Co-amorphous system for improving water solubility of dihydromyricetin and preparation method thereof

Abstract

The invention discloses a co-amorphous system for improving water solubility of dihydromyricetin and a preparation method thereof, the co-amorphous system comprises dihydromyricetin and a hydrophilic component according to a molar ratio of (2-1): (1-3), the hydrophilic component is chlorogenic acid, sodium taurine deoxycholate or disodium glycyrrhizinate, and the co-amorphous system is prepared by a reduced pressure evaporation method; the preparation method comprises the following steps: adding a solvent into dihydromyricetin and a hydrophilic component according to a certain proportion, dissolving, carrying out ultrasonic treatment to a clear state, then putting into a water bath at 50-70 DEG C, and carrying out rotary evaporation on the solvent under reduced pressure to obtain the dihydromyricetin-hydrophilic component co-amorphous system. The co-amorphous system prepared by the invention has the characteristic of improving the water solubility and stability of dihydromyricetin.

Description

Technical Field

[0001] The present invention relates to a co-amorphous system, in particular to a co-amorphous system for improving the water solubility of dihydromyricetin and a preparation method thereof. Background Art

[0002] Dihydromyricetin (DMY), also known as dihydromyricetin and ampelopsis, is a flavonoid compound widely found in herbal medicines. It exhibits pharmacological activities such as antibacterial, anti-inflammatory, antioxidant, hepatoprotective, and cardiovascular protection. However, DMY has low solubility and is classified as a Class II drug in the biopharmaceutics classification system. It has extremely poor oral absorption and a bioavailability of only 4.02%, making it difficult to effectively utilize in food and pharmaceutical preparations. In the prior art, there are documents that disclose eutectic systems, solid dispersion systems, microemulsion systems, etc. of dihydromyricetin to improve the solubility of dihydromyricetin, such as the dihydromyricetin and picolinic acid eutectic and its preparation method, composition and use with publication number CN118290383A, a dihydromyricetin solid dispersion and its preparation method and application in bullfrog preservation with publication number CN116268071A, and a dihydromyricetin agent with a biocompatible microemulsion as a carrier, preparation method and application with publication number CN108125947A.

[0003] A drug coamorphous system (CAS) is a state in which a drug and other low-molecular-weight excipients or drugs form an amorphous state, with the components linked by hydrogen and ionic bonds. Compared to amorphous forms alone, this system significantly improves drug solubility and dissolution, while also possessing enhanced physical stability and improved bioavailability. However, no research on coamorphous systems of dihydromyricetin has been published in the prior art. Summary of the Invention

[0004] The purpose of the present invention is to provide a co-amorphous system for improving the water solubility of dihydromyricetin and a preparation method thereof. The co-amorphous system prepared by the present invention has the characteristics of improving the water solubility and stability of dihydromyricetin.

[0005] The technical solution of the present invention is a co-amorphous system for improving the water solubility of dihydromyricetin, comprising dihydromyricetin and a hydrophilic component in a molar ratio of (2-1): (1-3), wherein the hydrophilic component is chlorogenic acid, sodium taurine deoxycholate or disodium glycyrrhizate, and is prepared by a reduced pressure evaporation method.

[0006] In the aforementioned co-amorphous system for improving the water solubility of dihydromyricetin, the hydrophilic component is chlorogenic acid, and the molar ratio of dihydromyricetin to chlorogenic acid is (1-2):(1-2).

[0007] In the aforementioned co-amorphous system for improving the water solubility of dihydromyricetin, the molar ratio of dihydromyricetin to chlorogenic acid is 1:2.

[0008] In the aforementioned co-amorphous system for improving the water solubility of dihydromyricetin, the hydrophilic component is sodium taurodeoxycholate, and the molar ratio of dihydromyricetin to sodium taurodeoxycholate is 1:(1-3).

[0009] In the aforementioned co-amorphous system for improving the water solubility of dihydromyricetin, the molar ratio of dihydromyricetin to sodium taurodeoxycholate is 1:3.

[0010] In the aforementioned co-amorphous system for improving the water solubility of dihydromyricetin, the hydrophilic component is disodium glycyrrhizate, and the molar ratio of dihydromyricetin to disodium glycyrrhizate is (1-2):(1-2).

[0011] In the aforementioned co-amorphous system for improving the water solubility of dihydromyricetin, the molar ratio of dihydromyricetin to disodium glycyrrhizate is 1:2.

[0012] The preparation method of the above-mentioned co-amorphous system comprises the following steps:

[0013] S1. Add a solvent to a certain proportion of dihydromyricetin and a hydrophilic component to dissolve the mixture, and ultrasonicate the mixture until the mixture is clear to obtain a clear solution;

[0014] S2. Place the clarified solution in a water bath at 50-70° C., and evaporate the solvent under reduced pressure to obtain a dihydromyricetin-hydrophilic component co-amorphous system.

[0015] In the above-mentioned preparation method, when the hydrophilic component is chlorogenic acid, the solvent is anhydrous ethanol; when the hydrophilic component is sodium taurine deoxycholate, the solvent is methanol; when the hydrophilic component is disodium glycyrrhizate, the solvent is methanol-water solution, and the volume ratio of methanol to water in the methanol-water solution is 4:1.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] The present invention adopts dihydromyricetin, chlorogenic acid, sodium taurine deoxycholate and disodium glycyrrhizinate in a certain molar ratio, and prepares a co-amorphous system of dihydromyricetin by a solvent volatilization method. The co-amorphous system of dihydromyricetin can significantly improve the solubility, dissolution, water solubility and permeability of dihydromyricetin, and can always maintain an amorphous state under high temperature and high humidity conditions for 180 days. The system has high physical stability and good compatibility with soluble starch, thereby greatly improving the bioavailability of dihydromyricetin. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 These are the PXRD patterns of DMY, CA, amorphous DMY, DMY-CA physical mixture and co-amorphous system samples.

[0019] Figure 2 These are the PXRD patterns of DMY, STD, DMY-STD physical mixture and co-amorphous system samples.

[0020] Figure 3 These are the PXRD patterns of DMY, Na2GA, DMY-Na2GA physical mixture and co-amorphous system samples.

[0021] Figure 4 These are the DSC graphs of DMY, CA, amorphous DMY, DMY-CA physical mixture and co-amorphous system samples.

[0022] Figure 5 It is the DSC graph of DMY, STD, DMY-STD physical mixture and co-amorphous system samples.

[0023] Figure 6 These are the DSC graphs of DMY, Na2GA, DMY-Na2GA physical mixture and co-amorphous system samples.

[0024] Figure 7 These are the FTIR spectra of DMY, CA, amorphous DMY, DMY-CA physical mixture and co-amorphous system samples.

