid may affect the activity of certain enzymes, thereby eliminating carcinogenic toxicity.
2.3 antibacterial, anti-inflammatory and antitoxic Properties
Ellagic acid has obvious bacteriostatic action, can inhibit various diseases and the growth of some fungi to a great extent, and can protect plants from being damaged by fungi. The property of ellagic acid is expected to participate in the treatment of tuberculosis in the future and prepare new drugs. Research shows that the metabolites urolithin A and urolithin B generated after the ellagic acid is absorbed can effectively relieve symptoms of mouse colon inflammation, can effectively inhibit various acute and chronic colitis, especially chronic colitis, and has good treatment effect. In addition, ellagic acid can be used for treating hepatotoxicity caused by excessive drinking. In addition, a certain dose of ellagic acid is also beneficial for alleviating nephrotoxic symptoms and has a certain reparative effect in many aspects.
2.4 Effect against human immunodeficiency Virus
According to the research, some ellagitannins and ellagic acids can inhibit Human Immunodeficiency Virus (HIV) and avian cytoma virus (AMV) and their action mechanism is different from other drugs which can inhibit DNA polymerase, but probably because they can inhibit adsorption of HIV to normal human cells, and Asanaka et al have shown through experiments that ellagitannins and oral ellagic acids can inhibit HIV and herpes virus.
2.5 other effects
Ellagic acid is effective in inhibiting eosinophils, and this property can be used for treating allergic inflammation. Ellagic acid has a blood coagulation function and can be used as a coagulant, since ellagic acid can effectively coagulate blood and shorten bleeding time, it is clinically used for separating blood plasma. The research shows that the ellagic acid can lower blood pressure and has a sedative effect; can also inhibit hepatotoxicity, thereby protecting liver. In addition, the ellagic acid can reduce the growth of skin wrinkles, relieve inflammation caused by ultraviolet rays, prevent skin pigmentation and protect the skin to a great extent.
The above properties of ellagic acid have been discovered and utilized by many scientists, with the prospect of being widely used in food processing, healthcare and cosmetic industries. However, ellagic acid is difficult to dissolve in water, alcohols and other safe organic solvents, so that the application of ellagic acid in medicines, foods, cosmetics and the like is greatly limited.
3. Preparation and application of sustained-release gel system
3.1 selection of gel matrix
The gel matrix of the sustained-release gel system used for food or medicine is mainly safe and reliable water-soluble high molecular compounds, the main varieties comprise natural, semi-synthetic and synthetic types, and the natural water-soluble high molecular compounds comprise starches, plant gums, seaweed gums, animal gums and microbial gums. Vegetable gums such as guar gum, locust bean gum, tamarind gum, gum arabic, pectin, fenugreek gum, konjac gum, and the like; the seaweed gel includes carrageenan, sodium alginate, agar, etc.; the microbial gum includes xanthan gum, gellan gum, pullulan, curdlan, etc.; the animal glue mainly comprises gelatin, fish glue, casein, sodium caseinate, chitin, chitosan, etc. The semisynthetic water-soluble polymer compound mainly comprises cellulose, starch and other derivatives prepared by hydrolysis, condensation, chemical modification and other processes, wherein the cellulose derivatives comprise hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose (CMC) and the like, and the modified starch derivatives comprise dextrin, starch, oxidized starch, acid modified starch, acetic starch, phosphoric acid starch, etherified starch, esterified starch, cross-linked starch and the like. The water-soluble polymer compound can be polyvinyl alcohol, polyvinylpyrrolidone, acrylic acid polymer such as Carbopol, and polyglycerol methacrylate such as Lubrazel.
3.2 Advances in ellagic acid sustained Release gel systems
Ellagic acid is a natural component with multiple effects and has been widely researched and developed. Researchers have also performed research work on related ellagic acid gel lines.
[ paper 1 ]: the formula proportion of the ellagic acid gel of the pomegranate is orthogonally designed (modern application pharmacy, No. 33, No. 12, page 1523-. The optimal prescription proportion is screened out by taking propylene glycol, carbomer-940 and the pH level of the gel as influencing factors and taking the appearance shape, spreadability, uniformity and centricity of the gel as investigation indexes. As a result, the indexes of 1.5 percent of carbomer-940, 15 percent of propylene glycol and the pH value of the gel are controlled within 4.0-5.0 to reach the optimal.
[ paper 2 ]: preparation of Pomegranate Ellagic Acid Inclusion Complex Gel and Its in Vitro Transdermal Permeation performance study (Procedia Engineering, Volume 174,2017, Pages724-731), (the objective of this work was to select the best formulation of Pomegranate Ellagic Acid hydroxypropyl- β -cyclodextrin (PEA-HP- β -CD), compare the Transdermal Permeation performance of PEA-HP- β -CD Inclusion Complex with that of the free drug in the Gel. When the dosage of the substrate carbomer 940 is 1.5g per 100g of the gel, the viscosity of the inclusion gel is moderate, and the stability is good. The result shows that the PEA-HP-beta-CD inclusion compound is preliminarily formed, the inclusion compound gel is reasonable in design, and the process is stable. With PEA as the carrier, the carbomer matrix gel inclusion compound enhances the drug effect on skin tissue).
