Drug-drug eutectic mixture of piperine-pterostilbene as well as preparation method and application of drug-drug eutectic mixture

Abstract

The invention provides a piperine-pterostilbene medicine-medicine eutectic mixture as well as a preparation method and application of the piperine-pterostilbene medicine-medicine eutectic mixture. The eutectoid is prepared by adopting a mixed heating method or a solvent evaporation method, and is simple, convenient, efficient, low in cost and easy to industrialize. The melting point of the prepared eutectic mixture is obviously reduced, the eutectic mixture is in a liquid state at normal temperature, and the eutectic mixture has a synergistic anti-oxidation effect. The eutectoid can be directly used as an oil phase to be further prepared into a nanoemulsion, so that the dosage of auxiliary materials is reduced, and meanwhile, the drug loading capacity is remarkably improved.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a eutectic mixture consisting of piperine and pterostilbene, a preparation method of the piperine-ptterostilbene eutectic mixture, and applications of the eutectic mixture. Background Art

[0002] Piperine exists in plants of the genus Piper and is the main component of the edible and medicinal plant Piper. Piperine belongs to the amide alkaloids and has analgesic, sedative, anti-inflammatory, antidepressant, and anti-tumor activities. It is also an important bioavailability enhancer, but its own bioavailability is low. The solubility of piperine in water is less than 1 mg / mL, and it has good lipid solubility.

[0003] Pterostilbene exists in many Chinese herbal medicines and berries (such as grapes and blueberries). It is widely available and inexpensive. Pterostilbene has a variety of pharmacological activities, such as anti-tumor, anti-inflammatory, antioxidant, anti-aging, and cardiovascular protection. Pterostilbene is a methylated derivative of resveratrol and has higher bioavailability than resveratrol. Pterostilbene is almost insoluble in water (0.03 mg / mL) and has good lipid solubility.

[0004] The prior art "A piperine solid dispersion and its preparation method and application" (Yang Jianhong et al., CN116115612A) discloses a piperine solid dispersion, which uses a small molecular weight organic acid or inorganic mesoporous particles as a carrier, and piperine is dispersed in the carrier material in an amorphous form, thereby significantly increasing the solubility and dissolution rate of the drug. The prior art "Preparation and in vitro and in vivo study of piperine-theanine co-amorphous complexes" (Huang Lihua et al., Journal of Nanjing University of Chinese Medicine, 2021) discloses a co-amorphous complex formed by piperine and the water-soluble excipient theanine in a molar ratio of 1:1, which can significantly improve the in vitro dissolution and oral absorption of piperine. The above technologies all require the use of a large amount of excipients to form.

[0005] The prior art "Preparation of scutellarin-piperine co-amorphous complex and evaluation of its in vitro release" (Yan Hongmei et al., Chinese Herbal Medicine, 2015) discloses a co-amorphous complex formed by scutellarin and piperine in a mass ratio of 1:1, which can simultaneously improve the in vitro solubility of the two components, but it cannot change the melting point of the complex and remains in a solid state. The prior art "Characterization and in vitro dissolution evaluation of Ligustrum lucidum triterpenoid-piperine co-amorphous complex" (Yu Danni et al., Chinese Herbal Medicine, 2018) discloses a co-amorphous complex formed by Ligustrum lucidum triterpenoid and piperine in a mass ratio of 1:1, which can significantly improve the solubility and solubility of Ligustrum lucidum triterpenoid and inhibit the dissolution and dissolution of piperine. The above-mentioned amorphous substances are all for the purpose of increasing the solubility or solubility of the raw material drug. The effect of the amorphous substances on the bioavailability is unknown, and the effect of the amorphous substances on the in vivo efficacy of the two components is also unknown, especially the above-mentioned amorphous substances cannot change the melting point of the complex and remain in a solid state.

