CN118420586A - Dihydroquercetin and picolinic acid eutectic crystal, preparation method, pharmaceutical composition and application thereof - Google Patents

Abstract

The present invention belongs to the field of medical technology, and discloses a dihydroquercetin and picolinic acid cocrystal, a preparation method, and a composition and use thereof. Specifically, the present invention discloses a new dihydroquercetin and picolinic acid cocrystal with dihydroquercetin (such as formula a) as a pharmaceutical active ingredient and picolinic acid (such as formula b) as a cocrystal ligand; a preparation method of dihydroquercetin and picolinic acid cocrystal; and the use of dihydroquercetin and picolinic acid cocrystal as a pharmaceutical active ingredient in the preparation of antioxidant, free radical scavenging, cell protection, and antiviral.

Description

Dihydroquercetin and picolinic acid cocrystal and preparation method and pharmaceutical composition and use thereof

Technical Field

The present invention discloses a cocrystal of dihydroquercetin and picolinic acid, a preparation method thereof, and a composition and use thereof. Specifically, the present invention discloses a cocrystal formed by dihydroquercetin and picolinic acid; a preparation method of the cocrystal of dihydroquercetin and picolinic acid; and the use of the cocrystal of dihydroquercetin and picolinic acid as a pharmaceutical active ingredient in the preparation of anti-oxidation, free radical scavenging and cell protection, anti-viral, anti-diabetic and anti-tumor drugs, belonging to the field of medical technology.

Background technique

Dihydroquercetin (Taxifolin), with a molecular formula of C ₁₅ H ₁₂ O ₇ , has a molecular structure as shown in a. Dihydroquercetin is a dihydroflavonol compound belonging to the P vitamin family, also known as (2R,3R)-3,3',4',5,7-pentahydroxyflavone, taxifolin, taxifolin, etc. It is widely found in larch, Douglas fir, Scots pine, etc. It has multiple pharmacological effects such as antioxidant, anti-tumor, anti-apoptosis, anti-inflammatory, protection of myocardial cells, hypoglycemic, improvement of endothelial cell function, anti-platelet aggregation, and influence on bone metabolism ^[1-4] . At the same time, it has a good protective effect on the liver and has a positive protective effect on brain damage caused by reperfusion. In recent years, it has attracted more and more attention. However, due to its poor water solubility and low bioavailability, it cannot be promoted in clinical applications. Wu Weiwei ^[5] prepared dihydroquercetin nanopowder and dihydroquercetin-γ-cyclodextrin inclusion complex to improve its solubility. Literature research shows that dihydroquercetin has been reported in two crystal forms (I and II) ^[6] , of which crystal form I is dihydroquercetin dipentahydrate, and its crystal structure has been reported, while dihydroquercetin crystal form II is a hydrate but its crystal structure has not been reported. The present invention is based on the principle of crystal engineering, using dihydroquercetin as the active pharmaceutical ingredient (API) and picolinic acid as the cocrystal former (CCF). The molecular formula of picolinic acid is C ₆ H ₅ NO ₂ , and its structural formula is shown in b.

According to domestic and foreign patent and literature searches, there is no report on the co-crystal of dihydroquercetin and picolinic acid.

Summary of the invention

One of the purposes of the present invention is to provide a state and description method of a co-crystal of dihydroquercetin and picolinic acid.

The second object of the present invention is to provide a method for preparing a co-crystal of dihydroquercetin and picolinic acid.

The third object of the present invention is to provide a mixed solid medicine containing a pure co-crystal of dihydroquercetin and picolinic acid, or a co-crystal of dihydroquercetin and picolinic acid in any non-zero ratio, and a composition thereof.

The fourth object of the present invention is to provide a pharmaceutical composition using dihydroquercetin and picolinic acid cocrystal as active ingredients, wherein the daily dosage is in the range of 5 to 3000 mg. The pharmaceutical composition includes tablets, capsules, pills, injection preparations, and sustained-release or controlled-release preparations.

