High-dispersion curcumin nano suspension and preparation method thereof

Abstract

The invention relates to the technical field of natural pigments, in particular to a high-dispersion curcumin nano suspension and a preparation method thereof. The curcumin nano suspension is prepared from the following raw materials: 7 to 11 parts of curcumin, 0.2 to 0.5 part of xanthan gum, 0.1 to 0.5 part of gellan gum, 10 to 15 parts of glycerol and 150 to 300 parts of water. According to the high-dispersion curcumin nano suspension provided by the invention, the particle size of curcumin can be regulated and controlled through a synergistic process of'glycerol premixing wetting 'and'long-time high-speed stirring dispersion', and the problems of complicated preparation conditions, poor stability and non-uniform particle size of a curcumin water-phase dispersion liquid are solved. Besides, a composite colloid network structure formed by xanthan gum and gellan gum in a limited proportion has strong steric hindrance and gel characteristics, forms a thickening and stable synergistic effect, can effectively inhibit Brownian motion and gravity settling of curcumin particles, and improves the water-phase dispersion uniformity of the curcumin particles.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of natural pigments, and particularly relates to a highly dispersed curcumin nanosuspension and a preparation method thereof. BACKGROUND

[0002] The information disclosed in this Background section is only for the purpose of increasing the understanding of the background of the present application and should not be taken as an acknowledgement or any form of suggestion that this information forms prior art with respect to any patentable matter of the present application.

[0003] Curcumin is a chemical component extracted from the rhizomes of some plants in Zingiberaceae and Araceae, and its molecular formula is C 21 H 20 O6, and its relative molecular weight is 368.39. Curcumin is a tautomeric structure of benzene ring diketone and enone. Studies have shown that curcumin can not only be used as a natural colorant, but also has the effects of anti-inflammatory and muscle regeneration, alcohol protection and liver protection, and anticancer.

[0004] However, curcumin is a highly hydrophobic molecule with poor water solubility and low chemical stability, and it is easy to precipitate in an aqueous system, which leads to poor product uniformity, low bioavailability, and limits its application.

[0005] Nanosuspension is a colloidal dispersion system of pure drug submicron particles. Unlike the traditional matrix-based nanosystem, nanosuspension does not require carrier materials. It is a stable system formed by dispersing nanoscale drug particles in water through the stabilizing effect of the charge effect and steric effect of surfactants. The preparation of nanosuspension of poorly soluble drugs can effectively overcome the problem of low bioavailability of drugs, increase the stability of drugs and improve the efficacy, so that the drugs can better play their roles.

[0006] However, the current curcumin nanosuspension has problems of difficult accurate control of particle size and uneven particle size during preparation. In addition, nanoparticles have extremely high surface energy, and in order to reduce the energy of the system, they will strongly tend to aggregate with each other, which leads to precipitation, and ultimately leads to the problem of poor stability of curcumin nanosuspension. SUMMARY

[0007] In order to overcome the above problems, the present application provides a highly dispersed curcumin nanosuspension and a preparation method thereof.

[0008] To achieve the above technical purposes, the technical scheme adopted by the present application is as follows: The first aspect of the present application provides a highly dispersed curcumin nanosuspension, and the raw materials thereof include: Curcumin 7-11 parts, xanthan gum 0.2-0.5 parts, gellan gum 0.1-0.5 parts, glycerol 10-15 parts and water 150-300 parts.

[0009] In a second aspect of the present application, a preparation method of the high-dispersion curcumin nanosuspension of the first aspect is provided, comprising the following steps: (1) adding glycerol into water, and mixing uniformly to obtain a glycerol aqueous solution; (2) sequentially adding xanthan gum and gellan gum into the glycerol aqueous solution, mixing uniformly, then adding curcumin, and preliminarily stirring and dispersing to obtain a suspension, and continuously stirring and dispersing to obtain the high-dispersion curcumin nanosuspension.

[0010] In one or more embodiments, in step (1), the water is ultrapure water.

[0011] In one or more embodiments, in step (1), the temperature of the reaction system is 20-30 ℃.

[0012] In one or more embodiments, in step (1), the method for mixing uniformly comprises stirring at a speed of 300-600 rpm for 8-15 min.

[0013] In one or more embodiments, in step (2), the temperature of the reaction system is 20-30 ℃.

[0014] In one or more embodiments, in step (2), the stirring is continuously performed during the addition of xanthan gum and gellan gum, and the stirring speed is 300-600 rpm.

