CN115154458A - Preparation method of quercetin-metformin hydrochloride compound hypoglycemic drug - Google Patents
Preparation method of quercetin-metformin hydrochloride compound hypoglycemic drug Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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Abstract
The invention discloses a preparation method of a quercetin-metformin hydrochloride compound hypoglycemic drug, which comprises the following steps: step A: uniformly mixing quercetin and metformin hydrochloride to obtain a mixed raw material; and B, step B: adding methanol into the mixed raw materials, and carrying out compound reaction on the quercetin and the metformin hydrochloride in the mixed raw materials by adopting a liquid adding grinding method or a solvent volatilization method to obtain the quercetin-metformin hydrochloride compound hypoglycemic medicament. The invention adopts a liquid adding grinding method or a solvent volatilization method to compound quercetin and metformin hydrochloride to form a quercetin-metformin hydrochloride compound hypoglycemic drug (Qu-Mh); the quercetin in the Qu-Mh compound medicine has higher solubility and bioavailability than pure quercetin.
Description
Technical Field
The invention relates to the technical field of compound hypoglycemic drugs. In particular to a preparation method of a quercetin-metformin hydrochloride compound hypoglycemic drug.
Background
Although the flavonoid compound has various pharmacological applications, it shows low oral bioavailability due to its poor water solubility. To solve this problem, many promising strategies have been developed and applied, such as the use of absorption enhancers, structural transformations (prodrugs, glycosylation) and pharmaceutical technologies (carrier complexes, nanotechnology, co-crystals). These formulation methods are effective in improving the oral bioavailability of flavonoids by increasing their solubility, dissolution rate and permeability, preventing their degradation or metabolism in the gastrointestinal tract, or delivering them directly to their physiological target. Quercetin (Qu) is a key member of the flavonoid family and can be extracted from various vegetables and fruits, such as onions, apples, berries, nuts, seeds, bark, flowers, teas, brassica vegetables and leaves. Modern pharmacological studies have shown that quercetin has multiple biological functions on human health, including cardiovascular protection, antiulcer, antiallergic, anticancer, anti-inflammatory, antidiabetic and cataract prevention. An increasing number of in vivo studies have demonstrated that quercetin Qu can also be considered an antioxidant as it can inhibit xanthine oxidase by reducing the formation of free radicals, altering antioxidant defenses and inhibiting lipids.
Metformin (Mh) is a medicament with extremely strong hydrophilicity, the absorption half-reduction period of metformin is 0.9-2.6 h, and the bioavailability is 50% -60%, but due to the over-strong dissolving capacity, metformin is discharged with urine in an original shape after being used, the removal half-reduction period is 1.7-4.5h, and 90% of metformin is removed in 12h. It is absorbed mainly from the small intestine, and after entering the human body, it is not bound to plasma proteins, but it is rapidly distributed in a plurality of tissues of the human body, mainly in the intestinal wall, and it has the function of lowering blood sugar by increasing the sensitivity of peripheral tissues to insulin.
The main limitation of the quercetin molecule is poor oral bioavailability due to low solubility, which is the opposite of the problem faced by metformin. Therefore, research on preparing a compound (Qu-Mh) of quercetin and metformin to improve the solubility of the drug and improve the bioavailability of the quercetin and the metformin is an important approach for solving the application limitations of the quercetin and the metformin at present.
Disclosure of Invention
Therefore, the technical problem to be solved by the present invention is to provide a method for preparing a quercetin-metformin hydrochloride compound hypoglycemic drug, so as to solve the problem that when quercetin and metformin hydrochloride are used for lowering blood sugar, the oral bioavailability of the meletin is poor due to over-solubility and low metformin hydrochloride due to over-strong dissolving ability.
In order to solve the technical problems, the invention provides the following technical scheme:
a preparation method of a quercetin-metformin hydrochloride compound hypoglycemic drug comprises the following steps:
step A: uniformly mixing quercetin and metformin hydrochloride to obtain a mixed raw material;
and B: adding methanol into the mixed raw materials, and carrying out compound reaction on quercetin and metformin hydrochloride in the mixed raw materials by adopting a liquid adding grinding method or a solvent volatilization method [ phenolic hydroxyl on the quercetin and amino of the metformin react ] to obtain the quercetin-metformin hydrochloride compound hypoglycemic medicament.