[ paper 3]The study was conducted To evaluate pharmacokinetic parameters of ellagic acid alone and in combination with Aloe gel powder in rabbits using a validated HPLC method (Synergy, Volume 2, Issue 4, 2015, Pages 25-30) in the presence of Aloe gel powder. The prepared double-layer floating tablet of ellagic acid aloe gel powder is used for treating helicobacter pylori gastric ulcer. Pharmacokinetic parameters of aloic acid were evaluated. For this purpose, a comparison was made between standard ellagic acid preparations and double-layer floating tablets using high performance liquid chromatography. The linear range of the method is 0.026-1.3 ug/ml, r2The detection limit is 0.017ug/ml and the quantification limit is 0.026ug/ml when the product is equal to 0.997. The pharmacokinetic analysis result shows that the maximum average blood concentration of ellagic acid in the standard substance is 0.261 +/-0.019 ug/ml, and the maximum average blood concentration 30min before the test is 0.270 +/-0.019 ug/ml. The half-life of the standard product is 0.144 plus or minus 0.05h, and the half-life of the test product is 1.361 plus or minus 0.105 h. The area under the curve of the standard sample and the test sample is 0.502 plus or minus 0.02ug/ml and 0.550 plus or minus 0.02ug/ml respectively. Two-factor analysis of variance was performed on the data at 95% confidence intervals using the Bonferroni multivariate comparison method, with no statistical difference in p-values (p)>0.0001). The results show that the addition of aloe gel powder has no effect on the absorption of ellagic acid).
[ paper 4] expanding the patent of Gastric regenerative medicine Form in the discovery of the value of Gastric retention in the Treatment of Gastric Ulcers with Aloe vera Gel Powder (Current Drug Delivery, Volume 11, Issue 2,2014, Pages 287 and 297), the novel Delivery system overcomes the limitations of the traditional Delivery method but in ayurvedic, this concept has not yet been practiced to a large extent. Therefore, the potential of oral drugs has not been fully explored at present. Therefore, there is an increasing need for the incorporation of concepts NDDS that do not deliver herbal ingredients. The present study was aimed at providing and retaining both herbal ingredients in the stomach to better combat H.pylori-induced gastric ulcers. The aim is to prepare a double-layer floating agent of ellagic acid and aloe gel powder by reasonably combining excipients, so that the drug release reaches the minimum time within 4 h. Formulation F9 contained 100mg HPMC K15M, 27mg rosemary ketone, 80mg mannitol and effervescent agent, with a ratio of 1:2 having a drug release of 92% and ideal floating properties. In vivo studies showed that the combination of ellagic acid and aloe vera had a 75% inhibition of ulcers, whereas the rate of inhibition of ulcers in the ellagic acid group alone was 57%. Suggesting the use of a double-layer floating tablet for the treatment of gastric ulcer). .
[ paper 5 ]: a chitosan/beta-glycerophospho thermo-sensitive gel for the delivery of an inflammatory acid for the treatment of brain cancer (biomaterials, Volume 31, Issue 14,2010, Pages 4157 and 4166), the development of a chitosan/beta-glycerophosphate (Ch/beta-GP) thermo-sensitive gel is reported herein. The chemical structure, surface morphology and viscoelasticity of Ch/beta-GP gel were characterized. The in vitro release rate of ellagic acid loaded Ch/beta-GP gels and the degradation rate of chitosan were examined. The anti-tumor effect of ellagic acid-loaded Ch/beta-GP gel on human U87 glioblastoma and rat C6 glioma cells was evaluated by cell activity assays. The MTS method measures cell number and activity. Ch/beta-GP solutions form a thermal gel at room temperature, the gelation temperature and time of which are influenced by the pH. The lysozyme increased the ellagic acid release rate by a factor of 2.5. Chitosan dialysate with a final pH of 6.3 can significantly reduce the beta-GP required for the gel, thus significantly improving the biocompatibility of the gel (p < 0.001). Chitosan gels containing 1% (w/v) ellagic acid significantly reduced the viability of U87 cells and C6 cells (p <0.01 and p <0.001, respectively) compared to chitosan gels.
[ paper 6] Biodegradable in situ gelling system for biochemical and biochemical acid loaded nanoparticles evaluation of the antioxidant capacity against cyclosporin-induced rat nephrotoxicity of Biodegradable in situ gelling system for evaluation of the antioxidant capacity against cyclosporin-induced rat nephrotoxicity (Journal of Controlled Release, Volume 118, Issue 1,2007, Pages 27-37), Ellagic Acid (EA) is an effective antioxidant, and is marketed as a nutritional supplement. The pharmacological activity of the compound has been reported in various disease models, but the application of the compound is limited due to the low bioavailability of the compound because of the poor biological and pharmaceutical properties of the compound. The objective of this study was to develop a chitosan-glycerophosphate (C-GP) in situ gel system for subcutaneous injection of Ellagic Acid (EA). Ellagic acid is added to a system with Propylene Glycol (PG) and Triethanolamine (TEA) as co-solvents, and on the other hand, the ellagic acid-loaded PLGA nanoparticles (np) are dispersed in a gel system with water. The mechanical, rheological and swelling properties of these in situ gel systems were fully characterized. These systems are liquid at room temperature and gel-like at 37 ℃. The EA-C-GP system showed an initial burst release in vitro, with about 85% of the drug released within 12 hours and then stably released within 160 hours, and on the other hand, ellagic acid nanoparticles embedded in the C-GP system were released continuously within 360 hours. Histopathological analysis indicated no inflammatory response upon administration, indicating that these formulations were safe during the study. In addition, EA-C-GP and EA-np-C-GP gels were evaluated for their antioxidant capacity. The data show that EA-C-GP gel and EA-np-C-GP gel show activity at 10-fold lower doses compared to oral ellagic acid, whereas EA-np-C-GP gel is 150-fold more active than oral Ellagic Acid (EA). The preparation of Ellagic Acid (EA) nanoparticles and the dosage of C-GP system were reduced by 15 times compared to EA-C-GP gel. Taken together, these results indicate that the bioavailability of ellagic acid can be improved by subcutaneous injection of simple EA or EA-nps).
