Quercetin pill for reducing hypertension by improving vascular endothelial function

Abstract

The invention discloses a quercetin pill for reducing hypertension by improving the vascular endothelial function, and relates to the technical field of quercetin pharmaceutical preparations. Comprising quercetin, eucommia ulmoides extract, hydroxypropyl-beta-cyclodextrin and hydroxypropyl methylcellulose. The quercetin pill can be used for preparing medicines for preventing and / or treating vascular endothelial dysfunction related cardiovascular diseases, especially hypertension closely related to a vascular endothelial injury mechanism. Quercetin promotes synthesis and release of nitric oxide of vascular endothelial cells, and NO is a powerful vasodilator and can diffuse to vascular smooth muscle cells, activate guanylate cyclase and increase cyclic guanosine monophosphate in the cells, so that the vascular smooth muscles are relaxed, blood vessels are expanded, and the vascular endothelial function is improved. In addition, quercetin can inhibit expression of inflammatory adhesion molecules and recruitment of inflammatory cells, so that inflammatory response of vascular endothelium is relieved. The problem that the use of quercetin in the aspect of reducing hypertension is limited in the prior art is solved.

Description

Technical Field

[0001] This invention relates to the field of quercetin pharmaceutical preparation technology, specifically to a quercetin pill that lowers hypertension by improving vascular endothelial function. Background Technology

[0002] Hypertension, a major challenge in global public health, has a pathological mechanism closely linked to vascular endothelial dysfunction. Vascular endothelial cells maintain vascular tone by secreting reactive substances such as nitric oxide (NO). However, hypertensive patients often experience increased oxidative stress and exacerbated inflammation, leading to endothelial cell damage, decreased NO bioavailability, and an imbalance of vasoconstrictor factors. This cascade reaction not only directly increases hypertension levels but also exacerbates the risk of cardiovascular complications by promoting atherosclerosis and vascular remodeling. Quercetin, a naturally occurring polyphenol compound with the chemical structure 3,3',4',5,7-pentahydroxyflavone, can improve endothelial function through multi-target effects: its multiple hydroxyl groups can directly scavenge free radicals such as superoxide anions, reducing oxidative stress damage to the endothelium; simultaneously, by activating the expression of endothelial nitric oxide synthase (eNOS), it enhances NO synthesis and release, thereby restoring vasodilatory capacity and reducing peripheral resistance.

[0003] Despite its significant cardiovascular protective effects, quercetin faces significant challenges in clinical translation. This compound belongs to the flavonol subclass of the flavonoid family. Its planar, rigid molecular structure results in a water solubility of only about 0.011 mg / mL, making it prone to precipitation in the gastrointestinal environment, with oral bioavailability of less than 5%. More importantly, quercetin may cause local irritation under acidic gastric conditions, posing a risk of gastrointestinal mucosal damage with long-term use. Existing research attempts to improve its solubility and biocompatibility through structural modifications (such as glycosylation and liposome encapsulation) or dosage form improvements (such as nanocrystal formulations), but no product has yet simultaneously addressed both improved bioavailability and gastrointestinal tolerability. This directly leads to inconsistent clinical efficacy of existing quercetin supplements.

[0004] Developing novel quercetin formulations that target and improve vascular endothelial function has dual strategic value in addressing unmet medical needs. From a clinical perspective, nearly half of the approximately 1.4 billion hypertensive patients worldwide suffer from endothelial dysfunction. Traditional antihypertensive drugs (such as calcium channel blockers and ACE inhibitors) primarily target hemodynamic regulation and lack mechanisms for directly repairing endothelial damage. If quercetin formulations can achieve precise delivery by improving bioavailability, they have the potential to fill this treatment gap. From a market perspective, drugs derived from natural products have achieved a compound annual growth rate of 8.2% due to their safety advantages. If dosage form limitations can be overcome, quercetin drugs can not only open up new areas in cardiovascular preventative medicine, but their transformation from a nutritional supplement to a prescription drug will also create a multi-billion dollar market, particularly with significant potential in developed countries experiencing rapid aging populations. Summary of the Invention

[0005] In view of this, the main objective of the present invention is to provide a quercetin pill that lowers hypertension by improving vascular endothelial function. By increasing the water solubility of quercetin and reducing its irritation to the gastrointestinal tract, its bioavailability is improved, thus solving the problem of the limited use of quercetin in lowering hypertension in the prior art.

[0006] The technical solution of this invention is implemented as follows:

[0007] The present invention provides a first solution: a quercetin pill for lowering hypertension by improving vascular endothelial function, comprising 100-200g quercetin, 80-100g Eucommia ulmoides extract and 50-70g hydroxypropyl-β-cyclodextrin.

[0008] In a preferred embodiment of the present invention, 20g of lactose is also included.

[0009] This invention provides a second solution: a method for preparing quercetin pills that lower hypertension by improving vascular endothelial function, comprising:

[0010] Step 1: Raw material processing: Weigh out 100g of quercetin, 80g of Eucommia ulmoides extract, 50g of hydroxypropyl-β-cyclodextrin, and 20g of lactose;

[0011] Step 1.1: Preparation of quercetin nanocrystals:

[0012] Step 1.2: Preparation of Eucommia ulmoides iridoid extract;

[0013] Step 2: Active ingredient complex;

[0014] Feeding: Mix quercetin nanocrystal powder and hydroxypropyl-β-cyclodextrin in a 1:1 molar ratio;

[0015] Hot melt extrusion: A twin-screw extruder is used, with a temperature gradient set from 80℃ in the feeding zone to 120℃ in the extrusion zone, and a rotation speed of 50 rpm.

[0016] Rapid cooling and pulverization: The extrudate is rapidly cooled with liquid nitrogen and then processed by an air jet mill and passed through a 100-mesh sieve to obtain an amorphous solid dispersion;

[0017] Step 3: Granulation of the total mixture;

[0018] Dry mixing: Add 150g of quercetin-cyclodextrin complex, 80g of Eucommia ulmoides extract and 20g of lactose into the mixer in sequence, with a total mixing time of 20min and a mixing uniformity RSD ≤ 2%.

