Environment-friendly curcumin nanocrystal and preparation method thereof

Abstract

This invention discloses an environmentally friendly curcumin nanocrystal and its preparation method, relating to the field of nanoparticle technology. The nanocrystal has a core-shell structure, with a core of curcumin crystals and a shell of hepatin peptide molecules bonded together by intermolecular forces. The average particle size of the nanocrystal is 50-200 nanometers, and it is completely dispersed and stable in an aqueous phase, containing no organic solvents or synthetic surfactants. This invention utilizes a pectin-chitosan complex to microencapsulate the nanocrystal, enabling it to resist gastric acid degradation and target release to the colon, thus precisely acting on the gut-hepatic axis and significantly improving bioavailability and hepatoprotective efficacy. While completely avoiding organic solvents and synthetic stabilizers, it simultaneously solves four major industry challenges related to curcumin: solubility, stability, targeted delivery, and synergistic efficacy, providing a new technical path for developing high-end, naturally derived hepatoprotective products.

Description

Technical Field

[0001] This invention relates to the field of nanoparticle technology, and in particular to an environmentally friendly curcumin nanocrystal and its preparation method. Background Technology

[0002] Curcumin has become a key research focus in the field of functional foods and health products due to its excellent antioxidant, anti-inflammatory, and hepatoprotective activities. However, its poor water solubility, low chemical stability, and poor bioavailability severely limit its practical application. To overcome these limitations, nanocrystal technology has become a key solution. Common methods include nanoprecipitation and high-pressure homogenization. A typical preparation scheme uses amphiphilic polymers (such as polyvinylpyrrolidone and poloxamer) or synthetic surfactants (such as sodium dodecyl sulfate and Tween-80) as stabilizers to prepare curcumin nanocrystals in a mixed system of organic solvents (such as acetone and ethanol) and water via antisolvent precipitation, thereby improving its water dispersibility and solubility.

[0003] While existing technologies can prepare curcumin nanocrystals, they fall short in terms of environmental and biocompatibility. Most methods rely on synthetic polymers or chemical surfactants as stabilizers and organic solvents as dispersion media, potentially leading to chemical residue risks. As health products increasingly demand "natural origin," "clean label," and "ultimate safety," existing preparation methods struggle to meet market demands for completely green, chemical-free curcumin nanocrystal delivery systems. This limitation restricts curcumin's application potential in high-end health products, particularly in functional beverages and dietary supplements where safety is paramount. Summary of the Invention

[0004] In view of the aforementioned existing problems, the present invention is proposed.

[0005] Therefore, the present invention provides a file encryption method that solves the problems of chemical residues and insufficient biocompatibility caused by the reliance on synthetic additives and organic solvents in the prior art.

[0006] To solve the above-mentioned technical problems, the present invention provides the following technical solution: In a first aspect, the present invention provides an environmentally friendly curcumin nanocrystal, comprising: the nanocrystal having a core-shell structure, wherein the core is a curcumin crystal nucleus and the outer shell is a stable layer formed by hepatin peptide molecules bound together by intermolecular forces; the average particle size of the nanocrystal is 50-200 nanometers, and the nanocrystal is completely dispersed and stable in an aqueous phase, and does not contain organic solvents or synthetic surfactants.

[0007] As a preferred embodiment of the environmentally friendly curcumin nanocrystals of the present invention, the hepatin peptide has a molecular weight of less than 1000 Daltons and contains an active fragment with a hydrophobic amino acid sequence, which binds to the curcumin crystal core through hydrophobic interactions.

[0008] As a preferred embodiment of the environmentally friendly curcumin nanocrystals of the present invention, the outer shell of the nanocrystals is further combined with natural active ingredients from medicinal and edible plants. The natural active ingredients are selected from one or more of Hovenia dulcis extract, Pueraria lobata extract, and vine tea extract (dihydromyricetin), which together with the hepatoprotein peptides form a mixed stabilizing layer.