[0015] In one or more embodiments, in step (2), during the preliminary stirring and dispersing, the stirring speed is 300-600 rpm, and the stirring time is 10-120 min.

[0016] In one or more embodiments, in step (2), during the continuous stirring and dispersing, the stirring speed is 1000-2000 rpm, and the stirring time is 12-240 h.

[0017] In one or more embodiments, the particle size of the curcumin nanoparticles in the curcumin nanosuspension is 80-130 nm, and the average particle size is 103 nm.

[0018] The present application has the following beneficial effects: (1) The high dispersion curcumin nanosuspension provided by the present application can regulate the particle size of curcumin by the synergistic process of 'glycerol premixing wetting' and 'long time high speed stirring dispersion', and solves the problem of uneven particle size. In addition, the composite colloidal network structure formed by xanthan gum and gellan gum in a limited ratio has strong steric hindrance and gel characteristics, forming a synergistic effect of thickening and stabilization, which can effectively inhibit the Brownian motion and gravity sedimentation of curcumin particles, improve the dispersion uniformity, and the particle size distribution is more uniform. Experiments have proved that the high dispersion curcumin nanosuspension provided by the present application has no stratification and no significant precipitation after standing at room temperature for 90 days, and the stability is much better than that of samples using only single colloid or short time dispersion.

[0019] (2) The raw materials of the high dispersion curcumin nanosuspension provided by the present application are food grade or pharmaceutical auxiliary material grade, safe and non-toxic, and the curcumin nanosuspension can be directly used as raw material and directly added to the terminal products of various aqueous systems, such as beverages, health products and pharmaceutical products.

[0020] (3) Good process reproducibility: the formula provided by the present application is accurate, and the process parameters are clear, which provides clear and reliable basis for scaling up from laboratory to industrial production, and is easy to realize large-scale production. BRIEF DESCRIPTION OF DRAWINGS

[0021] The drawings accompanying the specification of the present application serve to provide further understanding of the present application, and the schematic embodiments of the present application and the description thereof serve to explain the present application, and do not constitute undue limitation on the present application.

[0022] Figure 1 The figure is the initial state and the state after standing for 90 days of the high dispersion curcumin nanosuspension prepared in Example 1; Figure 2 The figure is the low-power transmission microscope image of the high dispersion curcumin nanosuspension prepared in Example 1; the insert is the particle size distribution graph; Figure 3 The figure is the state of the suspensions prepared in Comparative Examples 1-4 after standing for 7 days; wherein a-d are Comparative Example 1, Comparative Example 2, Comparative Example 3 and Comparative Example 4, respectively; Figure 4 The figure is a schematic diagram of the relative content detection of curcumin in the suspensions prepared in Example 2 with different amounts of curcumin; Figure 5 The figure is the relative content of curcumin in the high dispersion curcumin nanosuspension prepared in Example 3 after standing at room temperature for 0-90 days. DETAILED DESCRIPTION

[0023] It should be noted that the following detailed description is exemplary in nature and is intended to provide further description of the application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0024] It is to be understood that the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is also to be understood that the term "comprising" as used herein is intended to mean "including but not limited to."

[0025] At present, there are problems of difficult to accurately control particle size and uneven particle size in the preparation process of curcumin nanosuspension. In addition, nanoparticles have extremely high surface energy, in order to reduce the system energy, they will strongly tend to aggregate with each other, and then cause precipitation, ultimately leading to the problem of poor stability of curcumin nanosuspension.

[0026] To achieve the above technical purposes, the technical scheme adopted by the present application is as follows: The first typical embodiment of the present application provides a high dispersion curcumin nanosuspension, the raw materials of which include: Curcumin 7-11 parts, xanthan gum 0.2-0.5 parts, gellan gum 0.1-0.5 parts, glycerol 10-15 parts and water 150-300 parts.

[0027] The glycerol and water are mixed according to the defined ratio to obtain a glycerol aqueous solution. The glycerol aqueous solution with a defined concentration can not only improve the hydrophilic environment of curcumin through its hydrogen bond effect, but also will not affect the efficiency of the subsequent dispersion process due to the high viscosity.

[0028] The limitation of the ratio of curcumin to composite colloid (xanthan gum and gellan gum) can ensure that a sufficient amount of colloid can fully wrap curcumin to form nanoparticles. In addition, the limitation of the ratio of xanthan gum to gellan gum is the key to exert the best suspension and stability effect. Among them, xanthan gum provides high pseudoplasticity and good suspension force, while gellan gum can form a soft and shear-resistant three-dimensional network structure, and the combination of the two forms a strong and stable steric hindrance effect, effectively preventing the settlement and aggregation of curcumin.

