Berberine hydrochloride ternary co-amorphous substance as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and discloses a berberine hydrochloride ternary co-amorphous substance as well as a preparation method and application thereof. The molar ratio of berberine hydrochloride, L-arginine and curcumin in the ternary co-amorphous substance is 1: 1: 1. The berberine hydrochloride ternary co-amorphous substance is prepared from berberine hydrochloride, L-arginine and curcumin according to the molar ratio of 1: 1: 1 through the processes of ball milling, reduced pressure rotary evaporation and the like. According to the berberine hydrochloride co-amorphous substance, the solubility of curcumin in pure water is improved by about 3 times. According to the ternary co-amorphous form, the dissolution rate of curcumin is remarkably increased, meanwhile, the dissolution rate of berberine hydrochloride is effectively delayed, and the slow release effect is achieved. And the ternary co-amorphous substance has high physical stability and long-term stability. Certain application prospects are realized in the aspects of protecting the liver, resisting oxidation, resisting bacteria and resisting tumors.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a ternary co-amorphous substance. Background Art

[0002] Berberine hydrochloride is a natural isoquinoline alkaloid, also known as berberine hydrochloride, which was initially isolated from Coptis chinensis and has a long history of application in traditional Chinese medicine. Berberine hydrochloride has various pharmacological effects, including lipid-lowering and anti-inflammatory effects, treatment of insulin resistance, treatment of cardiovascular diseases, neuroprotection, inhibition of chondrocyte apoptosis and cartilage degeneration, anti-cancer and antibacterial properties.

[0003] L-arginine is a guanidine-containing basic amino acid with various pharmacological activities. L-arginine can lower blood pressure and promote vasodilation, and improve endothelial function. L-arginine can induce and stimulate the secretion of adrenaline, and then lower the blood glucose level of hyperglycemic patients; L-arginine has the effect of protecting the liver, and can convert the ammonia produced in the body into non-toxic urea through circulation and excrete it from the body through urine, thereby reducing the concentration of ammonia in the blood of hyperammonemic patients, and can also be used for the treatment of various patients with hepatic coma and abnormal alanine aminotransferase in viral hepatitis; in addition, L-arginine can enhance human immunity and regulate the growth of tumor cells; L-arginine also promotes muscle protein synthesis and wound healing by stimulating the secretion of growth hormone. L-arginine is widely added to sports supplements (to promote muscle growth), antioxidant foods and foods for special medical purposes.

[0004] Curcumin and its derivatives are the active ingredients of turmeric, which is a herbal preparation extracted from the rhizomes of turmeric. Curcumin has antioxidant, anti-inflammatory, antibacterial, antimutagenic, liver-protecting, antifibrotic and anti-steatosis effects. It is reported that curcumin has a wide range of pharmacological effects as an antibiotic, antioxidant and anti-inflammatory agent, and has a positive effect on the treatment of cancer, aging, diabetes, neurological and cardiovascular diseases. Curcumin has low toxicity, few side effects, wide drug sources, low cost and convenient administration, and has broad medicinal value and development prospects. However, curcumin has the characteristics of low water solubility, chemical instability and rapid metabolism, which greatly affect its oral bioavailability and efficacy.

[0005] Drug co-amorphous systems are homogeneous amorphous systems formed by two or more drug active ingredients (APIs) or APIs and excipients through non-covalent interactions such as hydrogen bonds, π-π stacking, and van der Waals forces. Compared with traditional crystalline drugs, co-amorphous systems have become an important strategy for improving the properties of poorly soluble drugs by inhibiting recrystallization, increasing solubility, and enhancing bioavailability. Their physicochemical properties directly affect drug stability, dissolution behavior, and clinical application potential. Many drugs have improved physical and chemical stability by being prepared as co-amorphous drugs. With the rapid development of drug research in recent years, co-amorphous drugs have obvious advantages in increasing drug solubility, dissolution rate, and stability, which will surely inject new vitality into the research and development of new drugs.

