Quercetin-cordyceps militaris polysaccharide solid self-nano emulsification drug delivery system as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines and health-care foods, and particularly relates to a quercetin-cordyceps militaris polysaccharide solid self-nano emulsification drug delivery system as well as a preparation method and application of the quercetin-cordyceps militaris polysaccharide solid self-nano emulsification drug delivery system. The drug delivery system is prepared by mixing cordyceps militaris polysaccharide and a liquid quercetin self-nano emulsification precursor system, and spray-drying; the solid-to-liquid ratio of the cordyceps militaris polysaccharide to the liquid quercetin self-nano emulsification precursor system is 1 g: 3 mL-3 g: 1 mL. According to the present invention, the QUE-CMP-S-SNEDDS provided by the present invention has characteristics of good slow release ability and high oral bioavailability. Animal experiment results prove that the QUE-CMP-S-SNEDDS can remarkably reduce the fasting blood glucose level of a diabetic model mouse, effectively improve the pancreatic beta cell function of the mouse, and meanwhile, can remarkably relieve the pathological state of liver lipid metabolism disorder of the mouse.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and health food technology, specifically relating to a quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsification drug delivery system, its preparation method, and its application. Background Technology

[0002] Quercetin (QUE), a natural flavonoid compound, exerts its antidiabetic activity by promoting glucose uptake, enhancing glycogen synthesis and storage, and stimulating insulin secretion. However, its clinical translation and application are significantly limited: its water solubility is extremely low (only 0.06 mg / ml at 25 °C), resulting in limited absorption in the gastrointestinal tract; its oral bioavailability in rats is <17%, and in humans, it is only about 1%. To improve its bioavailability, various drug delivery systems have been developed and applied, including lipid delivery systems (liposomes, nanoemulsions, etc.), self-nanoemulsion drug delivery systems (SNEDDS), polymer nanoparticle and vesicle drug delivery systems, etc.

[0003] Among them, SNEDDS has the advantages of rapid onset of action, simple preparation, and flexible dosage that can be increased or decreased proportionally. The system is an isotropic homogeneous mixture composed of an oil phase, an emulsifier, and a co-emulsifier. After oral administration, it comes into contact with gastrointestinal fluid under the mechanical action of gastrointestinal peristalsis and can spontaneously emulsify to form an oil-in-water nanoemulsion. It can be rapidly and uniformly dispersed in the gastrointestinal tract, significantly improving the gastrointestinal contact area and absorption efficiency of the drug. At the same time, it can effectively protect the encapsulated poorly soluble drugs, preventing them from being degraded by gastrointestinal enzymes, and can also reduce the influence of the first-pass effect in the liver, thereby greatly improving the oral bioavailability of the drug.

[0004] However, liquid SNEDDS (L-SNEDDS) are prone to drug precipitation and phase separation during long-term storage, exhibiting poor storage stability. Furthermore, their unpleasant taste and strong odor significantly reduce patient medication adherence. To address these issues, solidification using a solid carrier with high adsorption capacity for liquids is a commonly used technical approach. Various methods exist for converting L-SNEDDS into solid SNEDDS (S-SNEDDS), primarily including inert carrier surface adsorption, extrusion spheroidization, melt granulation, and spray drying. Among these, spray drying can prepare submicron to micron-sized particles, offering advantages such as higher drug loading, better flowability, and more uniform particle size distribution. However, existing solid carriers (such as nano-silica A-200, hydroxypropyl methylcellulose, polyvinyl alcohol, and magnesium stearate) have significant limitations: for example, A-200 can lead to decreased compressibility of the formulation at high concentrations and may trigger toxic reactions; magnesium stearate's strong hydrophobicity reduces the dissolution rate of the formulation, affecting drug release efficiency.

[0005] Therefore, it is of great significance to develop a new solid carrier-borne quercetin self-nanoemulsion drug delivery system. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to address the shortcomings of the prior art by providing a quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsion drug delivery system. This drug delivery system integrates the anti-diabetic activities of Cordyceps militaris polysaccharide and quercetin, and combines the high-efficiency delivery advantages of solid self-nanoemulsion drug delivery system to effectively solve the technical problems of poor water solubility and low oral bioavailability of quercetin.