[0029] The second typical embodiment of the present application provides a preparation method of the high dispersion curcumin nanosuspension of the first aspect, which comprises the following steps: (1) adding glycerol into water, and mixing uniformly to obtain a glycerol aqueous solution; (2) adding xanthan gum and gellan gum into the glycerol aqueous solution in sequence, mixing uniformly, then adding curcumin, and obtaining a suspension after preliminary stirring and dispersion; and obtaining a curcumin nanosuspension after continuous stirring and dispersion.

[0030] In one or more embodiments, in step (1), the water is ultrapure water.

[0031] In one or more embodiments, in step (1), the temperature of the reaction system is 20-30 ℃.

[0032] In one or more embodiments, in step (2), the temperature of the reaction system is 20-30 ℃.

[0033] The limitation of the reaction temperature during the reaction is crucial for achieving sufficient depolymerization and stable dispersion of curcumin molecules. The subsequent experimental results show that the stability of the curcumin nanosuspension decreases with the increase of the temperature of the reaction system.

[0034] In one or more embodiments, in step (1), the method for mixing uniformly includes stirring at a speed of 300-600 rpm for 8-15 min.

[0035] In one or more embodiments, in step (2), the stirring is kept during the addition of xanthan gum and gellan gum, and the stirring speed is 300-600 rpm.

[0036] In one or more embodiments, in step (2), during the preliminary stirring and dispersion, the stirring speed is 300-600 rpm, and the stirring time is 10-120 min.

[0037] In one or more embodiments, in step (2), during the continuous stirring and dispersion, the stirring speed is 1000-2000 rpm, and the stirring time is 12-240 h. On the one hand, the strong mechanical shear force can effectively break the curcumin aggregates into fine particles, and at the same time, the molecular chains of xanthan gum and gellan gum are fully stretched and hydrated, forming a dense colloid network. On the other hand, the dispersion time is the key to achieving the physical and chemical equilibrium. It ensures the complete hydration of the colloid molecules and the full formation of the network structure; the fine curcumin particles are gradually "fixed" and "wrapped" in the formed colloid network, achieving uniform distribution on the microscopic scale; this process is not only "mixing", but also a "structuring" process.

[0038] In one or more embodiments, the particle size of the curcumin nanoparticles in the high-dispersion curcumin nanosuspension is 80-130 nm, and the average particle size is 103 nm.

[0039] The high-dispersion curcumin nanosuspension provided by the application can regulate the particle size of curcumin and solve the problem of uneven particle size through the synergistic process of "glycerol premixing wetting" and "long-time high-speed stirring dispersion". In addition, the composite colloidal network structure formed by xanthan gum and gellan gum in a limited ratio has strong steric hindrance and gel characteristics, forming a synergistic effect of thickening and stabilization, which can effectively inhibit the Brownian motion and gravitational sedimentation of curcumin particles and improve the uniformity of dispersion. Experiments have proved that the high-dispersion curcumin nanosuspension provided by the application has no stratification and no significant precipitation after standing at room temperature for 90 days, and the stability is much better than that of samples using only a single colloid or short-time dispersion.

[0040] In order for those skilled in the art to more clearly understand the technical solutions of the present application, the technical solutions of the present application will be described in detail below in combination with specific examples.

[0041] In the following examples, the purity of curcumin powder is ≥95%, xanthan gum and gellan gum are food grade; glycerol is pharmaceutical grade with a purity of 99.5%.

[0042] Example 1 (1) 8 g of glycerol was added to 180 mL of ultrapure water, stirred at a speed of 500 rpm for 10 min to form a clear and uniform glycerol aqueous solution.

[0043] (2) Under the condition of continuous stirring (speed of 500 rpm), 0.5 g of xanthan gum and 0.25 g of gellan gum were slowly and uniformly added to the glycerol aqueous solution in sequence, and stirring was continued for 20 min; then curcumin powder was slowly and uniformly added, and stirring was continued for 60 min to make all the solid powders preliminarily dispersed in the liquid to form a suspension. Then, the stirring speed was set to 1500 rpm, and stirring was continued for 120 h.