In the preparation method of the quercetin-metformin hydrochloride compound hypoglycemic drug, in the step A, the mass ratio of substances of quercetin and metformin hydrochloride is 1: (0.5-2.0).
In the preparation method of the quercetin-metformin hydrochloride compound hypoglycemic drug, in the step A, the mass ratio of the quercetin to the metformin hydrochloride is 1.
In the step B, the operation method of the liquid adding grinding method comprises the following steps: and (3) placing the mixed raw materials in a mortar, grinding in the same direction, dripping methanol into the mixed raw materials in the grinding process, and drying the ground product after grinding to obtain the quercetin-metformin hydrochloride composite hypoglycemic medicament.
The preparation method of the quercetin-metformin hydrochloride composite hypoglycemic medicament has the advantages that the grinding time is 10-20 min, and the ratio of the dropping volume of the methanol to the total substance amount of the mixed raw materials is 200-500 mu L/mmol; the drying temperature is 40-60 ℃, and the drying time is 1-2 h.
The preparation method of the quercetin-metformin hydrochloride compound hypoglycemic medicament has the advantages that the grinding time is 15min, and the ratio of the dropping volume of methanol to the total substance amount of the mixed raw materials is 300 mu L/mmol; the drying temperature is 50 ℃ and the drying time is 2h. The grinding reaction is carried out in a dropwise adding mode, so that the two reaction raw materials can be uniformly mixed and fully react.
In the step B, the solvent volatilization method comprises the following steps:
step (B-1): the methanol is evaporated completely by a rotary evaporator and heated for standby;
step (B-2): putting the mixed raw materials into ultrasonic equipment, and adding the methanol treated in the step (B-1) into the mixed raw materials while carrying out ultrasonic treatment until the mixed raw materials are completely dispersed to obtain a mixed dispersion liquid;
step (B-3): sealing and shading the mixed dispersion liquid by using a preservative film (the volatilization speed of a solvent can be reduced, and the raw materials are fully compounded), placing the mixture in a water bath, stirring the mixture, carrying out water bath reaction, and obtaining a reaction mixed system after the reaction is finished;
step (B-4): and cooling the reaction mixed system to room temperature, standing for crystallization, drying the crystallized product, and obtaining the quercetin-metformin hydrochloride composite hypoglycemic drug after drying.
In the step (B-1), methanol is heated to 45-55 ℃, and is kept warm for standby (the methanol in the temperature range can fully dissolve the quercetin and the metformin hydrochloride so as to be beneficial to the compound reaction of the quercetin and the metformin hydrochloride); in the step (B-2), the addition amount of the methanol is based on the standard that the mixed raw materials are just completely dissolved, so that the two raw materials can fully participate in the reaction at the concentration, and more target products can be precipitated under the subsequent crystallization condition.
The preparation method of the quercetin-metformin hydrochloride compound hypoglycemic medicament comprises the step (B-3), wherein the water bath reaction temperature is 40-60 ℃, and the water bath reaction time is 25-35 min; in the step (B-4), the drying temperature is 40-60 ℃, and the drying time is 2-4 h.
The preparation method of the quercetin-metformin hydrochloride compound hypoglycemic medicament comprises the step (B-3), wherein the water bath reaction temperature is 50 ℃, and the water bath reaction time is 30min; in the step (B-4), the drying temperature is 50 ℃, and if the drying temperature is too high, the crystal structure of the target product can be damaged; the drying time was 3h.
The technical scheme of the invention achieves the following beneficial technical effects:
the invention adopts a liquid adding grinding method or a solvent volatilization method to compound quercetin and metformin hydrochloride to form a quercetin-metformin hydrochloride compound hypoglycemic drug (Qu-Mh); the quercetin in the Qu-Mh compound medicine has higher solubility and bioavailability than pure quercetin. The Quercetin-metformin hydrochloride compound hypoglycemic medicament (Qu-Mh) prepared by the invention is used for treating diabetic mice, and the result shows that the Qu-Mh compound has a synergistic hypoglycemic effect on the diabetic mice.
