Caffeine inclusion compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of alkaloid preparation, and discloses a caffeine inclusion compound as well as a preparation method and application thereof. The preparation method comprises the following steps: dissolving a cationic cyclodextrin derivative and an anionic cyclodextrin derivative in water, adding caffeine, heating to 65-80 DEG C at a heating rate of 1-5 DEG C / min, and carrying out ultrasonic-assisted wrapping under ultrasonic waves; and finally, drying and crushing to obtain the caffeine inclusion compound. Caffeine is coated with a cationic cyclodextrin derivative and an anionic cyclodextrin derivative, and the caffeine inclusion compound with small particle size and large specific surface area is prepared by controlling the dosage of the caffeine, the cationic cyclodextrin derivative and the anionic cyclodextrin derivative and optimizing the process under the assistance of an ultrasonic coating technology. The caffeine inclusion compound can significantly improve the water solubility of caffeine and the stability of caffeine in an aqueous solution, and is more beneficial to the application of caffeine in cosmetics and drugs.

Description

Technical Field

[0001] The present invention belongs to the technical field of alkaloid preparation, and particularly relates to a caffeine inclusion compound, a preparation method thereof, and an application thereof. Background Art

[0002] Caffeine is a methylxanthine alkaloid compound, which widely exists in various plants such as coffee, cocoa, and tea. Caffeine has the effects of enhancing the skin barrier, anti-aging, antioxidant, photoprotection, photo-stability, improving periorbital edema and dark circles, preventing hair loss and promoting hair growth, promoting fat decomposition, and promoting blood circulation, and is widely used in cosmetics. As a central nervous system stimulant, caffeine also has functions including treating the respiratory diseases of premature infants, relieving pain, and combating sleepiness, and is applied to prescription drugs; at the same time, caffeine is used as an auxiliary ingredient in some over-the-counter drugs to enhance the effects of other drugs. In recent years, with the in-depth research on caffeine, its applications in cosmetics and drugs have become more and more extensive, and its market application value has also been widely recognized.

[0003] However, in practical applications, caffeine also has many limitations. For example, due to its poor water solubility, to a certain extent, it affects the applications of caffeine in cosmetics and drugs. Specifically, the solubility of caffeine in water at room temperature is only 2.2 g / 100 mL, which is slightly soluble. Although the solubility can be significantly increased at high temperatures, such as reaching 60 g / 100 mL at 80°C; however, in actual production and applications, when mixed or processed with other materials, many materials cannot tolerate such high temperatures. And when caffeine is first dissolved by heating and then cooled and mixed with other materials for processing, obvious crystallization problems of caffeine will occur. Therefore, the low water solubility of caffeine increases the processing difficulty of caffeine in cosmetics and drugs, and also affects the exertion of the value of caffeine.

[0004] Therefore, there is an urgent need to provide a method for improving the water solubility of caffeine. Summary of the Invention

[0005] The present invention aims to at least solve one of the technical problems existing in the above-mentioned prior art. For this purpose, the present invention provides a caffeine inclusion compound, a preparation method thereof, and an application thereof. The caffeine inclusion compound prepared by the present invention can significantly improve the water solubility and stability of caffeine in an aqueous solution, and is more conducive to the applications of caffeine in cosmetics and drugs.

[0006] The present invention provides a preparation method of a caffeine inclusion compound.

[0007] Specifically, a preparation method of a caffeine inclusion compound includes the following steps:

[0008] Dissolve the cationic cyclodextrin derivative and the anionic cyclodextrin derivative in water, then add caffeine, and heat it to 65 - 80 °C at a heating rate of 1 - 5 °C / min, and then perform ultrasonic-assisted encapsulation under ultrasonic waves; finally, dry and pulverize to obtain the caffeine inclusion compound;

[0009] The mass ratio of the cationic cyclodextrin derivative to the anionic cyclodextrin derivative is 1:(1.5 - 4);

[0010] The total mass of the cationic cyclodextrin derivative and the anionic cyclodextrin derivative is (1.5 - 5) times the mass of the caffeine.

[0011] In some embodiments of the present invention, the cationic cyclodextrin derivative is methylated cyclodextrin; the anionic cyclodextrin derivative is carboxymethylated cyclodextrin.