[0007] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0008] The first aspect of this invention provides a quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsification drug delivery system, wherein the drug delivery system is prepared by spray drying a mixture of Cordyceps militaris polysaccharide and a liquid quercetin self-nanoemulsification precursor system; the solid-liquid ratio of the Cordyceps militaris polysaccharide and the liquid quercetin self-nanoemulsification precursor system is 1 g:3 mL to 3 g:1 mL.

[0009] The liquid quercetin self-emulsifying precursor system comprises the following components in the following proportions: 20-40% by volume of oil phase, 30-60% by volume of emulsifier, 0-20% by volume of co-emulsifier, and 1-5% by mass of quercetin.

[0010] A second aspect of this invention provides a method for preparing a quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsion drug delivery system, comprising the following steps:

[0011] Step 1: Add quercetin to the oil phase and mix evenly. Then add emulsifier and co-emulsifier in sequence and continue stirring until the system forms a clear and transparent homogeneous liquid. After centrifugation, take the supernatant to obtain the liquid quercetin self-nanoemulsified precursor system.

[0012] Step 2: Mix Cordyceps militaris polysaccharide and liquid quercetin from the nanoemulsion precursor system evenly and grind thoroughly until the two are fused together to form a uniform, lump-free mixture;

[0013] Step 3: Suspend the mixture obtained in Step 2 in distilled water to fully disperse it into a homogeneous suspension. Spray dry the suspension to obtain the quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsion drug delivery system.

[0014] In step one, the oil phase is selected from any one or a combination of several of the following: polyoxyethylene castor oil glyceryl ester (Labrafil M1944CS, LMCS), caprylic / capric triglyceride (Capmul MCM, CMCM), propylene glycol monocaprylate (Capryol 90, C90), glyceryl oleate (Glyceryl Monooleate, GMO), and propylene glycol dicaprylate / dicapric / capric acid ester (Capmul PG-8, PG8).

[0015] In some embodiments of the present invention, the oil phase is in LMCS or CMCM.

[0016] The emulsifier is selected from any one or a combination of several of Tween 20, Tween 80, Span 80, polyethylene glycol 40 (PGE-40), polyoxyethylene castor oil (EL-35), and C90.

[0017] In some embodiments of the present invention, the emulsifier is selected from any one of Tween 80, EL-35 or C90.

[0018] In step one, the co-emulsifier is selected from any one or a combination of several of propylene glycol, Transcutol P (TP), polyethylene glycol 200 (PGE-200), polyethylene glycol 400 (PGE-400), and polyethylene glycol 600 (PGE-600).

[0019] In some embodiments of the present invention, the co-emulsifier is propylene glycol or PGE-400.

[0020] In step one, the centrifugation process parameters are: centrifugation at a speed of 10000 r / min for 20 min.

[0021] In step three, the solid-liquid ratio of the mixture and distilled water is 1 g: 50 mL.

[0022] In step three, the spray drying process parameters are: inlet temperature 115 ℃ and outlet temperature 55 ℃.

[0023] The third aspect of this invention provides the application of a quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsification drug delivery system in the preparation of hypoglycemic food products.

[0024] The fourth aspect of this invention provides the use of a quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsion drug delivery system in the preparation of drugs for the treatment and / or prevention of diabetes.

[0025] In some embodiments of the present invention, the diabetes is type 2 diabetes.

[0026] In some embodiments of the present invention, a quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsifying drug delivery system was successfully prepared by the above preparation method. After 4 weeks of administration to a type 2 diabetic mouse model, the quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsifying drug delivery system provided by the present invention demonstrated a better blood glucose lowering level compared to traditional free quercetin and traditional solid-carrier-based self-nanoemulsifying drug delivery systems. This proves the application prospects of the quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsifying drug delivery system in the preparation of blood glucose-lowering foods and / or drugs.

