Quercetin solid dispersion with high drug loading capacity and preparation method thereof
By combining quercetin with carrier materials, a solid dispersion of high drug loading is prepared, which solves the problems of low drug loading, poor solubility and dissolution in the prior art, and achieves high bioavailability and industrial applicability of quercetin.
Patent Information
- Application Number
- CN202411836098.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-13
- Publication Date
- 2025-04-15
AI Technical Summary
The existing quercetin solid dispersion has low drug loading, poor solubility and dissolution, which limits its bioavailability and the applicability of large-scale industrial production.
A high drug-loaded quercetin solid dispersion is prepared by combining quercetin with carrier materials such as polyethylene glycols, povidones, surfactants, organic acids, sugar alcohols, etc. using organic solvents and heating and stirring.
It improves the drug loading, solubility and dissolution of quercetin, enhances its bioavailability, and makes it have good stability in water, making it suitable for large-scale industrial production.
Smart Images
Figure BDA0005186747970000081 
Figure BDA0005186747970000091
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of food raw materials, and in particular to a quercetin solid dispersion and a preparation method thereof. Background Art
[0002] Flavonoids are plant secondary metabolites. They are a class of compounds with a 2-phenylchromone structure that are widely found in traditional Chinese medicines, with C6-C3-C6 as the basic skeleton. According to the structure, they can be divided into flavonoids, isoflavones, flavonols, dihydroflavonoids, flavanones, anthocyanins, etc. Some exist in the plant body in the form of oxygen glycosides or carbon glycosides, and the other part exists in a free form. There are many types of flavonoids, and some monomeric compounds are present in large amounts in plants. They have significant pharmacological activities and have pharmacological effects such as neuroprotection, cardiovascular protection, digestive system regulation, anti-tumor, antiviral, hypoglycemic, and anti-inflammatory.
[0003] Quercetin belongs to the class of flavonol compounds. It is one of the most abundant bioflavonoids in the human diet. Quercetin is a natural antioxidant that removes free radicals in the body, stimulates the immune system through different signaling pathways, regulates enzyme activity, changes the mitotic cycle, changes gene expression, and provides significant protection at all stages of the pathogenic process by inhibiting, reversing or delaying the occurrence of diseases. Quercetin has a wide range of biological activities, including expectoration, cough relief, asthma relief, lowering blood pressure, reducing capillary fragility, lowering blood lipids, dilating coronary arteries, and increasing coronary blood flow; it has antioxidant, anti-diabetic, anti-inflammatory, antiviral, antibacterial and anti-cancer effects. However, due to its structural peculiarity, it has very low solubility in water and is unstable; it is also unstable in gastrointestinal fluid, has a serious first-pass effect, and has very low bioavailability, which greatly limits its application.
[0004] The drug loading in the solid dispersion will affect the drug release mechanism. The literature shows that when the drug loading is low, the drug and the polymer are released synergistically, and the drug can be released quickly; when the drug loading is high, the polymer is difficult to release from the solid dispersion, thus affecting the drug release. At present, the quercetin solid dispersion prepared in the literature has a very low drug loading in order to improve the bioavailability, and is not suitable for large-scale industrial production. Therefore, it is necessary to develop a high-drug loading preparation while ensuring a quercetin solid dispersion with good solubility, high dissolution, and suitable for large-scale industrial production. Summary of the invention
[0005] The purpose of the present invention is to provide a quercetin solid dispersion in view of the shortcomings of the prior art.
[0006] In a first aspect, the present invention provides a quercetin solid dispersion, wherein the drug loading of the preparation is greater than 15%.
[0007] In some embodiments, the drug loading of the formulation is greater than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 90%.
[0008] In some embodiments, the solubility of the solid dispersion in a phosphate buffer solution at pH 7.0 for 2 h is greater than 68%.
[0009] In some embodiments, the quercetin includes but is not limited to quercetin dihydrate, quercetin anhydrous or quercetin monohydrate, dihydroquercetin.
[0010] In some embodiments, the solid dispersion further comprises a carrier material, including but not limited to one or a combination of polyethylene glycols, povidones, surfactants, organic acids, and sugar alcohols.
[0011] In some embodiments, the carrier materials are povidones and sugar alcohols.
[0012] In some embodiments, the povidones include, but are not limited to, one or a combination of PVP K15, PVP K25, PVP K30, PVP K60, and PVP K90.
[0013] In some embodiments, sugar alcohols include, but are not limited to, one or a combination of fructose, sucrose, lactose, galactose, mannitol, sorbitol, and xylitol.
