Curcumin pharmafood self-microemulsifying nanoemulsion oral liquid for improving fatty liver and relieving joint inflammation, and preparation method and use thereof

Abstract

The application discloses a curcumin pharmafood self-microemulsifying nanoemulsion oral liquid for improving fatty liver and relieving arthritis inflammation, a preparation method and application thereof, and belongs to the technical field of functional preparations. The application aims at three problems of curcumin, flavones and saponins, i.e. low water solubility, poor stability and low oral bioavailability, constructs a SMEDDS self-microemulsifying nano delivery system, and prepares a uniform and stable nanoemulsion oral liquid by limiting specific raw material compounding ratio and a mild preparation process. It is verified through experiments that the preparation liquid droplet particle size is uniform and controllable, the active retention rate is greater than or equal to 93.5% after storage at room temperature for 6 months, and the oral bioavailability is 8.12 times higher than that of a traditional formula; the fatty liver liver lipid deposition can be significantly improved, liver damage can be repaired, and the release of arthritis inflammation factors can be effectively inhibited, so that the double-target-point efficacy is improved. The formula is scientific, the process is simple, mass production is possible, the data are detailed, and the application is highly innovative, effectively solves the bottleneck of the prior art, has high industrialization value and patent barriers, and can be widely applied to the preparation field of liver protection, anti-inflammatory and joint protection functional oral preparations.

Description

Technical Field

[0001] This invention relates to the fields of functional food preparations with medicinal and edible properties, nanodelivery technology, and liver-protecting and anti-inflammatory functional preparations. Specifically, it relates to a curcumin composite nanoemulsion oral liquid based on the SMEDDS self-microemulsification delivery system, its preparation process, and novel applications for dual indications, particularly suitable for intervention of metabolic fatty liver and treatment of inflammatory joint problems. Background Technology

[0002] Curcumin, natural flavonoids, and natural saponins are all nationally recognized active ingredients that are both medicinal and edible, possessing clear physiological activities such as liver protection, lipid reduction, anti-oxidation, anti-inflammation, and metabolic regulation. Among them, curcumin can effectively inhibit abnormal fat deposition in the liver, reduce transaminase levels, and improve non-alcoholic fatty liver disease damage, while also effectively inhibiting the release of inflammatory factors and relieving joint inflammation. Flavonoids can help regulate lipid metabolism and enhance the liver's antioxidant capacity. Saponins can reduce inflammation and pain and improve metabolic disorders. The combination of these three components can create a synergistic effect of liver protection and anti-inflammation.

[0003] However, these active ingredients currently face three major industry-wide technical bottlenecks that severely restrict their industrial application and actual efficacy: First, they have extremely low water solubility. Curcumin is almost insoluble in water, and flavonoids and saponins have limited water solubility, making them prone to precipitation in conventional aqueous formulations. Second, they have poor stability. They are easily oxidized, decomposed, and degraded under conditions of light, high temperature, and room temperature storage, resulting in short product shelf life. Third, their oral bioavailability is extremely low. The active ingredients are destroyed by gastric acid and undergo severe first-pass metabolism in the liver, resulting in an absorption rate of less than 5% for ordinary oral formulations. The effective ingredients cannot reach the liver and joint targets, significantly reducing their efficacy.

[0004] Existing technologies mostly use simple water-soluble, alcohol-soluble, and ordinary emulsification methods to prepare oral liquids, which have not solved the core delivery problem and have defects such as layered precipitation, poor stability, low absorption efficiency, and unclear efficacy. A few nano-formulation technologies rely on complex equipment such as high-pressure homogenization and ultrasonic disruption, which are costly and difficult to mass-produce. Moreover, they have not optimized the formulation and process for the dual targets of fatty liver lipid deposition and joint inflammation, lack precise and suitable industrialization technical solutions, and lack complete experimental data support, resulting in insufficient innovation and practicality.

[0005] To address the shortcomings of existing technologies, this invention innovatively employs the SMEDDS self-microemulsification delivery system, combined with a specific ratio of medicinal and edible homologous compound components. Through precise formulation ratios and low-temperature, mild preparation processes, it thoroughly solves three major pain points. At the same time, through multiple control experiments, stability tests, and efficacy tests, the product's advantages are verified, achieving dual targeted effects of liver protection, anti-inflammation, and joint protection. It possesses significant technological innovation and industrialization advantages. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and provide a highly stable, highly bioavailable, and mass-producible curcumin composite nanoemulsion oral liquid. This solves the core problems of poor water solubility, weak stability, and low oral absorption rate of traditional food and medicine homologous active ingredients. At the same time, it clarifies its unique new uses in the treatment of fatty liver and the relief of joint inflammation, and the technical effect is supported by complete testing experiments, comparative data, and efficacy data.