[0027] Beneficial effects:

[0028] 1. The QUE-CMP-S-SNEDDS prepared by this invention has excellent intestinal targeted drug release characteristics. Within 6 hours, its quercetin release rate in simulated gastric juice is 13.1%, and its release rate in simulated small intestinal juice is 92.9%, showing an ideal sustained-release curve.

[0029] 2. Animal experiments confirmed that after oral administration of QUE-CMP-S-SNEDDS to mice, the area under the plasma concentration-time curve (AUC) of QUE within 24 h was 3.45 times higher than that of free QUE administered orally, and 1.54 times higher than that of the quercetin-A200-solid self-nanoemulsion drug delivery system (QUE-A200-S-SNEDDS) prepared with A-200 as a solid carrier. This significantly improved the oral bioavailability of QUE, and the effect of QUE-CMP-S-SNEDDS was better than that of QUE-A200-S-SNEDDS.

[0030] 3. Animal experiments have confirmed that QUE-CMP-S-SNEDDS can significantly reduce fasting blood glucose levels in diabetic model mice, effectively improve the function of pancreatic β cells in mice, and significantly alleviate the pathological state of lipid metabolism disorder in the liver of mice. In diabetic model mice, its hypoglycemic effect in all aspects is superior to that of QUE-A200-S-SNEDDS. Attached Figure Description

[0031] The present invention will be further described in detail below with reference to the accompanying drawings, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0032] Figure 1 The images show actual samples of L-SNEDDS (A) and QUE-L-SNEDDS (B) in Example 1 of this invention.

[0033] Figure 2 The images show the FT-IR spectra of CMP and QUE-CMP-S-SNEDDS in Embodiment 1 of the present invention.

[0034] Figure 3The changes in 24-hour blood drug concentrations (AUC) of QUE, QUE-A200-S-SNEDDS and QUE-CMP-S-SNEDDS in mice in Example 1 of this invention.

[0035] Figure 4 The release curves of quercetin in simulated gastric juice and simulated small intestinal juice are shown in Example 1 of this invention.

[0036] Figure 5 The effects of QUE-A200-S-SNEDDS and QUE-CMP-S-SNEDDS on fasting blood glucose levels in type 2 diabetic mice in Example 1 of this invention.

[0037] Figure 6 This invention relates to the effects of QUE-A200-S-SNEDDS and QUE-CMP-S-SNEDDS on glucose metabolism levels in type 2 diabetic mice in Example 1 of this invention.

[0038] Figure 7 This invention relates to the effects of QUE-A200-S-SNEDDS and QUE-CMP-S-SNEDDS on liver lipid metabolism levels in type 2 diabetic mice in Example 1 of this invention. Detailed Implementation

[0039] The present invention will be further described in detail below with reference to specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0040] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0041] Example 1:

[0042] This embodiment provides a quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsification drug delivery system (QUE-CMP-S-SNEDDS). This system uses Cordyceps militaris polysaccharide (CMP) as a solid carrier and carries a quercetin self-nanoemulsification precursor system (QUE-L-SNEDDS). CMP has multiple biological activities, including antioxidant, antitumor, hypoglycemic, immune enhancement, antibacterial and anti-inflammatory effects. Using it as a solid carrier for liquid SNEDDS can not only effectively improve the storage stability and palatability of the formulation and overcome the defects of existing synthetic carriers such as toxicity risks and dissolution inhibition, but also produce synergistic effects with the loaded drug, further enhancing the comprehensive therapeutic effect on type 2 diabetes mellitus (T2DM).

[0043] The specific preparation steps of QUE-CMP-S-SNEDDS are as follows:

[0044] Step 1: Dissolve 0.8 g of quercetin (QUE) in 4 mL of polyoxyethylene ricinoleate (Labrafil M1944CS, LMCS), and stir thoroughly in a 37 ℃ water bath. Then add 12 mL of Tween 80 (T80) and 4 mL of propylene glycol, and continue stirring until a clear, transparent, homogeneous liquid is formed. Centrifuge at 10000 r / min for 20 min, and collect the supernatant to obtain QUE-L-SNEDDS. Simultaneously, prepare a self-nanoemulsifying precursor system without QUE (L-SNEDDS) using the same materials and proportions as a blank control.