[0014] In some embodiments, the dosage ratio of quercetin to povidone is 10:1-1:50.
[0015] In some embodiments, the dosage ratio of quercetin to povidone is 5:1-1:30.
[0016] In some embodiments, the dosage ratio of quercetin to povidone is 2:1-1:15.
[0017] In some embodiments, the usage ratio of quercetin to sugar alcohols is 20:1-1:10.
[0018] In some embodiments, the ratio of quercetin to sugar alcohols is 10:1-1:5.
[0019] In some embodiments, the usage ratio of quercetin to sugar alcohols is 8:1-1:2.
[0020] In some embodiments, the usage ratio of povidone and sugar alcohol is 50:1-1:10.
[0021] In some embodiments, the usage ratio of povidone and sugar alcohol is 30:1-1:5.
[0022] In some embodiments, the usage ratio of povidone and sugar alcohol is 20:1-1:2.
[0023] In some embodiments, the method for preparing the solid dispersion comprises the following steps:
[0024] (1) Dissolving quercetin and a carrier material in an organic solvent, heating and stirring, and reacting to obtain a mixed solution.
[0025] (2) Drying the mixed solution to obtain the product.
[0026] In some embodiments, the organic solvent includes, but is not limited to, one or more combinations of ethanol, ethyl acetate, methanol, ethanol, and acetone.
[0027] In some embodiments, the reaction temperature is 20-180°C.
[0028] In some embodiments, the reaction time is 0.5-10 h.
[0029] In a second aspect, the quercetin solid dispersion provided by the present invention further comprises a food-acceptable additive.
[0030] In a third aspect, the quercetin solid dispersion provided by the present invention is used in the preparation of health foods, dietary supplements and / or foods with anti-inflammatory, antioxidant, anti-thrombotic, blood sugar lowering, blood lipid lowering, cardiovascular protection, liver protection, and anti-allergic effects.
[0031] In some embodiments, the quercetin solid dispersion is used to prepare health foods, dietary supplements and / or foods for relieving, treating, and improving symptoms of dyspnea, chest tightness and shortness of breath, cough, nasal congestion, rhinitis, and lung nodules.
[0032] Beneficial effects:
[0033] The present invention provides a quercetin solid dispersion, which improves the solubility and dissolution rate of the quercetin raw material while maintaining a high drug loading, and the preparation has good stability in water. It is speculated that this may be because the state of the drug dispersed in the carrier material has changed. The state of the drug dispersed in the carrier material is related to the relative content of the drug in the solid dispersion. When the content is low, the quercetin raw material exists in the quercetin solid dispersion in an amorphous state; when the content is high, quercetin may be dispersed in the solid dispersion in a molecular state.
[0034] The reason for the change in the drug state may be that the increase in temperature during the reaction process helps to disperse the drug in a molecular state. The dissolution rate of the drug is different in different dispersion states, and the dissolution rate of the molecular dispersion state is greater than the dissolution rate of the amorphous state. At the same time, the drug is dispersed in a molecular state into a solid dispersion, which can increase the surface area of the drug dissolution and increase the solubility.
[0035] At the same time, the solid dispersion prepared by the present invention has good stability in water, which is conducive to realizing large-scale commercial production.
[0036] Terminology
[0037] Solid dispersion refers to a dispersed system in solid form formed by uniformly dispersing the drug in a highly dispersed state such as molecular, amorphous, or microcrystalline state in a carrier.
[0038] The drug loading of the solid dispersion in the present invention refers to the amount of drug contained in a unit mass of the solid dispersion, and is calculated as follows: drug loading = (mass of drug in the solid dispersion / mass of the solid dispersion) * 100%.
[0039] PVP K15 is polyvinylpyrrolidone K15.
[0040] PVP K25 is polyvinylpyrrolidone K25.
[0041] PVP K30 is polyvinylpyrrolidone K30.
[0042] PVP K60 is polyvinylpyrrolidone K60.
[0043] PVP K90 is polyvinylpyrrolidone K90. BRIEF DESCRIPTION OF THE DRAWINGS
[0044] none DETAILED DESCRIPTION
[0045] In order to facilitate the understanding of those skilled in the art, the present invention is further described below in conjunction with embodiments, and the contents mentioned in the implementation modes are not intended to limit the present invention.