[0019] Pulping: Hydroxypropyl methylcellulose was dissolved in purified water at 60°C and cooled to room temperature;

[0020] For soft materials: spray in adhesive, control humidity at 25%;

[0021] Centrifuge granulation: Place the above soft material into a centrifuge and set the speed to 200 rpm;

[0022] The temperature was set to 40℃, resulting in 0.8mm spherical particles.

[0023] Step 4: Coating and Packaging;

[0024] Use Eudragit L100-55, with aluminum-plastic blister packs and desiccant for outer packaging, and store in a sealed container.

[0025] In a preferred embodiment of the present invention, the preparation process of Eucommia ulmoides iridoid extract includes:

[0026] Subcritical water extraction: The crude powder of Eucommia ulmoides was put into the extraction vessel and dynamically countercurrently extracted three times with pH 4.0 acetic acid aqueous solution at 120℃ and 5MPa for 30 min each time.

[0027] Resin purification: The extract was passed through an AB-8 macroporous resin column and eluted with a gradient of ethanol concentration from 30% to 70%, and the iridoid fraction was collected.

[0028] Spray drying: The concentrate was sterilized by passing it through a 0.22μm filter membrane and then spray dried to obtain a pale yellow powder.

[0029] In a preferred embodiment of the present invention, the preparation process of quercetin nanocrystals includes:

[0030] Feeding: Weigh 100g of quercetin raw material and disperse it in purified water containing 0.5% Tween-80 at a liquid ratio of 1:10;

[0031] High-pressure homogenization: A homogenizer was used to cycle the particles at 1500 bar for 5 times, and the particle size was monitored in real time until it was ≤200nm.

[0032] Freeze-drying: Add a freeze-drying protectant of trehalose:mannitol = 1:1, pre-freeze to -50℃, and vacuum dry for 24 hours to obtain nanocrystalline powder.

[0033] The present invention provides a third solution: a quercetin pill that lowers hypertension by improving vascular endothelial function, comprising 100-200g quercetin, 80-100g Eucommia ulmoides extract, 50-70g hydroxypropyl-β-cyclodextrin and 50g microcrystalline cellulose.

[0034] This invention provides a fourth solution: a method for preparing quercetin pills that lower hypertension by improving vascular endothelial function, comprising:

[0035] Step 1: Raw material processing:

[0036] Weigh out 150g of quercetin, 90g of Eucommia ulmoides extract, 60g of hydroxypropyl-β-cyclodextrin, and 50g of microcrystalline cellulose;

[0037] Step 1.1: Preparation of quercetin nanocrystals;

[0038] Feeding: Weigh 150g of quercetin raw material and disperse it in purified water containing 0.5% Tween-80 at a material-to-liquid ratio of 1:10;

[0039] High-pressure homogenization: A homogenizer was used to cycle the particles at 1500 bar for 5 times, and the particle size was monitored in real time until it was ≤200nm.

[0040] Freeze-drying: Add a freeze-drying protectant of trehalose:mannitol = 1:1, pre-freeze to -60℃, and vacuum dry for 24 hours to obtain nanocrystalline powder;

[0041] Step 1.2: Preparation of Eucommia ulmoides iridoid extract;

[0042] Step 2: Active ingredient complex;

[0043] Feeding: Mix quercetin nanocrystal powder and hydroxypropyl-β-cyclodextrin in a 1:1 molar ratio;

[0044] Hot melt extrusion: A twin-screw extruder is used, with a temperature gradient set from 80℃ in the feeding zone to 120℃ in the extrusion zone, and a rotation speed of 50 rpm.

[0045] Rapid cooling and pulverization: The extrudate is rapidly cooled with liquid nitrogen and then processed by an air jet mill and passed through a 100-mesh sieve to obtain an amorphous solid dispersion;

[0046] Step 3: Granulation of the total mixture;

[0047] Dry mixing: Add 200g of quercetin-cyclodextrin complex, 90g of Eucommia ulmoides extract and 50g of microcrystalline cellulose to the mixer in sequence. The total mixing time is 20min and the mixing uniformity RSD is ≤2%.

[0048] Pulping: Hydroxypropyl methylcellulose was dissolved in purified water at 60°C and cooled to room temperature;

[0049] For soft materials: spray in adhesive, control humidity at 25-30%;

[0050] Centrifuge granulation: Place the above soft material into a centrifuge and set the speed to 200-300 rpm;

[0051] When the temperature is set to 50℃, spherical particles of 0.8-1.2mm are generated;

[0052] Step 4: Coating and Packaging;

[0053] Use Eudragit L100-55, with aluminum-plastic blister packs and desiccant for outer packaging, and store in a sealed container.

[0054] In a preferred embodiment of the present invention, the preparation process of Eucommia ulmoides iridoid extract includes:

[0055] Subcritical water extraction: The crude powder of Eucommia ulmoides was put into the extraction vessel and dynamically countercurrently extracted three times with pH 4.0 acetic acid aqueous solution at 120℃ and 5MPa for 30 min each time.

[0056] Resin purification: The extract was passed through an AB-8 macroporous resin column and eluted with a gradient of ethanol concentration from 30% to 70%, and the iridoid fraction was collected.

[0057] Spray drying: The concentrate is sterilized by a 0.22μm filter membrane and then spray dried at an inlet air temperature of 180℃ to obtain a light yellow powder.

[0058] The present invention provides a fifth solution: a quercetin pill for lowering hypertension by improving vascular endothelial function, comprising 100-200g quercetin, 80-100g Eucommia ulmoides extract and 50-70g hydroxypropyl-β-cyclodextrin, and further comprising 50g hydroxypropyl methylcellulose and 20g lactose.

[0059] This invention provides a sixth solution: a method for preparing quercetin pills that lower hypertension by improving vascular endothelial function, comprising:

[0060] Step 1: Raw material processing:

[0061] Weigh out 200g of quercetin, 100g of Eucommia ulmoides extract, 70g of hydroxypropyl-β-cyclodextrin, 50g of microcrystalline cellulose, and 20g of lactose.

