Daidzein ion pair compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly discloses daidzein ion pair compounds as well as a preparation method and application thereof. The daidzein ion pair compound disclosed by the invention is prepared from daidzein and counter ions through a solvent evaporation method, the molar ratio of daidzein to counter ions is 2: (1-4), and the drug loading capacity is 10-50%. Crystal lattices and dimer structures of daidzein are broken through the action of ion hydrogen bonds; meanwhile, the ion pairs can directly change the solubility, the fat solubility and the permeability of the medicine without changing the chemical structure and the pharmacological action of the medicine; and the obtained daidzein ion pair compound improves the solubility and dissolution rate of insoluble drugs, has high drug loading capacity and good stability, and can be further prepared into liposomes, microspheres, particles and patches, and the preparation method is simple and easy to operate.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines and relates to a soybean aglycone ion pair compound, a preparation method thereof and application thereof in a pharmaceutical intermediate. Background Art

[0002] Daidzein (7,4'-diphenolic hydroxy isoflavone, Daidzein), also known as kudzu root soybean flavonoids, daidzein, soybean flavonoids or soybean yellow, is widely found in beans, grains, fruits, vegetables and other plants, as well as foods such as tofu. The highest content is in soybeans, averaging 676-1001 mg / kg, and it belongs to the class of soybean isoflavone compounds. Modern studies have shown that daidzein can have multiple pharmacological effects such as anti-osteoporosis, anti-tumor, cardiovascular and cerebrovascular protection, bidirectional regulation of estrogen, anti-oxidation, improving the body's immunity and affecting the endocrine system. However, daidzein contains two phenolic hydroxyl groups, which can form intermolecular hydrogen bonds, resulting in poor water solubility and fat solubility, affecting oral absorption, and thus limiting the effect of clinical application.

[0003] At present, in order to solve the problem of poor solubility of daidzein, researchers have adopted many methods, such as the Chinese invention patent CN 110156736 A, which discloses "daidzein amino acid ester prodrugs, salts thereof, and preparation and application thereof". This technology uses daidzein and L-configuration amino acids as raw materials, and modifies the phenolic hydroxyl groups at the 7-position and 4'-position of daidzein by carbonylation reagents, alkaline catalysts and aprotic solvents to obtain daidzein amino acid ester prodrugs and pharmaceutically acceptable salts thereof. Although this invention significantly improves the water solubility and fat solubility of daidzein, the preparation method is complicated, and the organic solvents used are of many types and large quantities, which are difficult to remove and easily cause industrial pollution.

[0004] Chinese invention patent CN 108836944 A discloses "a soybean aglycone long-circulation liposome oral lyophilized preparation and its preparation method". This technology uses soybean aglycone, egg yolk phospholipids, cholesterol, DPPE-MPEG2000, solubilizer and lyophilization protectant as raw materials, and adopts thin film ultrasound method and freeze drying method to obtain soybean aglycone long-circulation liposome oral lyophilized preparation. This preparation has a sustained release effect, can prolong the residence time and half-life in the body, and improve blood drug concentration and bioavailability. However, the production cost of the freeze drying method is high, and the large volume of liposomes increases the difficulty of targeting.

[0005] In addition, an ion pair refers to a pair of ions formed by two ions with opposite charges combined by Coulomb attraction. Unlike prodrugs, drugs with ionizable groups combine with counterions to form ion pairs, which can directly change the physicochemical properties of the drug (such as solubility, lipid solubility and permeability, etc.) without changing its chemical structure and pharmacological effects. In recent years, mabuterol, strychnine, dexmedetomidine and bisoprolol have been successfully prepared and marketed through ion pair technology.

[0006] The present invention first uses the ion pair drug loading technology to prepare the daidzein ion pair compound, and improves the solubility of daidzein by forming hydrogen bonds between the phenolic hydroxyl group of daidzein and the amino group of amino acids. At the same time, the prepared daidzein ion pair compound of the present invention has good stability and meets the clinical requirements. Summary of the Invention

[0007] In view of this, the purpose of the present invention is to provide a daidzein ion pair compound that significantly improves the solubility and dissolution rate of daidzein, thereby improving its bioavailability, and is technically feasible and has a simple preparation process, aiming at the problems existing in the prior art.