[0025] Figure 8 These are the FTIR patterns of DMY, STD, DMY-STD physical mixture and co-amorphous system samples.

[0026] Figure 9 These are the FTIR spectra of DMY, Na2GA, DMY-Na2GA physical mixture and co-amorphous system samples.

[0027] Figure 10 Polarized light micrographs of DMY, CA, DMY-CA-PM-3, amorphous DMY, and DMY-CA-CAs-3 samples.

[0028] Figure 11 These are the Raman spectra of DMY, STD, DMY-STD physical mixture and co-amorphous system samples.

[0029] Figure 12 These are the SEM images of DMY, STD, DMY-STD physical mixture and co-amorphous system samples; A is DMY, B is STD, C is DMY-STD-PM-3, and D is DMY-STD-CAs-3.

[0030] Figure 13 These are the XPS spectra of DMY, Na2GA, DMY-Na2GA physical mixture and co-amorphous system samples.

[0031] Figure 14 It is the supersaturated powder dissolution curve of DMY, DMY amorphous, DMY-CA physical mixture and co-amorphous system samples in 0.1M HCl buffer.

[0032] Figure 15 These are the supersaturated powder dissolution curves of DMY, DMY-STD physical mixture, and co-amorphous system samples in different media; a is DMY, b is DMY-STD-PM3, c is DMY-STD-CAs-3, A is 0.1 M HCl, B is pH 4.5 PBS, C is pH 6.8 PBS, and D is water.

[0033] Figure 16 This is the supersaturated powder dissolution curve of DMY, DMY-Na2GA physical mixture and co-amorphous system samples in pH 6.8 PBS.

[0034] Figure 17 are the PXRD results of amorphous DMY and DMY-CA-CAs-3 after storage at 40°C and 75% RH for 180 days; ae are the PXRD patterns of amorphous DMY prepared freshly and stored for 5, 10, 15, and 60 days, respectively; fk are the PXRD patterns of DMY-CA-CAs-3 prepared freshly and stored for 15, 30, 60, 90, and 180 days, respectively.

[0035] Figure 18 This is the PXRD result of DMY-STD-CAs-3 after storage at 40°C and 75% RH for 90 days.

[0036] Figure 19 This is the PXRD result of the stability of DMY-Na2GA-CAs-3 at 40℃ and 75%RH.

[0037] Figure 20 These are the PXRD spectra of different samples after being mixed with soluble starch and stored for 2 months at 40°C and 75% RH; among them, ad are the PXRD spectra of soluble starch freshly prepared, stored for 15 days, 1 month, and 2 months, eh are the PXRD spectra of the physical mixture of amorphous DMY and soluble starch freshly prepared, stored for 15 days, 1 month, and 2 months, and Figure il is the PXRD spectra of the physical mixture of DMY-CA-CAs-3 and soluble starch freshly prepared, stored for 15 days, 1 month, and 2 months.

[0038] Figure 21Figure 5 is the PXRD spectrum of DMY-STD-CAs-3 mixed with soluble starch and stored in a closed environment at 40°C and 75% RH for one month; a is the freshly prepared soluble starch, b is the soluble starch after 30 days of storage, c is the physical mixture of freshly prepared soluble starch and DMY-STD-CAs-3, and d is the physical mixture of soluble starch and DMY-STD-CAs-3 after 30 days of storage.

[0039] Figure 22 This is the PXRD spectrum of DMY-Na2GA-CAs-3 mixed with microcrystalline cellulose and stored in a sealed environment at 40°C and 75% RH.

[0040] Figure 23 The following are the dynamic moisture absorption performance curves of DMY-STD-CAs-3, DMY, STD, and DMY-STD-PM-3; A is DMY-STD-CAs-3, B is DMY, C is STD, and D is DMY-STD-PM-3. DETAILED DESCRIPTION

[0041] The present invention will be further described below with reference to the examples, but they are not intended to limit the present invention.

[0042] Example 1:

[0043] The co-amorphous system for improving the water solubility of dihydromyricetin was prepared by dihydromyricetin and chlorogenic acid with a molar ratio of 2:1 via reduced pressure evaporation and was designated as DMY-CA-CAs-1.

[0044] Example 2: A co-amorphous system for improving the water solubility of dihydromyricetin was prepared by evaporating dihydromyricetin and chlorogenic acid at a molar ratio of 1:1 under reduced pressure, and was designated as DMY-CA-CAs-2.

[0045] Example 3: A co-amorphous system for improving the water solubility of dihydromyricetin was prepared by dihydromyricetin and chlorogenic acid in a molar ratio of 1:2 via reduced pressure evaporation, and was designated as DMY-CA-CAs-3.

[0046] The preparation method of dihydromyricetin-chlorogenic acid co-amorphous system is as follows:

[0047] S1. Weigh dihydromyricetin and chlorogenic acid in a certain molar ratio, add anhydrous ethanol to dissolve, and sonicate until clear to obtain a clear solution;

[0048] S2. The clarified solution was placed in a 60° C. water bath, the solvent was evaporated under reduced pressure and vacuum dried to obtain a dry sample, which was a dihydromyricetin-chlorogenic acid co-amorphous system, denoted as DMY-CA-CAs.

[0049] Example 4:

[0050] The co-amorphous system for improving the water solubility of dihydromyricetin was prepared by dihydromyricetin and sodium taurine deoxycholate with a molar ratio of 1:1 via reduced pressure evaporation and was designated as DMY-STD-CAs-1.

[0051] Example 5:

[0052] The co-amorphous system for improving the water solubility of dihydromyricetin was prepared by dihydromyricetin and sodium taurine deoxycholate with a molar ratio of 1:2 via reduced pressure evaporation and was designated as DMY-STD-CAs-1.

[0053] Example 6:

[0054] The co-amorphous system for improving the water solubility of dihydromyricetin was prepared by dihydromyricetin and sodium taurine deoxycholate with a molar ratio of 1:3 via reduced pressure evaporation and was designated as DMY-STD-CAs-1.

[0055] The preparation method of dihydromyricetin-sodium taurine deoxycholate co-amorphous system is as follows:

[0056] S1. Weigh dihydromyricetin and sodium taurine deoxycholate in a certain molar ratio, add methanol to dissolve, and sonicate until clear to obtain a clear solution;

[0057] S2. The clarified solution was placed in a 60° C. water bath, the solvent was evaporated under reduced pressure and vacuum dried to obtain a dry sample, which was a dihydromyricetin-sodium taurine deoxycholate co-amorphous system, denoted as DMY-STD-CAs.