3.3 influencing factors for the preparation of ellagic acid sustained-release gel systems
On the premise of selecting safe and reliable water-soluble polymer materials as the gel matrix, the influence of factors such as the dosage of the water-soluble polymer materials, the adding mode of the water-soluble polymer materials, the dissolving temperature and time, the stirring speed, the reinforced dispersion and the like must be considered. In order to obtain the ellagic acid sustained-release gel system with moderate hardness, good elasticity and high transparency, the influence factors such as the dissolving temperature, the dissolving time, the dosage and proportion of the water-soluble high polymer material and the like must be considered, and the release degree of the ellagic acid coated by the sustained-release material is also considered. The powerful dispersing equipment mainly adopts a common powerful stirrer, a high-frequency oscillator, an ultrasonic oscillator and other equipment.
3.4 Main Performance indices of ellagic acid sustained Release gel systems
Whether the ellagic acid sustained-release gel system can meet the application requirements or not is determined by the following main detection indexes: (1) the forming performance of the gel is that after the mixed system of the ellagic acid and the water-soluble polymer material is cooled to about 50 ℃, the mixed system is poured into a mould and then cooled to room temperature, and whether the gel can be formed or not is observed; (2) hardness of gel: testing the hardness of the formed ellagic acid gel, wherein the ellagic acid gel is too soft or too hard and does not meet the requirement; (3) elasticity of the gel, whether or not it is breakable; (4) release rate of gel-coated ellagic acid in aqueous solution:
disclosure of Invention
According to the items of the Baidu encyclopedia, the Huaxia chemical industry network, and the Goodpasture chemical industry network, pure ellagic acid is poorly soluble in water, alcohol, soluble in alkali, pyridine, and dimethyl sulfoxide (DMSO), and insoluble in ether. In 2017, 10 and 27 days, and a carcinogen list published by international cancer research institution of world health organization is preliminarily prepared for reference, pyridine has a certain toxic effect in a 2B carcinogen list, DMSO has certain toxicity, has permeability to human skin, has an irritation to eyes, can burn skin and cause skin irritation, and high volatile concentration can cause headache, dizziness and sedation. Ellagic acid is easily soluble in alkali, but is poor in stability in an alkaline solution, is easily decomposed, and is denatured and dissolved. Thus, neither base, pyridine nor dimethyl sulfoxide is suitable as a solvent for ellagic acid.
The invention aims to solve the technical problems that the ellagic acid has low solubility in water and poor biological and pharmaceutical properties, so that the ellagic acid has low bioavailability and limited application, the biological application of the ellagic acid in medicines, foods and cosmetics is seriously influenced, and the function of the ellagic acid cannot be fully exerted.
In order to solve the technical problems, the invention provides a sustained-release gel system which is loaded with ellagic acid with higher mass concentration and has better release performance in an aqueous solution and a preparation method thereof.
An ellagic acid sustained release gel: the method comprises the following steps: 0.1-0.6 wt% of ellagic acid, no more than 3.0 wt% of gel matrix, wherein the gel matrix is carrageenan or a mixture of carrageenan and locust bean gum.
Furthermore, the ellagic acid slow-release gel has the ellagic acid mass concentration of 0.2-0.5%, preferably 0.2-0.3%; the mass concentration of the gel matrix is 1.8 to 2.8%, preferably 2.0 to 2.5%, and more preferably 2.0%.
In the method, the mass concentration of the water-soluble polymer gel matrix is increased, the mass concentration of the loadable ellagic acid is increased, and when the mass concentration of the water-soluble polymer gel matrix reaches 2.0%, the mass concentration of the ellagic acid can reach 0.5%.
Further, the mixing mass ratio of the carrageenan and the locust bean gum of the ellagic acid sustained-release gel is 1.0:3.0-3.0:2.0, preferably 2.0:3.0-3.0: 2.0; further preferably 3.0: 2.0.
Furthermore, the water used for preparing the ellagic acid sustained-release gel is deionized water, distilled water or ultrapure water.
The gel may also be added with other cosmetic or food functional auxiliary components or medicinal auxiliary components such as humectant, antiseptic, chelating agent, essence, antioxidant, whitening agent, biological product, plant extract or auxiliary medicine, etc., with the addition type and amount selected according to specific needs.
The purity of the water-soluble polymer material used as the gel matrix and other used auxiliary components in the method is food grade or above.
The preparation method of the ellagic acid sustained-release gel comprises the following steps:
weighing ellagic acid, adding sterilized water, and performing ultrasonic-assisted dispersion and dissolution assistance to obtain an ellagic acid mixed dispersion system; adding the gel matrix into the ellagic acid mixed dispersion system, heating and stirring at constant temperature until the solution is fully dissolved and uniformly mixed, standing for defoaming, and then pouring into a mold for cooling and shaping to obtain the gel containing ellagic acid.
The preparation method comprises the steps of heating water to 85-90 ℃ for 20-30min for sterilization, and then cooling to 45-55 ℃ for ultrasonic-assisted dispersion and dissolution assistance.
The preparation method is characterized in that the ultrasonic power is 120W-360W, preferably 240W; dispersing and dissolving for 30-120 min, preferably 60 min.
The preparation method comprises the steps of adding the gel matrix into the ellagic acid mixed dispersion system, heating and stirring at 60-90 ℃, preferably 80-90 ℃, and further preferably 85 ℃.
The preparation method has the stirring speed of 100-800 rpm, preferably 500-700rpm, and further preferably 600 rpm; the stirring time is 10-60min, preferably 30 min.
In the preparation method, the defoaming time after the gel matrix is stirred, mixed and dissolved is 10-60min, preferably 30 min.
Further, the preparation method of the ellagic acid sustained-release gel comprises the following steps:
firstly, a certain mass of ellagic acid and other auxiliary components with higher tolerance temperature to be added are placed in a certain volume of sterilized water, the water is heated in ultrasonic generation equipment, ultrasonic is used for assisting dispersion, then a certain mass of gel matrix is added into the water, the gel matrix is heated, stirred and mixed, fully dissolved for a certain time, then cooled to a certain temperature, added with other auxiliary components with lower tolerance temperature to be added, the mixture is continuously stirred for a period of time under heat preservation, and then the mixture is poured into a mould for cooling and molding after heat preservation and defoaming for a certain time.