[0006] The prior art "A Pterostilbene Exosome Liposome, Preparation Method, Application and Cosmetics" (Wei Juan et al., CN118161410A) discloses a Pterostilbene Exosome Liposome, the exosome liposome has a 3-fold increase in skin permeability, and the drug content is 0.5% to 3%. The prior art "A Skin Melanin Inhibitor and Its Preparation Method and Application" (Xiang Nanxi et al., CN117919107A) discloses a method for preparing a Pterostilbene Nanocomposite with high-efficiency drug delivery, the nanocomposite particles are only between 10 and 100 nm, and the drug content is 0.1% to 5%. The exosome and nanocomposite improve the skin permeability and drug delivery rate of Pterostilbene, but the preparation process is complicated and requires the addition of a large amount of excipients to form.

[0007] The prior art "Study on Solid Dispersion of Dragon's Blood Extract and Its Bioavailability" (Li Yun, Nanjing University of Chinese Medicine, 2012) discloses a method for preparing a solid dispersion of pterostilbene, which has a bioavailability that is two times higher and a drug content of 25%. Although the above solid dispersion improves the bioavailability of the drug, it requires the addition of excipients and has a complicated preparation process.

[0008] Prior art "A Novel, Extremely Bioavailable Cocrystal of Pterostilbene" (Lídia Bofill et al., Crystal Growth & Design, 2021) discloses a method for preparing a pterostilbene drug-drug cocrystal without adding excipients, and the bioavailability is increased by 2 times. The above cocrystal has a two-fold increase in bioavailability, but the preparation method is relatively complicated, and the effect of the cocrystal on the drug activity is not clear.

[0009] Methods for improving the bioavailability of drugs include making them into microcapsules, inclusion compounds, lipid complexes, etc., but the above dosage forms usually require the addition of a large amount of excipients or require complex processes.

[0010] Eutectic mixture is a mixture of two or more substances. Under a specific composition ratio, the melting point of the mixture is lower than the melting point of any single component. Eutectic mixture can not only improve the bioavailability of drugs and promote drug absorption, but also can be used as a drug carrier.

[0011] Different from the above-mentioned technologies, the drug-drug eutectic involved in the present invention is based on the interaction between piperine and pterostilbene, does not require the addition of any carrier or excipient, and has a simple process and a stable product. Summary of the invention

[0012] The purpose of the present invention is to provide a eutectic of piperine and pterostilbene. The above system can form a eutectic without adding any auxiliary materials, the drug loading reaches 100%, and the cost and dosage of the preparation are greatly reduced.

[0013] Another object of the present invention is to provide a method for preparing a eutectic of piperine and pterostilbene.

[0014] Another object of the present invention is to provide the use of the eutectic in the preparation of a preparation, that is, to use the eutectic as a preparation intermediate to further prepare a nanoemulsion.

[0015] Specifically, the present invention provides the following technical solutions: A low eutectic is composed of piperine and pterostilbene, both active ingredients of traditional Chinese medicine, without adding any functional auxiliary materials, and the molar ratio of piperine to pterostilbene is in the range of 4:6-6:4.

[0016] Preferably, the molar ratio of piperine to pterostilbene is 5:5.

[0017] The present invention also provides a method for preparing the eutectic, namely, a solvent evaporation method and a mixing heating method.

[0018] The solvent evaporation method is to weigh appropriate amounts of piperine and pterostilbene, completely dissolve them in a solvent, recover most of the solvent under reduced pressure, and then evaporate naturally to obtain a piperine-ptterostilbene eutectic. Preferred solvents are ethanol, dichloromethane, acetone, ethyl acetate, and mixed solvents thereof; more preferably, the solvent is ethanol.

[0019] The mixed heating method is to weigh appropriate amounts of piperine and pterostilbene, mix them evenly and heat them until they are molten to obtain a piperine-ptterostilbene eutectic. Preferably, the mixture is heated in the range of 80-105°C until they are completely melted and transparent, and then cooled to obtain a eutectic.

[0020] The piperine-pterostilbene eutectic provided by the invention has a simple preparation method, low price and good reproducibility.