[0058] Example 7:

[0059] The co-amorphous system for improving the water solubility of dihydromyricetin was prepared by dihydromyricetin and disodium glycyrrhizinate with a molar ratio of 2:1 via reduced pressure evaporation and was designated as DMY-Na2GA-CAs-1.

[0060] Example 8:

[0061] The co-amorphous system for improving the water solubility of dihydromyricetin was prepared by dihydromyricetin and disodium glycyrrhizinate with a molar ratio of 1:1 via reduced pressure evaporation and was designated as DMY-Na2GA-CAs-2.

[0062] Example 9:

[0063] The co-amorphous system for improving the water solubility of dihydromyricetin was prepared by dihydromyricetin and disodium glycyrrhizinate with a molar ratio of 1:2 via reduced pressure evaporation and was designated as DMY-Na2GA-CAs-3.

[0064] The preparation method of the co-amorphous system of dihydromyricetin and disodium glycyrrhizinate is as follows:

[0065] S1. Weigh dihydromyricetin and disodium glycyrrhizinate in a certain molar ratio, add methanol-water with a volume ratio of 4:1 to dissolve, sonicate at room temperature until completely dissolved and clear, and continue stirring for 2 hours to obtain a clear saturated solution;

[0066] S2. Place the clarified saturated solution in a 60° C. water bath, rotary evaporate the solvent under reduced pressure, and dry in vacuo to obtain a dry sample, which is a dihydromyricetin-sodium taurine deoxycholate co-amorphous system, denoted as DMY-STD-CAs.

[0067] Comparative Example 1:

[0068] The dihydromyricetin-chlorogenic acid physical mixture was prepared by weighing dihydromyricetin and chlorogenic acid at a molar ratio of 2:1, vortexing for 30 minutes to mix, and obtaining the dihydromyricetin-chlorogenic acid physical mixture, which was recorded as DMY-CA-PM-1.

[0069] Comparative Example 2:

[0070] The dihydromyricetin-chlorogenic acid physical mixture was prepared by weighing dihydromyricetin and chlorogenic acid at a molar ratio of 1:1, vortexing for 30 minutes to mix, and obtaining the dihydromyricetin-chlorogenic acid physical mixture, which was recorded as DMY-CA-PM-2.

[0071] Comparative Example 3:

[0072] The dihydromyricetin-chlorogenic acid physical mixture was prepared by weighing dihydromyricetin and chlorogenic acid at a molar ratio of 1:2, vortexing for 30 minutes to mix, and obtaining the dihydromyricetin-chlorogenic acid physical mixture, which was recorded as DMY-CA-PM-3.

[0073] Comparative Example 4:

[0074] The dihydromyricetin-sodium taurodeoxycholate physical mixture was prepared by weighing dihydromyricetin and sodium taurodeoxycholate at a molar ratio of 1:1, vortexing for 30 minutes to mix, and obtaining the dihydromyricetin-sodium taurodeoxycholate physical mixture, which was designated as DMY-STD-PM-1.

[0075] Comparative Example 5:

[0076] The dihydromyricetin-sodium taurodeoxycholate physical mixture was prepared by weighing dihydromyricetin and sodium taurodeoxycholate at a molar ratio of 1:2, vortexing for 30 minutes to mix, and obtaining the dihydromyricetin-sodium taurodeoxycholate physical mixture, which was designated as DMY-STD-PM-2.

[0077] Comparative Example 6:

[0078] The dihydromyricetin-sodium taurodeoxycholate physical mixture was prepared by weighing dihydromyricetin and sodium taurodeoxycholate at a molar ratio of 1:3, vortexing for 30 minutes to mix, and obtaining the dihydromyricetin-sodium taurodeoxycholate physical mixture, which was designated as DMY-STD-PM-3.

[0079] Comparative Example 7:

[0080] The dihydromyricetin-disodium glycyrrhizate physical mixture was prepared by weighing dihydromyricetin and disodium glycyrrhizate at a molar ratio of 2:1, vortexing for 30 minutes to mix, and obtaining the dihydromyricetin-disodium glycyrrhizate physical mixture, which was recorded as DMY-Na2GA-PM-1.

[0081] Comparative Example 8:

[0082] The dihydromyricetin-disodium glycyrrhizate physical mixture was prepared by weighing dihydromyricetin and disodium glycyrrhizate in a molar ratio of 1:1, vortexing for 30 minutes to mix, and obtaining the dihydromyricetin-disodium glycyrrhizate physical mixture, which was recorded as DMY-Na2GA-PM-2.

[0083] Comparative Example 9:

[0084] The dihydromyricetin-disodium glycyrrhizate physical mixture was prepared by weighing dihydromyricetin and disodium glycyrrhizate at a molar ratio of 1:2, vortexing for 30 minutes to mix, and obtaining the dihydromyricetin-disodium glycyrrhizate physical mixture, which was recorded as DMY-Na2GA-PM-3.

[0085] The products prepared in the above examples and comparative examples were subjected to solid-state characterization tests and performance test tests respectively:

[0086] Preparation of dihydromyricetin (DMY) amorphous form:

[0087] S1. Weigh a certain molar ratio of dihydromyricetin, add anhydrous ethanol to dissolve, and sonicate until clear to obtain a clear solution;

[0088] S2. Place the clarified solution in a 60°C water bath, evaporate the solvent under reduced pressure, and dry in vacuo to obtain a dry sample, which is amorphous dihydromyricetin.

[0089] 1.PXRD detection:

[0090] Crystalline DMY, crystalline CA, STD, Na2GA, amorphous DMY, DMY physical mixture, and DMY co-amorphous system were collected using an X-ray powder diffractometer with a CuKα radiation source. Detection conditions: scanning range 2θ 5-50°, scanning speed 10° / min. The X-ray spectra of different samples are shown in Figure 2. Figure 1-Figure 3 shown.

[0091] Figure 1 In the spectra, the spectra of crystalline DMY and crystalline CA exhibit typical crystal characteristics; the spectrum of amorphous DMY lacks any diffraction peaks, indicating that it has successfully transformed from a crystalline to an amorphous state. The DMY-CA co-amorphous system of Examples 1-3 displays typical amorphous characteristics, such as a camel-shaped halo, and the characteristic diffraction peaks of the crystalline state disappear, preliminarily indicating that the DMY co-amorphous system was successfully prepared by the reduced pressure evaporation method of DMY and CA. Furthermore, the DMY-CA physical mixture still exhibits the characteristic crystalline peaks of DMY and CA, indicating that the simple physical mixing of DMY and CA does not change the solid form of DMY.