Drawings
FIG. 1 XRD patterns of Qu, mh and Qu-Mh prepared in the present example (in the figure: a-Qu; b-Mh; c-Qu + Mh physical mixing; d-Qu-Mh prepared by solvent evaporation method; e-Qu-Mh prepared by liquid-adding grinding method);
FIG. 2 FT-IR spectra of Qu, mh and prepared Qu-Mh in examples of the present invention;
FIG. 3 UV-map of Qu, mh and Qu-Mh prepared in the example of the present invention;
FIG. 4 is a diagram showing the structure of Qu according to the embodiment of the present invention;
FIG. 5 TG analysis charts of Qu, mh and Qu-Mh prepared in the example of the present invention;
FIG. 6 DTG analysis graphs of Qu, mh and prepared Qu-Mh in the example of the present invention;
FIG. 7 is a graph showing a standard curve of Qu according to an embodiment of the present invention;
FIG. 8 solubility of Qu-Mh in water, PBS (pH =6.8 or 1.2) in an example of the present invention;
FIG. 9 is a graph showing the absorbance of Qu and Qu-Mh in water at different wavelengths and times;
FIG. 10 is a graph showing the solubility curves of Qu and Qu-Mh in water in the example of the present invention;
FIG. 11 is a graph showing absorbance at different wavelengths and at different times in PBS (pH = 6.8) for Qu and Qu-Mh in the examples of the present invention;
FIG. 12 is a graph showing the solubility of Qu and Qu-Mh in PBS (pH = 6.8) in examples of the present invention;
FIG. 13 is a graph showing absorbance at different wavelengths at different times in PBS (pH = 1.2) for Qu and Qu-Mh in the example of the present invention;
FIG. 14 is a graph showing the solubility of Qu and Qu-Mh in PBS (pH = 1.2) in examples of the present invention.
Detailed Description
1. Reagents used in this example
The metformin hydrochloride and the quercetin used in the embodiment are both produced by Shanghai Yi En chemical technology, inc., and the purity of the metformin hydrochloride and the quercetin is 97wt%; the methanol used was analytically pure and was obtained from Xin platinum speciality chemical Co., ltd, tianjin. The used instruments and equipment are all common instruments and equipment sold in the market.
2. Experimental methods
2.1 preparation of Quercetin-metformin hydrochloride composite hypoglycemic drug
Liquid adding grinding method: accurately weighing reaction raw materials of quercetin and metformin hydrochloride (quercetin Qu:30.2mg,0.1mmol; metformin hydrochloride Mh:16.6mg, 0.1mmol) according to the mass ratio of 1; uniformly and fully grinding for 15min in the same direction, and dripping 30 mu L of methanol every 5min in the process (namely dripping 30 mu L of methanol respectively in the 5 th min and the 10 th min, and dripping 60 mu L of methanol in total), wherein the ratio of the dripping volume of the methanol to the total substance amount of the mixed raw materials is 300 mu L/mmol; and after grinding, drying the ground product at 50 ℃ for 2 hours to obtain the quercetin-metformin hydrochloride compound hypoglycemic drug, collecting the product, and performing scanning analysis by using an X-ray polycrystal diffractometer.
Solvent volatilization method: firstly, carrying out rotary evaporation on methanol for completely preparing and heating to 50 ℃ for later use by using a rotary evaporator, accurately weighing quercetin Qu and metformin hydrochloride Mh according to the mass ratio of 1; sealing and shading by using a preservative film, and stirring in a water bath at 50 ℃ for 30min by using a conical flask; standing and cooling at room temperature after the reaction is finished, and drying the product obtained after crystallization at 50 ℃ for 3h; the product was collected and analyzed by scanning with an X-ray polycrystal diffractometer.
2.2 detection of physicochemical Properties of Quercetin-metformin hydrochloride Complex hypoglycemic drug (Qu-Mh)
2.2.1X-ray polycrystal diffraction
Wiping the sample carrying table by absolute ethyl alcohol, pouring dried and ground sample particle powder into the sample carrying table after the sample carrying table is volatilized, concentrating a sample to be detected at the center of a groove of an inner ring of the sample carrying table as much as possible, pressing the surface by a ground glass sheet to flatten a working surface as much as possible; pressing a button to open the equipment door, placing the tested sample on the test rack, and closing the equipment door after confirming that the sample loading platform is placed correctly; and modifying proper test parameters and modes, filling the sample code, clicking to start scanning the sample, and testing.