[0006] Regarding berberine hydrochloride, its release rate in vivo is too fast, and the drug is rapidly metabolized, unable to maintain an effective concentration. Curcumin, due to its low solubility, high permeability, and low bioavailability, seriously affects their clinical applications. In addition, it has been reported that the solubility and dissolution rate of drugs can be improved by preparing co-amorphous substances. For example, tryptophan and ofloxacin are freeze-dried to prepare a co-amorphous substance in a weight ratio of 1:1, increasing the solubility of ofloxacin by more than 10 times. In order to reduce the release rate of berberine hydrochloride, improve the solubility, bioavailability, and stability of curcumin, and exert the effect of drug combination, it is necessary to develop a preparation method for a ternary co-amorphous substance of berberine hydrochloride. Summary of the Invention

[0007] To address the above technical problems, the present invention proposes a ternary co-amorphous substance of berberine hydrochloride, its preparation method, and application. The ternary co-amorphous substance of berberine hydrochloride is formed by combining berberine hydrochloride, L-arginine, and curcumin in a molar ratio of 1:1:1. This co-amorphous substance significantly increases the solubility and dissolution rate of curcumin in pure water, while effectively delaying the dissolution rate of berberine hydrochloride, achieving a sustained-release effect. Moreover, this co-amorphous substance has excellent physical stability and can be used as an active ingredient to prepare drug combinations or health product combinations for the treatment or prevention of colon cancer and liver protection.

[0008] To achieve the above object, the technical solution of the present invention is realized as follows:

[0009] A ternary co-amorphous substance of berberine hydrochloride, which is composed of berberine hydrochloride, L-arginine, and curcumin. This ternary co-amorphous substance of berberine hydrochloride can reduce the dissolution rate of berberine hydrochloride and improve the dissolution performance of curcumin.

[0010] Furthermore, the molar ratio of the above berberine hydrochloride, L-arginine, and curcumin is 1:1:1.

[0011] Furthermore, the glass transition temperature of the above-mentioned ternary co-amorphous berberine hydrochloride is 118.2 °C; the X-ray powder diffraction pattern has no sharp diffraction peaks, and the XRD pattern presents classic broad and diffuse peaks.

[0012] A preparation method of the above-mentioned ternary co-amorphous berberine hydrochloride is as follows: Dissolve berberine hydrochloride, L-arginine and curcumin with a molar ratio of 1:1:1 in a solvent, and then evaporate the solvent by rotary evaporation under reduced pressure and dry it under vacuum to obtain the product.

[0013] The above-mentioned solvent is at least one of methanol, ethanol, acetonitrile and acetone.

[0014] The temperature for rotary evaporation of the solvent under reduced pressure is 35 - 65 °C.

[0015] Furthermore, the temperature for rotary evaporation of the solvent under reduced pressure is 45 - 55 °C.

[0016] Another preparation method of the above-mentioned ternary co-amorphous berberine hydrochloride is as follows: Mix and ball-mill berberine hydrochloride, L-arginine and curcumin in a ball mill to obtain the product.

[0017] Furthermore, the rotation speed of the above-mentioned ball milling is 1000 - 3000 r / min, and the ball milling time is 15 - 40 min.

[0018] The application of the above-mentioned ternary co-amorphous berberine hydrochloride in the preparation of pharmaceutical compositions or health products for anti-tumor, antioxidant, antibacterial, hypoglycemic or liver protection.

[0019] The beneficial effects of the present invention are as follows:

[0020] The powder X-ray diffraction pattern, DSC pattern, infrared spectrum and solid-state nuclear magnetic carbon spectrum of the ternary co-amorphous berberine hydrochloride disclosed in the present invention are different from those of the berberine hydrochloride crystal, L-arginine crystal and curcumin crystal reported in the existing patents. Therefore, the solid form is a ternary co-amorphous berberine hydrochloride form that is completely different from the prior art. By measuring the equilibrium solubility and in vitro dissolution curve, it is found that the ternary co-amorphous berberine hydrochloride significantly improves the solubility and dissolution rate of curcumin, and at the same time effectively delays the dissolution rate of berberine hydrochloride, achieving a sustained-release effect. In addition, the prepared ternary co-amorphous berberine hydrochloride has excellent long-term stability and is expected to become a new solid form for the development of pharmaceutical products. Description of the Drawings

[0021] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the accompanying drawings required for the description of the embodiments or the prior art. Obviously, the accompanying drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other accompanying drawings can be obtained based on these drawings.