[0044] During the entire dispersion process of steps (1) and (2), the experimental environment temperature needs to be kept constant at 25 ℃, and the whole process needs to be operated in the dark to prevent curcumin from degrading due to light. When the dispersion process is carried out for 24 h, 48 h, 72 h and 96 h, the materials attached to the container wall can be briefly paused and mixed to ensure the uniformity of mixing.

[0045] After the dispersion is completed, a high-dispersion curcumin nanosuspension is obtained, Figure 1 The physical picture of the high-dispersion curcumin nanosuspension is shown in Fig. 1. Figure 1 As can be seen from Fig. 1, the curcumin nanosuspension is orange yellow, has uniform texture and good fluidity, and no particles or precipitates can be observed under naked eye observation.

[0046] The morphology and size of the sample were characterized by transmission electron microscopy (HT-7700), which proved that the curcumin in the high-dispersity curcumin nanosuspension was curcumin nanoparticles with a particle size of 80-130 nm and an average particle size of 103 nm. Figure 2 .

[0047] The high-dispersity curcumin nanosuspension was placed at room temperature and observed for 90 days, and the results are shown in Figure 1 . No layering, water separation or obvious precipitation occurred in the curcumin nanosuspension, proving its excellent physical stability. At the same time, further detection of the average particle size of the curcumin nanoparticles showed no significant change.

[0048] Comparative Example 1 This comparative example is compared with Example 1, and the time for continuous stirring in step (2) is shortened.

[0049] Under the condition of continuous stirring (500 rpm), 0.5 g of xanthan gum and 0.25 g of gellan gum were slowly and uniformly added to the glycerol aqueous solution, and stirring was continued for 20 min; then curcumin powder was slowly and uniformly added, and stirring was continued for 60 min to preliminarily disperse all the solid powder in the liquid to form a suspension. Then, the stirring speed was set to 1500 rpm, and stirring was continued for 48 h.

[0050] The other methods are exactly the same as in Example 1.

[0051] As shown in a of Figure 3 , the suspension prepared in this comparative example has a slight visible particle feeling in the initial state. After standing at room temperature for 30 days, curcumin precipitates appear at the bottom of the bottle, and the supernatant is still orange yellow, which is significantly lower than the product of Example 1 in terms of dispersion stability and uniformity. This shows that long-time stirring is crucial for the stable dispersion of curcumin molecules.

[0052] At the same time, further detection of the average particle size of the curcumin nanoparticles in the suspension showed that the average particle size was 1-4 μm.

[0053] Comparative Example 2 This comparative example is compared with Example 1, and the temperature during the entire dispersion process is adjusted to 37 °C.

[0054] The other methods are exactly the same as in Example 1.

[0055] As shown in b of Figure 3 , after the dispersion is completed, the initial state of the suspension is thin and has strong fluidity. After standing at room temperature for 7 days, curcumin precipitates appear at the bottom of the bottle, and the supernatant is light orange yellow, which is significantly lower than the product of Example 1 in terms of dispersion stability and uniformity. This shows that keeping the experimental environment temperature constant at 20 °C-30 °C is crucial for the stable dispersion of curcumin molecules.

[0056] The average particle size of the curcumin nanoparticles in the suspension was further detected to be 1-4 μm.

[0057] Comparative Example 3 In comparison with Example 1, only xanthan gum was used as the colloid in this comparative example.

[0058] The other methods were the same as in Example 1.

[0059] After the dispersion was completed, the suspension had a certain viscosity, but after standing at room temperature for 7 days, the system showed a phase separation phenomenon (Fig. 2c), and there was a soft precipitate at the bottom, which could be re-dispersed by slight shaking, but the long-term stability was not as good as that of Example 1. This indicates that the combination of xanthan gum and gellan gum in a limited ratio has a synergistic effect in improving the long-term structural stability of the nanoparticles and preventing phase separation, which is better than the use of a single colloid. Figure 3

[0060] The average particle size of the curcumin nanoparticles in the suspension was further detected to be 1-4 μm.

[0061] Comparative Example 4 In comparison with Example 1, only gellan gum was used as the colloid in this comparative example.

[0062] The other methods were the same as in Example 1.

[0063] After the dispersion was completed, the suspension had a certain viscosity, but after standing at room temperature for 7 days, the system showed a phase separation phenomenon (Fig. 2c), and there was a soft precipitate at the bottom, which could be re-dispersed by slight shaking, but the long-term stability was not as good as that of Example 1. This indicates that the combination of xanthan gum and gellan gum in a limited ratio has a synergistic effect in improving the long-term structural stability of the nanoparticles and preventing phase separation, which is better than the use of a single colloid. Figure 3

[0064] The average particle size of the curcumin nanoparticles in the suspension was further detected to be 1-4 μm.