2.2.2 Fourier transform Infrared
The infrared spectrometry of the experiment is carried out by adopting a potassium bromide tabletting method, and in order to reduce the influence, high-purity potassium bromide is used, an agate mortar is used for grinding the potassium bromide to be less than 200 meshes before use, and the potassium bromide is placed under a digital display infrared baking lamp for baking to remove the residual moisture in the reagent and the sample. The blank KBr pellet was scanned and the background was subtracted. A small amount of sample is taken and fully ground and mixed with potassium bromide powder (the mass ratio of the experimental sample to the potassium bromide is 1 to 100) for tabletting, and most absorption peaks in a spectrogram are generally required to be within a light transmittance range of 80 to 20 percent. After scanning is finished, recording an FT-IR (Fourier transform infrared) image of an experimental sample by a Fourier infrared spectrometer, wherein the measuring wave number range is 4000-400 cm -1 。
2.2.3 thermogravimetric analysis
An instrument for detecting the temperature-mass change relationship of a substance by thermogravimetry is called a thermogravimetric analyzer. Adjusting test conditions after the machine is preheated: in N 2 Under the atmosphere, the temperature range is room temperature-800 ℃, and the heating rate is 10 ℃/min. And (4) after balancing, putting the balance into two ceramic crucibles, and resetting after the mass readings on the instrument are stable after 3 min. This is achieved byWhen the sample is put in the crucible, the crucible can be taken out and put back into the instrument. After 3min, the instrument is started to operate to start testing the sample after the mass reading on the instrument is stable.
2.2.4 absorption Curve of the Material
The method comprises the steps of firstly carrying out baseline scanning on a blank solvent by using an ultraviolet spectrophotometer, and then measuring an absorption curve of a sample to be measured in a wavelength range of 200-500 nm after the sample to be measured is dissolved.
2.2.5 Quercetin Standard Curve
Preparing 2mg/mL of quercetin absolute ethyl alcohol solution as stock solution, respectively taking stock solutions with different volumes in 10mL volumetric flasks, carrying out constant volume to obtain quercetin solutions of 40 mu g/mL, 35 mu g/mL, 30 mu g/mL, 25 mu g/mL, 20 mu g/mL, 15 mu g/mL, 10 mu g/mL and 0.5 mu g/mL, measuring the absorbance value of each solution at each 372nm by using an ultraviolet-visible spectrophotometry and drawing a standard curve.
2.2.6 solubility
Solubility in deionized water: weighing 5mg of each of Qu and Qu-Mh samples into a conical flask, adding 100mL of deionized water, placing on a universal shaker, respectively sampling 5mL at 0, 2, 5, 10, 20, 30, 45, 60, 90 and 120min under the condition of 80 rpm oscillation at room temperature, filtering through a 0.22 mu m filter membrane, carrying out full-wavelength scanning by utilizing an ultraviolet-visible spectrophotometer, recording the absorbance at 368nm, calculating the solubility in the deionized water through a standard curve, and drawing the curve.
Solubility in PBS pH = 1.2: the procedure was as above, and deionized water was replaced with phosphate buffer solution pH = 1.2.
Solubility in PBS pH = 6.8: the procedure was as above, the deionized water was replaced with phosphate buffered solution pH = 6.8.
2.2.7 hypoglycemic Activity Studies
1) Establishment of animal model
This example was induced by selection of Streptozotocin (STZ) reagent, which was dissolved in 0.1 mmol. Multidot.L -1 Citric acid buffer, pH =4.4, ice bath, ready to use, used up within 5min, injection 40mg (kg. D) for 5 consecutive days (d) -1 Mice fasted for 12h before each injection; determination of fasting after 72h injectionBlood glucose, mice with fasting plasma glucose greater than 11.1mmol/L were included in the diabetes model.
2) In vivo blood glucose level detection
After the diabetic mouse model is successfully established, randomly grouping: a normal control group, a diabetes model + compound drug treatment group, and a diabetes model + single drug treatment group, wherein each group contains 10 patients. The treatment intervention is carried out for 4 weeks, the mental, nutritional, activity, diet and other conditions of each group of mice are observed in the experimental process, and blood is collected every week to measure the blood sugar value after fasting for 12 hours.