[0045] Step 2: In a 2:1 (w / v) ratio, take 6 g of CMP and 3 mL of QUE-L-SNEDDS and place them in a mortar. Grind slowly until fully combined to form a homogeneous, lump-free mixture.

[0046] Step 3: The mixture is suspended in distilled water at a solid-liquid ratio of 1:50 (w / v) to fully disperse it into a homogeneous suspension. The suspension is then spray-dried (inlet temperature 115 ℃, outlet temperature 55 ℃) to obtain QUE-CMP-S-SNEDDS.

[0047] Figure 1 The images show actual samples of L-SNEDDS and QUE-L-SNEDDS from Example 1. Figure 1 In this context, A stands for L-SNEDDS, and B stands for QUE-L-SNEDDS. Figure 1 It can be seen that the liquid changed from yellow to dark brown after being coated with QUE.

[0048] The structures of CMP and QUE-CMP-S-SNEDDS were characterized. Figure 2 The FT-IR spectra of CMP and QUE-CMP-S-SNEDDS are shown below. Figure 2 In the image, A represents the FT-IR spectrum of the CMP image. Figure 2 Image B shows the FT-IR spectrum of the QUE-CMP-S-SNEDDS. Figure 2 It can be seen that the FT-IR spectrum of QUE-CMP-S-SNEDDS, compared to CMP, is at 1248.68 cm⁻¹ -1 The characteristic absorption peak of the phenolic hydroxyl (Ar-O) stretching vibration structure of QUE is added at 942.44 cm⁻¹. -1 With 528.62 cm -1 The presence of additional out-of-plane bending vibration characteristic peaks of the QUE benzene ring indicates that QUE has been successfully incorporated into the composite system.

[0049] To verify the sustained-release capability of QUE-CMP-S-SNEDDS, following the preparation method of QUE-CMP-S-SNEDDS, a quercetin-A200 solid self-emulsifying drug delivery system (QUE-A200-S-SNEDDS) was prepared as a control using nano-silica A200 as a solid carrier. The difference was that CMP was replaced with A-200, while other preparation steps remained unchanged.

[0050] Eight-week-old male db / db mice (SPF grade, provided by Yangzhou University Medical Center) were randomly divided into three groups and administered QUE, QUE-CMP-S-SNEDDS, and QUE-A200-S-SNEDDS by gavage, respectively, at a dose of 600 mg / kg. All three samples were dispersed in distilled water to form a homogeneous suspension. Blood samples were collected via tail vein into anticoagulant tubes at 0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h after gavage. Serum was collected by centrifugation, and the serum quercetin content was determined by high-performance liquid chromatography. Figure 3 The changes in 24-hour plasma concentrations (AUC) of QUE, QUE-A200-S-SNEDDS, and QUE-CMP-S-SNEDDS in mice were calculated by... Figure 3 It can be seen that the blood concentration of QUE-CMP-S-SNEDDS was significantly higher than that of free QUE and QUE-A200-S-SNEDDS, reaching 4.64 μg / mL 8 hours after administration. The AUC within 24 hours was 3.45 times that of free QUE and 1.54 times that of QUE-A200-S-SNEDDS, respectively, which significantly improved the oral bioavailability of quercetin and was more effective than that of QUE-A200-S-SNEDDS.

[0051] The release rate of QUE from QUE-CMP-S-SNEDDS in simulated gastric and small intestinal fluids was analyzed using an in vitro simulated digestion release experiment. The specific experimental steps are as follows:

[0052] Dissolve 0.1 g of QUE-CMP-S-SNEDDS in 10 mL of deionized water and mix with 10 mL of simulated gastric electrolyte solution (containing 3.1 g / L NaCl, 1.1 g / L KCl, 0.6 g / L NaHCO3, 0.15 g / L CaCl2·2H2O, and 236 mg / L pepsin, adjusted to pH 2.5 with 0.1 M HCl). Incubate the mixture in a constant temperature shaking incubator at 37°C and 80 rpm for 2 hours to simulate the gastric digestion stage. After incubation, adjust the pH to 7.0 with 0.1 M NaOH. Then add an equal volume (1:1, v / v) of simulated small intestinal electrolyte solution (containing 5.4 g / L NaCl, 0.65 g / L KCl, 0.3 g / L NaHCO3, and 0.25 g / L CaCl2·2H2O, adjusted to pH 7.0 with 0.1 M NaOH). Simultaneously, trypsin solution (7%, w / v), bile salt solution (4%, w / v), and 5.2 mg of trypsin were added to the system. The mixture was incubated at 37°C and 80 rpm for 4 hours, maintaining pH 7.0, to simulate the small intestinal digestion stage. During the simulated digestion, 1 mL of sample was collected every hour. The collected sample was boiled to inactivate the protease, followed by centrifugation at 3000 rpm for 20 minutes. The supernatant was used to determine the QUE content. Each treatment was repeated three times to ensure the reliability of the results. The formula for calculating the QUE release rate is as follows:

[0053]

[0054] Figure 4 Release curves of quercetin from QUE-CMP-S-SNEDDS in simulated gastric and small intestinal fluids. Figure 4 It can be seen that QUE-CMP-S-SNEDDS has excellent intestinal targeted drug release characteristics. Within 6 hours, the release rate of QUE in simulated gastric fluid is 13.1%, and the release rate in simulated small intestinal fluid is 92.9%, showing an ideal sustained-release curve.

[0055] The application of QUE-CMP-S-SNEDDS in glucose and lipid metabolism disorders in diabetic mice was further characterized, and the specific steps are as follows:

[0056] Eight-week-old male db / db mice (SPF grade, provided by Yangzhou University Medical Center) were used to establish a type 2 diabetes mellitus (T2DM) model using a high-fat diet combined with streptozotocin. The successfully modeled mice were randomly divided into three groups of 10 mice each: a model control group (saline), a QUE-A200-S-SNEDDS group (600 mg / kg QUE-A200-S-SNEDDS), and a QUE-CMP-S-SNEDDS group (600 mg / kg QUE-CMP-S-SNEDDS). The mice were administered the drug once daily by gavage for four weeks. Fasting blood glucose levels, glucose metabolism, and hepatic lipid metabolism were characterized to evaluate the drug's efficacy.

[0057] Figure 5 The effects of QUE-A200-S-SNEDDS and QUE-CMP-S-SNEDDS on fasting blood glucose levels in type 2 diabetic mice. Figure 5 It can be seen that the fasting blood glucose level of mice in the QUE-CMP-S-SNEDDS group decreased to 11.05±3.00 mmol / L, which was 59.3% lower than that of the control group (27.18±2.41 mmol / L) (p<0.01), and was significantly better than that of the QUE-A200-S-SNEDDS group (15.90±1.34 mmol / L, a decrease of 41.5%) (p<0.01).

[0058] Figure 6 The effects of QUE-A200-S-SNEDDS and QUE-CMP-S-SNEDDS on glucose metabolism in type 2 diabetic mice were investigated. Figure 6 In this table, A represents the insulin resistance index, B represents the insulin sensitivity index, and C represents the pancreatic β-cell function index. Figure 6It can be seen that the insulin resistance index in the QUE-CMP-S-SNEDDS group decreased to 13.13±2.09, a 48.7% reduction compared to the control group (25.59±2.62) (p<0.01), significantly better than the QUE-A200-S-SNEDDS group (19.90±1.90, a 22.24% reduction) (p<0.01); the islet sensitivity index increased to 0.0057±0.0006, which is 3.2 times that of the control group (0.0018±0.0006). The quercetin solid self-nanoemulsion drug delivery system prepared with CMP as a solid carrier is superior to A-200 in improving hyperglycemia symptoms and restoring pancreatic function. The regulatory effect of CMP on T2DM further enhances the hypoglycemic efficacy of this drug delivery system. The results indicate that the quercetin solid self-nanoemulsion drug delivery system prepared with CMP as a solid carrier is superior to A-200 in improving hyperglycemia symptoms and restoring pancreatic function.