[0022] Figure 1 It is the powder X-ray diffraction pattern of the ternary co-amorphous substance of berberine hydrochloride prepared in Example 1.

[0023] Figure 2 It is the differential scanning calorimetry spectrum of the ternary co-amorphous substance of berberine hydrochloride prepared in Example 1.

[0024] Figure 3 It is the Fourier transform infrared spectrum of the ternary co-amorphous substance of berberine hydrochloride prepared in Example 1.

[0025] Figure 4 It is the solid-state nuclear magnetic carbon spectrum of the ternary co-amorphous substance of berberine hydrochloride prepared in Example 1.

[0026] Figure 5 It is the XRD spectrum of the physical stability test of the ternary co-amorphous substance of berberine hydrochloride prepared in Example 1.

[0027] Figure 6 It is the pure water dissolution curve of the ternary co-amorphous substance of berberine hydrochloride prepared in Example 1.

[0028] Figure 7 It is the dissolution curve of the ternary co-amorphous substance of berberine hydrochloride prepared in Example 1 in pH 4.5 buffer solution. Detailed implementation manners

[0029] The following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0030] The raw materials used in the present invention are as follows:

[0031] Berberine hydrochloride, with the chemical name of 5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxol[5,6-a]quinazoline hydrochloride, and the molecular formula of C 20 H 18 ClNO4, and the structural formula is:

[0032]

[0033] L-Arginine, chemical name: 2-Amino-5-guanidinovaleric acid, molecular formula: C6H 14 N4O2, structural formula:

[0034]

[0035] Curcumin, chemical name: (E,E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, molecular formula: C 21 H 20 O6, structural formula:

[0036]

[0037] Example 1

[0038] The preparation method of the ternary co-amorphous product of berberine hydrochloride in this example is as follows:

[0039] 0.2199 g of berberine hydrochloride, 0.0871 g of L-arginine, and 0.1845 g of curcumin were added to 80 mL of methanol, and ultrasonic dissolution was carried out at room temperature to obtain a clear solution. This clear solution was subjected to rotary evaporation under reduced pressure at 50 °C to remove the solvent, and vacuum dried at 60 °C for 24 h to obtain 0.4915 g of a black-purple powder, which is the ternary co-amorphous product of berberine hydrochloride.

[0040] Example 2

[0041] The preparation method of the ternary co-amorphous product of berberine hydrochloride in this example is as follows:

[0042] 0.2199 g of berberine hydrochloride, 0.0871 g of L-arginine, and 0.1845 g of curcumin were added to 80 mL of ethanol, and ultrasonic dissolution was carried out at room temperature to obtain a clear solution. This clear solution was subjected to rotary evaporation under reduced pressure at 50 °C to remove the solvent, and vacuum dried at 60 °C for 24 h to obtain 0.4915 g of a black-purple powder, which is the ternary co-amorphous product of berberine hydrochloride.

[0043] Example 3

[0044] The preparation method of the ternary co-amorphous product of berberine hydrochloride in this example is as follows:

[0045] 0.2199 g of berberine hydrochloride, 0.0871 g of L-arginine, and 0.1845 g of curcumin were added to 80 mL of a methanol-ethanol (50:50, v / v) mixed solvent, and ultrasonic dissolution was carried out at room temperature to obtain a clear solution. This clear solution was subjected to rotary evaporation under reduced pressure at 50 °C to remove the solvent, and vacuum dried at 60 °C for 24 h to obtain 0.4915 g of a black-purple powder, which is the ternary co-amorphous product of berberine hydrochloride.