[0021] The antioxidative property of the piperine-pterostilbene eutectic provided by the invention is improved compared with the raw material medicine, is superior to the non-eutectic mixture of piperine, pterostilbene, or piperine and pterostilbene in the same amount, and has obvious synergistic effect.

[0022] The present invention uses the piperine-pterostilbene eutectic as a preparation intermediate and further prepares it into a nanoemulsion, that is, it is prepared by using an appropriate amount of the eutectic as an oil phase and pharmaceutical excipients.

[0023] In summary, the inventors have found through unexpected research that a piperine-pterostilbene eutectic can be prepared by a solvent evaporation method and a mixed heating method, and the eutectic has a strong antioxidant capacity. In addition, no auxiliary materials are required in the process of preparing the eutectic, which saves costs, has good repeatability, and excellent stability. Moreover, the eutectic is liquid at room temperature, which changes the physical state of piperine and pterostilbene, providing more possibilities for their preparation applications, for example, it can be used as the oil phase of a nanoemulsion. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 These are appearance pictures, micrographs and polarized images of piperine-pterostilbene eutectic mixtures of different proportions prepared by solvent evaporation method using ethanol as solvent in Examples 1, 2, 3 and Comparative Examples 1-8.

[0025] Figure 2 These are appearance pictures, micrographs and polarized images of piperine-pterostilbene eutectic mixtures prepared by evaporation method using organic solutions of different proportions as solvents in Examples 4 to 11 and Comparative Examples 9 to 14.

[0026] Figure 3 These are the appearance pictures, micrographs and polarized images of piperine-pterostilbene eutectic mixtures of different proportions prepared by the mixed heating method in Examples 5, 6 and 7.

[0027] Figure 4 These are the appearance pictures, micrographs and polarized images of the piperine-pterostilbene eutectic mixtures prepared by the grinding method in Comparative Examples 12, 13 and 14.

[0028] Figure 5 The DSC spectra of the physical mixture of piperine-pterostilbene raw materials in different molar ratios and the DSC spectra of the piperine-pterostilbene eutectic mixture and its physical mixture.

[0029] Figure 6The XRD spectra, infrared spectra and UV spectra of the physical mixtures of piperine-pterostilbene eutectic and its raw material drug in different molar ratios in Examples 1, 2 and 3 are shown.

[0030] Figure 7 These are the test results of the antioxidant function of the piperine-pterostilbene eutectic mixture and the raw material drug in Example 2.

[0031] Figure 8 The calculation results of the synergistic antioxidant performance of the piperine-pterostilbene eutectic mixture and the raw material in Example 2.

[0032] Fig. 9 The particle size distribution of nanoemulsions prepared by using eutectic mixtures and adding other oil phases and using eutectic mixtures as oil phase

[0033] The technical solutions obtained in the embodiments of the present invention will be described clearly and completely below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. DETAILED DESCRIPTION

[0034] Example 1: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 4:6), mix the two natural products evenly and dissolve them in ethanol, remove the ethanol to obtain piperine-pterostilbene eutectic (see attached Figure 1 e, liquid under microscope, no residual solid, no obvious polarization).

[0035] Example 2: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in ethanol, remove the ethanol to obtain piperine-pterostilbene eutectic (see attached Figure 1 f, liquid under microscope, no residual solid, no obvious polarization).

[0036] Example 3: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 6:4), mix the two natural products evenly and dissolve them in ethanol, remove the ethanol to obtain piperine-pterostilbene eutectic (see attached Figure 1 g, liquid under microscope, no residual solid, no obvious polarization).

[0037] Example 4: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in ethanol (75%)-ethyl acetate (25%), remove the solvent to obtain piperine-pterostilbene eutectic (see attached Figure 2 c, liquid under microscope, no residual solid, no obvious polarization).

[0038] Example 5: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in ethanol (50%)-dichloromethane (50%), remove the solvent to obtain piperine-pterostilbene eutectic (see attached Figure 2 d, liquid under microscope, no residual solid, no obvious polarization).

[0039] Example 6: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in ethanol (50%)-acetone (50%), remove the solvent to obtain piperine-pterostilbene eutectic (see attached Figure 2 e, liquid under microscope, no residual solid, no obvious polarization).