[0059] Figure 7 The effects of QUE-A200-S-SNEDDS and QUE-CMP-S-SNEDDS on hepatic lipid metabolism levels in type 2 diabetic mice were investigated. Figure 7 In the diagram, A represents total cholesterol in the liver, B represents triglycerides in the liver, C represents low-density lipoprotein cholesterol in the liver, and D represents high-density lipoprotein cholesterol in the liver. Figure 7It can be seen that, in terms of hepatic lipid metabolism, the total cholesterol content in the liver of the QUE-CMP-S-SNEDDS group was 0.0321±0.0037 mg / g tissue, which was 60.3% lower than that of the control group (0.0808±0.0066) (p<0.01), significantly better than that of the QUE-A200-S-SNEDDS group (0.0681±0.0038 mg / g tissue, a decrease of 15.72%) (p<0.01); the liver triglyceride content was 0.2385±0.0232 mg / g tissue, which was 56.5% lower than that of the control group (0.5482±0.0479) (p<0.01), significantly better than that of the QUE-A200-S-SNEDDS group (0.4095±0.0620). The liver low-density lipoprotein cholesterol content was 0.0197±0.0034 mg / g tissue, which was significantly lower than the control group (0.0426±0.0063) by 53.8% (p<0.01), and significantly better than the QUE-A200-S-SNEDDS group (0.0339±0.0039 mg / g tissue, a decrease of 20.42%) (p<0.01); the liver high-density lipoprotein cholesterol content increased to 0.0244±0.0031 mg / g tissue, which was 2.7 times that of the control group (0.0090±0.0015) (p<0.01), and significantly better than the QUE-A200-S-SNEDDS group (0.0164±0.0037 mg / g tissue, which was 1.82 times that of the control group) (p<0.01). The results showed that the quercetin solid self-nanoemulsion drug delivery system prepared with CMP as a solid carrier was more effective than A-200 in regulating lipid metabolism disorders. The regulatory effect of CMP on lipid metabolism in T2DM further enhanced the lipid metabolism improvement efficacy of the drug delivery system.

[0060] Example 2:

[0061] This embodiment provides a quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsification drug delivery system (QUE-CMP-S-SNEDDS), which uses Cordyceps militaris polysaccharide as a solid carrier and carries a quercetin self-nanoemulsification precursor system.

[0062] The specific preparation steps of QUE-CMP-S-SNEDDS are as follows:

[0063] Step 1: Dissolve 0.6 g of QUE in 6 mL of Capmul MCM (CMCM), stir thoroughly in a 37 ℃ water bath, then add 11 mL of polyoxyethylene castor oil (EL-35) and 3 mL of polyethylene glycol 400 (PGE-400), and continue stirring until a clear, transparent, homogeneous liquid is formed. Centrifuge at 10000 r / min for 20 min, and collect the supernatant to obtain QUE-L-SNEDDS.

[0064] Step 2: Take 4g of CMP and 8 mL of QUE-L-SNEDDS in a mortar at a ratio of 1:2 (w / v) and grind slowly until fully combined to form a uniform, lump-free mixture.

[0065] Step 3: The mixture is suspended in distilled water at a solid-liquid ratio of 1:50 (w / v) to fully disperse it into a homogeneous suspension. The suspension is then spray-dried (inlet temperature 115 ℃, outlet temperature 55 ℃) to obtain QUE-CMP-S-SNEDDS.

[0066] QUE-A200-S-SNEDDS were prepared using the preparation method described in Example 2, except that CMP was replaced with A200, and the performance was evaluated using the same efficacy evaluation experimental method as described in Example 1.