The fifth object of the present invention is to provide a co-crystal of dihydroquercetin and picolinic acid, which has superior properties to dihydroquercetin in terms of solubility.

The sixth object of the present invention is to provide the use of dihydroquercetin and picolinic acid cocrystals and mixed solid substances containing dihydroquercetin and picolinic acid cocrystals as raw materials for active pharmaceutical ingredients in the preparation of antioxidant, free radical scavenging and cell protection, antiviral, antidiabetic and antitumor drugs.

In order to solve the above technical problems, the present invention adopts the following technical solutions:

1. Morphological characteristics of dihydroquercetin and picolinic acid cocrystal samples:

1.1 The dihydroquercetin and picolinic acid co-crystal of the present invention is a co-crystal formed by dihydroquercetin and picolinic acid in a molar ratio of 1:1.

1.2 The dihydroquercetin and picolinic acid cocrystal of the present invention, when analyzed by single crystal X-ray diffraction, exhibits monoclinic symmetry, a space group of P2 ₁ /c, and unit cell parameters of: α=90°, β=103.423°, γ=90°. unit cell volume Molecular formula MF = C ₁₅ H ₁₂ O ₇ · C ₆ H ₅ NO ₂ . FIG1 shows the molecular stereostructure projection diagram of dihydroquercetin and picolinic acid cocrystal, FIG2 shows the unit cell stacking diagram of dihydroquercetin and picolinic acid cocrystal along the a axis, and Table 1 shows the non-hydrogen atom coordinate parameters of dihydroquercetin and picolinic acid cocrystal.

Table 1 Non-hydrogen atomic coordinate parameters of dihydroquercetin and picolinic acid cocrystal

1.3 The dihydroquercetin and picolinic acid cocrystals of the present invention, when analyzed by powder X-ray diffraction using CuK _α radiation experimental conditions, the diffraction peak position 2-Theta value (°) or d value The relative intensity peak height value (Height%) or peak area value (Area%) of the diffraction peak is expressed as follows (Table 2, Figure 3); the theoretical powder diffraction pattern of the cocrystal of dihydroquercetin and picolinic acid, the experimental powder diffraction pattern, and the superposition of the powder X-ray diffraction patterns of the dihydroquercetin and picolinic acid samples are shown in Figure 4. As shown in Figure 4, the PXRD pattern of the cocrystal of dihydroquercetin and picolinic acid is different from the PXRD patterns of dihydroquercetin and picolinic acid, indicating that a new phase is formed, and the theoretical powder pattern of the cocrystal of dihydroquercetin and picolinic acid is basically consistent with the experimental powder pattern, indicating that the obtained cocrystal of dihydroquercetin and picolinic acid is a pure crystalline product.

Table 2 Powder X-ray diffraction peaks of dihydroquercetin and picolinic acid cocrystal samples

1.4 The dihydroquercetin and picolinic acid cocrystals of the present invention, when analyzed by attenuated total reflection Fourier transform infrared spectroscopy, have infrared spectrum characteristic peaks at 3672, 3421, 3086, 2987, 2884, 2723, 2630, 2161, 1661, 1627, 1594, 1521, 1472, 1444, 1388, 1358, 1293, 1271, 1210, 1188, 1154, 1142, 1082, 1027, 1010, 996, 952, 861, 823, 814, 783, 758, 685, and 669 cm ^-1 , wherein the allowable deviation of the infrared spectrum characteristic peaks is ± 2 cm ^-1 ( FIG. 5 ).

1.5 The dihydroquercetin and picolinic acid cocrystals involved in the present invention, when analyzed using differential scanning calorimetry, show that in the range of 30 to 270°C, when the heating rate is 10°C per minute, there is an endothermic peak at 218°C±3°C in its DSC spectrum; the DSC comparison spectrum of dihydroquercetin, picolinic acid and dihydroquercetin and picolinic acid cocrystals is shown in Figure 6. The DSC spectrum of dihydroquercetin and picolinic acid cocrystals is significantly different from that of dihydroquercetin and picolinic acid in terms of the number and position of endothermic/exothermic peaks, indicating that dihydroquercetin and picolinic acid cocrystals are a new cocrystal substance.