[0062] Step 1.1: Preparation of quercetin nanocrystals:

[0063] Feeding: Weigh 200g of quercetin raw material and disperse it in purified water containing 0.5% Tween-80 at a material-to-liquid ratio of 1:10;

[0064] High-pressure homogenization: A homogenizer was used to cycle the particles at 1500 bar for 5 times, and the particle size was monitored in real time until it was ≤200nm.

[0065] Freeze-drying: Add a freeze-drying protectant of trehalose:mannitol = 1:1, pre-freeze to -60℃, and vacuum dry for 24 hours to obtain nanocrystalline powder;

[0066] Step 1.2: Preparation of Eucommia ulmoides iridoid extract;

[0067] Subcritical water extraction: The crude powder of Eucommia ulmoides was put into the extraction vessel and dynamically countercurrently extracted three times with pH 4.0 acetic acid aqueous solution at 120℃ and 5MPa for 30 min each time.

[0068] Resin purification: The extract was passed through an AB-8 macroporous resin column and eluted with a gradient of ethanol concentration from 30% to 70%, and the iridoid fraction was collected.

[0069] Spray drying: The concentrate is sterilized by a 0.22μm filter membrane and then spray dried at an inlet air temperature of 180℃ to obtain a light yellow powder;

[0070] Step 2: Active ingredient complex;

[0071] Feeding: Mix quercetin nanocrystal powder and hydroxypropyl-β-cyclodextrin in a 1:1 molar ratio;

[0072] Hot melt extrusion: A twin-screw extruder is used, with a temperature gradient set from 80℃ in the feeding zone to 120℃ in the extrusion zone, and a rotation speed of 50 rpm.

[0073] Rapid cooling and pulverization: The extrudate is rapidly cooled with liquid nitrogen and then processed by an air jet mill and passed through a 100-mesh sieve to obtain an amorphous solid dispersion;

[0074] Step 3: Granulation of the total mixture;

[0075] Dry mixing: Add 250g of quercetin-cyclodextrin complex, 100g of Eucommia ulmoides extract, 50g of microcrystalline cellulose and 20g of lactose into the mixer in sequence. The total mixing time is 20min and the mixing uniformity RSD is ≤2%.

[0076] Pulping: Hydroxypropyl methylcellulose was dissolved in purified water at 60°C and cooled to room temperature;

[0077] For soft materials: spray in adhesive, control humidity at 25-30%;

[0078] Centrifuge granulation: Place the above soft material into a centrifuge and set the speed to 200-300 rpm;

[0079] When the temperature is set to 60℃, spherical particles of 0.8-1.2mm are generated;

[0080] Step 4: Coating and Packaging;

[0081] Use Eudragit L100-55, with aluminum-plastic blister packs and desiccant for outer packaging, and store in a sealed container.

[0082] Compared with the prior art, the present invention provides a quercetin pill that lowers hypertension by improving vascular endothelial function, and has the following beneficial effects:

[0083] This invention improves the bioavailability of quercetin through nanotechnology, combines the multi-target mechanism of action of Eucommia ulmoides, and innovatively applies subcritical extraction and hot-melt extrusion technology to achieve synergistic regulation of vascular endothelial function while ensuring the stability of the formulation, thus solving the problem of limited use of quercetin in lowering hypertension in the prior art.

[0084] This invention improves the bioavailability of quercetin by increasing its water solubility and reducing its irritation to the gastrointestinal tract. The resulting quercetin pills can effectively improve vascular endothelial function and lower blood pressure. Attached Figure Description

[0085] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0086] Figure 1 This is a diagram showing the changes in cell scratch patterns under a microscope and the effects of different drugs on cells after 12 hours of intervention.

[0087] Figure 2 This is a cell migration distance analysis diagram of the present invention;

[0088] Figure 3 This is a diagram showing the results of Masson staining of the rat thoracic aorta in this invention;

[0089] Figure 4 This is a schematic diagram of the process flow of the present invention.

[0090] Among them: Figure 1In the figure, Figure (a) shows the changes in the blank control group (WKY) after 12 hours of drug intervention, Figure (b) shows the changes in the model group (SHR) after 12 hours of drug intervention, Figure (c) shows the changes in the Dgal+AngII+quercetin pills (HPS) (in this invention) after 12 hours of drug intervention, and Figure (d) shows the changes in the Dgal+AngII+quercetin (XY) drug intervention after 12 hours. Detailed Implementation

[0091] The preparation and research of quercetin pills for improving vascular endothelial function and lowering hypertension will be further described in detail below with reference to the accompanying drawings and embodiments of the present invention.

[0092] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other. The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0093] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the exemplary embodiments as described in this application. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0094] It should be noted that the terms "first," "second," etc., in the specification, claims, and accompanying drawings of this application are used to distinguish similar objects and are not necessarily used to describe a specific order or sequence. It should be understood that such data can be interchanged where appropriate so that the embodiments of this application described herein can be implemented, for example, in orders other than those illustrated or described herein. Furthermore, the terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusion; for example, a process, method, system, product, or apparatus that comprises a series of steps or units is not necessarily limited to those steps or units explicitly listed, but may include other steps or units not explicitly listed or inherent to such processes, methods, products, or apparatus.

[0095] For ease of description, spatial relative terms such as "above," "on top of," "on the upper surface of," "above," etc., are used herein to describe the spatial positional relationship of a device or feature as shown in the figures to other devices or features. It should be understood that spatial relative terms are intended to encompass different orientations in use or operation beyond the orientation of the device as described in the figures. For example, if the device in the figures were inverted, a device described as "above" or "on top of" other devices or structures would subsequently be positioned as "below" or "under" other devices or structures. Thus, the exemplary term "above" can include both "above" and "below." The device may also be positioned in other different ways (rotated 90 degrees or in other orientations), and the spatial relative descriptions used herein will be interpreted accordingly.

[0096] Example 1: A quercetin pill that lowers hypertension by improving vascular endothelial function, the main ingredients of which include: quercetin and Eucommia ulmoides extract; the excipients of which include: hydroxypropyl-β-cyclodextrin, hydroxypropyl methylcellulose, lactose, microcrystalline cellulose or one or more; the coating solution is Eudragit L100-55.