[0008] In order to achieve the above object, the technical solution of the present invention is as follows:

[0009] A daidzein ion pair compound, which is composed of a daidzein molecule and a counter ion, and the counter ion improves the dissolution of the drug, which is 2 to 5 times higher than that of the raw drug, and the molar ratio of the daidzein molecule to the counter ion is 2:(1-4), and the drug loading is 10% to 50%.

[0010] Among them, the daidzein group is composed of crystal form II, belonging to the orthorhombic crystal system, and the space group is P2 1 2 1 2 1 , and an asymmetric unit includes one daidzein molecule. As Figure 1 shown, two daidzein molecules form intermolecular hydrogen bonds through 7-OH and 4'-OH, and the arrangement of the crystal lattice and the formation of hydrogen bonds lead to an increase in the intermolecular force of daidzein and a decrease in its water solubility.

[0011] Moreover, as Figure 2 shown, an ionic hydrogen bond is formed between the amino group of the counter ion and the phenolic hydroxyl group of the drug molecule, breaking the dimer structure of the drug molecule and improving the water solubility of the drug.

[0012] In addition, the bonding agent is any one or several of L-arginine, L-lysine, glutamic acid, threonine, phenylalanine, succinic acid, nicotinamide and gallic acid, and its molar ratio to the daidzein molecule is (1-4):2. L-arginine and L-lysine are preferred, and the results are shown in Table 1.

[0013] Table 1 Influence of different counter ions on the solubility of daidzein (72h)

[0014]

[0015] Note: All values are

[0016] The molar ratio of the above counter ion to daidzein is 1:1.

[0017] The present invention also claims the preparation method of the above-mentioned daidzein ion pair compound, which is to mix daidzein and counter ion and then prepare the ion pair compound by solvent evaporation method.

[0018] Specifically, a preparation method of a daidzein ion pair compound includes the following steps:

[0019] 1) Add 20 mL of 70% methanol (V / V) to the physical mixture of API and counter ion with different molar ratios. First, stir on a magnetic stirrer for 30 min at a rotation speed of 300 r / min to completely dissolve the drug.

[0020] 2) Ultrasonic the solution, filter it with a 0.22 μm filter membrane, place the filtrate in a fume hood, and let it stand for 3 - 5 d to naturally evaporate to dryness, then the ion pair compound can be obtained.

[0021] Preferably, in the above steps 1) and 2), the temperature is room temperature and the ultrasonic time is 60 min.

[0022] Another object of the present invention is to provide the application of the daidzein ion pair compound in the medical field.

[0023] In some application scenarios, it also includes the application of the daidzein ion pair compound in drug intermediates.

[0024] Specifically, the daidzein-arginine ion pair compound exists as 5 - 10 μm bone spur-shaped crystals, and the daidzein-lysine ion pair compound exists as hexagonal columnar crystals with a diameter of about 2 μm, as Figure 3 shown; and the daidzein ion pair compound can be further prepared into liposomes, microspheres, microparticles and patches.

[0025] According to the above technical solutions, compared with the prior art, the present invention provides a daidzein ion pair compound, its preparation method and application, and has the following excellent effects:

[0026] 1. An ion hydrogen bond is formed between the daidzein molecule and the counter ion in the daidzein ion pair compound of the present invention, breaking the dimer structure of the drug molecule and significantly increasing the solubility and dissolution rate.

[0027] 2. The daidzein molecule combines with the counter ion to form an ion pair, which can directly change the solubility, lipophilicity and permeability of the drug without changing its chemical structure and pharmacological effects.

[0028] 3. The daidzein ion pair compound of the present invention can achieve rapid release in an aqueous medium under non-sink conditions, with the cumulative dissolution amount not less than 60% within 20 to 120 minutes, and a kind of microparticle with a particle size not greater than 2.0 μm will be formed after dissolution, and there is no obvious aggregation within 12 hours, which is helpful for gastrointestinal absorption.