2. Characteristics of the preparation method of dihydroquercetin and picolinic acid cocrystal and mixed solid material:

2.1 The preparation method of dihydroquercetin and picolinic acid cocrystals of the present invention is to feed dihydroquercetin and picolinic acid in a molar ratio of 1:1, and prepare dihydroquercetin picolinic acid by a mechanochemical method. The mechanochemical method is preferably a liquid-adding ball milling method, wherein the ball-to-material ratio of the liquid-adding ball milling method is 1:1 to 10:1, preferably 4:1 to 6:1; the ball milling speed is 20r/min to 400r/min; the liquid-added organic solvent is selected from any one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isopentanol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane, and cyclohexane, and the mixed solvent is prepared by combining different proportions; the amount of liquid added is 0.01 to 100 ml; the grinding time is 0.1 to 10 hours.

2.2 The preparation method of dihydroquercetin and picolinic acid cocrystals of the present invention is as follows: dihydroquercetin and picolinic acid are put into a clean container in a molar ratio of 1:1, an organic solvent is added to form a suspension, and the suspension is stirred at room temperature for 0.5 to 4 days. The obtained suspension is dried by solvent evaporation, filtered and dried naturally, or filtered and vacuum dried to obtain dihydroquercetin and picolinic acid cocrystals. The organic solvent is preferably selected from any one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isopentanol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane, and cyclohexane, and the mixed solvent is prepared by combining different proportions; the total mass of dihydroquercetin and picolinic acid and the solid-liquid ratio of the organic solvent are kept within the range of 1 mg/ml to 500 mg/ml.

2.3 The present invention relates to a method for preparing a cocrystal of dihydroquercetin and picolinic acid, wherein dihydroquercetin and picolinic acid are added in a molar ratio of 1:1, and a solution crystallization method is used to prepare the cocrystal of dihydroquercetin and picolinic acid. The solvent type of the solution crystallization method is a mixed solvent prepared by combining any one or more organic solvents in different proportions; the organic solvent is selected from any one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isopentanol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane, and cyclohexane in different proportions; the crystallization temperature is 4-60°C, and the crystallization time is 12h-30d.

2.4 The mixed solid material containing dihydroquercetin and picolinic acid cocrystal and other components involved in the present invention is prepared by mixing the dihydroquercetin and picolinic acid cocrystal component prepared by the above method with other chemical components in any non-zero ratio and in a conventional manner.

3. Characteristics of the composition, dosage and pharmaceutical preparation composition of dihydroquercetin and picolinic acid cocrystal:

3.1 The pharmaceutical composition of the present invention is characterized in that it contains an effective dose of dihydroquercetin and picolinic acid co-crystal, or a mixed solid material containing dihydroquercetin and picolinic acid co-crystal and a pharmaceutically acceptable carrier.

3.2 The pharmaceutical composition of the present invention uses dihydroquercetin and picolinic acid cocrystal as active pharmaceutical ingredients, and the daily dosage is in the range of 5 to 3000 mg.

3.3 The pharmaceutical composition involved in the present invention is characterized in that the pharmaceutical composition is various tablets, capsules, pills, injection preparations, sustained-release preparations or controlled-release preparations.

3.4 The present invention relates to the use of dihydroquercetin and picolinic acid cocrystals or mixed solid materials containing dihydroquercetin and picolinic acid cocrystals in any proportion in the preparation of antioxidant, free radical scavenging and cell protection, antiviral, antidiabetic and antitumor drugs.

The present invention relates to a pharmaceutical composition with the dihydroquercetin and picolinic acid cocrystal of the present invention as active ingredients. The pharmaceutical composition can be prepared according to methods known in the art. The dihydroquercetin and picolinic acid cocrystal components of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants to prepare any dosage form suitable for human or animal use. The content of the dihydroquercetin and picolinic acid cocrystal of the present invention in the pharmaceutical composition is in the range of 10% to 90% by weight.