[0092] Figure 2 In the spectrum, crystalline DMY, STD, and DMY-STD-PM-3 all correspond to their respective crystal characteristic diffraction peaks. Among them, DMY has strong crystal diffraction peaks at 9.07°, 10.40°, 12.17°, 17.06°, 23.54°, 25.86°, and 27.23°, while STD has crystal diffraction peaks at 5.6°, 9.7°, 11.2°, 13.7°, 15.9°, 16.8°, 19.4°, 20.2°, 24.3°, 25.7°, 26.9°, and 27.5°. A mixed diffraction peak of DMY and STD appears in DMY-STD-PM-3, which is a simple superposition of the two peaks, indicating that there is no interaction, indicating that the simple physical mixing of DMY and STD does not change the solid form of DMY. However, no characteristic diffraction peaks of crystals were found in the spectra of DMY-STD-CAs of Examples 4-6, proving that the DMY co-amorphous system was successfully prepared by the reduced pressure evaporation method of DMY and STD.

[0093] Figure 3 In the spectrum, crystalline DMY exhibits strong crystal diffraction peaks at 9.07°, 10.40°, 12.17°, 17.06°, 23.54°, 25.86°, and 27.23°. Only a broad halo is observed in the diffraction pattern of Na2GA, indicating its amorphous state. Characteristic peaks of DMY are observed in the physical mixture of DMY and Na2GA, indicating that the simple physical mixing of DMY and Na2GA does not change the solid form of DMY. However, no characteristic peaks of DMY are observed in the DMY-Na2GA-CAs of Examples 7-9, demonstrating that the reduced pressure evaporation method of DMY and Na2GA successfully prepared a DMY co-amorphous system.

[0094] 2.DSC detection:

[0095] The thermal behaviors of DMY, CA, amorphous DMY, DMY-CA-CAs-3, DMY-CA-PM-3, STD, DMY-STD-CAs-3, and DMY-STD-PM-3 were detected by differential scanning calorimetry, respectively. The detection conditions were: nitrogen atmosphere, flow rate of 50 mL / min, heating rate of 10°C / min, and temperature range of 30-300°C.

[0096] The DSC test results of DMY, CA, amorphous DMY, DMY-CA-CAs-3 and DMY-CA-PM-3 are shown in Figure 2. Figure 4 As shown. Figure 4 As can be seen in the figure, DMY and CA exhibit distinct melting endothermic peaks at 252.2°C and 201.8°C, respectively, corresponding to their respective melting points. Amorphous DMY exhibits a melting point similar to that of crystalline DMY during heating. The endothermic peak of the DMY-CA-PM-3 physical mixture is a superposition of the endothermic peaks of DMY and CA. No significant endothermic peaks are observed in the DSC spectrum of DMY-CA-CAs-3, and the characteristic parameter, glass transition temperature (Tg), is 135.9°C, indicating that DMY and CA form a single-phase co-amorphous system.

[0097] The DSC test results of DMY, STD, DMY-STD-CAs-3, and DMY-STD-PM-3 are as follows Figure 5 As shown. Figure 5 As can be seen in the DSC spectrum of DMY-STD-CAs-3, DMY has a sharp melting peak at 252.2°C, corresponding to its melting point, indicating that it is crystalline; STD has a broad endothermic melting peak at 199.9°C. In the physical mixture of DMY-STD-PM-3, non-sharp melting peaks were observed at 201.1°C and 249.4°C, respectively, indicating that DMY and STD formed a crystalline melting mixture under continuous heating, with weak intermolecular interactions occurring during the melting process. The DSC spectrum of DMY-STD-CAs-3 does not show melting peaks for DMY and STD, and the characteristic parameter, glass transition temperature (Tg), is shown at 150.4°C, indicating that DMY and STD form a single-phase co-amorphous system.

[0098] The DSC test results of DMY, Na2GA, DMY-Na2GA-CAs-3 and DMY-Na2GA-PM-3 are as follows Figure 6 As shown. Figure 6It can be seen from the graph that DMY has an obvious melting endothermic peak at 252.2℃, while there is no obvious melting peak in the spectrum of Na2GA. A single glass transition temperature (Tg) appears at 216.11℃, indicating that it is amorphous. In the DMY-Na2GA physical mixture, an inconspicuous melting peak is shown at 247℃, indicating that during the heating process, the molten DMY and Na2GA produce a weak mutual influence. In DMY-Na2GA-CAs-3, the melting peak completely disappears, and the characteristic parameter glass transition temperature Tg is 235.13℃, indicating that it is completely amorphous.

[0099] 3. FTIR detection:

[0100] DMY, CA, amorphous DMY, DMY-CA-CAs-3, DMY-CA-PM-3, STD, DMY-STD-PM-3, DMY-STD-CAs-3, Na2GA, DMY-Na2GA-PM-3, and DMY-Na2GA-CAs-3 were ground and mixed with KBr until no obvious particles were present, and then compressed into transparent sheets using a hydraulic press. Each sample was analyzed by Fourier transform infrared spectroscopy at 4000 cm -1 -400cm -1 Scan within the range and set the resolution to 4cm -1 , the number of scans is 32 times.

[0101] The FTIR test results of DMY, CA, amorphous DMY, DMY-CA-CAs-3 and DMY-CA-PM-3 are shown in Figure 2. Figure 7 As shown. Figure 7 It can be seen from the DMY spectrum that 3345 cm -1 The broad and blunt strong peak at 1640 cm corresponds to the stretching vibration peak of phenolic hydroxyl group; -1 The strong peak at 1472 cm corresponds to the carbonyl stretching vibration peak. -1 The strong peak at 1160cm corresponds to the C=C stretching vibration peak; -1 The strong peak at 3345cm corresponds to the stretching vibration peak of -COC-. -1 Move to 3356cm -1 The stretching vibration peak of C=C is 1472cm -1 Move to 1464cm -1 , indicating that DMY molecules may interact with each other and adjacent phenolic hydroxyl groups may bind to each other. The CA spectrum shows a variety of characteristic peaks, 3374cm -1 The strong peak at 1687cm corresponds to the stretching vibration peak of the hydroxyl group on the benzene ring; -1The strong peak at 1518 cm is the mixed stretching vibration peak of the ester bond and C=O in the carboxyl group; -1 、1443cm -1 The strong peak at 2292 cm corresponds to the benzene ring stretching vibration peak; -1 The weak peak at corresponds to the vibration peak of -OH in the carboxyl group. In the spectrum of DMY-CA-PM-3, characteristic peaks corresponding to DMY and CA appear, and the chemical shift does not change. The peak shape is slightly broadened, indicating that there is no intermolecular interaction between the physical mixture groups. In the spectrum of DMY-CA-CAs-3, the hydroxyl stretching vibration peak is assigned to 3341cm -1 Compared with DMY and CA, the hydroxyl stretching vibration peaks shifted 4 cm downfield. -1 、33cm -1 , CA 2292cm -1 The weak hydroxyl vibration peak at 37° disappeared, indicating that there was an intermolecular interaction between the phenolic hydroxyl group in DMY and the carboxyl group in CA.