[0046] Example 4

[0047] The preparation method of the ternary co-amorphous substance of berberine hydrochloride in this example is as follows:

[0048] 0.2199 g of berberine hydrochloride, 0.0871 g of L-arginine, and 0.1845 g of curcumin were added to 100 mL of acetonitrile, and ultrasonic dissolution was carried out at room temperature to obtain a clear solution. This clear solution was rotary evaporated under reduced pressure at 50 °C to remove the solvent, and then vacuum dried at 60 °C for 24 h to obtain 0.4915 g of a black-purple powder, which is the ternary co-amorphous substance of berberine hydrochloride.

[0049] Example 5

[0050] The preparation method of the ternary co-amorphous substance of berberine hydrochloride in this example is as follows:

[0051] 0.2199 g of berberine hydrochloride, 0.0871 g of L-arginine, and 0.1845 g of curcumin were mixed evenly and then added to a ball milling tank. The ball milling tank was placed on a vibrating ball mill and ball milled at a rotation speed of 1500 r / min for 30 minutes. After 30 minutes, 0.4915 g of the black-purple powder in the ball milling tank was scraped out to obtain the ternary co-amorphous substance of berberine hydrochloride.

[0052] Example 6

[0053] The preparation method of the ternary co-amorphous substance of berberine hydrochloride in this example is as follows:

[0054] 0.2199 g of berberine hydrochloride, 0.0871 g of L-arginine, and 0.1845 g of curcumin were mixed evenly and then added to a ball milling tank. The ball milling tank was placed on a vibrating ball mill and ball milled at a rotation speed of 1000 r / min for 40 minutes. After 40 minutes, the black-purple powder in the ball milling tank was scraped out to obtain the ternary co-amorphous substance of berberine hydrochloride.

[0055] Example 7

[0056] The preparation method of the ternary co-amorphous substance of berberine hydrochloride in this example is as follows:

[0057] 0.2199 g of berberine hydrochloride, 0.0871 g of L-arginine, and 0.1845 g of curcumin were mixed evenly and then added to a ball milling tank. The ball milling tank was placed on a vibrating ball mill and ball milled at a rotation speed of 3000 r / min for 15 minutes. After 15 minutes, the black-purple powder in the ball milling tank was scraped out to obtain the ternary co-amorphous substance of berberine hydrochloride.

[0058] Example 8

[0059] The preparation method of the ternary co-amorphous substance of berberine hydrochloride in this embodiment is as follows:

[0060] Mix 0.2199 g of berberine hydrochloride, 0.0871 g of L-arginine, and 0.1845 g of curcumin evenly, then add them into a ball milling jar. Place the ball milling jar on a vibrating ball mill and mill at a speed of 2000 r / min for 20 minutes. After 20 minutes, scrape out the black-purple powder in the ball milling jar to obtain the ternary co-amorphous substance of berberine hydrochloride.

[0061] Example of implementation effect

[0062] (1) Powder X-ray diffraction experiment

[0063] The experiment used a Rigaku Smart Lab X-ray powder diffractometer (Cu Kα radiation; λ = 1.5406 Å; 40 kV; 40 mA) to collect the PXRD patterns of all solid samples. Each sample was placed separately on a single-crystalline silicon sample stage, pressed into a smooth surface, and then placed on a rotating stage. Data was collected in reflection mode, the scanning speed was 0.02° / step, and the 2θ scanning range was 3 - 50° at a speed of 20° / min. The experimental results are as Figure 1 shown. The PXRD pattern of the berberine hydrochloride raw material showed characteristic diffraction peaks at diffraction angles 2θ of: 7.2°, 8.7°, 9.2°, 13.1°, 14.1°, 16.4°, 20.5°, 21.1°, 24.6°, 25.6°, 26.6°; the PXRD pattern of the L-arginine raw material showed characteristic peaks at diffraction angles 2θ of: 11.1°, 15.0°, 16.7°, 17.3°, 18.3°, 19.4°, 23.1°, 27.6°, 32.6°, 33.7°; the PXRD pattern of the curcumin raw material showed characteristic diffraction peaks at diffraction angles 2θ of: 7.9°, 8.8°, 12.2°, 14.5°, 17.2°, 21.1°, 23.2°, 24.6°, 25.6°. This indicates that the three raw materials have typical crystal structures. The PXRD pattern of the ternary co-amorphous substance of berberine hydrochloride prepared in Example 1 did not have sharp diffraction peaks, indicating that it was not in a crystalline state but in an amorphous state.