The ellagic acid in the above method is prepared from Galla chinensis or flos Lonicerae raw material, or industrial tannic acid, or pericarpium Granati by extracting, separating and purifying (industrial, food grade or product with purity of above 98%). The preparation of ellagic acid is divided into three types, namely a chemical synthesis method, a chemical degradation method and a natural product degradation method. Wherein, the chemical synthesis method takes gallic acid (ester) as raw material, and the gallic acid (ester) is oxidized and coupled under the condition of oxidant; the chemical degradation method comprises degrading Galla chinensis or flos Lonicerae with chemical agent such as sodium bicarbonate and sodium hydroxide; the natural product degradation method mainly utilizes microorganisms capable of producing tannase such as Aspergillus niger and Aspergillus kawachii to decompose ellagitannin. The extraction method of ellagic acid mainly utilizes the solubility of ellagic acid to extract from pomegranate rind, raspberry, tea leaves, etc. At present, the methods for extracting ellagic acid mainly include ultrasonic extraction and acid hydrolysis, ethyl acetate extraction, hydrolysis, separation and precipitation, and the like.
The invention also provides the application of the ellagic acid sustained-release gel in medicines, health care, foods and cosmetics.
Further, the gel is dissolved in water to obtain the gel release solution for use.
When the ellagic acid gel is applied to medicines, health care and foods, a certain amount of ellagic acid and other appropriate additives such as preservatives, bioactive substances and the like are coated in the gel by the method, the gel is hermetically packaged and can be eaten after being opened, and the effects of bacteriostasis, inflammation prevention, cancer prevention and the like can be achieved in gastrointestinal tracts; when the skin care product is applied to cosmetics, a certain mass of ellagic acid and other appropriate additives such as preservatives, humectants and the like can be coated in gel by the method, and the gel is hermetically packaged.
The invention has the beneficial effects that:
1. the slow-release gel system of the invention has simple components: ellagic acid, water-soluble polymer gel matrix material and water, and is safe and reliable. According to specific application of the product, cosmetic or food functional auxiliary components or pharmaceutical auxiliary components with proper types and contents such as humectant, antiseptic, chelating agent, essence, antioxidant, whitening agent, biological product, plant extract or auxiliary medicine, etc. can be added;
2. the water-soluble polymer gel matrix material has low consumption, and the mass concentration of the ellagic acid can reach 0.5 percent according with the highest content standard of the ellagic acid in national cosmetics.
3. The preparation process of the sustained-release gel system is simple.
4. The ellagic acid has good antibacterial and antiseptic properties, so that the ellagic acid sustained-release gel system prepared by the invention has good stability, long storage time and convenient packaging, carrying and transportation under the condition of not adding or adding a small amount of other antibacterial and antiseptic substances.
5. Through auxiliary dispersion, higher-dosage ellagic acid can be loaded in the gel, the release speed of the ellagic acid is high after the gel is placed in water, and an ellagic acid solution with a concentration much higher than that of an ellagic acid saturated aqueous solution can be obtained within 20-30 min.
6. The invention is helpful to solve the problem that the application of ellagic acid in the fields of medicines, foods, cosmetics and the like is greatly limited due to the low solubility of ellagic acid in water, and can further promote the biological application of ellagic acid.
Drawings
FIG. 1 shows the release of Ellagic Acid (EA) in 100mL of aqueous solution at 37 ℃ for various periods of time in 1g of sustained release gel system coated with Ellagic Acid (EA) of different mass concentrations prepared under optimized conditions;
wherein: the abscissa represents the release time/min, and the ordinate represents the concentration/(mg/L) and the release rate (%) of ellagic acid released, respectively.
FIG. 2 shows the release of ellagic acid in 100mL of water at 37 deg.C for different time periods in a 10g sustained-release ellagic acid gel system (the mass concentration of ellagic acid coated in the gel is 0.2%) prepared under optimized conditions;
wherein: the abscissa represents the release time/min, and the ordinate represents the concentration/(mg/L) and the release rate (%) of ellagic acid released, respectively.
FIG. 3 inhibition of tyrosinase by ellagic acid emulsions and ellagic acid gel release solutions;
wherein: the abscissa represents the mass concentration/mg/L of ellagic acid in the system, and the ordinate represents the inhibition rate (%) of the system on the mating aminidase.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which are not intended to limit the invention.
1. Method for measuring mass concentration of ellagic acid
1.1 preparation of Standard Curve for ellagic acid aqueous solution
AEO-9 (polyoxyethylene lauryl ether) is selected to solubilize the ellagic acid. Weighing 0.0050g of ellagic acid, adding 1% AEO-9 solution to a constant volume of 500ml, stirring at a magnetic stirring speed of 600r/min for 1.5h to prepare a standard solution of 10mg/L, sequentially diluting with 1% AEO-9 solution to obtain standard solutions of 1.0mg/L, 2.0mg/L, 4.0mg/L, 6.0mg/L and 8.0mg/L, taking 1% AEO-9 solution as reference, measuring by ultraviolet spectrophotometry, performing linear regression with ultraviolet spectrum absorbance as ordinate and ellagic acid concentration as abscissa to obtain regression equation y1＝0.052x-0.0076，R2＝0.9998。
1.2 determination of the saturated solubility of ellagic acid in Water
Placing ellagic acid in a certain volume of water in excess, respectively sealing and placing in constant-temperature water bath pots at different temperatures, keeping warm and dissolving for more than 6 days, shaking the container at intervals during the period to ensure that ellagic acid is dissolved in water at different temperatures to reach saturation, filtering, then respectively placing a certain volume of ellagic acid saturated solution at different temperatures in a volumetric flask, adding AEO-9 solution for constant volume to prepare 1% AEO-9 solution containing ellagic acid, determining the concentration of ellagic acid according to the standard curve, and calculating to obtain the saturated solubility of ellagic acid in water at different temperatures.