[0012] In some embodiments of the present invention, the mass ratio of the cationic cyclodextrin derivative to the anionic cyclodextrin derivative is 1:(2 - 3.5).

[0013] In some embodiments of the present invention, the total mass of the cationic cyclodextrin derivative and the anionic cyclodextrin derivative is (1.5 - 3) times the mass of the caffeine; preferably, the total mass of the cationic cyclodextrin derivative and the anionic cyclodextrin derivative is (1.8 - 2.5) times the mass of the caffeine.

[0014] In some embodiments of the present invention, the heating rate is 1.5 - 3 °C / min.

[0015] In some embodiments of the present invention, the heating process is to heat to 70 - 80 °C, preferably 75 - 80 °C.

[0016] In some embodiments of the present invention, the power of the ultrasonic wave is 100 - 300 W.

[0017] In some embodiments of the present invention, the ultrasonic-assisted encapsulation process is carried out under stirring, and the stirring speed is 20 - 80 r / min; preferably, the stirring speed is 30 - 60 r / min.

[0018] In some embodiments of the present invention, the time of ultrasonic-assisted encapsulation is 0.5 - 3 hours; preferably, the time of ultrasonic-assisted encapsulation is 1 - 2 hours.

[0019] The present invention also provides a caffeine inclusion compound.

[0020] Specifically, a caffeine clathrate is prepared by the above method; the specific surface area of the caffeine clathrate is greater than 3000 m2 / kg, Dv(50) is less than 6 μm, and Dv(90) is less than 30 μm.

[0021] The present invention also provides an application of the above caffeine clathrate.

[0022] Specifically, an application of the above caffeine clathrate in the preparation of cosmetics.

[0023] Specifically, an application of the above caffeine clathrate in the preparation of pharmaceuticals.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] In the present invention, caffeine is coated with a cationic cyclodextrin derivative and an anionic cyclodextrin derivative, and the cationic cyclodextrin derivative and the anionic cyclodextrin derivative alternately adsorb caffeine under the action of ultrasonic waves to form a multi-layer coating structure; by controlling the amounts of caffeine, the cationic cyclodextrin derivative, and the anionic cyclodextrin derivative, the process is optimized, and the non-polar molecules of caffeine are wrapped in the multi-layer structure of the cationic and anionic cyclodextrin derivatives, thereby preparing a caffeine clathrate with small particle size and large specific surface area. This caffeine clathrate can significantly improve the water solubility of caffeine and its stability in aqueous solution, and is more conducive to the application of caffeine in cosmetics and pharmaceuticals. Description of the Drawings

[0026] Figure 1 is the appearance diagram of pure caffeine and the caffeine clathrate prepared in Example 1;

[0027] Figure 2 is the particle size distribution diagram of the caffeine clathrate prepared in Example 1;

[0028] Figure 3 is the particle size distribution diagram of the caffeine clathrate prepared in Example 2;

[0029] Figure 4 is the particle size distribution diagram of the caffeine clathrate prepared in Example 3;

[0030] Figure 5 is the particle size distribution diagram of the caffeine clathrate prepared in Example 4;

[0031] Figure 6 is the particle size distribution diagram of the caffeine clathrate prepared in Comparative Example 1;

[0032] Figure 7 is the particle size distribution diagram of the caffeine clathrate prepared in Comparative Example 2;

[0033] Figure 8 is the particle size distribution diagram of the caffeine clathrate prepared in Comparative Example 3;

[0034] Figure 9 Particle size distribution diagram of the caffeine clathrate prepared in Comparative Example 4;

[0035] Figure 10 Particle size distribution diagram of a competing caffeine product;

[0036] Figure 11 Time-dissolution percentage curve of pure caffeine;

[0037] Figure 12 Time-dissolution percentage curve of the caffeine clathrate prepared in Example 1;

[0038] Figure 13 Time-dissolution percentage curve of the caffeine clathrate prepared in Comparative Example 2;

[0039] Figure 14 Time-dissolution percentage curve of the caffeine clathrate prepared in Comparative Example 3. Detailed implementation manners

[0040] In order to make the technical solutions of the present invention more clearly understood by those skilled in the art, the following examples are listed for illustration. It should be noted that the following examples do not limit the scope of protection required by the present invention.