3 results and discussion
3.1 phase of Quercetin-metformin hydrochloride composite hypoglycemic drug (Qu-Mh)
X-ray polycrystalline diffraction can also be used to determine the crystallinity of a powder sample. Physically mixing quercetin, metformin hydrochloride and two drugs, and the XRD patterns of Qu-Mh prepared by the two preparation methods are shown in figure 1. The XRD topographies of the three compounds are significantly different. The main diffraction peaks of the metformin hydrochloride bulk drug are sharp at 12.16 °, 17.6 °, 24.4824 °, 31.2103 ° and 37.0831 ° peaks, and the diffraction peak is strong, which indicates that the crystal form of the metformin hydrochloride is a very good crystal form; the main diffraction peaks of the quercetin bulk drug are 10.697 °, 12.397 °, 15.7352 °, 23.8127 ° and 27.2437 °; the XRD spectrogram of the physical mixed powder of the two medicines is the superposition of characteristic diffraction peaks of the two medicines; the main diffraction peaks of Qu-Mh are 17.5691 degrees, 22.2673 degrees, 23.1431 degrees, 27.12 degrees and 28.2018 degrees. Although the peak type of Qu-Mh is duller than that of the former two, the positions and the intensities of diffraction peaks are obviously different, a new diffraction peak appears and a raw material diffraction peak disappears, and the three have obvious differences, so that the nanocrystalline (salt) Qu-Mh prepared from quercetin and metformin hydrochloride is further proved to form a unique crystal form; furthermore, as can be seen from the comparison of the overall peak intensities, the solvent evaporation method is better than the liquid-added milling method for preparing the complex crystals, because the reaction proceeds more fully in the solution.
3.2 molecular Structure of Quercetin-metformin hydrochloride Complex hypoglycemic drug (Qu-Mh)
FT-IR analysis results of Mh, qu, and Qu-Mh (Qu-Mh produced by solvent evaporation) are shown in FIG. 2, in which hydrochloric acidThe infrared spectrum of the metformin can be seen at 3372 and 3299cm -1 Absorption peak of (2) is-NH 2 3160cm of asymmetric and symmetric stretching vibration -1 1627cm at an absorption peak of-NH -1 Absorption peak of (2) is C = N expansion and contraction vibration, 1476, 1448cm -1 The nearby double absorption peak is a methyl C-H symmetric bending vibration absorption peak. From the infrared spectrum of quercetin, it can be seen that the peak value is 1665cm -1 The absorption peak appeared at (1) is a tensile vibration absorption peak of C = O, 1610cm -1 The absorption peak of (2) is the vibration absorption peak of benzene ring skeleton, 1562cm -1 、1521cm -1 The absorption peaks of (a) are respectively the B-ring and A-ring benzene ring stretching vibration absorption peaks, 1382cm -1 The absorption peak of (a) is the in-plane bending absorption peak of-OH, and the most obvious absorption peak in the whole spectrum is 3401cm -1 The stretching vibration of-OH as an absorption peak appears at the position, which indicates that hydroxyl and carbonyl form intramolecular hydrogen bonds, thereby improving the stability of the molecule. In the infrared spectrogram of Qu-Mh, the two drugs react after being compounded, and the peak shapes of some absorption peaks are changed due to the generation of new functional groups, such as 3000-3400 cm -1 The absorption peak of (a) becomes broad and blunt, some absorption peak positions are red-shifted or blue-shifted, and in addition, a new absorption peak appears.
It can be seen from FIG. 3 that quercetin has relatively strong absorptions at 255nm and 372nm, which is associated with the analysis of the structure of quercetin scheme 4, where the absorption at 255nm is due to the electron transition of the n → π (ring A) benzoyl group, which is band II, and the absorption at 372nm is due to the electron transition of the π → π (ring B) cinnamoyl system, which is band I. The ultraviolet absorption spectrum of the metformin shows that a strong absorption peak appears only at 238nm, which indicates that a K absorption band exists, and the UV absorption spectrum is probably caused by the conjugated system formed by two double bonds. The ultraviolet spectrum of the Qu-Mh after the composition simultaneously shows the ultraviolet absorption peak of a double bond conjugated system and the composition of two chromophores.