[0097] The preparation method includes: first, mixing the quercetin-cyclodextrin complex, Eucommia ulmoides extract and excipients evenly to obtain a mixture; then, making the mixture into a soft mass; using a centrifuge to make the mixed soft mass into spherical pellets; finally, coating the pellets with a coating material to obtain quercetin pellets.

[0098] The following is the specific process for preparing quercetin pills using quercetin:

[0099] Example 1:

[0100] A quercetin pill comprising 100g quercetin, 80g Eucommia ulmoides extract, 50g hydroxypropyl-β-cyclodextrin, and 20g lactose;

[0101] Its specific preparation process includes:

[0102] Step 1: Raw material processing: Weigh out 100g of quercetin, 80g of Eucommia ulmoides extract, 50g of hydroxypropyl-β-cyclodextrin, and 20g of lactose;

[0103] Step 1.1: Preparation of quercetin nanocrystals:

[0104] Feeding: Weigh 100g of quercetin raw material and disperse it in purified water containing 0.5% Tween-80 (material-to-liquid ratio 1:10);

[0105] High-pressure homogenization: Avestin EmulsiFlex-C5 homogenizer was used, and the homogenizer was cyclically processed at 1500 bar for 5 times, with the particle size monitored in real time to ≤200nm;

[0106] Freeze-drying: Add freeze-drying protectant (trehalose:mannitol = 1:1), pre-freeze to -50℃, and vacuum dry for 24 hours to obtain nanocrystalline powder;

[0107] Step 1.2: Preparation of Eucommia ulmoides iridoid extract

[0108] Subcritical water extraction: The crude powder of Eucommia ulmoides was put into the extraction vessel and dynamically extracted three times (30 min each time) with pH 4.0 acetic acid aqueous solution at 120℃ and 5 MPa.

[0109] Resin purification: The extract was passed through an AB-8 macroporous resin column and eluted with a gradient (ethanol concentration 30% → 70%) to collect the iridoid fraction;

[0110] Spray drying: The concentrate is sterilized by a 0.22μm filter membrane and then spray dried (inlet air temperature 180℃) to obtain a light yellow powder (pine resin alcohol diglucoside ≥5%).

[0111] Step 2: Active ingredient complex

[0112] Feeding: Mix quercetin nanocrystal powder and hydroxypropyl-β-cyclodextrin in a 1:1 molar ratio;

[0113] Hot melt extrusion: A Leistritz Nano-16 twin-screw extruder was used, with a temperature gradient set (feeding zone 80℃ → extrusion zone 120℃) and a rotation speed of 50 rpm.

[0114] Rapid cooling and pulverization: The extrudate is rapidly cooled with liquid nitrogen and then processed by an air jet mill and passed through a 100-mesh sieve to obtain an amorphous solid dispersion;

[0115] Step 3: Granulation of total mixture

[0116] Dry mixing: Add 150g of quercetin-cyclodextrin complex, 80g of Eucommia ulmoides extract and 20g of lactose into the mixer in sequence, with a total mixing time of 20min and a mixing uniformity RSD ≤ 2%.

[0117] Pulping: Hydroxypropyl methylcellulose was dissolved in purified water (5% concentration) at 60℃ and cooled to room temperature;

[0118] To make soft material: spray in adhesive, control humidity at 25% (it can be formed into a ball by hand, but will crumble when lightly pressed);

[0119] Centrifuge granulation: Place the above soft material into a centrifuge and set the speed to 200 rpm;

[0120] The temperature was set to 40℃, resulting in 0.8mm spherical particles.

[0121] Step 4: Coating and Packaging

[0122] It uses Eudragit L100-55 (coating solution), and the outer packaging uses aluminum-plastic blister packs (amber-colored light-proof material) + desiccant, and is stored in a sealed container.

[0123] Example 2:

[0124] A quercetin pill comprising 150g quercetin, 90g Eucommia ulmoides extract, 60g hydroxypropyl-β-cyclodextrin and 50g hydroxypropyl methylcellulose.

[0125] Its specific preparation process includes:

[0126] Step 1: Raw material processing:

[0127] Weigh out 150g of quercetin, 90g of Eucommia ulmoides extract, 60g of hydroxypropyl-β-cyclodextrin, and 50g of microcrystalline cellulose. Step 1.1: Preparation of quercetin nanocrystals

[0128] Feeding: Weigh 150g of quercetin raw material and disperse it in purified water containing 0.5% Tween-80 (material-to-liquid ratio 1:10);

[0129] High-pressure homogenization: Avestin EmulsiFlex-C5 homogenizer was used, and the homogenizer was cyclically processed at 1500 bar for 5 times, with the particle size monitored in real time to ≤200nm;

[0130] Freeze-drying: Add freeze-drying protectant (trehalose:mannitol = 1:1), pre-freeze to -60℃, and vacuum dry for 24 hours to obtain nanocrystalline powder;

[0131] Step 1.2: Preparation of Eucommia ulmoides iridoid extract

[0132] Subcritical water extraction: The crude powder of Eucommia ulmoides was put into the extraction vessel and dynamically extracted three times (30 min each time) with pH 4.0 acetic acid aqueous solution at 120℃ and 5 MPa.

[0133] Resin purification: The extract was passed through an AB-8 macroporous resin column and eluted with a gradient (ethanol concentration 30% → 70%) to collect the iridoid fraction;

[0134] Spray drying: The concentrate is sterilized by a 0.22μm filter membrane and then spray dried (inlet air temperature 180℃) to obtain a light yellow powder (pine resin alcohol diglucoside ≥5%).

[0135] Step 2: Active ingredient complex

[0136] Feeding: Mix quercetin nanocrystal powder and hydroxypropyl-β-cyclodextrin in a 1:1 molar ratio;

[0137] Hot melt extrusion: A Leistritz Nano-16 twin-screw extruder was used, with a temperature gradient set (feeding zone 80℃ → extrusion zone 120℃) and a rotation speed of 50 rpm.