[0007] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: This invention innovatively constructs a medicinal and edible homologous complex active system of curcumin, flavonoids and saponins, paired with a suitable self-microemulsifying carrier system. Without the need for complex equipment, it spontaneously forms nano-sized droplets upon contact with body fluids at room temperature, significantly improving water solubility, storage stability and intestinal absorption rate, reducing first-pass metabolism, and allowing the active ingredients to precisely target the liver and joint inflammation sites. Attached Figure Description

[0008] Figure 1 The particle size distribution curve of the nanoemulsion oral liquid of the present invention after emulsification: The horizontal axis of the figure is the droplet size (nm), and the vertical axis is the proportion of particle distribution; the curve is the particle size distribution of the sample of Example 1 of the present invention, showing that the particle size of the formulation of the present invention after emulsification is concentrated in 20-80nm, with uniform particle size, dispersion coefficient PDI < 0.2, and excellent system stability. Figure 2 The bar chart comparing the activity retention rate of this invention with that of ordinary formulas after 6 months of storage at room temperature is as follows: the horizontal axis is divided into three groups of samples: Example 1 of this invention, ordinary water-soluble comparative example 1, and conventional emulsified comparative example 2; the vertical axis is the retention rate of active ingredients (%); the bars represent the retention values ​​of curcumin, total flavonoids, and total saponins after 6 months of storage, which are used to prove that the activity of this invention is lower and the stability is stronger after long-term storage. Figure 3 The in vitro 24-hour dissolution rate comparison curves of each group of samples: the horizontal axis is the dissolution time (h), and the vertical axis is the cumulative dissolution rate (%); the three curves are, in order, Example 1 of the present invention, the ordinary water-soluble formulation, and the conventional emulsified formulation, demonstrating the rapid and continuous dissolution advantages of the formulation of the present invention compared with the ordinary formulation. Figure 4 Comparison of liver tissue pathological sections in a fatty liver model rat: There are 4 groups of sections in total, namely, blank control group, high-fat model group, ordinary formula intervention group, and intervention group of the present invention, which are used to visually demonstrate the efficacy of the present invention in significantly reducing liver lipid deposition and repairing liver damage. Comparison of liver lipid deposition in the experimental groups of the present invention. Figure 5A bar chart comparing the levels of inflammatory factors in rats with joint inflammation: the horizontal axis represents the control group, model group, standard formula group, and experimental group of this invention; the vertical axis represents the concentration of inflammatory factors. The two bars represent the levels of TNF-α and IL-6, respectively, to demonstrate that this invention can significantly inhibit inflammatory factors in vivo and alleviate joint inflammation. The differences in the inhibitory effects of TNF-α and IL-6 inflammatory factors among the groups are shown. Specific Implementation

[0009] Formula by weight: 1.5 parts curcumin, 3.0 parts puerarin, 2.5 parts astragaloside, 25 parts medium-chain triglycerides, 45 parts polyoxyethylene hydrogenated castor oil, 12 parts propylene glycol, 1.0 part steviol glycosides, and purified water to make up to 100 parts.

[0010] Preparation steps: 1. Preparation of oil phase: Take medium-chain triglycerides, keep them in a water bath at 45°C, add curcumin, puerarin, and astragaloside, stir at a constant temperature for 25 minutes until completely dissolved, and obtain a clear and transparent oil phase; 2. Preparation of emulsion matrix: Polyoxyethylene hydrogenated castor oil and propylene glycol are added sequentially to the oil phase, and the mixture is stirred at 45°C for 30 min to form a uniform, transparent, self-microemulsifying concentrated matrix. 3. Aqueous phase preparation: Add steviol glycosides to purified water, stir to dissolve at room temperature, and let stand for 10 minutes to remove bubbles; 4. Volume adjustment and molding: The aqueous phase is slowly added dropwise to the emulsion matrix at a rate of 2 mL / s, stirred at 120 r / min at room temperature for 15 min, and then diluted with purified water. After filtration and sterilization, the final nanoemulsion oral solution is obtained.

[0011] Curcumin 0.5 parts, mulberry leaf flavonoids 1.0 part, gynostemma pentaphyllum saponins 0.8 parts, olive oil 15 parts, Tween 80 30 parts, glycerin 8 parts, sweetener 0.5 parts, purified water to make up to 100 parts, prepared according to the same process as in Example 1.

[0012] Curcumin 3.0 parts, sea buckthorn flavonoids 5.0 parts, ginsenosides 4.0 parts, MCT 35 parts, polyoxyethylene hydrogenated castor oil 60 parts, polyethylene glycol 400 20 parts, sweetener 2.0 parts, purified water to make up to 100 parts, prepared according to the same process as in Example 1.

[0013] Using the same active ingredient content as in Example 1, curcumin, flavonoids, and saponin powders were directly dissolved in purified water, stirred and dissolved using conventional methods, without adding an emulsifying carrier, to prepare a common oral aqueous solution.