1.3 determination of ellagic acid concentration in ellagic acid sustained-release gel release solution
Respectively putting certain mass of gel loaded with ellagic acid with different concentrations into a 100mL volumetric flask, adding distilled water to constant volume, and measuring the ultraviolet spectrum absorbance change at 37 deg.C within 30min (time gradient: 5min, 10min, 15min, 20min, 25min, 30 min). A sample is taken out of a graduated test tube, 1mL of AEO-9 solution with the concentration of 10% is added in advance, 9mL of gel release liquid is added into the graduated test tube each time, the mixture is shaken up, and distilled water with the same volume as the volume of the sample release liquid is added into a volumetric flask after sampling. And (3) taking a 1% AEO-9 solution as a reference, measuring the absorbance of the sample solution, and calculating the actual concentration and the release rate of the released ellagic acid according to a standard curve.
Example 1:
the preparation method of the ellagic acid sustained-release gel system comprises the steps of firstly heating a certain volume of water to 85-90 ℃ for 30min for sterilization, then cooling to about 45 ℃, adding a certain mass of ellagic acid, putting the ellagic acid into ultrasonic generation equipment, carrying out ultrasonic dispersion for about 1h at a constant temperature, then adding a certain mass of water-soluble polymer gel matrix into the water, stirring and dissolving at about 85 ℃ and about 600rpm, stirring for about 30min, then cooling to about 50 ℃ while stirring, stopping stirring, carrying out heat preservation and defoaming for about 30min, and pouring fluid into a mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from Carrageenan (having an English name: Carrageenan, Chinese name: Eucheuma Gelatinosum Gum, agar Gum, carrageenin, the same below) and locust bean gum (having an English name: locustbean gum, Chinese name: locust bean gum, carob bean gum, the same below) according to the mass ratio of 3.0:2.0, the total mass concentration of the gel matrix is 2.0%, the mass concentration of ellagic acid is 0.5%, and the water-mixing mass is controlled to prepare the ellagic acid sustained-release gel system with the total mass concentration of 2.5%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min is 35.2%, and the release concentration is 13.75 mg/L.
Example 2:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid of certain mass, placing into ultrasonic wave generation equipment with power of 240w, ultrasonically dispersing at constant temperature for about 1h, adding water-soluble polymer gel matrix of certain mass into water at about 85 deg.C and 600rpm for stirring and dissolving, stirring for about 30min, cooling to about 50 deg.C while stirring, stopping stirring, keeping the temperature and defoaming for about 30min, and pouring fluid into mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 3.0:2.0, the total mass concentration of the gel matrix is 2.0%, the mass concentration of ellagic acid is 0.3%, and the water-doped mass is controlled to prepare an ellagic acid sustained-release gel system with the total mass concentration of 2.3%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min is 42.8%, and the release concentration is 10.01 mg/L.
Example 3:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid of certain mass, placing into ultrasonic wave generation equipment with power of 240w, dispersing and dissolving at constant temperature for about 1h, adding water soluble polymer gel matrix of certain mass into water at about 85 deg.C and 600rpm, stirring for about 30min, cooling to about 50 deg.C under stirring, stopping stirring, keeping the temperature and defoaming for about 30min, and pouring the fluid into a mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 3.0:2.0, the total mass concentration of the gel matrix is 2.0%, the mass concentration of ellagic acid is 0.2%, and the water-doped mass is controlled to prepare an ellagic acid sustained-release gel system with the total mass concentration of 2.2%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min is 46.8%, and the release concentration is 7.32 mg/L.
Example 4:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid of certain mass, placing into ultrasonic wave generation equipment with power of 240w, strongly dissolving for about 1 hr at constant temperature, adding water soluble polymer gel matrix of certain mass into water, stirring and dissolving at about 85 deg.C and 600rpm, stirring for about 30min, cooling to about 50 deg.C under stirring, stopping stirring, keeping the temperature and defoaming for about 30min, and pouring the fluid into a mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 3.0:2.0, the total mass concentration of the gel matrix is 2.0%, the mass concentration of ellagic acid is 0.1%, and the water-adding mass is controlled to prepare an ellagic acid sustained-release gel system with the total mass concentration of 2.1%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min reaches 66.3%, and the release concentration is 5.27 mg/L.
Example 5:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid of certain mass, placing into ultrasonic wave generation equipment with power of 240w, strongly dissolving for about 1 hr at constant temperature, adding water soluble polymer gel matrix of certain mass into water, stirring and dissolving at about 85 deg.C and 600rpm, stirring for about 30min, cooling to about 50 deg.C under stirring, stopping stirring, keeping the temperature and defoaming for about 30min, and pouring the fluid into a mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 3.0:2.0, the total mass concentration of the gel matrix is 2.0%, the mass concentration of ellagic acid is 0.05%, and the water-adding mass is controlled to prepare an ellagic acid sustained-release gel system with the total mass concentration of 2.05%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min is 72.6%, and the release concentration is 2.92 mg/L.
Example 6:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid of certain mass, placing into ultrasonic wave generation equipment with power of 120w, strongly dissolving for about 2.0h at constant temperature, adding water-soluble polymer gel matrix of certain mass into water at about 85 deg.C and 600rpm, stirring for about 30min, cooling to about 50 deg.C under stirring, stopping stirring, keeping the temperature for defoaming for about 30min, and pouring fluid into mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 3.0:2.0, the total mass concentration of the gel matrix is 2.0%, the mass concentration of ellagic acid is 0.5%, and the water-doped mass is controlled to prepare an ellagic acid sustained-release gel system with the total mass concentration of 2.5%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min is 34.8%, and the release concentration is 13.59 mg/L.