[0138] Rapid cooling and pulverization: The extrudate is rapidly cooled with liquid nitrogen and then processed by an air jet mill and passed through a 100-mesh sieve to obtain an amorphous solid dispersion;

[0139] Step 3: Granulation of total mixture

[0140] Dry mixing: Add 200g of quercetin-cyclodextrin complex, 90g of Eucommia ulmoides extract and 50g of microcrystalline cellulose to the mixer in sequence. The total mixing time is 20min and the mixing uniformity RSD is ≤2%.

[0141] Pulping: Hydroxypropyl methylcellulose was dissolved in purified water (5% concentration) at 60℃ and cooled to room temperature;

[0142] For making soft materials: spray in adhesive, control humidity at 25-30% (it can be formed into a ball when squeezed by hand, but will crumble when lightly pressed);

[0143] Centrifuge granulation: Place the above soft material into a centrifuge and set the speed to 200-300 rpm;

[0144] When the temperature is set to 50℃, spherical particles of 0.8-1.2mm are generated;

[0145] Step 4: Coating and Packaging

[0146] It uses Eudragit L100-55 (coating solution), and the outer packaging uses aluminum-plastic blister packs (amber-colored light-proof material) + desiccant, and is stored in a sealed container.

[0147] Example 3

[0148] A quercetin pill comprises 200g quercetin, 100g Eucommia ulmoides extract, 70g hydroxypropyl-β-cyclodextrin, 50g hydroxypropyl methylcellulose, and 20g lactose.

[0149] Its specific preparation process includes:

[0150] Step 1: Raw material processing:

[0151] Weigh out 200g of quercetin, 100g of Eucommia ulmoides extract, 70g of hydroxypropyl-β-cyclodextrin, 50g of microcrystalline cellulose, and 20g of lactose.

[0152] Step 1.1: Preparation of quercetin nanocrystals:

[0153] Feeding: Weigh 200g of quercetin raw material and disperse it in purified water containing 0.5% Tween-80 (material-to-liquid ratio 1:10).

[0154] High-pressure homogenization: An Avestin EmulsiFlex-C5 homogenizer was used, with 5 cycles of 1500 bar pressure, and the particle size was monitored in real time to ≤200nm.

[0155] Freeze-drying: Add freeze-drying protectant (trehalose:mannitol = 1:1), pre-freeze to -60℃, and vacuum dry for 24 hours to obtain nanocrystalline powder.

[0156] Step 1.2: Preparation of Eucommia ulmoides iridoid extract

[0157] Subcritical water extraction: The crude Eucommia ulmoides powder was added to the extraction vessel and dynamically countercurrently extracted three times (30 min each time) with a pH 4.0 acetic acid aqueous solution at 120℃ and 5 MPa.

[0158] Resin purification: The extract was passed through an AB-8 macroporous resin column and eluted with a gradient (ethanol concentration 30% → 70%) to collect the iridoid fraction.

[0159] Spray drying: The concentrate is sterilized by passing it through a 0.22μm filter membrane and then spray dried (inlet air temperature 180℃) to obtain a pale yellow powder (pine resin alcohol diglucoside ≥5%).

[0160] Step 2: Active ingredient complex

[0161] Feeding: Mix quercetin nanocrystal powder and hydroxypropyl-β-cyclodextrin in a 1:1 molar ratio;

[0162] Hot melt extrusion: A Leistritz Nano-16 twin-screw extruder was used, with a temperature gradient set (feeding zone 80℃ → extrusion zone 120℃) and a rotation speed of 50 rpm.

[0163] Rapid cooling and pulverization: The extrudate is rapidly cooled with liquid nitrogen and then processed by an air jet mill and passed through a 100-mesh sieve to obtain an amorphous solid dispersion;

[0164] Step 3: Granulation of total mixture

[0165] Dry mixing: Add 250g of quercetin-cyclodextrin complex, 100g of Eucommia ulmoides extract, 50g of microcrystalline cellulose and 20g of lactose into the mixer in sequence. The total mixing time is 20min and the mixing uniformity RSD is ≤2%.

[0166] Pulping: Hydroxypropyl methylcellulose was dissolved in purified water (5% concentration) at 60℃ and cooled to room temperature;

[0167] For making soft materials: spray in adhesive, control humidity at 25-30% (it can be formed into a ball when squeezed by hand, but will crumble when lightly pressed);

[0168] Centrifuge granulation: Place the above soft material into a centrifuge and set the speed to 200-300 rpm;

[0169] When the temperature is set to 60℃, spherical particles of 0.8-1.2mm are generated;

[0170] Step 4: Coating and Packaging

[0171] It uses Eudragit L100-55 (coating solution), and the outer packaging uses aluminum-plastic blister packs (amber-colored light-proof material) + desiccant, and is stored in a sealed container.

[0172] Example 2:

[0173] like Figure 1 , Figure 2 , Figure 3 and Figure 4 As shown, unlike Example 1, this example examines the effects of different intervention methods on the migration and proliferation capacity of cells with endothelial injury at the cellular level, thereby verifying the effect of the quercetin pill of the present invention on improving vascular endothelial injury in spontaneous hypertension.

[0174] Laboratory supplies:

[0175] (1) Human aortic endothelial cells, purchased from Wuhan Fenghui Biotechnology Co., Ltd.;

[0176] (2) Spontaneously hypertensive rats (SHR) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0177] (3) Endothelial cell culture medium (ECM) (basal medium, fetal bovine serum (FBS), endothelial cell growth supplement (ECGS), penicillin / streptomycin solution (P / S) were all purchased from Sciencell;

[0178] (4) Galactose (D-gal), dimethyl sulfoxide (DMSO), microcrystalline cellulose, lactose, hydroxypropyl methylcellulose, phenylephrine (PE), acetylcholine (Ach), and Krebs-Henseleit buffer were purchased from Sigma.