[0102] The FTIR test results of DMY, STD, DMY-STD-PM-3 and DMY-STD-CAs-3 are as follows Figure 8 As shown. Figure 8 It can be seen from the DMY spectrum that 3345 cm -1 The broad and blunt strong peak at 1640 cm corresponds to the stretching vibration peak of phenolic hydroxyl group; -1 The strong peak at 1472 cm corresponds to the carbonyl stretching vibration peak. -1 The strong peak at 1160cm corresponds to the C=C stretching vibration peak; -1 The strong peak at 3637cm corresponds to the CH stretching vibration peak. -1 A weak OH stretching vibration peak is shown at 3415 cm -1 、1642cm -1 The strong NH and C=O stretching vibration peaks are shown at 1205cm -1 、1052cm -1 There is a strong SO 3- Stretching vibration peak. The spectrum of the DMY-STD-PM-3 physical mixture is a simple superposition of the absorption peaks of DMY and STD, indicating that there is no intermolecular interaction between the two after mechanical mixing; compared with DMY and STD alone, the SO 3- At 1205cm -1 The vibration peak at 1052cm -1 The vibration peak at 1044 cm -1 , at 3637cm -1The vibration peak at 3354 cm-1 disappears, which may be due to the destruction of the API crystal structure and disordered accumulation of the molecules, showing a short-range ordered and long-range disordered structure. At the same time, the characteristic peak of DMY phenolic hydroxyl group moves to 3354 cm-1. -1 , indicating that the SO 3- , OH functional groups interact with each other to form hydrogen bonds.

[0103] The FTIR test results of DMY, Na2GA, DMY-Na2GA-CAs-3 and DMY-Na2GA-PM-3 are as follows Figure 9 As shown. Figure 9 It can be seen from the DMY spectrum that 3345 cm -1 The broad and blunt strong peak at 1640 cm corresponds to the stretching vibration peak of phenolic hydroxyl group; -1 The strong peaks at 1079 and 1030 cm correspond to the carbonyl stretching vibration peaks. -1 The peak at 3414 cm in the Na2GA spectrum corresponds to the -COC- stretching vibration peak. -1 The strong peak at 1610 cm corresponds to the hydroxyl stretching vibration peak. -1 The strong peak at corresponds to the carbonyl stretching vibration peak. In the DMY-Na2GA physical mixture, due to the addition of Na2GA, the carbonyl characteristic peak of DMY becomes slightly broadened, and the stretching vibration peak intensity of -COC- slightly decreases, but the chemical shift remains the same; while the characteristic peak in DMY-Na2GA-CAs-3 undergoes obvious peak shift or peak width, and the chemical shift of phenolic hydroxyl group changes to 3390cm -1 The chemical shift of the carbonyl group changes to a lower wave number of 1636 cm -1 The peak width is obvious, and the stretching vibration peak of -COC- almost disappears. The above results indicate that there is intermolecular hydrogen bond interaction between DMY and Na2GA in DMY-Na2GA-CAs-3.

[0104] 4. Polarized light microscope detection:

[0105] The morphologies of DMY, CA, amorphous DMY, DMY-CA-CAs-3 and DMY-CA-PM-3 were observed using polarized light microscopy. The results of polarized light microscopy are shown in Figure 2. Figure 10 As shown. Figure 10 It can be seen that birefringence occurs in DMY, CA and DMY-CA physical mixtures, while amorphous DMY and DMY-CA-CAs-3 appear irregular fragments and lack the birefringence characteristic of crystals, indicating that DMY-CA-CAs-3 is completely amorphous.

[0106] 5. Raman detection:

[0107] The powder samples of DMY, STD, DMY-STD-PM-3, and DMY-STD-CAs-3 were flattened with glass slides to obtain a flat surface for Raman spectroscopy analysis. The scanning range was 4000-400 cm -1 , set the excitation light wavelength to 532nm, the excitation light power to 200mW, the average number of scans to 3, and the resolution to 2-3cm -1 The Raman spectra of each sample are as follows: Figure 11 As shown. Figure 11 It can be seen that the bending vibration peaks of CH on the benzene ring in DMY are at 1354 and 1478 cm -1 The bending vibration peak of phenolic hydroxyl group is at 1275cm -1 The stretching vibration peak of NH in STD is at 3407cm -1 The stretching vibration peaks of CH on the STD ring are at 2872 and 2957 cm -1 The vibration peak of sulfonic acid group is at 1446cm -1 The Raman spectrum of the DMY-STD physical mixture is simply a superposition of the spectra of the two raw materials, while the bending vibration peak of the DMY phenolic hydroxyl group in DMY-STD-CAs-3 moves to 1281 cm -1 The vibration peak of the sulfonic acid group in STD shifts to 1457 cm -1 The peaks are degenerate and disappear between 1200 and 1500. This indicates that in DMY-STD-CAS, the phenolic hydroxyl group of DMY and the SO 3- Intermolecular interactions are formed through hydrogen bonds.

[0108] 6.SEM detection:

[0109] The morphologies of DMY, STD, DMY-STD-PM-3, and DMY-STD-CAs-3 were analyzed using scanning electron microscopy. Each sample was fixed on conductive tape and sputtered with gold. Scanning electron micrographs were taken at an accelerating voltage of 5 kV. The SEM results of each sample are shown in Figure 2. Figure 12 As shown, A is DMY, B is STD, C is DMY-STD-PM-3, and D is DMY-STD-CAs-3. Figure 12As can be seen, the appearance and particle shape of DMY, STD, MY-STD-PM-3, and DMY-STD-CAs-3 differ significantly. DMY crystals appear as elongated prismatic crystals, while STD crystals appear as irregularly sized particles or agglomerates. Prismatic crystals, particles, or agglomerates were observed in DMY-STD-PM-3, representing a superposition of DMY and STD API crystals, indicating that the physical mixture is a simple blend of the two APIs, with no new phases formed. DMY-STD-CAs-3, on the other hand, appears as irregularly sized, sharp-edged flakes resembling large fragments. The absence of separate physical states of DMY and STD suggests the formation of a uniform, single, co-amorphous phase, a significant shift from the microscopic morphology of DMY, STD, and DMY-STD-PM-3.