Example 7:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid of certain mass, placing into ultrasonic wave generation equipment with power of 240w, strongly dissolving for about 1 hr at constant temperature, adding water soluble polymer gel matrix of certain mass into water at about 85 deg.C and 600rpm, stirring for about 30min, cooling to about 50 deg.C under stirring, stopping stirring, keeping the temperature for defoaming for about 30min, and pouring the fluid into a mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 3.0:2.0, the total mass concentration of the gel matrix is 2.5%, the mass concentration of ellagic acid is 0.6%, and the water-doped mass is controlled to prepare an ellagic acid sustained-release gel system with the total mass concentration of 3.1%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min reaches 32.4%, and the release concentration is 16.7 mg/L.
Example 8:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid of certain mass, placing into ultrasonic wave generation equipment with power of 240w, strongly dissolving for about 1 hr at constant temperature, adding water soluble polymer gel matrix of certain mass into water at about 85 deg.C and 600rpm, stirring for about 30min, cooling to about 50 deg.C under stirring, stopping stirring, keeping the temperature for defoaming for about 30min, and pouring the fluid into a mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 1.0:1.0, the total mass concentration of the gel matrix is 2.0%, the mass concentration of ellagic acid is 0.5%, and the water-doped mass is controlled to prepare an ellagic acid sustained-release gel system with the total mass concentration of 2.5%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min reaches 32.5%, and the release concentration is 12.70 mg/L.
Example 9:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid of certain mass, placing into ultrasonic wave generation equipment with power of 240w, dispersing and dissolving for about 1h at constant temperature, adding water soluble polymer gel matrix of certain mass into water at about 85 deg.C and 600rpm, stirring for about 30min, defoaming for about 30min, cooling to about 50 deg.C, and pouring fluid into mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 2.0:3.0, the total mass concentration of the gel matrix is 2.0%, the mass concentration of ellagic acid is 0.5%, and the water-doped mass is controlled to prepare an ellagic acid sustained-release gel system with the total mass concentration of 2.5%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min is 33.35%, and the release concentration is 13.03 mg/L.
Example 10:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid of certain mass, placing into ultrasonic wave generation equipment with power of 360w, dispersing and dissolving at constant temperature for about 0.5 hr, adding water soluble polymer gel matrix of certain mass into water at about 85 deg.C and 600rpm, stirring for about 30min, cooling to about 50 deg.C under stirring, stopping stirring, keeping the temperature and defoaming for about 30min, and pouring fluid into mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 3.0:2.0, the total mass concentration of the gel matrix is 2.0%, the mass concentration of ellagic acid is 0.5%, and the water-doped mass is controlled to prepare an ellagic acid sustained-release gel system with the total mass concentration of 2.5%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min is 34.7%, and the release concentration is 13.55 mg/L.
Example 11:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid of certain mass, placing into ultrasonic wave generation equipment with power of 240w, dispersing and dissolving at constant temperature for about 1.0h, adding water soluble polymer gel matrix of certain mass into water at about 85 deg.C and about 300rpm, stirring for about 120min, cooling to about 50 deg.C under stirring, stopping stirring, keeping the temperature and defoaming for about 30min, and pouring the fluid into a mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 3.0:2.0, the total mass concentration of the gel matrix is 2.0%, the mass concentration of ellagic acid is 0.5%, and the water-doped mass is controlled to prepare an ellagic acid sustained-release gel system with the total mass concentration of 2.5%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min is 34.1%, and the release concentration is 13.32 mg/L.
Example 12:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid of certain mass, placing into ultrasonic wave generation equipment with power of 240w, dispersing and dissolving at constant temperature for about 1.0h, adding water soluble polymer gel matrix of certain mass into water at about 85 deg.C and 900rpm, stirring for about 45min, cooling to about 50 deg.C under stirring, stopping stirring, keeping the temperature and defoaming for about 30min, and pouring fluid into mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 3.0:2.0, the total mass concentration of the gel matrix is 2.0%, the mass concentration of ellagic acid is 0.5%, and the water-doped mass is controlled to prepare an ellagic acid sustained-release gel system with the total mass concentration of 2.5%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min is 35.1%, and the release concentration is 13.71 mg/L.
Example 13:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid and glycerol of certain mass, placing into ultrasonic wave generation equipment with power of 240w, ultrasonically dispersing and dissolving for about 1h at constant temperature, adding water soluble polymer gel matrix of certain mass into water at about 85 deg.C and 600rpm, stirring for about 30min, cooling to about 50 deg.C under stirring, adding essence 0.1% and antiseptic 0.4%, stirring for about 30min, stopping stirring, keeping the temperature and defoaming for about 30min, and pouring the fluid into a mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 3.0:2.0, wherein the total mass concentration of the gel matrix is 2.0%, and the mass concentration of ellagic acid is 0.5%. The release rate of 10g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min reaches 36.3%, and the release concentration is 14.18 mg/L.
Example 14:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid and glycerol of certain mass, placing into ultrasonic wave generation equipment with power of 240w, ultrasonic dispersing and dissolving for about 60min at constant temperature, adding water soluble polymer gel matrix of certain mass into water at about 85 deg.C and 600rpm, stirring for about 30min, cooling to about 50 deg.C under stirring, adding active substance 0.5%, essence 0.1%, and antiseptic 0.4%, stirring for about 30min under continuous heat preservation, stopping stirring, defoaming for about 30min under heat preservation, and pouring fluid into mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 3.0:2.0, wherein the total mass concentration of the gel matrix is 2.0%, and the mass concentration of ellagic acid is 0.5%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min is 35.9%, and the release concentration is 14.02 mg/L.