[0029] 4. The present invention prepares the ion pair compound by the solvent evaporation method. The preparation method is simple, easy to operate, and the amount of organic solvent used is small and easy to remove. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the following drawings are only the embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained according to the provided drawings.

[0031] Figure 1 It is a dimer diagram of daidzein crystal form II of the present invention.

[0032] Figure 2 It is a schematic diagram of the daidzein ion pair compound of the present invention (a daidzein-arginine ion pair compound, b daidzein-lysine ion pair compound).

[0033] Figure 3 It is a scanning electron microscope image of the daidzein ion pair compound of the present invention (a daidzein, b arginine, c lysine, d daidzein-arginine ion pair, e daidzein-lysine ion pair).

[0034] Figure 4 It is the (a) powder X-ray diffraction pattern, (b) differential scanning calorimetry pattern, (c) infrared spectrum, (d) nuclear magnetic resonance hydrogen spectrum of the daidzein ion pair compound of the present invention.

[0035] Figure 5 It is the X-ray photoelectron spectroscopy of the daidzein ion pair compound of the present invention.

[0036] Figure 6 It is the dissolution curve of the daidzein ion pair compound of the present invention in an aqueous medium.

[0037] Figure 7 It is the computer simulation diagram of the daidzein ion pair compound of the present invention (a, b molecular surface electrostatic potential, c molecular dynamics simulation diagram, d hydrogen bond movement trajectory diagram, e hydrogen bond bond angle and bond length statistical chart).

[0038] Figure 8This is the storage stability test of the daidzein ion pair compound of the present invention (a daidzein, b daidzein-arginine ion pair, c daidzein-lysine ion pair). Detailed implementation manners

[0039] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts shall fall within the protection scope of the present invention.

[0040] The embodiment of the present invention discloses a preparation method of a daidzein ion pair compound.

[0041] To better understand the present invention, the following embodiments are used to further specifically elaborate the present invention, but it should not be construed as a limitation of the present invention. For those skilled in the art, some non-essential improvements and adjustments made according to the above invention content are also considered to fall within the protection scope of the present invention.

[0042] Next, the technical solutions of the present invention will be further described in conjunction with specific embodiments.

[0043] Example 1:

[0044] Prescription: Preparation of daidzein-arginine ion pair compound by solvent evaporation method (molar ratio 1 / 1)

[0045]

[0046]

[0047] Weigh 0.5085 g of daidzein and 0.3484 g of L-arginine. Add 20 mL of 70% methanol to the physical mixture of daidzein and L-arginine, and stir at 300 r / min on a magnetic stirrer at room temperature for 30 min to completely dissolve the drug;

[0048] Ultrasonic the solution at room temperature for 60 min, filter it with a 0.22 μm filter membrane, discard the insoluble matter, collect the filtrate and place it in a fume hood, and let it dry naturally for 3 - 5 days to obtain the ion pair compound.

[0049] Example 2:

[0050] Prescription: Preparation of daidzein-arginine ion pair compound by solvent evaporation method (molar ratio 1 / 2)

[0051]

[0052] Weigh 0.5085 g of daidzein and 0.6968 g of L-arginine. Add 20 mL of 70% methanol to the physical mixture of daidzein and L-arginine, and stir it on a magnetic stirrer at room temperature for 30 min at a rotation speed of 300 r / min to completely dissolve the drug.

[0053] Ultrasonicate the solution at room temperature for 60 min, filter it through a 0.22-μm filter membrane, discard the insoluble matter, collect the filtrate and place it in a fume hood, and let it stand for 3 - 5 days to naturally evaporate to dryness, then the ion pair compound can be obtained.

[0054] Example 3:

[0055] Prescription: Preparation of daidzein-arginine ion pair compound by solvent evaporation method (molar ratio 2 / 1)

[0056]

[0057] Weigh 0.5085 g of daidzein and 0.1742 g of L-arginine. Add 20 mL of 70% methanol to the physical mixture of daidzein and L-arginine, and stir it on a magnetic stirrer at room temperature for 30 min at a rotation speed of 300 r / min to completely dissolve the drug.