[0064] (2) Differential scanning calorimetry

[0065] The experiment was carried out in a differential scanning calorimeter of Netzsch Company, Germany. Weigh 5 - 8 mg of the sample to be tested and put it into an aluminum crucible. After sealing and piercing holes, put it into the instrument for measurement. Use an empty aluminum crucible as a reference. The test temperature was set to 30 - 300 °C, the heating rate was controlled at 10 K / min, and nitrogen with a flow rate of 40 mL / min was introduced as a protective gas. The experimental results are as Figure 2As shown in the figure. The endothermic peaks detected in the DSC curve of berberine hydrochloride at 83.5 °C and 135.9 °C correspond to lattice dehydration. The sharp peak detected at 191.8 °C is due to decomposition caused by a large but incomplete weight loss; the endothermic peaks detected in the DSC curve of L-arginine at 91.1 °C and 99.1 °C correspond to lattice dehydration, and the sharp peaks detected at 222.1 °C and 236.4 °C are decompositions caused by a large but incomplete weight loss; curcumin shows an endothermic melting peak at 182.2 °C. In the DSC curve of the ternary co-amorphous berberine hydrochloride prepared in Example 1, there is a characteristic endothermic peak of glass transition at 118.2 °C.

[0066] (3) Fourier transform infrared spectroscopy characterization

[0067] The experiment used a Fourier transform infrared spectrometer, and the samples were analyzed by the powder ATR method in the wavelength range of 500 - 4000 cm -1 to obtain the infrared spectra of the samples under study, with a resolution of 4 cm -1 , and scanned 32 times in total. The experimental results are as Figure 3 shown. The IR spectrum of the ternary co-amorphous berberine hydrochloride has characteristic peaks at 3322 cm -1 , 3154 cm -1 , 1670 cm -1 , 1619 cm -1 , 1268 cm -1 , 1218 cm -1 , 1100 cm -1 , 1027 cm -1 and 960 cm -1 . Compared with berberine hydrochloride, L-arginine, and curcumin, the saturated fatty ether C-O-C stretching vibration peak of berberine hydrochloride in the ternary co-amorphous berberine hydrochloride becomes broader, and the peak shift is from 1035, 1103, 1275 cm -1 to 1027, 1100, 1268 cm -1 ; for L-arginine, the N-H stretching vibration peaks shift from 3347 and 3255 cm -1 to 3322 and 3154 cm -1 ; the N-H bending vibration peak shifts from 1680 cm -1 to 1670 cm -1 ; the enol C-O peak of curcumin moves from 1283 cm -1 to 1268 cm -1 , and the superimposed characteristic peak of ν(C=C) and ν(C=O) conjugation moves from 1628 cm -1 to 1619 cm -1Movement. The above experimental results indicate that there may be hydrogen bond interactions between berberine hydrochloride, L-arginine, and curcumin, resulting in the formation of a new phase.

[0068] (4) Solid-state NMR carbon spectrum characterization

[0069] The experiment was carried out on a Bruker AVANCE III NMR spectrometer. The sample was loaded into a 4-mm rotor, rotated at a rate of 10.0 kHz, and the magic angle setting was calibrated using the KBr method. The detection resonance frequency was 100.625 MHz, and 480 scans were performed and collected for all samples. The detection results are as Figure 4 shown. The ternary co-amorphous of berberine hydrochloride has characteristic peaks at 181.5 ppm, 149.8 ppm, 142.7 ppm, 120.7 ppm, 108.2 ppm, 105.2 ppm, 55.5 ppm, and 28.0 ppm. As Figure 4 shown, compared with berberine hydrochloride, L-arginine, and curcumin, in the ternary co-amorphous of berberine hydrochloride, the positions of carbon atoms 14, 16, 17, 18, 19, and 20 related to the saturated fatty ether structure C-O-C in berberine hydrochloride have all shifted; for the L-arginine molecule, the peaks of carbon atoms 2, 3, 4, 5, and 6 related to the -NH+ structure have all shifted to a certain extent. The positions of carbon atoms 5, 7, 8, 9, 11, 12, 13, and 16 on the straight chain between the two benzene rings related to enol in curcumin have all shifted. This indicates that there may be hydrogen bond interactions between berberine hydrochloride, L-arginine, and curcumin, resulting in the formation of a new phase.