[0040] Example 7: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in dichloromethane, remove the dichloromethane to obtain piperine-pterostilbene eutectic (see attached Figure 2 f, liquid under microscope, no residual solid, no obvious polarization).

[0041] Example 8: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in dichloromethane (75%)-ethyl acetate (25%), remove the solvent to obtain piperine-pterostilbene eutectic (see attached Figure 2 i, liquid under microscope, no residual solid, no obvious polarization).

[0042] Example 9: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in dichloromethane (50%)-acetone (50%), remove the solvent to obtain piperine-pterostilbene eutectic (see attached Figure 2 j, liquid under microscope, no residual solid, no obvious polarization).

[0043] Example 10: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in acetone, remove the acetone to obtain piperine-pterostilbene eutectic (see attached Figure 2 k, liquid under microscope, no residual solid, no obvious polarization).

[0044] Example 11: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in acetone (75%)-ethyl acetate (25%), remove the solvent to obtain piperine-pterostilbene eutectic (see attached Figure 2 n, liquid under microscope, no residual solid, no obvious polarization).

[0045] Example 12: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 4:6), mix the two natural products evenly, heat them in the range of 80-105°C, and completely melt them into a transparent state to obtain piperine-pterostilbene eutectic (see attached Figure 3 a, liquid under microscope, no residual solid, no obvious polarization).

[0046] Example 13: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly, heat them in the range of 80-105°C, and completely melt them into a transparent state to obtain piperine-pterostilbene eutectic (see attached Figure 3 b, liquid under microscope, no residual solid, no obvious polarization).

[0047] Example 14: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 6:4), mix the two natural products evenly, heat them in the range of 80-105°C, and completely melt them into a transparent state to obtain piperine-pterostilbene eutectic (see attached Figure 3 c, liquid under microscope, no residual solid, no obvious polarization).

[0048] Example 15: Weigh an appropriate amount of the eutectic obtained in Example 1 into a crucible and scan it using differential scanning calorimetry. The test conditions for the physical mixture are: select a temperature range of 20-400 °C, and a heating rate of 10 °C / min (see Appendix Figure 5 a. The melting point of the physical mixture is significantly lower than that of the API, proving that there is a tendency to form a eutectic. The physical mixture with a ratio of 4:6 to 6:4 has a lower melting point). The test conditions for the eutectic are: select a temperature range of 10 to 200 °C and a heating rate of 10 °C / min (see Appendix Figure 5 b, the melting peak of the eutectic is smaller and the melting point is significantly lower than that of the physical mixture).

[0049] Example 16: Take an appropriate amount of the eutectic obtained in Example 1 and scan it using an X-ray powder diffraction analyzer. The measurement conditions are: scanning angle 2θ, step length 0.02°, scanning speed 5° / min, scanning range 5~90°, voltage 30 mA (see attached Figure 6 a. The co-amorphous substance in the embodiment has no obvious diffraction peaks, which proves that an amorphous substance is formed. In comparison, the physical mixture and the single raw material drug have obvious diffraction peaks, which are crystalline substances).

[0050] Example 17: Take an appropriate amount of the eutectic obtained in Example 1, grind it evenly with dry potassium bromide, press it into a transparent sheet and place it in an infrared measuring instrument at 4000-400 cm -1 Measured within the range of Figure 6 b)

[0051] Example 18: Take an appropriate amount of the eutectic obtained in Example 1, dissolve it in ethanol, take an appropriate amount in a quartz cuvette, scan it with an ultraviolet spectrophotometer, and measure it in the range of 200-600. (See Appendix Figure 6 c, compared with the raw material, the UV absorption spectrum of the mixture has a blue shift, indicating that the conjugation relationship between piperine and pterostilbene is reduced).