The dihydroquercetin and picolinic acid cocrystal of the present invention can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

The dosage form of the present invention is preferably a solid dosage form. The solid dosage form can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, aerosols (powders), sprays, etc.

The dihydroquercetin and picolinic acid cocrystal of the present invention can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

In order to prepare the dihydroquercetin and picolinic acid co-crystal tablets of the present invention, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

In order to prepare the dosing unit into a capsule, the active ingredient dihydroquercetin and picolinic acid cocrystal of the present invention can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient dihydroquercetin and picolinic acid cocrystal of the present invention can also be first made into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard capsule or a soft capsule. Various diluents, binders, wetting agents, disintegrants, and glidants used to prepare the dihydroquercetin and picolinic acid cocrystal tablets of the present invention can also be used to prepare the capsules of the dihydroquercetin and picolinic acid cocrystal of the present invention.

Furthermore, if necessary, colorants, preservatives, perfumes, flavoring agents or other additives may be added to the pharmaceutical preparations.

In order to achieve the purpose of medication and enhance the therapeutic effect, the drug of the present invention can be administered by any known administration method.

The dosage of the dihydroquercetin and picolinic acid cocrystal pharmaceutical composition of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual conditions of the patient or animal, the route of administration and the dosage form, etc. The above dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other treatment means.

The dihydroquercetin and picolinic acid cocrystal or composition of the present invention can be taken alone or used in combination with other therapeutic drugs or symptomatic drugs. When the dihydroquercetin and picolinic acid cocrystal of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

4. Beneficial technical effects of the present invention:

Safety, solubility, stability and bioactivity advantages of dihydroquercetin and picolinic acid cocrystals.

4.1 The dihydroquercetin and picolinic acid co-crystal of the present invention does not contain any crystallization solvent, and the co-crystal ligand picolinic acid used is safe to the human body and has good safety drug advantages.

4.2 The stability of the dihydroquercetin and picolinic acid cocrystal of the present invention is significantly better than that of dihydroquercetin ( FIG. 7 ).

4.3 The antioxidant activity of the dihydroquercetin and picolinic acid cocrystal of the present invention is significantly better than that of dihydroquercetin (Table 7).

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 Projection diagram of the molecular structure of dihydroquercetin and picolinic acid cocrystal

Figure 2 Crystal cell stacking diagram of dihydroquercetin and picolinic acid cocrystal along the a-axis

Figure 3 Powder X-ray diffraction pattern of dihydroquercetin and picolinic acid cocrystal

Figure 4 Theoretical powder diffraction pattern of dihydroquercetin and picolinic acid cocrystal, experimental powder diffraction pattern and superposition of powder X-ray diffraction patterns of dihydroquercetin and picolinic acid samples

Figure 5 Infrared absorption spectrum of dihydroquercetin and picolinic acid cocrystal

Figure 6 DSC comparison of dihydroquercetin, picolinic acid, and cocrystal of dihydroquercetin and picolinic acid

Figure 7 Stability spectrum of dihydroquercetin and picolinic acid cocrystal and dihydroquercetin

Detailed ways

In order to better illustrate the technical solution of the present invention, the following embodiments are given, but the present invention is not limited thereto.

Example 1

Preparation method of dihydroquercetin and picolinic acid cocrystal sample 1:

As shown in the table below, appropriate amounts of dihydroquercetin and picolinic acid were put into a mortar at a molar ratio of 1:1, an appropriate amount of organic solvent was added, and the mixture was manually ground for an appropriate time. Powder X-ray diffraction analysis was performed, and the diffraction pattern was consistent with Figure 3, indicating that the obtained sample was a cocrystal of dihydroquercetin and picolinic acid.