[0110] 7.XPS detection:

[0111] The XPS O1s spectra of DMY, Na2GA, DMY-Na2GA-CAs-3 and DMY-Na2GA-PM-3 are as follows Figure 13 As shown. Figure 13 It can be seen that the binding energy of hydroxyl in DMY is 531.08 eV, the binding energy of hydroxyl in Na2GA is 530.38 eV, DMY-Na2GA-PM-3 has a binding energy similar to that of hydroxyl in Na2GA, which is 530.48 eV, and the binding energy of hydroxyl in DMY-Na2GA-CAs-3 is 531.63 eV. Compared with the binding energy of DMY and hydroxyl in Na2GA, they are shifted to the high field by 0.55 and 1.15 eV, respectively, indicating that DMY and Na2GA have intermolecular interactions.

[0112] 8. Solubility experiment:

[0113] The DMY content was determined by HPLC. The HPLC conditions were as follows: a Diamonsil C18 column (250×4.6 mm, 5.0 μm); a detection wavelength of 291 nm; a flow rate of 1.0 mL / min; a column temperature of 28°C; an injection volume of 10 μL; and an isocratic elution of a mobile phase of methanol-0.05% phosphoric acid aqueous solution (73:27). A linear regression was performed with DMY mass concentration as the abscissa (X) and peak area as the ordinate (Y). The regression equation was Y=0.263.3X+0.1681(R 2 =0.9998).

[0114] Take the same amount of DMY, DMY amorphous, DMY co-amorphous system and DMY physical mixture with similar particle size range, place them in 0.1mol / L HCl buffer, pH 4.5 PBS, pH 6.8 PBS and water, seal them, keep the temperature at 37℃ and the oscillation frequency at 150r·min. -1 The supernatant was filtered through a 0.45 μm filter membrane, and the filtrate was taken. An appropriate amount of the filtrate was accurately measured and diluted with the mobile phase to an appropriate mass concentration. The peak area of the sample was determined according to the above chromatographic conditions, and the solubility was calculated. All experiments were repeated 3 times.

[0115] The saturated solubility results of DMY-CA co-amorphous system and DMY-CA physical mixture are shown in Table 1.

[0116] Table 1. Saturated solubility of each sample (x±s, n=3, mg / mL)

[0117]

[0118]

[0119] From the solubility test results in Table 1, it can be seen that the solubility of the co-amorphous system of DMY-CA is greater than the solubility of the raw material DMY, DMY amorphous and DMY-CA physical mixture, and the solubility of Example 3 is the best among the four solvents, maintaining the saturated solubility for at least 48 hours, and always maintaining a supersaturated state during the period without precipitation.

[0120] The saturated solubility results of the DMY-STD co-amorphous system and the DMY-STD physical mixture are shown in Table 2.

[0121] Table 2. Saturated solubility of each sample (x±s, n=3, mg / mL)

[0122]

[0123] Compared with the DMY group: ** P<0.01 *** P < 0.001; Comparison of each ratio between CAS group and PM group: ## P<0.01 ### P<0.001.

[0124] The solubility test results in Table 2 show that the solubility of the DMY-STD co-amorphous system is greater than that of the raw material DMY, DMY amorphous, and the DMY-STD physical mixture, and can maintain saturated concentration for at least 48 hours. Among them, DMY-STD-CAs-3 has the highest solubility in different media.

[0125] The saturated solubility results of the DMY-Na2GA co-amorphous system and the DMY-Na2GA physical mixture are shown in Table 3.

[0126] Table 3. Saturated solubility of each sample (x±s, n=3, mg / mL)

[0127]

[0128] The solubility test results in Table 3 show that the solubility of the DMY-Na2GA co-amorphous system is greater than that of the raw material DMY, DMY amorphous form, and the DMY-STD physical mixture, and can maintain saturated concentration for at least 48 hours. Among them, DMY-Na2GA-CAs-3 has the highest solubility in various media.

[0129] 9. Supersaturated powder dissolution test:

[0130] According to the Pharmacopoeia of the People's Republic of China 2020 edition General Chapter 0931 Dissolution and Release Determination Method 3, the mass exceeding the equilibrium solubility was selected to test the dissolution of the DMY-CA physical mixture and the co-amorphous system in 0.1 mol / L HCl buffer. The concentration-time curves of each sample under supersaturation are shown in Figure 2. Figure 14 shown.

[0131] The mass exceeding the equilibrium solubility was selected and the dissolution of DMY, DMY-STD-CAs-3 and DMY-STD-PM-3 was tested using the slurry method in 37°C water, 0.1 mol / L HCl buffer, pH 4.5 PBS and pH 6.8 PBS, respectively. The concentration-time curves of each sample under supersaturation are shown in Figure 2. Figure 15 shown.

[0132] The mass exceeding the equilibrium solubility was selected and the dissolution rate of DMY, DMY-Na2GA physical mixture and co-amorphous system was investigated in PBS at pH 6.8 using the slurry method. The concentration-time curves of each sample under supersaturated state are shown in Figure 2. Figure 16 shown.

[0133] from Figure 14From the overall dynamic trend, the dissolution of DMY in 0.1 M HCl medium always remains at the lowest level; the dissolution concentration of amorphous DMY is slightly greater than that of DMY, and the dissolution concentration of DMY in the DMY-CA physical mixture is slightly greater than that of amorphous DMY; DMY in the DMY-CA co-amorphous system is rapidly released at the beginning, reaching the highest concentration instantaneously, then rapidly decreasing first and then slowly decreasing to maintain a high-concentration saturation state at 2 h, and all are greater than the dissolution concentration of the DMY-CA physical mixture, where DMY-CA-CAs-1 < DMY-CA-CAs-2 < DMY-CA-CAs-3. In summary, the co-amorphous system of DMY-CA significantly improves the dissolution performance of DMY in a 0.1 mol / L HCl environment.

[0134] Figure 15 In it, a is DMY, b is DMY-STD-PM3, c is DMY-STD-CAs-3, A is 0.1 M HCl, B is pH 4.5 PBS, C is pH 6.8 PBS, and D is water. From Figure 15 It can be seen that the co-amorphous system shows better dissolution advantages than the physical mixtures of DMY and DMY-STD in different media. In DMY-STD-CAs-3, when DMY is in 0.1 M HCl, pH 4.5 PBS, pH 6.8 PBS, and water, it rapidly reaches the maximum mass concentration at 5 min, then rapidly decreases, and tends to balance after 90 min and maintains a relatively high concentration, and the overall is still significantly higher than that of DMY and the DMY-STD physical mixture. In summary, the co-amorphous system of DMY-STD can significantly improve the dissolution performance of DMY in four different pH environments.