[0052] Example 19: 2 ml of the eutectic obtained in Example 2 of different concentrations were taken into a graduated test tube, and 2 ml of 0.2 mmol / L DPPH free radical (2,2-biphenyl-1-picrylhydrazyl) ethanol solution was added respectively. After shaking, it was placed away from light for 30 min, and zeroed with 75% ethanol. The absorbance A was measured at 517 nm. Three parallel groups were made for each group, and the clearance rate was calculated with Vc as the control. The clearance rate calculation formula is as follows: DPPH clearance rate (%) = [1-(A1-A2) / A3]×100%, where A1 is the absorbance of the sample and DPPH, A2 is the absorbance of the sample and ethanol, and A3 is the absorbance of ethanol and DPPH (see Appendix Figure 7 a, the antioxidant capacity of the eutectic is significantly higher than that of piperine and pterostilbene, which shows that the eutectic of the two cooperates with each other in the antioxidant effect. Piperine can increase the antioxidant capacity of pterostilbene, and pterostilbene can also increase the antioxidant capacity of piperine. The two can promote each other). CompuSyn was used to calculate the synergistic index of piperine and pterostilbene with the eutectic on the DPPH scavenging rate. Figure 8 As shown in a, the CI of the eutectic is less than 1, indicating that the two have a synergistic effect.

[0053] Example 20: Take 0.5 ml of the low eutectic obtained in Example 2 of different concentrations, add 4.5 mL of 0.5 mol / LTris-HCl buffer (pH 8.2) and 0.5 mL of distilled water into a graduated test tube, mix well, keep warm at 25°C for 10 min, add 0.5 mL of 6 mmol / L pyrogallic acid, shake well, react accurately for 3 min, add 0.1 mL of 10 mol / L HCl solution to terminate the reaction, use 95% ethanol as a blank control, and measure the absorbance value A1 at 325 nm. Each group is made into 3 parallel groups, and the clearance rate is calculated with Vc as the control. The clearance rate calculation formula is: O2 - (Superoxide anion) clearance rate (%) = (A1 -A2) / A3×100%, where A2 is the absorbance of ethanol and sample solution; A3 is the absorbance obtained by replacing the sample solution with ethanol (see Appendix Figure 7b. The scavenging ability of the eutectic on superoxide anions is significantly higher than that of piperine and pterostilbene. The eutectic of the two can promote each other, that is, piperine can increase the antioxidant capacity of pterostilbene, and pterostilbene can increase the antioxidant capacity of piperine. The two can promote each other). CompuSyn was used to calculate the synergistic index of the scavenging rate of piperine, pterostilbene and the eutectic on superoxide anions. Figure 8 As shown in b, the CI of the eutectic is less than 1, indicating that the two have a synergistic effect.

[0054] Example 21: Take 2 test tubes and number them. Add 3.6 mL of ABTS (2-acrylamido-2-methylpropanesulfonic acid) solution and 0.4 mL of the test solution to test tube No. 1 as the test group (A2). Add 3.6 mL of ABTS solution and 0.4 mL of sample solvent solution (methanol) to test tube No. 2 as the blank group (A1). After fully mixing, react at room temperature in the dark for 5 minutes. Measure the absorbance value with an ultraviolet spectrophotometer at a wavelength of 734 nm (sample solvent zero calibration). Calculate the clearance rate using the following formula: ABTS clearance rate = (A1-A2) / A1×100% Wherein, A1 is the absorbance of the mixture of ABTS solution and sample solvent solution; A2 is the absorbance of the mixture of the test solution and ABTS solution (see Appendix Figure 7 c. The scavenging ability of the eutectic on ATBS is significantly higher than that of piperine and slightly higher than that of pterostilbene. The eutectic of the two can promote each other, that is, piperine can increase the antioxidant capacity of pterostilbene, and pterostilbene can increase the antioxidant capacity of piperine. The two can promote each other). CompuSyn was used to calculate the synergistic index of piperine and pterostilbene and the eutectic on ATBS scavenging rate. Figure 8 As shown in c, the CI of the eutectic is less than 1, indicating that the two have a synergistic effect.