[0058] Ultrasonicate the solution at room temperature for 60 min, filter it through a 0.22-μm filter membrane, discard the insoluble matter, collect the filtrate and place it in a fume hood, and let it stand for 3 - 5 days to naturally evaporate to dryness, then the ion pair compound can be obtained.

[0059] Example 4:

[0060] Prescription: Physical mixture of daidzein-arginine (molar ratio 1 / 2)

[0061]

[0062] Weigh 0.5085 g of daidzein and 0.6968 g of L-arginine, and after fully mixing evenly, the physical mixture of daidzein-arginine can be obtained.

[0063] In addition, to further elaborate on the non-obviousness of the present invention compared with the prior art, the inventor also conducted the following comparative experiments:

[0064] Comparative Example 1:

[0065] Prescription: Preparation of daidzein-lysine ion pair compound by solvent evaporation method (molar ratio 1 / 1)

[0066]

[0067] Weigh 0.5085 g of daidzein and 0.2924 g of L-lysine, and the specific preparation method is the same as that in Example 1.

[0068] Comparative Example 2:

[0069] Prescription: Preparation of daidzein-lysine ion pair compound by solvent evaporation method (molar ratio 1 / 2)

[0070]

[0071] Weigh 0.5085 g of daidzein and 0.5848 g of L-lysine, and the specific preparation method is the same as that in Example 2.

[0072] Comparative Example 3

[0073] Prescription: Preparation of daidzein-lysine ion pair compound by solvent evaporation method (molar ratio 2 / 1)

[0074]

[0075] Weigh 0.5085 g of daidzein and 0.1462 g of L-lysine, and the specific preparation method is the same as that in Example 3.

[0076] Comparative Example 4:

[0077] Prescription: Physical mixture of daidzein and lysine (molar ratio 1 / 1)

[0078]

[0079]

[0080] Weigh 0.5085 g of daidzein and 0.2924 g of L-lysine, and the specific preparation method is the same as that in Example 4.

[0081] Example 5: Elucidation of the formation mechanism of daidzein ion pair compound

[0082] 1. Powder X-ray diffraction pattern, differential scanning calorimetry pattern, infrared spectrum and nuclear magnetic resonance hydrogen spectrum of daidzein ion pair compound

[0083] 1.1 Experimental grouping

[0084] Daidzein, arginine, lysine, physical mixture of daidzein and arginine (preparation method see Example 4), daidzein-arginine ion pair (preparation method see Example 2), physical mixture of daidzein and lysine (preparation method see Comparative Example 4), daidzein-lysine ion pair (preparation method see Comparative Example 1).

[0085] 1.2 Result analysis

[0086] From Figure 4(a) As can be seen, in PXRD, the diffraction peak positions of daidzein and counterions in the physical mixture did not shift; however, the diffraction peaks of daidzein - amino acid in the ion - pair compound shifted. From Figure 4 (b) As can be seen, in DSC, no endothermic peaks of daidzein and counterions were observed in the physical mixture; however, new endothermic peaks were observed in the ion - pair compound. The results of PXRD and DSC indicate that new substances may be formed during the solvent evaporation process. From Figure 4 (c) As can be seen, in FTIR, the 3147.70 cm⁻¹ (O - H stretching vibration peak) in the arginine ion - pair blue - shifted to 3143.98 cm⁻¹, and the 3147.70 cm⁻¹ (O - H stretching vibration peak) in the lysine ion - pair blue - shifted to 3115.98 cm⁻¹. From Figure 4 (d) As can be seen, in 1 ¹H NMR, after the formation of the ion - pair, the resonance peak at 3.35 ppm shifted to 3.17 ppm. The results of FTIR and 1 ¹H NMR show that there is an interaction between the phenolic hydroxyl group of daidzein and the amino group of amino acids, forming a hydrogen bond.

[0087] 2. X - ray photoelectron spectroscopy of daidzein ion - pair compounds

[0088] 2.1 Experimental grouping

[0089] Arginine, lysine, daidzein - arginine ion - pair (the preparation method is shown in Example 2) and daidzein - lysine ion - pair (the preparation method is shown in Comparative Example 1).