[0041] The raw materials, reagents or devices used in the following examples and comparative examples can be obtained from conventional commercial channels or can be obtained by existing known methods without special instructions.

[0042] Example 1

[0043] A preparation method of a caffeine clathrate, comprising the following steps:

[0044] (1) In a clean 500 mL beaker, accurately measure 500 mL of purified water, and the conductivity of the purified water should be lower than 1.5 μS / cm. Place the beaker in a constant temperature water bath and set the water bath temperature to 25 °C ± 0.5 °C. Slowly add 25 g of methylated-β-cyclodextrin and 75 g of carboxymethylated-β-cyclodextrin, turn on the stirring device, and set the stirring speed to 45 r / min. Stir for 25 min to obtain a clear and transparent cyclodextrin solution;

[0045] (2) Add 50 g of caffeine (purity ≥ 99%) to the cyclodextrin solution prepared in step (1), start the heating device, and raise the solution temperature to 77 °C at a heating rate of 1.5 °C / min. During the heating process, continuously maintain a stirring speed of 45 r / min to obtain a mixture. After heating, start the ultrasonic device to perform ultrasonic-assisted encapsulation on the mixture, set the ultrasonic frequency to 40 kHz, the power to 100 W, and the ultrasonic-assisted encapsulation time to 1 hour to obtain an encapsulate solution;

[0046] (3) Spread the clathrate solution evenly on the tray in the forced-air oven, and control the thickness of the solution at 3 - 5 mm. Before putting it into the oven, preheat the tray in the oven at 70 °C for 10 minutes to reduce the impact of thermal shock on the structure of the clathrate. Put the tray containing the clathrate solution into the forced-air oven, and set the oven temperature at 70 °C. During the drying process, the material needs to be turned over every 6 hours. When the moisture content of the material is lower than 5%, the drying process ends. Select an ADS50 disk-type air classifier mill to crush the material. The spraying angle of the nozzle should be maintained at 30° ± 2° to ensure that the high-speed air flow can act on the material evenly. Set the crushing pressure of the air classifier mill at 0.4 MPa and the feeding frequency at 15 Hz. The temperature in the crushing chamber should be controlled at 25 °C ± 2 °C, and the pressure fluctuation range should be less than 0.02 MPa.

[0047] Observe the prepared coffee clathrate, and the results are as Figure 1 shown, where Figure 1 A in is the appearance diagram of pure caffeine raw material, Figure 1 and B in is the appearance diagram of the coffee clathrate prepared in Example 1. It can be seen from Figure 1 that the appearances of caffeine and the caffeine clathrate prepared in this example are both white fine powders, without obvious differences, and the experiments show that the coating touch feelings of the two are the same.

[0048] Example 2

[0049] A preparation method of a caffeine clathrate, comprising the following steps:

[0050] (1) In a clean 500 mL beaker, accurately measure 500 mL of purified water, and the conductivity of the purified water should be lower than 1.5 μS / cm. Place the beaker in a constant-temperature water bath, and set the water bath temperature at 25 °C ± 0.5 °C. Slowly add 30 g of methylated-β-cyclodextrin and 70 g of carboxymethylated-β-cyclodextrin, turn on the stirring device, and set the stirring speed at 45 r / min. Stir for 25 min to obtain a clear and transparent cyclodextrin solution;

[0051] (2) Add 40 g of caffeine (purity ≥ 99%) to the cyclodextrin solution prepared in step (1), start the heating device, and raise the solution temperature to 72 °C at a heating rate of 2.5 °C / min. During the heating process, continuously maintain the stirring speed of 45 r / min to obtain a mixture. After heating, start the ultrasonic device to perform ultrasonic-assisted encapsulation on the mixture, set the ultrasonic frequency at 40 kHz, the power at 100 W, and the ultrasonic-assisted encapsulation time at 1.5 hours to obtain a clathrate solution;