[0070] (5) Physical stability test

[0071] The test method for physical stability is to store the ternary co-amorphous of berberine hydrochloride in a drug comprehensive stability test chamber with a light intensity of 4500 Lx and a temperature of 60 °C. To confirm whether recrystallization has occurred during storage, XRD tests were performed on each sample at specific time points. The experimental results are as Figure 5 shown. The results indicate that the ternary co-amorphous of berberine hydrochloride is stable under high temperature of 60 °C and light condition of 4500 Lx, and there is no phenomenon of crystal transformation within one month, indicating that the ternary co-amorphous of berberine hydrochloride in this patent has excellent long-term stability.

[0072] (6) Equilibrium solubility test

[0073] The equilibrium solubility of the co-amorphous substance was determined by the oscillating flask method. 100 mg of the sample was added to 2 mL of pure water (containing 0.5% Tween-80), and the supersaturated solution was obtained by ultrasonic treatment for 10 min. Then the suspension was transferred to a tabletop constant temperature oscillator at 37 °C and oscillated for 48 h to reach the equilibrium state. The equilibrium solution was filtered through a 0.45 μm filter membrane, and then the filtrate was diluted to an appropriate concentration required for HPLC determination with pure water containing 0.5% Tween-80. The chromatographic column used in HPLC was a C18 column (4.6×150 mm, 5.0 μm). The mobile phase consisted of phase A, 0.2% phosphoric acid water, and phase B, methanol. The flow rate was 1.0 mL / min, and isocratic elution was adopted. The volume ratio of mobile phase A:B was 30:70. The detection wavelengths were: curcumin: 430 nm, berberine hydrochloride: 415 nm; the column temperature was 30 °C; the injection volume was 10 μL. The experimental results are shown in Table 1. The solubility of the original curcumin drug in pure water was 47.09 μg / mL, and the solubility of curcumin in the ternary co-amorphous berberine hydrochloride prepared in Example 1 in pure water was 151.92 μg / mL. The solubility of the raw material drug berberine hydrochloride in pure water was 4596.41 μg / mL, and the solubility of berberine hydrochloride in the ternary co-amorphous berberine hydrochloride was 3856.25 μg / mL. From the above data, it can be seen that the ternary co-amorphous berberine hydrochloride increased the solubility of curcumin in pure water by 3.22 times and decreased the solubility of berberine hydrochloride.

[0074] Table 1. Solubility data table

[0075]

[0076] (7) Dissolution test in pure water

[0077] The release test was carried out in an RC806ADK dissolution tester. The water bath temperature was 37 °C, and the instrument rotation speed was 100 rpm (ChP paddle method). To make the particle size of the powder uniform, the sample was first passed through a 100-mesh sieve (mesh number: 0.15 mm). Then the sample equivalent to 50 mg of CUR was dispersed in 250 mL of pure water containing 0.5% Tween-80. 2 mL of the suspension was extracted at fixed time points and filtered through a 0.45 μm nylon membrane filter, and then the sample concentration was detected by HPLC. The detection conditions were the same as those for the equilibrium solubility detection in Experimental Example 6.

[0078] The experimental results are as Figure 6As shown, the active pharmaceutical ingredient curcumin is slowly released in pure water. At the end of the release, that is, after 1440 minutes of curcumin release in the medium, the maximum cumulative release amount reaches 32.4%. However, the curcumin in the ternary co-amorphous form of berberine hydrochloride is rapidly released in pure water, and the cumulative release amount reaches 53.5% in 20 minutes, with the maximum cumulative release amount being 75.6%. The experimental results show that the curcumin in the ternary co-amorphous form of berberine hydrochloride can be rapidly released in pure water. The ternary co-amorphous form of berberine hydrochloride significantly increases the maximum cumulative release amount and dissolution rate of curcumin in pure water, and at the same time effectively delays the dissolution rate of berberine hydrochloride, achieving a sustained-release effect.