[0179] (5) Angiotensin II (AngII), purchased from MedChemExpress;

[0180] (6) Phosphate-buffered saline (PBS), purchased from Yamei Biotechnology;

[0181] (7) Tris buffered Tween wash buffer (TBST), purchased from Yamei Biotechnology;

[0182] (8) Protein lysis buffer (RIPA), purchased from Beyotime;

[0183] (9) Blocking solution, purchased from Genefist;

[0184] (10) β-action, purchased from Proteintech;

[0185] (11) Quercetin, purchased from Sinopharm Group;

[0186] (12) Sacubitril-valsartan, purchased from Sinopharm Group;

[0187] (13) All pipettes, centrifuges and other equipment used in the laboratory were purchased from ThermoFisher.

[0188] Experimental protocol

[0189] 1. By observing the effects of different intervention methods on the migration and proliferation capacity of cells damaged by endothelial injury at the cellular level, the effect of the quercetin pills of this invention on improving vascular endothelial injury in spontaneous hypertension was verified:

[0190] Human aortic endothelial cells were cultured in an incubator at 37°C, 5% CO2, and saturated humidity, with the medium changed every 24-48 hours. Once the cells reached 80% confluence, they were routinely passaged with 0.25% trypsin. Cells from passages 3-8 were used for experiments.

[0191] This study used a cell model constructed to simulate endothelial damage in hypertension, which was created by combining angiotensin II (AngII) with galactose (D-gal).

[0192] (1) Blank control group (WKY): No special treatment factors were added;

[0193] (2) Model group (SHR): D-gal + AngII (1μM) intervention for 24h;

[0194] (3) Dgal+AngII+Quercetin pill group (HPS): Endothelial cells were treated with D-gal for 72h, and Ang II was used for 1h followed by quercetin for 24h.

[0195] (4) Dgal+AngII+sacubitrilvalsartan group (XY): Endothelial cells were treated with D-gal for 72h, and then treated with Ang II for 1h followed by sacubitrilvalsartan for 24h.

[0196] get Figure 1 To observe the scratches under a microscope (from right to left: WKY, SHR, HPS, XY), Figure 2 Analysis of the migration distance of the scratches using Image J showed that the quercetin pill intervention group had the largest area of ​​cell migration, indicating that the quercetin pill group (the present invention) effectively improved the activity of endothelial cells.

[0197] One-way ANOVA using SPSS 26.0 software showed that P < 0.05 was statistically significant, with the quercetin pill group showing a significant difference, demonstrating its promoting effect on endothelial cell growth.

[0198] 2. By comparing blood pressure and vascular tone before and after intervention in spontaneously hypertensive rats (SHR), the effect of the quercetin pills of this invention on improving vascular endothelial damage in spontaneously hypertensive states was verified at the animal level:

[0199] Eight 10-month-old WKY rats were selected as the normal control group. Eight 10-month-old SPF-grade male spontaneously hypertensive rats were randomly divided into four groups.

[0200] The specific grouping methods and intervention measures are as follows:

[0201] (1) WKY group: normal control group rats, WKY rats, 8 rats, were given an equal amount of physiological saline by gavage every day;

[0202] (2) SHR group: 8 spontaneously hypertensive rats were given an equal amount of physiological saline by gavage every day;

[0203] (3) Quercetin pill (HPS) group: 8 spontaneously hypertensive rats were given 1g / kg by gavage daily;

[0204] (4) Sacubitril / valsartan (XY) group: eight spontaneously hypertensive rats were administered 7.4 mg / kg / day by gavage.

[0205] Blood pressure was measured three weeks before and after drug intervention, and the mean and standard deviation were calculated (Table 1). Samples were collected eight weeks after drug intervention. Rats in each group were anesthetized sequentially by intraperitoneal injection of 3% sodium pentobarbital (30 mg / kg). The rat thoracic aorta (sternum to diaphragm segment) was isolated. Part of the aorta was fixed in a fixative solution for sectioning; the other part was placed in 4°C pre-cooled Krebs-Henseleit buffer (components: NaCl 118 mM, KCl 4.7 mM, CaCl2 2.5 mM, MgSO4 1.2 mM, KH2PO4 1.2 mM, NaHCO3 25 mM, Glucose 11 mM) to remove peripheral fat and connective tissue. The aorta was microscopically sheared into 2-3 mm ring fragments (avoiding endothelial damage). The vascular rings were suspended on two stainless steel triangular hooks for vascular tension testing. Phenylephrine (PE) was added cumulatively to each ring. -9 Up to 10 -5 M) and acetylcholine (ACh, 10) -9 Up to 10 -5 M), simultaneously recording 10 -6MPE-induced maximum contractile tension and calculated relaxation rate: (PE tension – Ach tension) / PE tension × 100%.

[0206] get Figure 3 The results of Masson staining of the thoracic aorta of rats clearly show a large amount of blue collagen deposition in the aorta of SHR rats, indicating a significant tendency towards fibrosis. After intervention with quercetin pills, the blue collagen deposition in SHR rats decreased and the degree of aortic fibrosis was reduced, suggesting that quercetin pills have an ameliorative effect on vascular endothelium damaged by spontaneous hypertension.

[0207] (1) Table 1 shows the changes in blood pressure in rats after drug intervention.

[0208] Table 1: Changes in blood pressure in rats after drug intervention (mean ± standard deviation)

[0209]

[0210] *p<0.05**p<0.01.

[0211] LSD-t test was performed using SPSS 26.0 statistical software, with P < 0.05 considered statistically significant, indicating significant differences before and after the intervention. The difference in blood pressure between the quercetin pill group (HPS) and the sacubitril / valsartan group (XY) demonstrates that this invention can effectively lower blood pressure and is more effective than Western medicine.

[0212] (2) Table 2 shows the comparison of PE contraction force in each group after intervention.

[0213] Table 2: Comparison of PE contractility in each group after intervention

[0214]

[0215] Note: (▲▲ vs WKYp < 0.01; ** vs SHRp < 0.01; vs XYp < 0.01; bolded data in the HPS group in the table indicates optimal performance)

[0216] As shown in Table 2, PE contractility (induced by phenylephrine) is a key indicator for assessing basal vascular smooth muscle contraction and endothelial antagonism. Endothelial injury reduces the secretion of relaxing factors (such as NO), leading to enhanced PE contractility. In the experiment, both the quercetin and sacubitril / valsartan groups showed decreased PE tension, but the quercetin pill group exhibited significantly lower PE tension than the sacubitril / valsartan group (1.81g vs 3.28g, p<0.001), and was close to the PE tension of the normal group, directly verifying its ability to improve endothelial function and effectively reverse vascular hypertonicity.