[0009] Secondly, the present invention provides a method for preparing environmentally friendly curcumin nanocrystals, comprising: S1. preparing an aqueous solution containing hepatin peptides and adjusting its pH to 8.5-9.5; S2. Prepare an oil phase dispersion containing curcumin raw material; S3. In a continuous flow reactor, the aqueous solution and the oil dispersion are mixed in proportion and subjected to high-speed shearing to form a primary nanoemulsion; S4. The primary nanoemulsion is introduced into a temperature-controlled crystallization pipe, and acid is added to it to rapidly neutralize the pH of the system to 5.5-6.5. Curcumin and hepatin peptide are co-crystallized at 60-70°C to form a nano-co-crystallized suspension. S5. The nano-eutectic suspension is instantaneously cooled to obtain the final product.

[0010] This invention provides a method for preparing environmentally friendly curcumin nanocrystals, including, in step S1, the aqueous solution further comprising water extracts of one or more medicinal and edible plants selected from Hovenia dulcis, Pueraria lobata, vine tea, and Rosa rugosa.

[0011] This invention provides a method for preparing environmentally friendly curcumin nanocrystals, including, in step S2, the oil phase in the oil phase dispersion is food-grade medium-chain triglycerides, and the mass concentration of the curcumin raw material in the oil phase is not higher than 5%.

[0012] This invention provides a method for preparing environmentally friendly curcumin nanocrystals, comprising: the high-speed shearing rotation speed is not less than 10,000 rpm; and the volume ratio of the aqueous phase solution to the oil phase dispersion is (90~99):(10~1).

[0013] This invention provides a method for preparing environmentally friendly curcumin nanocrystals, including, in step S4, the acid solution is an aqueous solution of citric acid, lactic acid or malic acid, and the addition rate is controlled by a precision pump so that the pH of the system decreases from the initial value to the target range within 10-30 seconds.

[0014] The present invention provides a method for preparing environmentally friendly curcumin nanocrystals, including, in step S5, the instantaneous cooling is to cool the suspension from the crystallization temperature to below 10°C within 10 seconds.

[0015] This invention provides a method for preparing environmentally friendly curcumin nanocrystals, comprising, after step S5, a further step S6: mixing the nanocrystal suspension with a colon-targeting encapsulation material solution and spray-drying to prepare microcapsule powder with colon-targeting release characteristics; wherein the colon-targeting encapsulation material is a complex of pectin and chitosan. The beneficial effects of this invention are as follows: By using hepatin peptide self-assembly and pH-driven co-crystallization technology, environmentally friendly curcumin nanocrystals with a core-shell structure are constructed in a continuous flow reaction system. By precisely controlling the acid-base neutralization process, curcumin molecules and hydrophobic fragments of hepatin peptides are induced to co-crystallize through intermolecular forces at a specific temperature, forming a nanocomposite with curcumin as the core and hepatin peptides as the stable shell. This not only achieves efficient nano-sizing and stable dispersion of curcumin, but also endows its natural carrier with its own bioactivity. Through colon-targeted encapsulation technology, the nanocrystals are microencapsulated using a pectin-chitosan complex, enabling them to resist gastric acid degradation and target release to the colon, thereby precisely acting on the gut-hepatic axis and significantly improving bioavailability and liver-protective efficacy. Under the premise of completely avoiding organic solvents and synthetic stabilizers, this invention simultaneously solves four major industry challenges of curcumin: solubility, stability, targeted delivery, and synergistic efficacy, providing a new technical path for the development of high-end natural liver-protective products. Attached Figure Description

[0016] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the following description of the embodiments will be briefly introduced. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 The flowchart shows the process for environmentally friendly curcumin nanocrystals. Detailed Implementation

[0018] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

[0019] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0020] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0021] Reference Figure 1 This is one embodiment of the present invention, which provides an environmentally friendly curcumin nanocrystal and its preparation method, including the following steps: Example 1.

[0022] 1. Preparation of nano-eutectic S1. Preparation of the aqueous solution: Weigh 5.0 g of hepatin peptide powder (containing hydrophobic amino acid fragments) with a molecular weight of less than 1000 Daltons, add it to a reaction vessel containing 900 mL of purified water, and stir in a 45°C water bath until completely dissolved. Then, add an appropriate amount of 1 mol / L sodium hydroxide solution to precisely adjust the pH of the aqueous solution to 9.0.