[0052] (3) Spread the inclusion complex solution evenly on the tray in the forced-air oven, and control the thickness of the solution at 3 - 5 mm. Before putting it into the oven, preheat the tray in the oven at 70 °C for 10 minutes to reduce the impact of thermal shock on the structure of the inclusion complex. Put the tray containing the inclusion complex solution into the forced-air oven, and set the oven temperature at 70 °C. During the drying process, turn over the material once every 6 hours. When the moisture content of the material is lower than 5%, the drying process ends. Select an ADS50 disc-type air jet mill for the pulverization of the material. The spraying angle of the nozzle should be maintained at 30° ± 2° to ensure that the high-speed air flow can act on the material evenly. Set the pulverization pressure of the air jet mill at 0.4 MPa and the feeding frequency at 15 Hz. The temperature in the pulverization chamber should be controlled at 25 °C ± 2 °C, and the pressure fluctuation range should be less than 0.02 MPa.

[0053] Example 3

[0054] A preparation method of a caffeine inclusion complex, comprising the following steps:

[0055] (1) In a clean 500 mL beaker, accurately measure 500 mL of purified water, and the conductivity of the purified water should be lower than 1.5 μS / cm. Place the beaker in a constant temperature water bath, and set the water bath temperature at 25 °C ± 0.5 °C. Slowly add 25 g of methylated-β-cyclodextrin and 75 g of carboxymethylated-β-cyclodextrin, turn on the stirring device, and set the stirring speed at 45 r / min. Stir for 25 min to obtain a clear and transparent cyclodextrin solution;

[0056] (2) Add 60 g of caffeine (purity ≥ 99%) to the cyclodextrin solution prepared in step (1), start the heating device, and raise the solution temperature to 75 °C at a heating rate of 2.0 °C / min. During the heating process, continuously maintain the stirring speed at 45 r / min to obtain a mixture. After heating, start the ultrasonic device to perform ultrasonic-assisted encapsulation on the mixture, set the ultrasonic frequency at 40 kHz, the power at 100 W, and the ultrasonic-assisted encapsulation time at 1 hour to obtain an inclusion complex solution;

[0057] (3) Spread the inclusion complex solution evenly on the tray in the forced-air oven, and control the thickness of the solution at 3 - 5 mm. Before putting it into the oven, preheat the tray in an oven at 70 °C for 10 minutes to reduce the impact of thermal shock on the structure of the inclusion. Put the tray containing the inclusion complex solution into the forced-air oven, and set the oven temperature at 70 °C. During the drying process, the material needs to be turned over every 6 hours. When the moisture content of the material is lower than 5%, the drying process ends. Select an ADS50 disk-type air classifier mill for crushing the material. The spraying angle of the nozzle should be maintained at 30° ± 2° to ensure that the high-speed air flow can act on the material evenly. Set the crushing pressure of the air classifier mill at 0.4 MPa and the feeding frequency at 15 Hz. The temperature in the crushing chamber should be controlled at 25 °C ± 2 °C, and the pressure fluctuation range should be less than 0.02 MPa.

[0058] Example 4

[0059] This example provides a preparation method of a caffeine inclusion complex. The difference from Example 1 is that 20 g of methylated-β-cyclodextrin and 80 g of carboxymethylated-β-cyclodextrin are added in this example, and the rest of the preparation process is the same as that in Example 1.

[0060] Comparative Example 1

[0061] This comparative example provides a preparation method of a caffeine inclusion complex. The difference from Example 1 is that the amount of caffeine added in this comparative example is 100 g, and the rest of the preparation process is the same as that in Example 1.

[0062] Comparative Example 2

[0063] This comparative example provides a preparation method of a caffeine inclusion complex. The difference from Example 1 is that caffeine is added simultaneously when methylated-β-cyclodextrin and carboxymethylated-β-cyclodextrin are put in, and the rest of the preparation process is the same as that in Example 1. The specific feeding and ultrasonic-assisted encapsulation process is as follows:

[0064] Slowly put in 25 g of methylated-β-cyclodextrin, 75 g of carboxymethylated-β-cyclodextrin and 50 g of caffeine (purity ≥ 99%). Turn on the stirring device and set the stirring speed at 45 r / min. After stirring for 25 min, start the heating device and raise the solution temperature to 77 °C at a heating rate of 1.5 °C / min. During the heating process, continuously maintain the stirring speed of 45 r / min to obtain a mixture. After heating, start the ultrasonic device to perform ultrasonic-assisted encapsulation on the mixture. Set the ultrasonic frequency at 40 kHz, the power at 100 W, and the ultrasonic-assisted encapsulation time at 1 hour to obtain an inclusion complex solution;

[0065] Comparative Example 3

[0066] This comparative example provides a method for preparing a caffeine clathrate. The difference from Example 1 is that microwave-assisted encapsulation is used, and the rest of the preparation process is the same as in Example 1. The specific microwave-assisted encapsulation process is as follows: After heating, start the microwave equipment to perform microwave-assisted encapsulation on the mixture. Set the microwave frequency to 2.45 GHz, set the average power to 500 W, and the time for microwave-assisted encapsulation to 10 min to obtain a clathrate solution.

[0067] Comparative Example 4

[0068] This comparative example provides a method for preparing a caffeine clathrate. The difference from Example 1 is that 100 g of methylated-β-cyclodextrin is added, and carboxymethylated-β-cyclodextrin is not added, and the rest of the preparation process is the same as in Example 1.

[0069] Product effect test

[0070] (1) Particle size analysis and detection

[0071] Use the Mastersizer particle size analyzer of Malvern Instruments to conduct a comparative analysis of the particle sizes of the caffeine clathrates prepared in the examples, comparative examples, and competing caffeine products. Record the Dv(50), Dv(90), and specific surface area values. Dv(50): Also known as the median particle size, 50% of the particle sizes in the sample are smaller than this value; Dv(90): In the sample, 90% of the particle sizes are smaller than this value. The test results are shown in Table 1 and Figures 2 - 10 as shown.

[0072] Table 1

[0073]

[0074]

[0075] As can be seen from Table 1 and Figures 2 - 10 it can be known that the specific surface area of the caffeine clathrate prepared in the examples of the present invention is greater than 3000 m 2 / kg, up to 3535 m 2 / kg, significantly higher than that of the comparative examples. The particle size of the caffeine clathrate prepared in the examples of the present invention is also significantly lower than that of the comparative examples and competing products.

[0076] (2) Solubility test

[0077] Perform a solubility test on the caffeine clathrates prepared in the examples and comparative examples. The standard curve is established using HPLC to detect the caffeine content in the solution according to "SN / T 1781-2006 - Liquid Chromatography Method for Caffeine in Import and Export Cosmetics" and convert it into a percentage. With the stirring time as the abscissa and the dissolution percentage as the ordinate, plot the caffeine time-dissolution percentage curve.

[0078] The chromatographic conditions are as follows: Chromatographic column: C18, 5 μm, 250 mm * 4.6 mm or equivalent; Mobile phase: A methanol, B water; Flow rate: 1.0 mL / min; Ratio of mobile phase A to mobile phase B: 1:1; Detection wavelength: 275 nm; Injection volume: 10 μL; Column temperature: 30 °C.

[0079] The caffeine standard curve established by the above method is: y = 10124555.7x - 12101096.14, where y is the peak area and x is the caffeine concentration, R 2 = 0.99, x ∈ [0.034 mg / mL, 1.1 mg / mL], indicating that the standard curve has a good linear relationship between 0.034 mg / mL and 1.1 mg / mL.

[0080] Precisely weigh 300 mg of caffeine, the caffeine inclusion compounds prepared in the examples and comparative examples into a 150 mL beaker, inject 100 mL of deionized water, and stir at the same rate. Sampling is carried out at 1 min, 5 min, 10 min, 15 min, 20 min, and 25 min respectively. Calculate the caffeine content in the solution at different stirring times according to the standard curve method, and draw a dissolution curve with the stirring time as the abscissa and the caffeine dissolution percentage as the ordinate for the dissolution percentage of caffeine at different times. Record the dissolution percentages of the caffeine inclusion compounds prepared in each example and comparative example at 10 min and 20 min. The results are shown in Table 2 and Figures 11 - 14 as follows.