Table 3 Specific example of preparation method 1 of dihydroquercetin and picolinic acid cocrystal

Preparation method of dihydroquercetin and picolinic acid cocrystal sample 2:

As shown in the table below, appropriate amounts of dihydroquercetin and picolinic acid were put into a ball mill at a molar ratio of 1:1, an appropriate amount of organic solvent was added, an appropriate ball-to-material ratio was selected, an appropriate rotation speed was set, and the ball milling was performed for an appropriate time. A powder X-ray diffraction analysis was performed, and the diffraction pattern was consistent with Figure 3, indicating that the obtained sample was a cocrystal of dihydroquercetin and picolinic acid.

Table 4 Specific example of preparation method 2 of dihydroquercetin and picolinic acid cocrystal

Preparation method of dihydroquercetin and picolinic acid cocrystal sample 3:

As shown in the table below, appropriate amounts of dihydroquercetin and picolinic acid are taken in a molar ratio of 1:1 and put into a clean vial or conical flask, an appropriate amount of organic solvent is added, and the mixture is stirred at room temperature for an appropriate time. The insoluble matter is removed by filtration, and the filtrate is allowed to stand at room temperature until a solid precipitates, and the solid is filtered and dried or allowed to evaporate at room temperature. A powder X-ray diffraction analysis is performed, and the diffraction pattern is consistent with Figure 3, indicating that the obtained sample is a cocrystal of dihydroquercetin and picolinic acid.

Table 5 Specific example of preparation method 3 of dihydroquercetin and picolinic acid cocrystal

Preparation method of dihydroquercetin and picolinic acid cocrystal sample 4:

As shown in the table below, appropriate amounts of dihydroquercetin and picolinic acid are put into a clean vial or conical flask, and an appropriate amount of organic solvent is added to make a saturated solution, and dihydroquercetin and picolinic acid co-crystals are obtained by solvent evaporation method. The obtained crystals are dried and ground, and then subjected to powder X-ray diffraction analysis. The diffraction pattern is consistent with Figure 1, indicating that the obtained sample is a co-crystal of dihydroquercetin and picolinic acid.

Table 6 Specific example of preparation method 4 of dihydroquercetin and picolinic acid cocrystal

Example 2

Stability characteristics of dihydroquercetin and picolinic acid cocrystal:

Referring to the Guiding Principles for Accelerated Stability Studies of Solid Preparations in Part IV General Principles 9001 of the 2020 Edition of the Chinese Pharmacopoeia, dihydroquercetin and dihydroquercetin and picolinic acid cocrystal samples were placed under high temperature (60℃±1℃), high humidity (90%±5%, 25℃), and light (4500lx±500lx, 25℃) conditions, and taken out at 0 days, 5 days, and 10 days, respectively. The physical properties of the samples were determined by PXRD method. The phase change was investigated to investigate the difference in stability between the cocrystal of dihydroquercetin and picolinic acid and dihydroquercetin. The results showed that the PXRD pattern of dihydroquercetin after being placed at high temperature for 5 days showed new small diffraction peaks at 25.08° and 27.90°, while the PXRD pattern of the cocrystal of dihydroquercetin and picolinic acid did not change, indicating that the stability of the cocrystal of dihydroquercetin and picolinic acid was significantly better than that of dihydroquercetin, as shown in Figure 7.

Example 3

Antioxidant ability characteristics of dihydroquercetin and picolinic acid cocrystal:

The DPPH antioxidant screening model was used to investigate the difference in antioxidant capacity between dihydroquercetin and picolinic acid cocrystals and dihydroquercetin. The results showed that the antioxidant capacity of dihydroquercetin and picolinic acid cocrystals was superior to that of dihydroquercetin.