[0023] S2. Preparation of oil phase dispersion: Weigh 0.5 g of curcumin raw material with a purity greater than 95%, add it to 9.5 g of food-grade medium-chain triglycerides (MCT oil), and stir at 500 rpm for 30 minutes at 50°C to obtain a curcumin oil phase dispersion with a mass concentration of 5%.

[0024] S3. Formation of the primary nanoemulsion: A continuous flow reactor (equipped with an online high-speed shear mixer) was used. The aqueous solution obtained in step S1 and the oil dispersion obtained in step S2 were pumped separately into the online high-speed shear mixer at a volume ratio of 95:5 using precision feed pumps. The mixture was mixed at a shear speed of 15,000 rpm to form a homogeneous primary nanoemulsion.

[0025] S4. Co-crystallization reaction: The primary nanoemulsion obtained in step S3 is introduced into a temperature-controlled crystallization coil (set at 65°C). Simultaneously, a 0.5 mol / L citric acid aqueous solution is injected into the flow stream at the inlet of the crystallization coil at a specific flow rate using another precision pump. By controlling the acid flow rate, the pH of the entire mixing system is rapidly and uniformly reduced from 9.0 to 6.0 within approximately 20 seconds. Under these conditions, curcumin and the hydrophobic fragments of hepatoprotein peptides co-crystallize to form a nano-cocrystallized suspension.

[0026] S5. Instantaneous Cooling and Collection: The suspension flowing from the crystallization coil is immediately passed into a tubular cooler, reducing the material temperature from 65°C to 5°C within 5 seconds, yielding the final environmentally friendly curcumin-hepatin peptide nanocrystal suspension. Samples are taken and stored at 4°C.

[0027] 2. Product characterization and performance testing (1) Morphology and particle size: The product exhibited a regular near-spherical core-shell structure when observed by transmission electron microscopy. The average particle size was 118 nm and the polydispersity index was 0.15 when measured by dynamic light scattering laser particle size analyzer.

[0028] (2) Stability: The nano-cocrystal suspension was stored at 4℃ and 25℃ for 30 days. The average particle size and polydispersity index did not change significantly, and there was no obvious precipitation or flocculation, indicating that it has excellent dispersion stability in water.

[0029] (3) Component analysis: High performance liquid chromatography-mass spectrometry analysis showed that no organic solvents (such as acetone and ethanol) or synthetic surfactants (such as Tween-80 and PVP) were detected in the final product.

[0030] Example 2 The difference between this embodiment and Example 1 is that in step S1, after dissolving the hepatoprotein peptides, an additional 50 mL of Hovenia dulcis aqueous extract (0.1 g / mL based on crude drug concentration) and 30 mL of Pueraria lobata aqueous extract (0.1 g / mL based on crude drug concentration) were added, and then the pH was adjusted to 9.0. The final obtained nanocrystalline shell is a mixed stable layer composed of hepatoprotein peptides, Hovenia dulcis extract, and Pueraria lobata extract. The average particle size was determined to be 135 nm, and it exhibited good storage stability at 4°C. Furthermore, in vitro cell experiments showed a synergistic enhancement of its antioxidant activity compared to the product of Example 1.

[0031] Example 3 This embodiment adds a step for preparing colon-targeted microcapsules to the existing embodiment 1.

[0032] S6. Colon-Targeted Microencapsulation: The nano-cocrystal suspension obtained in step S5 of Example 1 was mixed evenly with a 2% (w / v) pectin-chitosan composite aqueous solution (pectin to chitosan mass ratio 2:1) at a volume ratio of 1:1. The mixture was spray-dried at an inlet air temperature of 160°C, an outlet air temperature of 85°C, and a peristaltic pump feed rate of 10 mL / min. The dried powder was collected to obtain curcumin nano-cocrystal microcapsule powder with colon-targeted release characteristics.

[0033] Performance testing: (1) Encapsulation efficiency and drug loading: The microcapsule encapsulation efficiency of curcumin was 92.5%, and the drug loading was 8.7%.

[0034] (2) In vitro simulated release: Using the in vitro release rate determination method in the Chinese Pharmacopoeia, the cumulative release rate was less than 10% in simulated gastric juice (pH 1.2) within 2 hours, and about 35% in simulated intestinal juice (pH 6.8) within 4 hours. However, when the medium was changed to simulated colonic juice (containing pectinase, pH 5.5), the cumulative release rate reached more than 85% within 8 hours, showing obvious colon-targeted release characteristics.