[0046] Example 1
[0047] 1 part of quercetin, 1 part of PVP K15, and 1 part of mannitol were dissolved in 10 mL of anhydrous ethanol, heated to room temperature (20° C.), and stirred in a water bath for 10 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0048] Example 2
[0049] 1 part of quercetin, 1.3 parts of PVP K15, and 0.7 parts of mannitol were dissolved in 20 mL of anhydrous ethanol, heated to 40° C., and stirred in a water bath for 9 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0050] Example 3
[0051] 1 part of quercetin, 2.3 parts of PVP K15, and 0.7 parts of mannitol were dissolved in 30 mL of anhydrous ethanol, heated to 60° C., and stirred in a water bath for 8 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0052] Example 4
[0053] 1 part of quercetin, 3.2 parts of PVP K30 and 0.8 parts of xylitol were dissolved in 40 mL of anhydrous ethanol, heated to 80° C., and stirred in a water bath for 6 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0054] Example 5
[0055] 1 part of quercetin, 4.2 parts of PVP K90, and 0.8 parts of sorbitol were dissolved in 60 mL of anhydrous ethanol, heated to 100° C., and stirred in a water bath for 4 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0056] Example 6
[0057] 1 part of quercetin, 1.8 parts of PVP K30 and 0.2 parts of xylitol were dissolved in 40 mL of anhydrous ethanol, heated to 60° C., and stirred in a water bath for 7 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0058] Example 7
[0059] 1 part of quercetin, 3.6 parts of PVP K30 and 0.4 parts of xylitol were dissolved in 60 mL of anhydrous ethanol, heated to 80° C., and stirred in a water bath for 6 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0060] Example 8
[0061] 1 part of quercetin, 5.5 parts of PVP K30 and 0.5 parts of xylitol were dissolved in 80 mL of anhydrous ethanol, heated to 100° C., and stirred in a water bath for 5 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0062] Example 9
[0063] 1 part of quercetin, 7.4 parts of PVP K15 and 0.6 parts of xylitol were dissolved in 100 mL of anhydrous ethanol, heated to 120° C., and stirred in a water bath for 3 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0064] Example 10
[0065] 1 part of quercetin, 9.4 parts of PVP K30 and 0.6 parts of mannitol were dissolved in 120 mL of anhydrous ethanol, heated to 150° C., and stirred in a water bath for 1 hour to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0066] Embodiment 11
[0067] 1 part of anhydrous quercetin, 11 parts of PVP K90, and 1 part of sorbitol were dissolved in 150 mL of anhydrous ethanol, heated to 180° C., and stirred in a water bath for 0.5 h to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0068] Example 12
[0069] 1 part of quercetin, 0.8 parts of PVP K90, and 0.2 parts of sorbitol were dissolved in 60 mL of anhydrous ethanol, heated to 80° C., and stirred in a water bath for 6 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0070] Embodiment 13
[0071] 1 part of quercetin, 1.8 parts of PVP K90, and 0.2 parts of sorbitol were dissolved in 80 mL of anhydrous ethanol, heated to 100° C., and stirred in a water bath for 5 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0072] Embodiment 14
[0073] 1 part of quercetin, 3.7 parts of PVP K90 and 0.3 parts of sorbitol were dissolved in 100 mL of anhydrous ethanol, heated to 120° C., and stirred in a water bath for 4 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0074] Embodiment 15
[0075] 1 part of quercetin, 0.9 parts of PVP K30 and 0.1 parts of xylitol were dissolved in 40 mL of anhydrous ethanol, heated to 60° C., and stirred in a water bath for 7 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0076] Example 16
[0077] 6 parts of quercetin, 3.5 parts of PVP K30, and 0.5 parts of xylitol were dissolved in 40 mL of anhydrous ethanol, heated to 60° C., and stirred in a water bath for 6 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0078] Embodiment 17
[0079] 7 parts of quercetin, 2.6 parts of PVP K30, and 0.4 parts of xylitol were dissolved in 40 mL of anhydrous ethanol, heated to 60° C., and stirred in a water bath for 8 hours to obtain a mixed solution; the mixed solution was dried under reduced pressure to obtain a product.
[0080] Example 18 Solubility Experiment
[0081] Prepare pH 7.0 phosphate buffer, take excess quercetin and the quercetin solid dispersion prepared in Example 6 and dissolve them in the buffer respectively, shake in a shaker in the dark at room temperature for 24 hours, centrifuge and aspirate the supernatant saturated solution, pass through a 0.45 μm filter membrane and then dilute appropriately, detect on the liquid phase, record the peak area, and calculate the equilibrium solubility of quercetin and the preparation in the solution by the standard curve method.