The diphenyl picrohydrazine free radical DPPH is a relatively stable lipid free radical with a free electron on its N. Its ethanol solution is purple and has the maximum absorption peak at 515nm. After adding antioxidants, DPPH captures an electron and pairs with the free electron, the purple fades and becomes a colorless substance. The absorption at 515nm disappears, and its fading degree is quantitatively related to the number of electrons it accepts. Based on this principle, the change in absorbance after the DPPH free radical reacts with the sample solution is detected by a spectrophotometer to reflect the ability of the sample to provide hydrogen atoms, remove free radicals and resist oxidation.

experimental method

An ethanol solution of DPPH free radical (25 μL/mL) was prepared, and 3 mL of the ethanol solution of DPPH free radical was mixed with 100 μL of ethanol solution, 100 μL of dihydroquercetin ethanol solution, and 100 μL of dihydroquercetin and picolinic acid cocrystal ethanol solution, respectively. The mixed samples were incubated in a 37°C water bath for 20 min, and then the absorbance was measured at a wavelength of 515 nm using a SpectraMax M5 spectrophotometer (Molecular Devices, USA).

Calculation method

Sample scavenging rate of lipid free radical DPPH (%) = (blank OD-sample OD)/blank OD×100%

In the formula, blank OD is the absorbance of the control group (without sample), and sample OD is the absorbance of the experimental group (containing dihydroquercetin and dihydroquercetin and picolinic acid cocrystal samples).

The DPPH radical scavenging antioxidant evaluation results of dihydroquercetin and picolinic acid cocrystal and dihydroquercetin are shown in Table 7

Table 7 Comparison of DPPH radical scavenging results between dihydroquercetin and picolinic acid cocrystal and dihydroquercetin

The results showed that in the range of 0.98-250 μM, the IC ₅₀ value of dihydroquercetin and picolinic acid cocrystal was 30.01 μM, which was significantly lower than that of dihydroquercetin 72.89 μM, indicating that the DPPH free radical scavenging ability of dihydroquercetin and picolinic acid cocrystal was significantly improved compared with dihydroquercetin.

Example 4

Preparation method 1 of combined pharmaceutical preparation (tablets):

A method for preparing a combined drug tablet, characterized in that dihydroquercetin and picolinic acid cocrystals and several excipients are used as auxiliary material components for preparing the combined drug tablets, and each tablet sample containing 10 to 500 mg of the cocrystal is prepared according to a certain ratio. Table 8 shows the tablet formula ratio:

Table 8 Preparation formula of dihydroquercetin and picolinic acid cocrystal combination drug tablets

The method of preparing a tablet preparation using dihydroquercetin and picolinic acid cocrystal as a raw material is as follows: several excipients are mixed evenly with the raw material and directly tableted; or the auxiliary materials are mixed and dry granulated and then mixed evenly with the raw material and then tableted.

Preparation method 2 of combined pharmaceutical preparation (tablets):

A method for preparing a combined drug tablet, characterized in that dihydroquercetin and picolinic acid cocrystals and several excipients are used as auxiliary material components for preparing the combined drug tablets, and each tablet sample containing 5 to 500 mg of the cocrystal is prepared according to a certain ratio. Table 9 shows the tablet formula ratio:

Table 9 Preparation formula of dihydroquercetin and picolinic acid cocrystal combination drug tablets

The method for preparing a tablet preparation using dihydroquercetin and picolinic acid cocrystal as a raw material is as follows: several excipients are mixed evenly with the raw material, an appropriate amount of 1% sodium hydroxymethylcellulose solution is added to make a soft material, sieve granules, dry the wet granules, sieve whole granules, add magnesium stearate and talcum powder, mix evenly, and press into tablets to obtain the tablet preparation.

Preparation method 2 of combined pharmaceutical preparation (capsules):

A method for preparing a combined drug capsule, characterized in that dihydroquercetin and picolinic acid cocrystals are used as raw materials, several excipients are used as auxiliary materials for preparing the combined drug capsule, and capsule samples with a drug content of 5 to 500 mg per tablet are prepared according to a certain ratio. Table 10 shows the capsule formula ratio:

Table 10 API and excipient formula of dihydroquercetin and picolinic acid cocrystal combination drug capsule preparation

The method for preparing capsules using dihydroquercetin and picolinic acid cocrystals as raw materials is as follows: uniformly mixing several excipients with the raw materials, adding an appropriate amount of 1% sodium hydroxymethylcellulose solution to prepare wet granules, drying and sieving the whole granules, adding magnesium stearate and mixing uniformly, and inserting the granules into capsules; or without using the granulation step, directly mixing the dihydroquercetin and picolinic acid cocrystals with several excipients and auxiliary materials, sieving, and directly filling the capsules to prepare the capsules.