[0135] From Figure 16 It can be seen that the DMY raw material always maintains the lowest apparent mass concentration in pH 6.8 phosphate buffer solution, the mass concentration of DMY-Na2GA-CAs is always greater than that of DMY and DMY-Na2GA-PM, and the dissolution performance of DMY is the best. In DMY-Na2GA-CAs, DMY shows a relatively slow release in DMY-Na2GA-CAs-1, the concentration gradually increases within the first 1 h, and after 1 h, its concentration gradually tends to balance, and the equilibrium concentration is about 5 times that of DMY; within the first 1 h, the mass concentration of DMY in DMY-Na2GA-CAs-2 is greater than that in DMY-Na2GA-CAs-3, and after 1 h, the mass concentration of DMY in DMY-Na2GA-CAs-3 exceeds that in DMY-Na2GA-CAs-2, and it always shows an upward trend over time throughout the process.

[0136] 10. Oil-water partition coefficient experiment:

[0137] Absorb an appropriate amount of n-octanol solution and mix it with the same volume of water. Shake at a constant temperature of (37±0.5)℃ for 24 hours. Let it stand for several hours, and separate the upper and lower layers to obtain water-saturated n-octanol and n-octanol-saturated aqueous solution for use.

[0138] The classic shake flask method was used to draw 4 mL of water-saturated n-octanol solution into a stoppered graduated test tube. Excessive amounts of DMY, DMY-CA-CAs-1, 2, 3 samples, and their physical mixtures were added to the solution. Ultrasonication was performed to fully dissolve the solution until a large amount of white insoluble precipitate appeared. The solution was then placed in a constant temperature oscillator at (37 ± 0.5) °C and an oscillation frequency of 150 r / min. -1 The mixture was shaken under the same conditions for 48 h, the upper oil phase was filtered through a 0.45 μm filter membrane, the filtrate was aspirated, and the mobile phase was added to dilute it to an appropriate range, and HCLC was performed to determine the chromatographic peak area.

[0139] Accurately pipette 2 mL of a water-saturated n-octanol solution containing DMY, DMY-CA-CAs-1, 2, 3, and their physical mixture into a stoppered centrifuge tube. Add 2 mL of the n-octanol-saturated aqueous solution to each tube. Place the stoppered tube in a constant-temperature shaker and shake under the same conditions for 48 hours. Separate the aqueous layer and filter through a 0.45 μm filter. Draw the filtrate and dilute it to an appropriate range with mobile phase. Perform HCLC analysis to measure the chromatographic peak area. The experimental results are shown in Table 4.

[0140] Table 4. Oil-water partition coefficients of each sample

[0141]

[0142] As shown in Table 2, the oil-water partition coefficient of the active pharmaceutical ingredient DMY is 1.16, indicating that DMY is more lipid-soluble than water-soluble. The dihydromyricetin-chlorogenic acid co-amorphous system has the lowest oil-water partition coefficient, indicating that the water solubility of DMY is enhanced after the formation of the co-amorphous system. Specifically, DMY-CA-CAs-3 < DMY-CA-CAs-2 < DMY-CA-CAs-1. The optimal LogP range for oral medications is 0-3, indicating that the water solubility of DMY is enhanced under the action of CA, but still remains within the optimal range, improving DMY's permeability.

[0143] 11. Physical stability test:

[0144] Crystallization of co-amorphous drugs during storage will affect their efficacy. Based on the saturated solubility and supersaturated powder dissolution results, DMY-CA-CAs-3, DMY-STD-CAs-3 and DMY-Na2GA-CA were used as samples. In accordance with the General Chapter 9103 of the 2020 edition of the Pharmacopoeia of the People's Republic of China - Guiding Principles for Stability Testing of Active Pharmaceutical Ingredients and Preparations, an accelerated test was conducted in a closed oven at 40°C and 75% RH to evaluate their physical stability during storage.

[0145] The PXRD results of DMY-CA-CAs-3 after 180 days of storage are as follows Figure 17 As shown in Figure 2, ae are the PXRD patterns of amorphous DMY prepared freshly and stored for 5, 10, 15, and 60 days, respectively; fk are the PXRD patterns of DMY-CA-CAs-3 prepared freshly and stored for 15, 30, 60, 90, and 180 days, respectively. Figure 17 As can be seen in the figure, amorphous DMY first began to show crystalline diffraction peaks after 5 days of storage, and more obvious crystalline diffraction peaks appeared after two months of storage, demonstrating that amorphous DMY is extremely unstable under high temperature and high humidity conditions and is prone to crystallization. However, after 180 days of storage under high temperature and high humidity conditions, the PXRD diffraction pattern of DMY-CA-CAs-3 still showed a halo pattern, with no evidence of crystallization. This indicates that DMY-CA-CAs-3 remained amorphous during storage, significantly improving its physical stability.

[0146] The PXRD results of DMY-STD-CAs-3 after 90 days of storage are as follows Figure 18 The results showed that after 90 days of storage, the PXRD pattern of DMY-STD-CAs-3 still showed diffuse diffraction rings and no crystal transformation occurred, indicating that it had good physical stability.

[0147] The PXRD results of DMY-Na2GA-CAs-3 after 90 days of storage are as follows Figure 19 The results show that the PXRD of DMY-Na2GA-CAs-3 after 90 days still shows a broad dispersion and no crystal transformation occurs, indicating good physical stability.

[0148] 12. Compatibility test of raw and auxiliary materials:

[0149] In accordance with the 2020 edition of the Pharmacopoeia of the People's Republic of China, General Chapter 9103 - Guidance for Stability Testing of Active Pharmaceutical Ingredients and Drug Products, as well as the Quality Design Guidelines, samples of DMY-CA-CAs-3 and DMY-STD-CAs-3 were weighed with soluble starch, and DMY-Na2GA-CAs-3 with microcrystalline cellulose (MCC) were weighed at a mass ratio of 1:1 and thoroughly mixed. The mixtures were then ground in a mortar and pestle for 2 minutes. The DMY-CA-CAs-3 mixtures were stored at 40°C and 75% RH for 2 months, the DMY-STD-CAs-3 mixtures were stored at 40°C and 75% RH for 1 month, and the DMY-Na2GA-CAs-3 mixtures were stored at 40°C and 75% RH for 1 month. The stability of the mixtures was then tested by PXRD.

[0150] The PXRD pattern of soluble starch mixed with DMY-STD-CAs-3 is as follows: Figure 20 As shown in the figure, ad are the PXRD patterns of soluble starch freshly prepared, stored for 15 days, 1 month, and 2 months, eh are the PXRD patterns of the physical mixture of amorphous DMY and soluble starch freshly prepared, stored for 15 days, 1 month, and 2 months, and figure il are the PXRD patterns of the physical mixture of DMY-CA-CAs-3 and soluble starch freshly prepared, stored for 15 days, 1 month, and 2 months. Figure 20 As can be seen in the PXRD diffraction pattern of DMY-CA-CAs-3 after two months of storage at 40°C and 75% RH in the presence of soluble starch, no new diffraction peaks appeared. Crystalline diffraction signals were detected in the PXRD spectrum of the starch / amorphous DMY mixture after 15 days, and the mixture was almost completely recrystallized after two months, maintaining a good stability. These results demonstrate that the mixture of DMY-CA-CAs co-amorphous sample and soluble starch exhibits good stability and can be used in solid dosage form development.