[0055] Example 22: Weigh one portion of the eutectic obtained in Example 1, use the eutectic mixture as the drug and oil phase (2%), polyethylene glycol 400 as the co-emulsifier (3.2%), and castor oil polyoxyethylene ether as the emulsifier (12.8%), and prepare a nanoemulsion by vortex oscillation. The particle size and potential of the obtained nanoemulsion are shown in Table 1, and the particle size distribution diagram is shown in the attached Fig. 9 a.

[0056] Example 23: Weigh one portion of the eutectic obtained in Example 1, use the eutectic mixture (2%) and isopropyl myristate (2%) as the oil phase, polyethylene glycol 400 as the co-emulsifier (3.2%), and castor oil polyoxyethylene ether as the emulsifier (12.8%), and prepare a nanoemulsion by vortex oscillation. The particle size and potential of the obtained nanoemulsion are shown in Table 1, and the particle size distribution diagram is shown in the attached Fig. 9 b.

[0057] Table 1 Particle size and potential of nanoemulsions obtained in Examples 22 and 23

[0058] Comparative Example 1: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 0:10), mix the natural products evenly and dissolve them in ethanol. After removing the ethanol, no eutectic was obtained (see Appendix Figure 1 a, there is obvious solid matter under the microscope, with polarized light).

[0059] Comparative Example 2: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 1:9), mix the two natural products evenly and dissolve them in ethanol. After removing the ethanol, no eutectic was obtained (see attached Figure 1 b, there is obvious solid matter under the microscope, and a small amount of polarized light can be seen).

[0060] Comparative Example 3: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 2:8), mix the two natural products evenly and dissolve them in ethanol. After removing the ethanol, it is found that a small part of the mixture is liquefied, but a large amount of solid remains (see attached Figure 1 c, there is liquid substance under the microscope, but it contains a large amount of solid matter and has a crystalline luster under polarized light).

[0061] Comparative Example 4: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 3:7), mix the two natural products evenly and dissolve them in ethanol. After removing the ethanol, it is found that most of the mixture is liquefied, but there is still a small amount of residual solid (see attached Figure 1 d, there is liquid substance under the microscope, which contains a small amount of solid matter and has no crystalline luster under polarized light).

[0062] Comparative Example 5: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 7:3), mix the two natural products evenly and dissolve them in ethanol. After removing the ethanol, it is found that a large amount of the mixture is liquefied, but there is still a small amount of residual solid (see attached Figure 1 h, there is a liquid substance under the microscope, which contains a small amount of solid and has no crystalline luster under polarized light).

[0063] Comparative Example 6: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 8:2), mix the two natural products evenly and dissolve them in ethanol. After removing the ethanol, it is found that a small amount of the mixture is liquefied, but a large amount of solid remains (see attached Figure 1 i, there is a liquid substance under the microscope, which contains a large amount of solids and has no crystalline luster under polarized light).

[0064] Comparative Example 7: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 9:1), mix the two natural products evenly and dissolve them in ethanol. After removing the ethanol, no eutectic was obtained (see attached Figure 1 j, it appears as a sticky solid substance under a microscope, contains a large amount of impurities, and has no crystalline luster under polarized light).

[0065] Comparative Example 8: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 10:0), mix the natural products evenly and dissolve them in ethanol. After removing the ethanol, no eutectic was obtained (see attached Figure 1 k, appears as a viscous solid substance under a microscope and has no crystalline luster under polarized light).

[0066] Comparative Example 9: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in a mixed solvent of ethanol (75%)-methanol (25%). After removing the solvent, it is found that most of the mixture is liquefied, but there is still a small amount of residual solid (see attached Figure 2 a, there is liquid substance under the microscope, but it contains a small amount of solid and no obvious polarization).

[0067] Comparative Example 10: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in a mixed solvent of ethanol (75%)-glacial acetic acid (25%). After removing the solvent, it is found that a small part of the mixture is liquefied, but a large amount of solid remains (see attached Figure 2 b, there is liquid substance under the microscope, but it contains a large amount of solid and no obvious polarization).