[0035] Comparative Example 1 This comparative example uses a traditional antisolvent precipitation method to prepare curcumin nanosuspension, in order to compare it with Example 1 of the present invention.

[0036] Weigh 0.5 g of curcumin and dissolve it in 50 mL of acetone to form the organic phase. Weigh 1.0 g of polyvinylpyrrolidone K30 and dissolve it in 950 mL of purified water to form the aqueous phase. Under magnetic stirring (800 rpm), quickly pour the organic phase into the aqueous phase and continue stirring for 2 hours to allow the acetone to evaporate. Then, centrifuge the resulting suspension at 10,000 rpm for 10 minutes, collect the precipitate, and resuspend it in pure water to obtain the curcumin nano-suspension.

[0037] Performance comparison: (1) Particle size and stability: The average particle size of the obtained suspension was 205 nm, but after being stored at 4℃ for 7 days, obvious stratification and particle size increase were observed.

[0038] (2) Composition analysis: Gas chromatography detected trace amounts of acetone residue (approximately 120 ppm). The product label must indicate that it contains the synthetic pharmaceutical excipient PVP K30.

[0039] (3) Environmental friendliness: The use of organic solvent acetone and synthetic polymer PVP does not meet the requirements of the "clean label". The process involves the volatilization of organic solvents, which poses safety and environmental risks.

[0040] Comparative Example 2 The difference between this comparative example and Example 1 is that hepatin peptides are not used; instead, an equal mass of the common food-grade emulsifier soybean lecithin is used. Furthermore, pH adjustment and induced crystallization are not performed; instead, ordinary nanoemulsions are prepared solely through high-speed shearing and homogenization.

[0041] Performance comparison: (1) Structural differences: Transmission electron microscopy shows a typical emulsion droplet structure with an irregular crystal core, which is only a physical coating.

[0042] (2) Chemical stability: In the accelerated test at 40°C, the curcumin content decreased by about 25% after one week, and the degradation rate was significantly higher than that of the product in Example 1 (content decrease <5%), indicating that the stabilizing and protective effect of phospholipids is weaker than that of the eutectic structure formed in this invention.

[0043] (3) Digestive stability: In the simulated gastrointestinal digestion experiment, the emulsion of Comparative Example 2 was largely destroyed and released curcumin during the gastric juice stage, while the nano-cocrystal of Example 1 showed a stronger ability to resist digestive juice erosion.

[0044] Comparative Example 3 The difference between this comparative example and Example 3 is that, instead of undergoing pH-controlled co-crystallization in step S4, the primary nanoemulsion obtained in step S3 is directly subjected to spray drying and microencapsulation in step S6.

[0045] Performance comparison: (1) Microcapsule structure: Scanning electron microscopy showed that the microcapsule surface of Comparative Example 3 was rough with more depressions and cracks, while the microcapsule surface of Example 3 was smooth and dense. This is because co-crystallization formed a denser and more rigid nanocore, which was better able to maintain structural integrity during spray drying.

[0046] (2) Targeted release performance: In the in vitro simulated release experiment, the microcapsules of Comparative Example 3 exhibited burst release in simulated intestinal fluid, with a cumulative release rate of 70% within 4 hours, while no further significant release was observed in simulated colonic fluid, indicating poor targeting. This is because a stable co-crystal was not formed, and curcumin remained in a free or simply encapsulated state within the microcapsules, making it prone to leakage in the early intestinal tract. In contrast, Example 3 demonstrated good colonic targeting with both pH and enzyme responses.

[0047] In summary, this invention utilizes hepatoprotein peptide self-assembly and pH-driven co-crystallization technology to construct environmentally friendly curcumin nanocrystals with a core-shell structure in a continuous flow reaction system. By precisely controlling the acid-base neutralization process, curcumin molecules and hydrophobic fragments of hepatoprotein peptides are induced to co-crystallize through intermolecular forces at a specific temperature, forming a nanocomposite with curcumin as the core and hepatoprotein peptides as the stable shell. This not only achieves efficient nano-sizing and stable dispersion of curcumin but also endows its natural carrier with its own bioactivity. Through colon-targeted encapsulation technology, the nanocrystals are microencapsulated using a pectin-chitosan complex, enabling them to resist gastric acid degradation and target release to the colon, thereby precisely acting on the gut-hepatic axis and significantly improving bioavailability and hepatoprotective efficacy. While completely avoiding organic solvents and synthetic stabilizers, this invention simultaneously solves four major industry challenges related to curcumin: solubility, stability, targeted delivery, and synergistic efficacy, providing a new technical path for developing high-end, naturally derived hepatoprotective products.