[0217] (3) Table 3 shows the comparison of ACh endothelium-dependent relaxation rates among the groups after intervention.

[0218] Table 3: Comparison of ACh endothelium-dependent relaxation rates among groups after intervention

[0219]

[0220] Note: (▲▲ vs WKYp < 0.01; ** vs SHRp < 0.01; vs XYp < 0.01; no significant difference in ns; bold data in the HPS group in the table indicates the best performance)

[0221] As shown in Table 3, ACh-dependent vasodilation directly assesses vascular endothelial function: ACh activates endothelial cell M3 receptors to activate eNOS, thereby promoting NO release and vasodilation. A decreased vasodilation rate (e.g., 34.8% in the SHR-C group vs. 87.5% in the WKY-C group) reflects endothelial damage and impaired NO synthesis, and is the gold standard for endothelial function. In the experiment, the quercetin pill group reached 83.5% (close to normal), significantly higher than the sacubitril / valsartan group (52.8%) (p<0.001), confirming its excellent endothelial repair effect. (Clinical threshold: <60% indicates endothelial dysfunction).

[0222] (4) Table 4 shows the comparison of eNOS (endothelial-type nitric oxide synthase) activity among the groups after intervention.

[0223] Table 4: Comparison of eNOS (endothelial nitric oxide synthase) activities among groups after intervention

[0224]

[0225] Note: (The p-value for HPS compared to WKY is 0.051, which is close to the critical value, but it can generally be considered that there is no significant difference; the data for the HPS group in bold in the table indicate that it has the best performance).

[0226] As shown in Table 4, eNOS catalyzes the production of NO from L-arginine, directly regulating vasodilation. Decreased eNOS activity leads to impaired NO synthesis, causing vasoconstriction and hypertension. In the experiment, the eNOS level in the quercetin pill group reached 7.92 U / mg (recovering to 91.2% of normal), significantly higher than the 4.32 U / mg level in the sacubitril / valsartan group (p<0.001), confirming that it repairs endothelial function by activating eNOS.

[0227] The results above show that the quercetin pills of the present invention can effectively improve vascular endothelial damage in spontaneous hypertension.

[0228] The above-described embodiments are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the appended claims.

Claims

1. A quercetin pill that lowers hypertension by improving vascular endothelial function, characterized in that: It includes 100-200g of quercetin, 80-100g of Eucommia ulmoides extract, and 50-70g of hydroxypropyl-β-cyclodextrin.

2. The quercetin pill as described in claim 1, which lowers hypertension by improving vascular endothelial function, is characterized in that: It also includes 20g of lactose.

3. A method for preparing quercetin pills as described in claim 2, which lowers hypertension by improving vascular endothelial function, characterized in that: include: Step 1: Raw material processing: Weigh out 100g of quercetin, 80g of Eucommia ulmoides extract, 50g of hydroxypropyl-β-cyclodextrin, and 20g of lactose; Step 1.1: Preparation of quercetin nanocrystals: Step 1.2: Preparation of Eucommia ulmoides iridoid extract; Step 2: Active ingredient complex; Feeding: Mix quercetin nanocrystal powder and hydroxypropyl-β-cyclodextrin in a 1:1 molar ratio; Hot melt extrusion: A twin-screw extruder is used, with a temperature gradient set from 80℃ in the feeding zone to 120℃ in the extrusion zone, and a rotation speed of 50 rpm. Rapid cooling and pulverization: The extrudate is rapidly cooled with liquid nitrogen and then processed by an air jet mill and passed through a 100-mesh sieve to obtain an amorphous solid dispersion; Step 3: Granulation of the total mixture; Dry mixing: Add 150g of quercetin-cyclodextrin complex, 80g of Eucommia ulmoides extract and 20g of lactose into the mixer in sequence, with a total mixing time of 20min and a mixing uniformity RSD ≤ 2%. Pulping: Hydroxypropyl methylcellulose was dissolved in purified water at 60°C and cooled to room temperature; For soft materials: spray in adhesive, control humidity at 25%; Centrifuge granulation: Place the above soft material into a centrifuge and set the speed to 200 rpm; The temperature was set to 40℃, resulting in 0.8mm spherical particles. Step 4: Coating and Packaging; Use Eudragit L100-55, with aluminum-plastic blister packs and desiccant for outer packaging, and store in a sealed container.

4. The method for preparing quercetin pills to lower hypertension by improving vascular endothelial function as described in claim 3, characterized in that: The preparation process of Eucommia ulmoides iridoid extract includes: Subcritical water extraction: The crude powder of Eucommia ulmoides was put into the extraction vessel and dynamically countercurrently extracted three times with pH 4.0 acetic acid aqueous solution at 120℃ and 5MPa for 30 min each time. Resin purification: The extract was passed through an AB-8 macroporous resin column and eluted with a gradient of ethanol concentration from 30% to 70%, and the iridoid fraction was collected. Spray drying: The concentrate was sterilized by passing it through a 0.22μm filter membrane and then spray dried to obtain a pale yellow powder.

5. The method for preparing quercetin pills to lower hypertension by improving vascular endothelial function as described in claim 3, characterized in that: The preparation process of quercetin nanocrystals includes: Feeding: Weigh 100g of quercetin raw material and disperse it in purified water containing 0.5% Tween-80 at a liquid ratio of 1:10; High-pressure homogenization: A homogenizer was used to cycle the particles at 1500 bar for 5 times, and the particle size was monitored in real time until it was ≤200nm. Freeze-drying: Add a freeze-drying protectant of trehalose:mannitol = 1:1, pre-freeze to -50℃, and vacuum dry for 24 hours to obtain nanocrystalline powder.

6. A quercetin pill as described in claim 1, which lowers hypertension by improving vascular endothelial function, characterized in that: It also includes 50g of microcrystalline cellulose.