[0068] Comparative Example 11: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in dichloromethane (75%)-methanol (25%). After removing the solvent, it is found that most of the mixture is liquefied, but there is still a small amount of residual solid (see attached Figure 2 g, there is liquid substance under the microscope, but it contains a small amount of solid and no obvious polarization).

[0069] Comparative Example 12: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in dichloromethane (75%)-glacial acetic acid (25%). After removing the solvent, it is found that most of the mixture is liquefied, but there is still a small amount of residual solid (see attached Figure 2 h, there is liquid substance under the microscope, but it contains a small amount of solid and no obvious polarization).

[0070] Comparative Example 13: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in acetone (75%)-methanol (25%). After removing the solvent, it is found that most of the mixture is liquefied, but there is still a small amount of residual solid (see attached Figure 2 l, there is liquid substance under the microscope, but it contains a small amount of solid and no obvious polarization).

[0071] Comparative Example 14: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and dissolve them in acetone (75%)-glacial acetic acid (25%). After removing the solvent, it is found that most of the mixture is liquefied, but there is still a small amount of residual solid (see attached Figure 2 m, there is liquid substance under the microscope, but it contains a small amount of solid and no obvious polarization).

[0072] Comparative Example 15: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 4:6), mix the two natural products evenly and grind them in a mortar. After grinding for 20 minutes, the mixed system becomes sticky and lumpy. After grinding for another 10 minutes, a sticky lump-like object is obtained, and no eutectic is obtained (see Figure 4 a, appears as a viscous solid substance under a microscope, with no obvious polarization).

[0073] Comparative Example 16: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 5:5), mix the two natural products evenly and grind them in a mortar. After grinding for 20 minutes, the mixed system becomes sticky and lumpy. After grinding for another 10 minutes, a sticky lump-like object is obtained, and no eutectic is obtained (see Figure 4 b, appears as a viscous solid substance under a microscope, with no obvious polarization).

[0074] Comparative Example 17: Weigh appropriate amounts of piperine and pterostilbene (molar ratio of 6:4), mix the two natural products evenly and grind them in a mortar. After grinding for 20 minutes, the mixed system becomes sticky and lumpy. After grinding for another 30 minutes, a sticky lump-like object is obtained, and no eutectic is obtained (see Figure 4 c, appears as a viscous solid substance under a microscope, with no obvious polarization).

Claims

1. A piperine-pterostilbene eutectic mixture, characterized in that: It is composed only of piperine and pterostilbene, and the total content of the two components accounts for 100%.

2. The eutectic mixture according to claim 1, characterized in that: The molar ratio of piperine to pterostilbene is 4:6-6:

4.

3. The eutectic mixture according to claim 2, characterized in that: The molar ratio of piperine to pterostilbene is 5:

5.

4. The eutectic mixture according to claim 1, characterized in that: At room temperature, the eutectic mixture is a viscous and transparent liquid substance, and its melting point is significantly lower than that of piperine and pterostilbene.

5. A method for preparing the eutectic mixture according to claim 1, characterized in that: The preparation method is prepared by a mixed heating method. After piperine and pterostilbene are evenly mixed, they are heated in the range of 80-105°C until they are completely melted, and then cooled to obtain a low eutectic.

6. A method for preparing the eutectic mixture according to claim 1, characterized in that: The preparation method is prepared by a solvent evaporation method, wherein piperine and pterostilbene are dissolved in an organic solvent, and after the drugs are completely dissolved, the solvent is removed to obtain a low eutectic.

7. The method for preparing a eutectic mixture according to claim 6, characterized in that: The organic solvent refers to one or more of ethanol, dichloromethane, acetone and ethyl acetate.

8. The eutectic mixture according to claim 1, characterized in that: The anti-oxidation performance of the low eutectic mixture is better than that of piperine, pterostilbene and the non-eutectic mixture of the same amount.

9. Use of the eutectic mixture according to claim 1 in preparing medicines, characterized in that: The eutectic can be used as an oil phase and further prepared into a nanoemulsion.

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