[0048] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. An environmentally friendly curcumin nanocrystal, characterized in that: The nano-cocrystal has a core-shell structure, with a core of curcumin crystals and a shell of hepatin peptide molecules bonded together by intermolecular forces. The average particle size of the nano-cocrystal is 50-200 nanometers, and the nano-cocrystal is completely dispersed and stable in the aqueous phase, without containing organic solvents or synthetic surfactants.

2. The environmentally friendly curcumin nanocrystals and their preparation method as described in claim 1, characterized in that: The hepatin peptide has a molecular weight of less than 1000 Daltons and contains an active fragment with a hydrophobic amino acid sequence, which binds to the curcumin crystal core through hydrophobic interactions.

3. The environmentally friendly curcumin nanocrystals and their preparation method as described in claim 2, characterized in that: The outer shell of the nano-cocrystal is also combined with natural active ingredients from medicinal and edible plants. These natural active ingredients are selected from one or more of the following: Hovenia dulcis extract, Pueraria lobata extract, and vine tea extract (dihydromyricetin). Together with the hepatoprotein peptide, they form a mixed stabilizing layer.

4. A method for preparing environmentally friendly curcumin nanocrystals, based on the environmentally friendly curcumin nanocrystals and preparation method according to any one of claims 1 to 3, characterized in that: include: S1. Prepare an aqueous solution containing hepatin peptides and adjust its pH to 8.5-9.5; S2. Prepare an oil phase dispersion containing curcumin raw material; S3. In a continuous flow reactor, the aqueous solution and the oil dispersion are mixed in proportion and subjected to high-speed shearing to form a primary nanoemulsion; S4. The primary nanoemulsion is introduced into a temperature-controlled crystallization pipe, and acid is added to it to rapidly neutralize the pH of the system to 5.5-6.

5. Curcumin and hepatin peptide are co-crystallized at 60-70°C to form a nano-co-crystallized suspension. S5. The nano-eutectic suspension is instantaneously cooled to obtain the final product.

5. The method for preparing environmentally friendly curcumin nanocrystals as described in claim 4, characterized in that: In step S1, the aqueous solution further includes water extracts of one or more medicinal and edible plants selected from Hovenia dulcis, Pueraria lobata, vine tea, and prickly pear.

6. The method for preparing environmentally friendly curcumin nanocrystals as described in claim 4, characterized in that: In step S2, the oil phase in the oil phase dispersion is food-grade medium-chain triglycerides, and the mass concentration of the curcumin raw material in the oil phase is not higher than 5%.

7. The method for preparing environmentally friendly curcumin nanocrystals as described in claim 4, characterized in that: In step S3, the rotation speed of the high-speed shear is not less than 10,000 rpm, and the volume ratio of the aqueous solution to the oil dispersion is (90~99): (10~1).

8. The method for preparing environmentally friendly curcumin nanocrystals as described in claim 4, characterized in that: In step S4, the acid solution is an aqueous solution of citric acid, lactic acid, or malic acid, and the addition rate is controlled by a precision pump so that the pH of the system drops from the initial value to the target range within 10-30 seconds.

9. The method for preparing environmentally friendly curcumin nanocrystals as described in claim 4, characterized in that: In step S5, the instantaneous cooling means cooling the suspension from the crystallization temperature to below 10°C within 10 seconds.

10. The method for preparing environmentally friendly curcumin nanocrystals as described in claim 4, characterized in that: After step S5, step S6 is also included: mixing the nano-cocrystal suspension with a colon-targeted embedding material solution and spray drying it to prepare microcapsule powder with colon-targeted release characteristics; the colon-targeted embedding material is a complex of pectin and chitosan.

Images