[0079] (8) Dissolution test in pH 4.5 buffer solution

[0080] The release test was carried out in an RC806ADK dissolution tester with a water bath temperature of 37 °C and an instrument rotation speed of 100 rpm (ChP paddle method). To make the particle size of the powder uniform, the sample was first passed through a 100-mesh sieve (mesh number: 0.15 mm). Then, a sample equivalent to 50 mg of CUR was dispersed in 250 mL of pH 4.5 buffer solution containing 0.5% Tween-80. At fixed time points, 2 mL of the suspension was extracted and filtered through a 0.45-μm nylon membrane filter, and then the sample concentration was detected by HPLC. The detection conditions were the same as those for the equilibrium solubility detection in Experimental Example 6.

[0081] The experimental results are as Figure 7 shown. The active pharmaceutical ingredient curcumin is slowly released in pure water, with the maximum cumulative release amount being 33.4%. However, the curcumin in the ternary co-amorphous form of berberine hydrochloride is rapidly released in pure water, and the cumulative release amount reaches 50.1% in 10 minutes, with the maximum cumulative release amount being 55.5%. The active pharmaceutical ingredient berberine hydrochloride reaches complete release in 30 minutes in the pH 4.5 buffer solution, and the maximum cumulative release amount of berberine hydrochloride in the ternary co-amorphous form of berberine hydrochloride is 94.9%. The experimental results show that the ternary co-amorphous form of berberine hydrochloride significantly increases the maximum cumulative release amount and dissolution rate of curcumin in the pH 4.5 buffer solution, and at the same time effectively delays the dissolution rate of berberine hydrochloride, achieving a sustained-release effect.

[0082] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A ternary co-amorphous substance of berberine hydrochloride, characterized in that, The ternary co-amorphous compound of berberine hydrochloride comprises berberine hydrochloride, L-arginine and curcumin.

2. The ternary co-amorphous substance of berberine hydrochloride according to claim 1, characterized in that, The molar ratio of berberine hydrochloride, L-arginine and curcumin is 1:1:

1.

3. The ternary co-amorphous substance of berberine hydrochloride according to claim 2, characterized in that, The glass transition temperature of the ternary co-amorphous compound of berberine hydrochloride is 118.2 °C.

4. The preparation method of the ternary co-amorphous substance of berberine hydrochloride according to any one of claims 1 to 3, characterized in that, The steps are as follows: Dissolve berberine hydrochloride, L-arginine and curcumin in a solvent, evaporate the solvent by rotary evaporation under reduced pressure, and dry in vacuum to obtain the product.

5. The preparation method of the ternary co-amorphous berberine hydrochloride according to claim 4, characterized in that, The solvent is at least one of methanol, ethanol, acetonitrile and acetone.

6. The preparation method of the ternary co-amorphous berberine hydrochloride according to claim 5, characterized in that, The temperature for rotary evaporation of the solvent under reduced pressure is 35-65 °C.

7. The preparation method of the ternary co-amorphous substance of berberine hydrochloride according to any one of claims 1 to 3, characterized in that, The steps are as follows: Mix and ball-mill berberine hydrochloride, L-arginine and curcumin to obtain the product.

8. The preparation method of the ternary co-amorphous berberine hydrochloride according to claim 7, characterized in that, The rotation speed of the ball-milling is 1000-3000 r / min, and the ball-milling time is 15-40 min.

9. Use of the ternary co-amorphous compound of berberine hydrochloride according to claim 1 in the preparation of a pharmaceutical composition or health product for anti-tumor, antioxidant or antibacterial purposes.

10. Use of the ternary co-amorphous compound of berberine hydrochloride according to claim 1 in the preparation of a pharmaceutical composition or health product for blood sugar lowering or liver protection.

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