[0151] The PXRD pattern of the mixture of soluble starch and DMY-STD-CAS-3 is as follows: Figure 21 As shown, a is the newly prepared soluble starch, b is the soluble starch after storage for 30 days, c is the physical mixture of the newly prepared soluble starch and DMY-STD-CAs-3, and d is the physical mixture of the soluble starch and DMY-STD-CAs-3 after storage for 30 days. Figure 21 It can be seen that after storage in a closed environment at 75% RH and 40°C for one month, both soluble starch and DMY-STD-CAS-3 maintained amorphous characteristics, no crystal signal was detected, and the physical stability was good, indicating that DMY-STD-CAS-3 and soluble starch have good compatibility and there is no interaction between the two components.

[0152] The PXRD pattern of the mixture of microcrystalline cellulose and DMY-Na2GA-CAs-3 is as follows Figure 22 As shown, from Figure 22 It can be seen that the newly prepared microcrystalline cellulose has an amorphous characteristic. After DMY-Na2GA-CAs-3 is mixed with microcrystalline cellulose and stored in a closed environment at 75% RH and 40°C for one month, the PXRD of the mixture still shows a wide dispersion and no crystal signal is detected, which is an amorphous characteristic, indicating that DMY-Na2GA-CAs-3 has good compatibility with microcrystalline cellulose and there is no interaction between the two components.

[0153] 13. Moisture absorption test:

[0154] The hygroscopicity of DMY, STD, DMY-STD-PM, and DMY-STD-CAs was tested at 25°C and 75% RH according to the Pharmacopoeia of the People's Republic of China (2020 edition), General Chapter 9103 - Hygroscopicity Test Guidelines. The results are shown in Table 5.

[0155] Table 5. Hygroscopicity of each sample (x±s, n=3, mg / mL)

[0156]

[0157] Compared with the DMY group: ** P < 0.01, *** P<0.001; compared with STD group: # P<0.05, ## P < 0.01, ### P<0.001.

[0158] ** P<0.01, *** P<0.001vsDMY group; # P<0.05, ## P<0.01, ### P<0.001vs STD group.

[0159] As shown in Table 5, the moisture absorption weight gain rates of STD and DMY-STD-PM are greater than 2%, indicating that they are hygroscopic; the moisture absorption weight gain rates of DMY and DMY-STD-CAs are both between 0.2% and 2%, indicating that they are slightly hygroscopic.

[0160] 14. Dynamic hygroscopicity test:

[0161] DMY, STD, DMY-STD-PM-3 and DMY-STD-CAs-3 were selected to further investigate the changes in moisture absorption with ambient humidity. The percentage of moisture absorption weight gain was calculated according to the general rule 9103-hygroscopicity test guideline of the 2020 edition of the Pharmacopoeia of the People's Republic of China. The results are shown in the table. Figure 23 , where A is DMY-STD-CAs-3, B is DMY, C is STD, and D is DMY-STD-PM-3.

[0162] from Figure 23 The moisture absorption of the four samples was positively correlated with ambient humidity. The critical relative humidity for DMY, STD, and DMY-STD-PM-3 was around 70% RH. The moisture absorption increments for DMY, STD, and DMY-STD-PM-3 at 25°C and 92.5% RH were (2.31±0.16)%, (4.26±0.25)%, and (5.03±0.30)%, respectively, indicating that STD and DMY-STD-PM-3 were sensitive to high humidity conditions. The moisture absorption increment for DMY-STD-CAs-3 was relatively small across all humidity environments, reaching (1.08±0.12)% at 25°C and 92.5% RH.

[0163] It should be understood that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Those skilled in the art may modify the technical solutions described in the above embodiments, or make equivalent replacements for some of the technical features therein; and all these modifications and replacements should fall within the scope of protection of the claims attached to the present invention.

Claims

1. A co-amorphous system for improving the water solubility of dihydromyricetin, characterized by: The invention comprises dihydromyricetin and a hydrophilic component in a molar ratio of (2-1):(1-3), wherein the hydrophilic component is chlorogenic acid, sodium taurine deoxycholate or disodium glycyrrhizate, and is prepared by a reduced pressure evaporation method.

2. The co-amorphous system for improving the water solubility of dihydromyricetin according to claim 1, characterized in that: The hydrophilic component is chlorogenic acid, and the molar ratio of dihydromyricetin to chlorogenic acid is (1-2):(1-2).

3. The co-amorphous system for improving the water solubility of dihydromyricetin according to claim 2, characterized in that: The molar ratio of dihydromyricetin to chlorogenic acid is 1:

2.

4. The co-amorphous system for improving the water solubility of dihydromyricetin according to claim 1, characterized in that: The hydrophilic component is sodium taurodeoxycholate, and the molar ratio of dihydromyricetin to sodium taurodeoxycholate is 1:(1-3).

5. The co-amorphous system for improving the water solubility of dihydromyricetin according to claim 4, characterized in that: The molar ratio of dihydromyricetin to sodium taurine deoxycholate is 1:

3.

6. The co-amorphous system for improving the water solubility of dihydromyricetin according to claim 1, characterized in that: The hydrophilic component is disodium glycyrrhizate, and the molar ratio of dihydromyricetin to disodium glycyrrhizate is (1-2):(1-2).

7. The co-amorphous system for improving the water solubility of dihydromyricetin according to claim 6, characterized in that: The molar ratio of the dihydromyricetin to disodium glycyrrhizate is 1:

2.

8. The method for preparing a co-amorphous system according to any one of claims 1 to 7, characterized in that: The following steps are involved: S1. Add a solvent to a certain proportion of dihydromyricetin and a hydrophilic component to dissolve the mixture, and ultrasonicate the mixture until the mixture is clear to obtain a clear solution; S2. Place the clarified solution in a water bath at 50-70° C., and evaporate the solvent under reduced pressure to obtain a dihydromyricetin-hydrophilic component co-amorphous system.

9. The preparation method according to claim 7, characterized in that: When the hydrophilic component is chlorogenic acid, the solvent is anhydrous ethanol; when the hydrophilic component is sodium taurine deoxycholate, the solvent is methanol; when the hydrophilic component is disodium glycyrrhizate, the solvent is methanol-water solution, and the volume ratio of methanol to water in the methanol-water solution is 4:1.

Images