7. A method for preparing a quercetin pill as described in claim 6, which lowers hypertension by improving vascular endothelial function, characterized in that: Step 1: Raw material processing: Weigh out 150g of quercetin, 90g of Eucommia ulmoides extract, 60g of hydroxypropyl-β-cyclodextrin, and 50g of microcrystalline cellulose; Step 1.1: Preparation of quercetin nanocrystals; Feeding: Weigh 150g of quercetin raw material and disperse it in purified water containing 0.5% Tween-80 at a material-to-liquid ratio of 1:10; High-pressure homogenization: A homogenizer was used to cycle the particles at 1500 bar for 5 times, and the particle size was monitored in real time until it was ≤200nm. Freeze-drying: Add a freeze-drying protectant of trehalose:mannitol = 1:1, pre-freeze to -60℃, and vacuum dry for 24 hours to obtain nanocrystalline powder; Step 1.2: Preparation of Eucommia ulmoides iridoid extract; Step 2: Active ingredient complex; Feeding: Mix quercetin nanocrystal powder and hydroxypropyl-β-cyclodextrin in a 1:1 molar ratio; Hot melt extrusion: A twin-screw extruder is used, with a temperature gradient set from 80℃ in the feeding zone to 120℃ in the extrusion zone, and a rotation speed of 50 rpm. Rapid cooling and pulverization: The extrudate is rapidly cooled with liquid nitrogen and then processed by an air jet mill and passed through a 100-mesh sieve to obtain an amorphous solid dispersion; Step 3: Granulation of the total mixture; Dry mixing: Add 200g of quercetin-cyclodextrin complex, 90g of Eucommia ulmoides extract and 50g of microcrystalline cellulose to the mixer in sequence. The total mixing time is 20min and the mixing uniformity RSD is ≤2%. Pulping: Hydroxypropyl methylcellulose was dissolved in purified water at 60°C and cooled to room temperature; For soft materials: spray in adhesive, control humidity at 25-30%; Centrifuge granulation: Place the above soft material into a centrifuge and set the speed to 200-300 rpm; When the temperature is set to 50℃, spherical particles of 0.8-1.2mm are generated; Step 4: Coating and Packaging; Use Eudragit L100-55, with aluminum-plastic blister packs and desiccant for outer packaging, and store in a sealed container.

8. The method for preparing quercetin pills for lowering hypertension by improving vascular endothelial function as described in claim 7, characterized in that: The preparation process of Eucommia ulmoides iridoid extract includes: Subcritical water extraction: The crude powder of Eucommia ulmoides was put into the extraction vessel and dynamically countercurrently extracted three times with pH 4.0 acetic acid aqueous solution at 120℃ and 5MPa for 30 min each time. Resin purification: The extract was passed through an AB-8 macroporous resin column and eluted with a gradient of ethanol concentration from 30% to 70%, and the iridoid fraction was collected. Spray drying: The concentrate is sterilized by a 0.22μm filter membrane and then spray dried at an inlet air temperature of 180℃ to obtain a light yellow powder.

9. A quercetin pill as described in claim 1, which lowers hypertension by improving vascular endothelial function, characterized in that: It also includes 50g of hydroxypropyl methylcellulose and 20g of lactose.

10. A method for preparing a quercetin pill as described in claim 9, which lowers hypertension by improving vascular endothelial function, characterized in that: Step 1: Raw material processing: Weigh out 200g of quercetin, 100g of Eucommia ulmoides extract, 70g of hydroxypropyl-β-cyclodextrin, 50g of microcrystalline cellulose, and 20g of lactose. Step 1.1: Preparation of quercetin nanocrystals: Feeding: Weigh 200g of quercetin raw material and disperse it in purified water containing 0.5% Tween-80 at a material-to-liquid ratio of 1:10; High-pressure homogenization: A homogenizer was used to cycle the particles at 1500 bar for 5 times, and the particle size was monitored in real time until it was ≤200nm. Freeze-drying: Add a freeze-drying protectant of trehalose:mannitol = 1:1, pre-freeze to -60℃, and vacuum dry for 24 hours to obtain nanocrystalline powder; Step 1.2: Preparation of Eucommia ulmoides iridoid extract; Subcritical water extraction: The crude powder of Eucommia ulmoides was put into the extraction vessel and dynamically countercurrently extracted three times with pH 4.0 acetic acid aqueous solution at 120℃ and 5MPa for 30 min each time. Resin purification: The extract was passed through an AB-8 macroporous resin column and eluted with a gradient of ethanol concentration from 30% to 70%, and the iridoid fraction was collected. Spray drying: The concentrate is sterilized by a 0.22μm filter membrane and then spray dried at an inlet air temperature of 180℃ to obtain a light yellow powder; Step 2: Active ingredient complex; Feeding: Mix quercetin nanocrystal powder and hydroxypropyl-β-cyclodextrin in a 1:1 molar ratio; Hot melt extrusion: A twin-screw extruder is used, with a temperature gradient set from 80℃ in the feeding zone to 120℃ in the extrusion zone, and a rotation speed of 50 rpm. Rapid cooling and pulverization: The extrudate is rapidly cooled with liquid nitrogen and then processed by an air jet mill and passed through a 100-mesh sieve to obtain an amorphous solid dispersion; Step 3: Granulation of the total mixture; Dry mixing: Add 250g of quercetin-cyclodextrin complex, 100g of Eucommia ulmoides extract, 50g of microcrystalline cellulose and 20g of lactose into the mixer in sequence. The total mixing time is 20min and the mixing uniformity RSD is ≤2%. Pulping: Hydroxypropyl methylcellulose was dissolved in purified water at 60°C and cooled to room temperature; For soft materials: spray in adhesive, control humidity at 25-30%; Centrifuge granulation: Place the above soft material into a centrifuge and set the speed to 200-300 rpm; When the temperature is set to 60℃, spherical particles of 0.8-1.2mm are generated; Step 4: Coating and Packaging; Use Eudragit L100-55, with aluminum-plastic blister packs and desiccant for outer packaging, and store in a sealed container.

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