Example 15:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid of certain mass and humectant 3%, placing into ultrasonic wave generation equipment with power of 240w, dispersing and dissolving at constant temperature for about 1h, adding water soluble polymer gel matrix of certain mass into water at about 85 deg.C and 600rpm, stirring for about 30min, cooling to about 50 deg.C under stirring, adding active substance 0.5%, essence 0.1%, and antiseptic 0.4%, stirring for 30min, stopping stirring, defoaming for 30min, and pouring fluid into mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 3.0:2.0, wherein the total mass concentration of the gel matrix is 2.0%, and the mass concentration of ellagic acid is 0.5%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min is 35.4%, and the release concentration is 13.83 mg/L.
Example 16:
the preparation method of ellagic acid gel system comprises heating water of certain volume to 85-90 deg.C for 30min for sterilization, cooling to about 45 deg.C, adding ellagic acid and glycerol of certain mass, placing into ultrasonic wave generation equipment with power of 240w, dispersing and dissolving at constant temperature for about 1h, adding water soluble polymer gel matrix of certain mass into water at about 85 deg.C and 600rpm, stirring for about 30min, cooling to about 50 deg.C under stirring, adding active substance 0.5%, essence 0.1%, and antiseptic 0.4%, stirring for about 30min, stopping stirring, defoaming for about 30min, and pouring fluid into mold for molding. The water-soluble polymer gel matrix material used in the preparation process is prepared from carrageenan and locust bean gum according to the mass ratio of 3.0:2.0, wherein the total mass concentration of the gel matrix is 2.0%, and the mass concentration of ellagic acid is 0.5%. The release rate of 1g of the ellagic acid gel in 100mL of aqueous solution at 37 ℃ for 30min reaches 36.2%, and the release concentration is 14.14 mg/L.
The method has the advantages that: the ellagic acid sustained-release gel system prepared by the method has simple components, is safe and reliable, can be formed when the total mass concentration of the composite water-soluble polymer gel matrix material is only 2.0 percent, has low cost, can reach 0.5 percent of the total mass of the gel by the mass concentration of the loaded ellagic acid, and has simple preparation method and process. The whole gel system is convenient to use, the ellagic acid can be slowly released after the gel system enters water, and the concentration of the ellagic acid in the water solution system can be far higher than that of the ellagic acid in a saturated blank water solution. According to the specific application of the product, cosmetic or food functional auxiliary components or pharmaceutical auxiliary components with proper types and contents, such as humectant, antiseptic, chelating agent, essence, antioxidant, biological or plant or animal based active substance or auxiliary medicine, etc. can be added. The method solves the problem that the application of ellagic acid in the fields of medicine, food, cosmetics and the like is affected due to the low solubility of ellagic acid in water, and promotes the biological application of ellagic acid.
Example 17 screening of Water-soluble Polymer Compound
The gel is mainly screened from common water-soluble polymer gel matrixes, and the influence of the types, the concentrations and the mass ratio of the water-soluble polymer matrixes, the dosage of ellagic acid, the dissolving temperature and the dissolving time on the gel forming condition is mainly considered, and the results are shown in table 1. The gel formation and the release concentration of 1g of the gel (with an ellagic acid addition concentration of 0.5%) in 100mL of water for 30min were used as main indicators.
TABLE 1 screening of Water-soluble Polymer gel matrix Material
Example 18 Elastatin Release from Elastatin gel
The amount of ellagic acid in the gel system was changed to prepare 100g of hydrogel system with ellagic acid mass concentrations of 0.05%, 0.1%, 0.2%, 0.3%, and 0.5%, wherein the total mass concentration of the gel matrix was 2.0% (the mass ratio of carrageenan to locust bean gum was 3.0: 2.0). Simulating a skin environment in a distilled water environment with the pH value of 6.86, putting 1.0g of gel (the mass of the contained ellagic acid is about one percent of the total mass of the ellagic acid used for preparing the gel) into 100mL of distilled water, carrying out water bath heat preservation in an environment with the temperature of 37 ℃ (the simulated skin temperature), calculating the content of the ellagic acid in a sample solution at each time within 30min, and testing the influence of the dosage of the ellagic acid on the release condition of a gel system. The results are shown in FIG. 1.
As can be seen from FIG. 1, the concentration and cumulative release rate of ellagic acid released from 1g of ellagic acid gel sample (containing ellagic acid at about 1/100 of the total ellagic acid loading) in 100mL of distilled water increased with time. As can be seen from the graphs in FIG. 1, when the mass concentration of ellagic acid in the gel is 0.5%, the release concentration of 1g of the gel in 100mL of water within 30min is 13.75mg/L, and the cumulative release rate is 35.2%, and when the mass concentration of ellagic acid in the gel is 0.3%, the release concentration within 30min is 10.01mg/L, and the cumulative release rate is 42.8%, and if the ellagic acid is required to be used within a short time, the ellagic acid is wasted to some extent. When the mass concentration of the ellagic acid in the gel is 0.05% and 0.1%, the accumulative release rate can reach 72.6% and 66.3% within 30min respectively, and the accumulative release rate is higher, but the effect is correspondingly reduced because the addition amount of the ellagic acid is less, the release concentration is lower overall. When the mass concentration of the ellagic acid in the gel is 0.2%, the release concentration of the ellagic acid in the gel reaches 7.32mg/L in 30min, the cumulative release rate can reach 46.8%, and the release effect is good on the whole. With the prolonged release time, the release amount and release rate of ellagic acid are further improved. For the application field that the gel needs to be used in a short time, such as within 30min, the release concentration and the release rate need to be considered comprehensively, and the hydrogel with the ellagic acid mass concentration of 0.2-0.3% is selected to be suitable. For application fields where the gel can be used for a long time, such as use as a pharmaceutical carrier, the gel containing ellagic acid at a high mass concentration can be used, and the biological effect of ellagic acid can be further exerted.