[0014] The method uses conventional edible oil and common emulsifier, emulsifies by high-speed stirring, and has a SMEDDS-free self-microemulsification system. The content of other active ingredients is the same as in Example 1.

[0015] Testing methods: The droplet size and PDI coefficient were measured using a dynamic light scattering particle size analyzer. The state of the system was observed visually at room temperature, and the differences in water solubility of each formulation were compared.

[0016] Experimental Results: The sample in Example 1 of this invention emulsified instantaneously upon contact with artificial gastric fluid, with an average particle size of 42 nm, a PDI of 0.16, uniform particle size distribution, and no aggregation or precipitation. The particle sizes in Examples 2 and 3 were 68 nm and 35 nm, respectively, both falling within the 20–80 nm protection range. In Comparative Example 1, a large amount of insoluble particulate matter was present in the ordinary aqueous solution, which completely separated into layers after standing for 30 minutes. In Comparative Example 2, the ordinary emulsion had a particle size of 320–550 nm, a PDI > 0.45, and the system was extremely unstable. The formulation of this invention increases the water solubility of poorly soluble medicinal and edible homologous components by more than 100 times, completely solving the precipitation problem.

[0017] Experimental conditions: Stored at room temperature (25℃) and relative humidity (60%) for 6 months in a sealed, light-protected environment. Samples were taken at 0, 3, and 6 months. The contents of curcumin, total flavonoids, and total saponins were determined by HPLC, and the activity retention rate was calculated. Conclusion: The SMEDDS delivery system of this invention can greatly enhance the antioxidant and anti-decomposition capabilities of active ingredients, and its long-term storage stability far exceeds that of traditional formulations.

[0018] The paddle method was used, with artificial gastric fluid (pH=1.2) and artificial intestinal fluid (pH=6.8) as dissolution media. The mixture was stirred at a constant temperature of 37℃ and 50r / min, and the cumulative dissolution rate was measured over 24 hours.

[0019] Experimental results: The cumulative dissolution rate of the sample of this invention was 89.6% after 2 hours and completely dissolved after 24 hours; the dissolution rate of the ordinary formulation in Comparative Example 1 was only 23.1% after 2 hours and less than 55% after 24 hours; the dissolution rate of the ordinary emulsification in Comparative Example 2 was 47.8% after 2 hours. The formulation of this invention has a fast dissolution rate and complete dissolution, which completely solves the problems of poor solubility and limited absorption of components.

[0020] Experimental animals: SD rats, randomly divided into three groups, administered the drug by gavage once, and blood was collected continuously to detect blood drug concentration and calculate relative bioavailability.

[0021] Experimental results: Compared with the ordinary water-soluble formula of Comparative Example 1 (bioavailability 100%), the relative bioavailability of the ordinary emulsified formula of Comparative Example 2 was 246%. The relative bioavailability of Example 1 of this invention reached 812%, which is 8.12 times higher than the traditional formula, greatly overcoming the destruction by gastric acid and the first-pass effect of the liver.

[0022] A rat model of non-alcoholic fatty liver disease was induced by a high-fat diet. After 4 weeks of continuous gavage intervention, serum ALT, AST, TC, TG and liver lipid deposition were detected.

[0023] Experimental results: In the model group, rat hepatocytes showed extensive fatty vacuolar degeneration and severe lipid accumulation; in the ordinary formula group, liver damage was slightly improved; in the experimental group of this invention, the structure of rat hepatocytes basically returned to normal, serum ALT decreased by 42.3%, AST decreased by 38.7%, TC decreased by 45.1%, and TG decreased by 40.2%, liver fat deposition significantly subsided, and the liver protection and lipid reduction effects were extremely significant.

[0024] A rat arthritis model was induced by adjuvant, and the serum levels of inflammatory factors TNF-α and IL-6 were measured after 3 weeks of continuous intervention.

[0025] Experimental results: The experimental group of this invention can significantly downregulate the level of inflammatory factors, with TNF-α content reduced by 53.6% and IL-6 content reduced by 49.8%, significantly relieving synovial inflammation, swelling and inflammatory infiltration, and the anti-inflammatory effect is far superior to ordinary compound formulas. Beneficial effects