Example 5

Dosage of dihydroquercetin and picolinic acid cocrystal combination drug 1 (tablet):

The pharmaceutical composition developed using dihydroquercetin and picolinic acid cocrystals as active pharmaceutical ingredients is characterized in that dihydroquercetin and picolinic acid cocrystals are used as active pharmaceutical ingredients, and the daily dosage is 150 mg, which can be prepared into 50 mg ordinary tablets for 3 times a day/one tablet each time, or 150 mg tablets for 1 time a day/one tablet each time.

Dosage of dihydroquercetin and picolinic acid cocrystal combination drug 2 (capsules):

The pharmaceutical composition developed using dihydroquercetin and picolinic acid cocrystals as active pharmaceutical ingredients is characterized in that dihydroquercetin and picolinic acid cocrystals are used as active pharmaceutical ingredients, and the daily dosage is 1200 mg, which can be prepared into 4 100 mg capsules 3 times a day/each time, or 2 300 mg capsules 2 times a day/each time.

Issues that need to be explained: There are many factors that affect the dosage of the active ingredients of the dihydroquercetin and picolinic acid cocrystal pharmaceutical composition involved in the present invention, such as: the patient's age, body surface area, administration route, number of administrations, and treatment purposes, resulting in different dosages for each medication; the absorption and blood drug concentrations between samples are different, which also cause the present invention to use the dihydroquercetin and picolinic acid cocrystal components. The appropriate dosage range is 0.05-300 mg/kg body weight, preferably 0.1-50 mg/kg body weight. When used, different total dosage plans of dihydroquercetin and picolinic acid cocrystal active ingredients should be formulated according to the actual treatment requirements of different situations, and can be completed in multiple or one-time administration.

references

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Claims (19)