3.3 thermodynamic Properties of Quercetin-metformin hydrochloride composite hypoglycemic drug (Qu-Mh)
According to the thermogravimetric curve of fig. 5, it can be seen that the first endothermic peak of quercetin is at 104 ℃, the weight loss is 5.31%, which is the weight lost by endothermic evaporation of water molecules, and the second endothermic peak is at 354 ℃, which is the main melting peak of quercetin. Metformin has two endothermic peaks (334 ℃ and 650 ℃), of which the main melting peak is at 334 ℃ and the temperature up to 650 ℃ is the end of the complete decomposition. The compound Qu-Mh (Qu-Mh prepared by a solvent evaporation method) contains a main endothermic peak, and the group of peaks are different from the endothermic peaks of Qu (354 ℃) and Mh (334 ℃), as shown in figure 6, the formation of Qu-Mh is further proved, and the crystal form is a main crystal form.
3.4 solubility Curve of Quercetin-metformin hydrochloride composite hypoglycemic drug (Qu-Mh)
In order to calculate the dissolution rate of the quercetin in the solution, a standard curve of the quercetin is accurately drawn: a =0.05671C-0.00164 (R) 2 = 0.99923). As shown in FIG. 7, the quercetin solution showed a good linear relationship in the range of 0.5-4 μ g/mL. Compared with the crystal type Qu, the solubility of the Qu is obviously improved by a Qu-Mh compound (the Qu-Mh prepared by a solvent volatilization method). As shown in FIGS. 8 to 14, solubility experiments show that Qu is almost insoluble in water, the maximum value of the solubility is 0.24 mug/mL after 30min, the solubility is 0.18 mug/mL after 2h, the solubility of Qu-Mh is rapidly increased to 2.85 mug/mL in water 45min before the water is dissolved, and then the solubility is stable, and the solubility reaches 2.87 mug/mL after 2h; the solubility of Qu-Mh in PBS mimicking gastric acidic conditions pH =1.2 gradually increased to 2.71 μ g/mL over 2h; the solubility of Qu-Mh in PBS at pH =6.8 under simulated intestinal acidic conditions gradually increased to 3.87 μ g/mL over 2h. The conclusion that the equilibrium solubility after the compound quercetin is dissolved for 2 hours at room temperature can be obviously concluded is that the solubility of the compound quercetin is the highest under the intestinal acidic condition and the solubility of the compound quercetin is the lowest under the gastric acidic condition, and the method lays the foundation for Qu as a promising compound to be developed into an effective drug product.
3.5 hypoglycemic Activity
Compared with a control group, the blood sugar of mice in a diabetes model group is continuously higher (P is less than 0.05), the blood sugar of a single group of metformin hydrochloride (Mh) and quercetin (Qu) is 84.0 percent and 61.0 percent (P is less than 0.05) of the model group at 4 weeks, the blood sugar of a Qu-Mh compound (Qu-Mh prepared by a solvent evaporation method) is only 54.8 percent (P is less than 0.05) of the model group, and the Qu-Mh compound has statistical difference (P is less than 0.05) compared with a single drug group, so that the Qu-Mh compound has the synergistic blood sugar reducing effect on the diabetes mice. The results are shown in Table 1.
TABLE 1 Effect of different Components on blood glucose levels (mmol/L) in diabetic mice
In the embodiment, the compound method of quercetin and metformin hydrochloride is researched, and Qu contains abundant hydroxyl, so that N-H8230, O or O-H8230, N hydrogen bond are probably formed with N in Mh. Therefore, in the embodiment, the composite Qu-Mh is prepared by a solvent evaporation method, and the appearance and the shape of the composite Qu-Mh are obviously different from those of Qu and Mh, are in a microsphere shape and are uniformly dispersed. Because different phases have different structures, each phase has a unique characteristic peak of X-ray diffraction angle, and slight difference of the structures can reflect that the diffraction angle in the diffraction spectrum is shifted. By comparing the characteristic diffraction peaks of Qu, mh, qu-Mh and Qu/Mh, the disappearance of the characteristic peak of the raw material and the generation of a new characteristic peak after the Qu and the Mh are compounded prove that a new phase is formed. The thermogravimetric analysis detection result shows that the thermal stability of the Qu-Mh is changed, and the infrared result is combined, so that the Qu and the Mh successfully form a compound Qu-Mh. The solubility of the complex Qu-Mh in water at room temperature for 2h was increased to 2.87 μ g/mL, and the solubility in PBS at pH =1.2 and pH =6.8 was 2.71 μ g/mL and 3.87 μ g/mL. The dissolution rate of Qu-Mh is obviously higher than that of Qu by the dissolution curve analysis, which shows that the solubility of Qu can be improved and the bioavailability can be improved by compounding. The results of the blood sugar reduction experiments show that the Qu-Mh compound has the effect of synergistically reducing the blood sugar of diabetic mice.