[0026] Compared with existing technologies, this invention has the following five core beneficial effects, demonstrating outstanding inventiveness and significant progress: 1. Completely solves three major pain points in the industry: Through SMEDDS self-microemulsification technology, poorly soluble active ingredients from food and medicine homology are completely water-soluble, storage stability is greatly improved, oral bioavailability is increased by more than 8 times, and technical problems that have long restricted the industrialization of curcumin, flavonoids and saponins are overcome. 2. Synergistic effect of components: Curcumin, flavonoids and saponins are precisely combined to form a dual synergistic effect of protecting the liver and lowering lipids and anti-inflammatory and analgesic effects. Unlike single-component products, it can achieve dual indications for the treatment of metabolic liver disease and inflammatory joint problems. 3. The process is extremely simple and can be mass-produced: the entire process is prepared at low temperature and room temperature, without the need for high-end equipment such as high-pressure homogenization and ultrasonic crushing. It has low energy consumption, high yield, and is suitable for large-scale industrial production. 4. Extremely high safety: All ingredients are food-grade and made from medicinal and edible raw materials. There are no hormones, no Western medicine ingredients, and no preservatives. It is mild and safe and suitable for long-term consumption. 5. Sufficient data support: Through multi-dimensional verification including particle size analysis, stability testing, dissolution testing, bioavailability testing, and animal efficacy testing, the technical effects are clear, the data is detailed, the patent is highly stable, and the risk of invalidation or rejection in the later stages can be effectively avoided.

Claims

1. A medicinal and edible microemulsion nanoemulsion oral liquid that improves fatty liver and relieves joint inflammation, characterized in that, The oral liquid comprises the following components in parts by weight: 0.5–3.0 parts curcumin, 1.0–5.0 parts flavonoid extracts from food and medicine sources, 0.8–4.0 parts saponin extracts from food and medicine sources, 15–35 parts edible oils, 30–60 parts nonionic surfactants, 8–20 parts co-surfactants, 0.5–2.0 parts sweeteners, and purified water to a total of 100 parts. The oral liquid is a SMEDDS self-microemulsifying system that can spontaneously emulsify upon contact with artificial gastric / intestinal fluid to form nanodroplets with a particle size of 20–80 nm.

2. The nanoemulsion oral solution according to claim 1, characterized in that: The flavonoid extract is one or more of the following: kudzu root flavonoids, mulberry leaf flavonoids, and sea buckthorn flavonoids; the saponin extract is one or more of the following: ginsenosides, astragalosides, and gypenosides; the mass ratio of the three components of curcumin, flavonoids, and saponins is 1:(1.2–2.0):(1.0–1.8).

3. The nanoemulsion oral solution according to claim 1, characterized in that: The edible oil is one or more of medium-chain triglycerides (MCT), olive oil, and flaxseed oil; the nonionic surfactant is one or two of polyoxyethylene hydrogenated castor oil and Tween 80; and the co-surfactant is one or more of propylene glycol, glycerin, and polyethylene glycol 400.

4. The nanoemulsion oral solution according to claim 1, characterized in that, In the self-microemulsifying carrier system, the mass ratio of surfactant to co-surfactant is (3–5):1, and the mass ratio of oil to water phase is 1:(2.5–4.0), which can ensure that there is no stratification or precipitation after standing at room temperature for 6 months, and the emulsification uniformity is stable.

5. A method for preparing a nanoemulsion oral liquid for improving fatty liver and relieving joint inflammation as described in any one of claims 1-4, characterized in that, It includes the following steps: (1) Preparation of oil phase: Take edible oil according to the ratio, heat it in a water bath to 40–55℃, add curcumin, flavonoid extract and saponin extract, stir at constant temperature for 15–30 min until completely dissolved, and obtain a transparent and homogeneous oil phase liquid. (2) Preparation of emulsion system: Add nonionic surfactant and co-surfactant to the oil phase liquid in sequence, stir at a constant temperature of 40–55℃ for 20–40 min to form a uniform and transparent self-microemulsifying concentrated matrix. (3) Aqueous phase preparation: Dissolve the sweetener in purified water, stir until completely dissolved, and let stand at room temperature to remove bubbles; (4) Volume adjustment and homogenization: The aqueous phase is slowly added dropwise to the self-microemulsifying concentrated matrix, stirred at low speed at room temperature for 10–20 min, purified water is added to the volume, and the mixture is allowed to stand to defoam and then filtered to remove bacteria, so as to obtain the self-microemulsifying nanoemulsion oral liquid.

6. The preparation method according to claim 5, characterized in that: In step (4), the drop rate is controlled at 1–3 mL / s and the stirring speed is 80–150 r / min. No high-pressure homogenization or ultrasonic treatment is required, and self-emulsification can be completed at room temperature.

7. A novel pharmaceutical use of the food-medicine homology derived microemulsion nanoemulsion oral liquid according to any one of claims 1-4, characterized in that: This is used to prepare functional oral formulations that improve non-alcoholic fatty liver disease, repair liver damage, and reduce blood lipid accumulation.

8. A novel pharmaceutical use of the food-medicine homology derived microemulsion nanoemulsion oral liquid according to any one of claims 1-4, characterized in that: It is used to prepare functional oral preparations that inhibit systemic low-grade inflammation, relieve osteoarthritis inflammation, and improve joint swelling and pain.

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