[0082] Table 1
[0083]
[0084]
[0085] The data in Table 1 show that the solubility of quercetin after forming a solid dispersion is better, which is 10.6 times that of the raw material.
[0086] Example 19 Dissolution Test
[0087] Quercetin and the quercetin solid dispersion prepared in Example 6 were used to obtain samples for dissolution experiments.
[0088] Dissolution Test:
[0089] (1) Prepare pH 7.0 phosphate buffer, dispense equal amounts into dissolution cups, and stir at 37°C and 250 rpm;
[0090] (2) Based on quercetin, take an appropriate amount of sample and dissolve it in pH 7.0 phosphate buffer and start timing;
[0091] (3) Take samples after 2 hours, filter and dilute, take the upper liquid phase, detect the quercetin content in the solution, and calculate the solubility.
[0092] Table 2
[0093] sample Dissolution rate in 2h / % Quercetin 3.56％ Example 6 82.40％
[0094] As can be seen from Table 2, the dissolution rate of Example 6 in 2 hours reaches 82.4%, which greatly improves the dissolution rate of the raw material.
[0095] Example 20 Stability test in aqueous solution
[0096] (1) Prepare pH 7.0 phosphate buffer;
[0097] (2) Based on quercetin, appropriate amounts of quercetin and the quercetin solid dispersion prepared in Example 6 were weighed and dissolved in equal amounts of buffer respectively, and the mixture was shaken at 37° C. and 250 rpm.
[0098] (3) Samples were taken at 0.5 h, 1 h, 2 h, 4 h and 6 h, filtered and diluted, the liquid phase was taken up, the quercetin content was detected, and the dissolution rate was calculated.
[0099] (4)The results are shown in Table 3.
[0100] Table 3
[0101] Time / h Quercetin Example 6 0.5 8.20％ 91.13％ 1 5.94％ 85.34％ 2 3.31％ 82.61％ 4 1.63％ 70.67％ 6 0.89％ 65.99％
[0102] It can be seen from Table 3 that the quercetin solid dispersion has good stability in water.
[0103] It should be understood that the detailed description of the technical solutions of the present invention by means of the preferred embodiments is illustrative rather than restrictive. A person skilled in the art may modify the technical solutions described in the embodiments, or replace some of the technical features by equivalents, based on reading the specification of the present invention; and these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A quercetin solid dispersion, characterized in that: The drug loading of the preparation is greater than 15%.
2. The solid dispersion according to claim 1, characterized in that The solubility of the solid dispersion in a phosphate buffer solution at pH 7.0 for 2 hours is greater than 68%.
3. The solid dispersion according to any one of claims 1 to 2, characterized in that It also contains carrier materials, which are one or a combination of polyethylene glycols, povidones, surfactants, organic acids, and sugar alcohols.
4. The solid dispersion according to claim 3, characterized in that The carrier materials are polyvidone and sugar alcohol.
5. The solid dispersion according to claim 4, characterized in that The dosage ratio of quercetin to povidone is 10:1-1:
50.
6. The solid dispersion according to claim 4, characterized in that The dosage ratio of quercetin to sugar alcohols is 20:1-1:
10.
7. The solid dispersion according to claim 4, characterized in that The dosage ratio of povidone and sugar alcohol is 50:1-1:
10.
8. The method for preparing a solid dispersion according to any one of claims 1 to 7, characterized in that: The following steps are included: (1) Dissolving quercetin and a carrier material in an organic solvent, heating and stirring, and reacting to obtain a mixed solution. (2) Drying the mixed solution to obtain the product.
9. The preparation method according to claim 8, characterized in that: The organic solvent is one or more of ethyl acetate, methanol, ethanol and acetone.
10. The preparation method according to claim 8, characterized in that: The reaction temperature is 20-180°C.
11. The quercetin solid dispersion according to any one of claims 1 to 10, further comprising a food-acceptable additive.
12. The quercetin solid dispersion according to any one of claims 1 to 11, wherein the quercetin solid dispersion is used in the preparation of health foods, dietary supplements and / or foods with anti-inflammatory, antioxidant, anti-thrombotic, hypoglycemic, hypolipidemic, cardiovascular protective and anti-allergic effects.
13. Use of the quercetin solid dispersion according to any one of claims 1 to 11 in preparing health foods, dietary supplements and / or foods for relieving, treating and improving symptoms of dyspnea, chest tightness and shortness of breath, cough, nasal congestion, rhinitis and pulmonary nodules.