[0081] Table 2

[0082]

[0083] From Table 2 and Figures 11 - 14 it can be seen that the solubility of the caffeine inclusion compounds prepared in the examples of the present invention is significantly better than that of the comparative examples. The solubility at 5 min is not less than 79%, the solubility at 10 min is greater than 90%, and the solubility at 20 min is not less than 98%.

[0084] (3) Stability experiment

[0085] Precisely weigh 10 g of the caffeine inclusion compounds prepared in the examples, comparative examples and the competing caffeine products into a 150 mL beaker, inject 100 mL of deionized water, heat to 50 °C, and stir until completely dissolved. Then place at 25 °C and 2 °C, observe the crystal precipitation situation, and judge the stability after dissolution. The test results are shown in Table 3.

[0086] Table 3

[0087] Group Crystal precipitation at 25°C Crystal precipitation at 2°C Example 1 No crystal precipitation in 4 h No crystal precipitation in 25 min Example 2 No crystal precipitation in 4 h No crystal precipitation in 25 min Example 3 No crystal precipitation in 4 h No crystal precipitation in 25 min Example 4 No crystal precipitation in 3.5 h Trace crystal precipitation in 25 min Comparative Example 1 No crystal precipitation in 3 h Trace crystal precipitation in 25 min Comparative Example 2 Trace crystal precipitation in 2.5 h Abundant crystal precipitation in 25 min Comparative Example 3 Trace crystal precipitation in 3 h Minor crystal precipitation in 25 min Comparative Example 4 Minor crystal precipitation in 3 h Abundant crystal precipitation in 25 min Competitor product Minor crystal precipitation in 4 h Minor crystal precipitation in 25 min

[0088] As can be seen from the data in Table 3, the stability of the caffeine inclusion compound prepared in the embodiment of the present invention after dissolution is significantly better than that of the caffeine inclusion compound prepared in the comparative example and the competing caffeine product.

[0089] The above-described embodiments merely represent several implementation manners of the present invention. The description thereof is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the appended claims.

Claims

1. A method for preparing a caffeine inclusion compound, characterized in that: The following steps are involved: The cationic cyclodextrin derivative and the anionic cyclodextrin derivative are dissolved in water, and then caffeine is added, and the temperature is increased to 65-80°C at a heating rate of 1-5°C / min, and then ultrasonic-assisted encapsulation is performed under ultrasonic wave; finally, the caffeine inclusion compound is obtained by drying and crushing; The mass ratio of the cationic cyclodextrin derivative to the anionic cyclodextrin derivative is 1:(1.5-4); The total mass of the cationic cyclodextrin derivative and the anionic cyclodextrin derivative is (1.5-5) times the mass of the caffeine.

2. The preparation method according to claim 1, characterized in that: The cationic cyclodextrin derivative is methylated cyclodextrin; and the anionic cyclodextrin derivative is carboxymethylated cyclodextrin.

3. The preparation method according to claim 2, characterized in that: The mass ratio of the cationic cyclodextrin derivative to the anionic cyclodextrin derivative is 1:(2-3.5).

4. The preparation method according to any one of claims 1 to 3, characterized in that The total mass of the cationic cyclodextrin derivative and the anionic cyclodextrin derivative is (1.5-3) times the mass of the caffeine.

5. The preparation method according to claim 1, characterized in that: The heating rate is 1.5-3°C / min; the heating process is heating to 70-80°C.

6. The preparation method according to claim 1, characterized in that: The power of the ultrasonic wave is 100-300W.

7. The preparation method according to claim 6, characterized in that: The ultrasonic-assisted wrapping process is carried out under stirring, and the stirring speed is 20-80 r / min; the ultrasonic-assisted wrapping time is 0.5-3 hours.

8. A caffeine inclusion compound, characterized in that: Prepared by the preparation method according to any one of claims 1 to 7; the specific surface area of ​​the caffeine inclusion compound is greater than 3000m 2 / kg, Dv(50) is less than 6μm, and Dv(90) is less than 30μm.

9. Use of the caffeine inclusion compound according to claim 8 in the preparation of cosmetics.

10. Use of the caffeine inclusion compound according to claim 8 in the preparation of medicines.

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