[0090] 2.2 Result analysis

[0091] From Figure 5 it can be seen that two diffraction peaks were found at 399.48 eV and 399.78 eV, corresponding to the free - NH of lysine 2 and =NH of arginine respectively. The diffraction peak of daidzein - arginine ion - pair at 400.88 eV corresponds to - NH 2 + , and the diffraction peak of daidzein - lysine ion - pair at 400.48 eV corresponds to - NH 3 + . The XPS results show that ion - pairs are formed between daidzein and arginine or lysine.

[0092] Example 6: Determination of the dissolution rate of daidzein and daidzein ion - pair compounds

[0093] 1. Experimental grouping

[0094] Daidzein, daidzein-arginine ion pair (for the preparation method, see Example 2), and daidzein-lysine ion pair (for the preparation method, see Comparative Example 1).

[0095] 2. Experimental method

[0096] According to the Chinese Pharmacopoeia (2020 Edition), the dissolution studies of daidzein and ion pair compounds were carried out at 37 ± 0.5 °C by the paddle method at 100 rpm. Deionized water was used as the dissolution medium. An appropriate amount of the bulk drug (5 mg) and the preparation (containing 5 mg of the bulk drug) were evenly scattered on the surface of 900 mL of the medium, and then 5 mL of samples were taken at 5, 10, 15, 20, 30, 45, 60, 90, and 120 min. The samples were filtered through a 0.22 μm water-based filter, and the corresponding volume of isothermal medium was replenished. The absorbance of the drug was measured at 249 nm using a liquid chromatograph.

[0097] 3. Result analysis

[0098] It can be seen from Figure 6 that compared with daidzein and other preparation groups, the daidzein-lysine ion pair compound (1 / 1) and the daidzein-arginine ion pair compound (1 / 2) have better dissolution curves in water. Compared with the bulk drug, the cumulative dissolution of the daidzein ion pair compound increased by 3 times. Moreover, in the aqueous medium, the cumulative dissolution of the ion pair compound after 90 min was above 65%.

[0099] Example 7: Computer simulation of daidzein ion pair compounds

[0100] 1. Experimental grouping

[0101] Daidzein-arginine ion pair (for the preparation method, see Example 2) and daidzein-lysine ion pair (for the preparation method, see Comparative Example 1).

[0102] 2. Test method

[0103] Materials Studio 2017 was used for the entire computer simulation process. The COMPASS II force field was used to represent the bonding and non-bonding interactions. The crystal structures of the molecules were obtained from the Cambridge Structural Database [Deposition Number: daidzein (1561888), L-arginine (855058), L-lysine (1042478)] and optimized using Forcite. Molecular docking was performed in the Blend module with daidzein as the base and the counterion as the screen to obtain the lowest energy framework of the ion pair. Then, energy optimization of the ion pair was carried out in the DMol3 module to obtain the electrostatic potential on the electron density isosurface. At the same time, the dipole moment and band gap of the ion pair were obtained using LDA(PWC) within DMol3. Finally, based on the actual ratio of daidzein to the counterion, an ion pair system was constructed in the Amorphous cell based on the SMART algorithm.

[0104] 3. Result Analysis

[0105] Table 2 Diffusion Coefficient and Cohesive Energy Density of Daidzein Ion Pair Compounds

[0106]

[0107] Table 3 Molecular Dipole Moment and Band Gap of Daidzein Ion Pair Compounds

[0108]

[0109] As can be seen from Table 2, the diffusion coefficient is often used to represent the lateral movement of drug molecules. The migration rate of daidzein in the arginine ion pair is faster than that in the lysine ion pair; the cohesive energy density is used to represent the strength of intermolecular interactions, and the interaction between daidzein and lysine is stronger.

[0110] As can be seen from Table 3, the dipole moment represents the vector of the charge distribution within a molecule. The larger the dipole moment, the greater the possibility of interaction between the molecule and other molecules. Compared with lysine, arginine has a higher potential for interaction with daidzein; a high band gap value corresponds to high chemical reactivity, indicating that the energy required to break the interactions within the system is low. Compared with lysine, the energy required to break the daidzein-arginine ion pair system is lower.