[0065] Comparative Example 5 In comparison with Example 1, the rotation speed and time of continuous stirring were adjusted in this comparative example.

[0066] Under the condition of continuous stirring (500 rpm), 0.5 g of xanthan gum and 0.25 g of gellan gum were slowly and uniformly added to the aqueous glycerol solution, and the stirring was continued for 20 min; then curcumin powder was slowly and uniformly added, and the stirring was continued for 60 min, so that all the solid powders were initially dispersed in the liquid to form a suspension. Subsequently, the stirring speed was set to 2500 rpm, and the stirring was continued for 2 h. ​​

[0067] Other methods are exactly the same as in Example 1.

[0068] After the stirring, the suspension shows an uneven state, there is obvious particle aggregation, and stratification and precipitation appear after 2 hours of standing. This proves that only relying on high shear force for a short time cannot realize long-term stable dispersion of curcumin in the specific colloid-glycerol-water system of the present application, and the process of "combining relatively mild shear force (1000-2000 rpm) with ultra-long time (12-240 hours)" adopted in the present application is the key to realize stable dispersion.

[0069] Example 2 The addition amount of curcumin is adjusted to 20 mg / mL, 40 mg / mL, 60 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL and 160 mg / mL. The amounts of colloid compound system, glycerol and water are the same as in Example 1. The preparation steps are the same as in Example 1.

[0070] Results: The suspensions obtained from different ratios of colloid / curcumin components have certain viscosity and stability, and all present orange yellow color. The greater the addition amount of curcumin, the relatively deeper the orange yellow color, and the greater the curcumin content in the final suspension. However, when the addition amount of curcumin reaches a certain amount, the curcumin content in the final suspension reaches saturation. This shows that under the condition of fixed colloid compound system, glycerol and water, if a suspension with higher curcumin content is desired, the addition amount of curcumin can be appropriately increased (within a certain range). Figure 4 ).

[0071] Example 3 After nanization of curcumin, the specific surface area is sharply increased, and the contact area with the adverse environment is also greatly increased, which may accelerate degradation. However, the high-dispersion curcumin nano-suspension prepared in the present application can still maintain a stable level of curcumin content (as shown in Table 3) after standing at room temperature for 90 days. Figure 5 .

[0072] The above only describes preferred embodiments of the present application and is not intended to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A highly dispersed curcumin nanosuspension, characterized in that, Its raw materials include: Curcumin 7-11 parts, xanthan gum 0.2-0.5 parts, gellan gum 0.1-0.5 parts, glycerin 10-15 parts, and water 150-300 parts.

2. The method for preparing the highly dispersed curcumin nanosuspension according to claim 1, characterized in that, Includes the following steps: (1) Add glycerin to water and mix well to obtain a glycerin aqueous solution; (2) Xanthan gum and gellan gum were added to the glycerol aqueous solution in sequence, and after mixing evenly, curcumin was added. After initial stirring and dispersion, a suspension was obtained; after continuous stirring and dispersion, a highly dispersed curcumin nano suspension was obtained.

3. The preparation method according to claim 2, characterized in that, In step (1), the temperature of the reaction system is 20~30℃.

4. The preparation method according to claim 2, characterized in that, In step (1), the method for mixing evenly includes stirring at a speed of 300-600 rpm for 8-15 minutes.

5. The preparation method according to claim 2, characterized in that, In step (2), the temperature of the reaction system is 20~30℃.

6. The preparation method according to claim 2, characterized in that, In step (2), continuous stirring is maintained during the addition of xanthan gum and gellan gum, with a stirring speed of 300-600 rpm.

7. The preparation method according to claim 2, characterized in that, In step (2), during the initial stirring and dispersion process, the stirring speed is 300-600 rpm and the stirring time is 10-120 min.

8. The preparation method according to claim 2, characterized in that, In step (2), during the continuous stirring and dispersion process, the stirring speed is 1000-2000 rpm and the stirring time is 12-240 h.

9. The preparation method according to claim 2, characterized in that, The curcumin nanoparticles in the highly dispersed curcumin nanosuspension have a particle size of 80~130 nm and an average particle size of 103 nm.

10. The preparation method according to claim 2, characterized in that, In step (1), the water is ultrapure water.

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