Claims (10)
1. A preparation method of a quercetin-metformin hydrochloride compound hypoglycemic drug is characterized by comprising the following steps:
step A: uniformly mixing quercetin and metformin hydrochloride to obtain a mixed raw material;
and B, step B: adding methanol into the mixed raw materials, and carrying out composite reaction on quercetin and metformin hydrochloride in the mixed raw materials by adopting a liquid adding grinding method or a solvent volatilization method to obtain the quercetin-metformin hydrochloride composite hypoglycemic medicament.
2. The method for preparing the quercetin-metformin hydrochloride composite hypoglycemic agent according to claim 1, wherein in the step A, the ratio of the amounts of the substances of quercetin and metformin hydrochloride is 1: (0.5-2.0).
3. The method for preparing the quercetin-metformin hydrochloride composite hypoglycemic agent according to claim 2, wherein in the step A, the mass ratio of the substances of quercetin and metformin hydrochloride is 1.
4. The method for preparing the quercetin-metformin hydrochloride composite hypoglycemic drug according to claim 1, wherein in the step B, the operation method of the liquid adding grinding method comprises the following steps: and (3) putting the mixed raw materials into a mortar, grinding the mixed raw materials along the same direction, dripping methanol into the mixed raw materials in the grinding process, and drying the ground product after grinding to obtain the quercetin-metformin hydrochloride composite hypoglycemic medicament.
5. The method for preparing the quercetin-metformin hydrochloride composite hypoglycemic drug according to claim 4, wherein the grinding time is 10-20 min, and the ratio of the dropping volume of methanol to the total substance amount of the mixed raw materials is 200-500 μ L/mmol; the drying temperature is 40-60 ℃, and the drying time is 1-2 h.
6. The method for preparing the quercetin-metformin hydrochloride composite hypoglycemic agent according to claim 5, wherein the grinding time is 15min, and the ratio of the dropping volume of methanol to the total substance amount of the mixed raw materials is 300 μ L/mmol; the drying temperature is 50 ℃, and the drying time is 2h.
7. The method for preparing the quercetin-metformin hydrochloride composite hypoglycemic drug according to claim 1, wherein in the step B, the solvent evaporation method comprises the following steps:
step (B-1): the methanol is evaporated completely by a rotary evaporator and heated for standby;
step (B-2): putting the mixed raw materials into ultrasonic equipment, and adding the methanol treated in the step (B-1) into the mixed raw materials while carrying out ultrasonic treatment until the mixed raw materials are completely dispersed to obtain a mixed dispersion liquid;
step (B-3): sealing the mixed dispersion liquid with a preservative film for shading, placing the mixed dispersion liquid in a water bath for stirring, performing water bath reaction, and obtaining a reaction mixed system after the reaction is finished;
step (B-4): and cooling the reaction mixed system to room temperature, standing for crystallization, drying the crystallized product, and obtaining the quercetin-metformin hydrochloride composite hypoglycemic drug after drying.
8. The method for preparing the quercetin-metformin hydrochloride composite hypoglycemic drug according to claim 7, wherein in the step (B-1), methanol is heated to 45-55 ℃, and the temperature is kept for standby; in the step (B-2), the amount of methanol added is such that the mixed raw materials are just completely dissolved.
9. The method for preparing the quercetin-metformin hydrochloride composite hypoglycemic agent according to claim 7, wherein in the step (B-3), the temperature of the water bath reaction is 40-60 ℃, and the time of the water bath reaction is 25-35 min; in the step (B-4), the drying temperature is 40-60 ℃, and the drying time is 2-4 h.
10. The method for preparing the quercetin-metformin hydrochloride composite hypoglycemic agent according to claim 9, wherein in the step (B-3), the temperature of the water bath reaction is 50 ℃, and the time of the water bath reaction is 30min; in the step (B-4), the drying temperature is 50 ℃ and the drying time is 3 hours.
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