[0111] From Figure 7 (e), the definition criteria for hydrogen bonds include the distance "r" and the angle "θ", specifically 150° < θ ∠ O-H…H-N < 180°, Any deviation of the distance "r" and the angle "θ" from their most probable regions will reduce the stability of hydrogen bonds in the system. The hydrogen bond angle of arginine is greater than that of lysine in the range of 90° - 150°, and the trend is opposite in the range of 150° - 180°. That is, the hydrogen bond formed by lysine and daidzein is more stable. In range, the number of hydrogen bonds of lysine is more than that of arginine, while the trend is opposite in range. That is, lysine has more short hydrogen bonds and fewer long hydrogen bonds. Therefore, the hydrogen bond formed by lysine and daidzein is more stable and the interaction is stronger.

[0112] Example 8: Storage Stability Test of Daidzein Ion Pair Compounds

[0113] 1. Experimental Grouping

[0114] Daidzein, daidzein-arginine ion pair (preparation method see Example 2), and daidzein-lysine ion pair (preparation method see Comparative Example 1).

[0115] 2. Test Method

[0116] According to the Guidelines for Stability Testing of Raw Drugs and Preparations in Part 4 of the Chinese Pharmacopoeia 2020 Edition, the stress testing of daidzein and its ion pair compounds was carried out in an open petri dish (high temperature: 50 ± 2 °C, high humidity: 75% ± 5%, strong light: 4500 ± 500 lx). Sampling was carried out at 0 day and 10 days for PXRD and solubility tests.

[0117] 3. Result Analysis

[0118] Table 4 Solubility (mg / mL) of Daidzein and Daidzein Ion Pair Compounds during 10-day Storage

[0119]

[0120] Note: All values are

[0121] From Table 4 and Figure 8 it can be seen that during storage, the crystallinity of the ion pair compound increased slightly; there was no significant difference in the solubility of the ion pair compound in water on the 10th day compared with the 0th day. The results show that the ion pair compound has storage stability.

[0122] The foregoing description of the disclosed embodiments enables those skilled in the art to practice or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A soybean aglycone ion pair compound, characterized in that The daidzein ion pair compound is composed of daidzein molecules and counterions, and the molar ratio of the daidzein molecules to the counterions is 2:N, and the drug loading is 10% to 50%; wherein the counterions are arginine and lysine.

2. A soybean aglycone ion pair compound according to claim 1, characterized in that, The daidzein molecule is composed of crystal form II, and two daidzein molecules form intermolecular hydrogen bonds through 7-OH and 4′-OH; an ionic bond is formed between the amino group of the counter ion and the phenolic hydroxyl group of the daidzein molecule, thereby forming a hydrophobic ion pair.

3. A daidzein ion pair compound according to any one of claims 1 to 2, characterized in that: The amount of the counter ion is 20% to 60% of the daidzein ion pair compound.

4. The daidzein ion pair compound according to claim 1, characterized in that: The molar ratio of the daidzein molecule to the counterion is N, which is 1-4.

5. The daidzein ion pair compound according to claim 1, characterized in that: The ion pair compound is prepared by mixing daidzein molecules and counterions and then using a solvent volatilization method. The specific preparation steps include: Step 1: Vacuum-dry the daidzein molecules and counterions, sieve and mix, add 20 mL of 70% methanol and stir on a magnetic stirrer for 30 min at a speed of 300 r / min to completely dissolve the drug, and then ultrasonicate for 60 min; Step 2: Filter the solution obtained in step 1 through a 0.22 μm filter membrane, discard the insoluble matter, and place the supernatant in a fume hood to dry naturally for 3 to 5 days to obtain the daidzein ion pair compound; In the steps 1 and 2, both are carried out at room temperature.

6. Use of the daidzein ion pair compound according to claim 1 in preparing medicines.

7. The use according to claim 6, characterized in that: The application of the daidzein ion pair compound in the preparation of drug intermediates.

8. The use according to claim 7, characterized in that: The daidzein ion pair compound exists in the form of 5-10 μm bone spur-shaped crystals, and the daidzein ion pair compound exists in the form of hexagonal columnar crystals with a diameter of about 2 μm. The daidzein ion pair compound can be further prepared into liposomes, microspheres, microparticles and patches.

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