Under the same conditions, 10g of the gel (the mass concentration of ellagic acid contained in the gel is 0.2%) was placed in 100mL of distilled water, and incubated in a water bath at 37 ℃ (simulated skin temperature), and the release of ellagic acid from the gel at each time point within 30min was measured, and the results are shown in FIG. 2.
As can be seen from FIG. 2, the release concentration and the cumulative release rate of ellagic acid produced by using 10.0g of the gel (the mass concentration of ellagic acid contained in the gel is 0.2%) both increased substantially linearly within 30min with the increase of the release time, and the ellagic acid release rate did not become slow, indicating that ellagic acid can be released over a long period of time. When the ellagic acid is released for 30min, the release concentration and the release rate of the ellagic acid are respectively 36.6mg/L and 17.2%, and the corresponding indexes of 1g of gel loaded with the same 0.2% ellagic acid concentration in 100mL of water within 30min are respectively 7.32mg/L and 46.8%, which indicates that the use amount of the gel in water is increased when the mass concentration of the ellagic acid contained in the gel is the same, and the ellagic acid release concentration is correspondingly increased within the same time, and when the ellagic acid concentration in the gel is higher or the use amount of the gel is larger, the ellagic acid concentration in the release solution can reach a concentration which is more than several times higher than that of a blank saturated ellagic acid aqueous solution at the same temperature, so that the defect that the application is influenced by the small solubility of the ellagic acid is overcome, the biological effect of the ellagic acid is fully exerted, but the release rate of the ellagic acid is reduced along with the increase of the ellagic acid concentration or the use amount of the gel. In practical application, the gel containing higher concentration of ellagic acid can be used or more amount of the gel can be used according to specific needs.
Example 19 determination of solubility of ellagic acid at different Normal temperatures
The results of the solubility measurements of ellagic acid at different ambient temperatures are shown in table 1.
TABLE 2 saturated mass concentrations (mg/L) of ellagic acid at different ambient temperatures
| Temperature/. degree.C | 20.0 | 30.0 |
| concentration/mg/L | 16.37 | 17.44 |
Example 20 inhibition of tyrosinase by Release fluids
Taking phosphoric acid buffer solution with pH of 6.8 as a solvent, and preparing 1 mmol/L-tyrosinase solution and 200U/mL tyrosinase solution. An ellagic acid emulsion having an ellagic acid concentration of 1.0mg/mL was prepared for use in accordance with CN111920766A an ellagic acid dispersion system and an emulsion prepared by the method in the preparation method thereof (example 20 in the patent application), and an ellagic acid releasing solution prepared in example 18 of the present invention was diluted into solutions to be tested having different concentrations. Preparing reaction liquid according to the table 3, mixing uniformly, keeping the temperature at 37 ℃ for accurate reaction for 10min, and measuring the absorbance at the wavelength of 475nm by taking each solution solvent to be measured as a blank control. Each group was tested in triplicate and the inhibition [% 1- (A) ]3-A4)/(A1-A2)]X 100% (reference 1)]Inhibition of tyrosinase Activity by several Natural plant extracts [ J]Chemistry study, 2013,24(03): 288-; reference [ 2]]Arroo R,Sari S,Barut B,et al. Flavones as tyrosinase inhibitors:kinetic studies in vitro and in silico[J]Phytochemical Analysis,2020,31(3): 314-. The results are shown in FIG. 3.
TABLE 3 composition of tyrosinase inhibition reaction solution
As can be seen from FIG. 3, when the ellagic acid concentration in the ellagic acid release solution of the present invention is 0.0145mg/mL and 0.0366mg/mL, respectively, the tyrosinase inhibition rates are 33.11% and 51.3%, respectively, while the ellagic acid concentration in the ellagic acid emulsion is 0.15mg/mL and 0.30mg/mL, respectively, the tyrosinase inhibition rates are 22.7% and 52.1%, respectively, and the other concentrations measured and the corresponding tyrosinase inhibition rates have similar relationships. Therefore, when the same tyrosinase inhibition rate is achieved, the concentration of the ellagic acid in the ellagic acid release solution is only about one tenth of that of the ellagic acid in the ellagic acid emulsion, and the slow release of the ellagic acid is realized after the gel prepared by selecting an appropriate gel matrix is loaded with the appropriate amount of the ellagic acid, so that the concentration of the ellagic acid in the liquid can be greatly improved, and the bioactive effect of the ellagic acid can be fully exerted.
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| CN118203517A (en) * | 2024-03-13 | 2024-06-18 | 科乐美(广州)生物科技有限公司 | A natural composition with sustained-release repair function and its preparation method and application |
| CN118340768A (en) * | 2024-05-09 | 2024-07-16 | 中国农业大学 | Application of ellagic acid in preparation of medicines for reducing polymyxin cytotoxicity and/or neurotoxicity and nephrotoxicity, pharmaceutical composition and application |
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| EP4555997A1 (en) * | 2023-11-15 | 2025-05-21 | Science4Beauty Sp. z o.o. | Water-soluble composition comprising urolithin |
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| CN115806680A (en) * | 2022-12-02 | 2023-03-17 | 厦门爱逸零食研究所有限公司 | A kind of guar gum and carrageenan compound and its preparation method and application |
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| CN118340768A (en) * | 2024-05-09 | 2024-07-16 | 中国农业大学 | Application of ellagic acid in preparation of medicines for reducing polymyxin cytotoxicity and/or neurotoxicity and nephrotoxicity, pharmaceutical composition and application |
| CN118340768B (en) * | 2024-05-09 | 2024-11-12 | 中国农业大学 | Application of ellagic acid in preparing drugs for reducing polymyxin cytotoxicity and/or neurotoxicity and nephrotoxicity, pharmaceutical composition and application |
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