1. A co-crystal of dihydroquercetin and picolinic acid, characterized in that dihydroquercetin and picolinic acid form a co-crystal in a molar ratio of 1:1. 2. The co-crystal of dihydroquercetin and picolinic acid according to claim 1, characterized in that, when analyzed by single crystal X-ray diffraction, it exhibits monoclinic symmetry, the space group is P2 ₁ /c, and the unit cell parameters are: α=90°, β=103.423°, γ=90°. unit cell volume 3. The dihydroquercetin and picolinic acid cocrystal according to claim 1, characterized in that when powder X-ray diffraction analysis is performed using CuK _α radiation experimental conditions, the diffraction peak position: 2-Theta value (°) or d value And the relative intensity of the diffraction peak: the peak height value (Height%) or the peak area value (Area%) has the following characteristics: 4. The dihydroquercetin and picolinic acid cocrystal according to claims 1-3, characterized in that when analyzed by infrared spectroscopy, there are infrared spectrum characteristic peaks at 3672, 3421, 3086, 2987, 2884, 2723, 2630, 2161, 1661, 1627, 1594, 1521, 1472, 1444, 1388, 1358, 1293, 1271, 1210, 1188, 1154, 1142, 1082, 1027, 1010, 996, 952, 861, 823, 814, 783, 758, 685, and 669 cm ^-1 , wherein the allowable deviation of the infrared spectrum characteristic peak is ±2 cm ^-1 . 5. The dihydroquercetin and picolinic acid cocrystal according to claims 1-3, characterized in that when analyzed using differential scanning calorimetry technology, there is an endothermic peak at 218°C±3°C in the DSC spectrum when the heating rate is 10°C per minute. 6. A method for preparing a co-crystal of dihydroquercetin and picolinic acid, characterized in that dihydroquercetin and picolinic acid are added in a molar ratio of 1:1, and the co-crystal of dihydroquercetin and picolinic acid is prepared by a mechanochemical method. 7. The preparation method according to claim 6, wherein the mechanochemical method is preferably a solvent-assisted grinding method, i.e., dihydroquercetin and picolinic acid raw materials with a molar ratio of 1:1 are placed in a mortar or a ball mill and mixed, an organic solvent is added to the mixed powder, and the mixed powder is ground and collected at room temperature to obtain dihydroquercetin and picolinic acid cocrystals, wherein the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isopentanol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane or cyclohexane; the ball mill speed is 20 r/min to 400 r/min, the liquid addition amount is 0.01 to 100 ml; the grinding time is 0.1 to 10 hours. 8. A method for preparing a cocrystal of dihydroquercetin and picolinic acid, characterized in that dihydroquercetin and picolinic acid are added in a molar ratio of 1:1 into a clean container, an organic solvent is added to form a suspension, and the suspension is stirred at room temperature for 0.1 to 4 days. The obtained suspension is dried by solvent evaporation, filtered and dried naturally, or filtered and vacuum dried to obtain a cocrystal of dihydroquercetin and picolinic acid. 9. The preparation method according to claim 8, wherein the organic solvent used is selected from any one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane, and cyclohexane, and the mixed solvent is prepared by combining them in different proportions; the solid-liquid ratio of the total mass of dihydroquercetin and picolinic acid to the organic solvent is maintained in the range of 1 mg/ml to 500 mg/ml. 10. A method for preparing a cocrystal of dihydroquercetin and picolinic acid, characterized in that dihydroquercetin and picolinic acid are added into a clean container at a molar ratio of 1:1 by a solvent volatilization method, an organic solvent is added and mixed uniformly to form a saturated solution, and the cocrystal of dihydroquercetin and picolinic acid is obtained by the solvent volatilization method. 11. The preparation method according to claim 10, wherein the organic solvent used is selected from a single solvent system of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane or cyclohexane, or a mixed solvent prepared by the above solvents in different proportions, with a crystallization temperature of 4-60°C and a crystallization time of 12h-30d. 12. A mixed solid material containing dihydroquercetin and picolinic acid cocrystals and other ingredients, characterized in that the amount of the dihydroquercetin and picolinic acid cocrystals according to any one of claims 1 to 3 is 1-99.9%, preferably 10-99.9%, more preferably 50-99.9%, and most preferably 85-99.9%. 13. A pharmaceutical composition, characterized in that it contains an effective dose of the dihydroquercetin and picolinic acid cocrystal according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier. 14. A pharmaceutical composition, characterized in that it contains an effective dose of the dihydroquercetin and picolinic acid cocrystal mixed solid material according to claim 12 and a pharmaceutically acceptable carrier. 15. The pharmaceutical composition according to any one of claims 13 or 14, characterized in that the daily dosage of the co-crystal of dihydroquercetin and picolinic acid is in the range of 5 to 3000 mg. 16. The pharmaceutical composition according to any one of claim 13 or claim 14, characterized in that the pharmaceutical composition is selected from tablets, capsules, pills or injection preparations. 17. The pharmaceutical composition according to any one of claim 13 or claim 14, characterized in that the pharmaceutical composition is selected from a sustained-release preparation or a controlled-release preparation. 18. Use of the dihydroquercetin and picolinic acid cocrystal according to any one of claims 1 to 3 and/or the dihydroquercetin and picolinic acid cocrystal mixed solid material according to claim 12 in the preparation of antioxidant, free radical scavenging and cell protection, antiviral, antidiabetic and antitumor drugs. 19. Use of the pharmaceutical composition according to any one of claims 13 or 14 in the preparation of anti-oxidation, free radical scavenging and cell protection, anti-viral, anti-diabetic and anti-tumor drugs.