[0067] In terms of glucose metabolism, the fasting blood glucose level of mice in the QUE-CMP-S-SNEDDS group prepared in this embodiment decreased to 12.64±1.54 mmol / L, which was 53.5% lower than that of the control group (27.18±2.41 mmol / L) (p<0.01), and significantly better than that of the QUE-A200-S-SNEDDS group (16.10±1.13 mmol / L, a decrease of 40.8%) (p<0.01). Regarding pancreatic function, the insulin resistance index in the QUE-CMP-S-SNEDDS group decreased to 14.57±1.32, a 44.7% reduction compared to the control group (26.33±1.94) (p<0.01), significantly better than the QUE-A200-S-SNEDDS group (21.30±1.40, a 19.10% reduction) (p<0.01); the pancreatic sensitivity index increased to 0.0059±0.0010, which was 3 times that of the control group (0.0020±0.0008). The glycemic index of quercetin was significantly higher than that of the QUE-A200-S-SNEDDS group (0.0038±0.0015, 1.9 times that of the control group) (p<0.01); the pancreatic β-cell function index increased to 40.65±2.47, which was 2.2 times that of the control group (18.11±3.42) (p<0.01), significantly higher than that of the QUE-A200-S-SNEDDS group (32.35±2.86, 1.79 times that of the control group) (p<0.01). These results indicate that the quercetin solid self-nanoemulsion drug delivery system prepared with CMP as a solid carrier is superior to A-200 in improving hyperglycemic symptoms and restoring pancreatic function. The regulatory effect of CMP on T2DM further enhances the hypoglycemic efficacy of this drug delivery system.

[0068] Regarding hepatic lipid metabolism, the total cholesterol content in the liver of the QUE-CMP-S-SNEDDS group was 0.0348±0.0023 mg / g tissue, a decrease of 59.0% compared to the control group (0.0849±0.0049) (p<0.01), significantly better than the QUE-A200-S-SNEDDS group (0.0515±0.0047 mg / g tissue, a decrease of 39.34%) (p<0.01); the liver triglyceride content was 0.2946±0.0315 mg / g tissue, a decrease of 50.4% compared to the control group (0.5941±0.0385) (p<0.01), significantly better than the QUE-A200-S-SNEDDS group (0.3674±0.0471). The liver low-density lipoprotein cholesterol content was 0.0232±0.0048 mg / g tissue, a decrease of 51.5% compared with the control group (0.0478±0.0055) (p<0.01), which was significantly better than the QUE-A200-S-SNEDDS group (0.0346±0.0069 mg / g tissue, a decrease of 27.62%) (p<0.01); the liver high-density lipoprotein cholesterol content increased to 0.0213±0.0051 mg / g tissue, which was 1.9 times that of the control group (0.0113±0.0078) (p<0.01), which was significantly better than the QUE-A200-S-SNEDDS group (0.0184±0.0089 mg / g tissue, which was 1.63 times that of the control group) (p<0.01). The results showed that the quercetin solid self-nanoemulsion drug delivery system prepared with CMP as a solid carrier was more effective than A-200 in regulating lipid metabolism disorders. The regulatory effect of CMP on lipid metabolism in T2DM further enhanced the lipid metabolism improvement efficacy of the drug delivery system.

[0069] Example 3:

[0070] This embodiment provides a quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsification drug delivery system (QUE-CMP-S-SNEDDS), which uses Cordyceps militaris polysaccharide as a solid carrier and carries a quercetin self-nanoemulsification precursor system.

[0071] The specific preparation steps of QUE-CMP-S-SNEDDS are as follows:

[0072] Step 1: Dissolve 0.5 g of QUE in 2.5 mL of LMCS, stir thoroughly in a 37 ℃ water bath, then add 5.5 mL of C90 and 2 mL of propylene glycol, and continue stirring until a clear and transparent homogeneous liquid is formed. Centrifuge at 10000 r / min for 20 min, and collect the supernatant to obtain QUE-L-SNEDDS.

[0073] Step 2: In a 3:1 (w / v) ratio, take 6g of CMP and 2 mL of QUE-L-SNEDDS and place them in a mortar. Grind slowly until fully combined to form a homogeneous, lump-free mixture.

[0074] Step 3: The mixture is suspended in distilled water at a solid-liquid ratio of 1:50 (w / v) to fully disperse it into a homogeneous suspension. The suspension is then spray-dried (inlet temperature 115℃, outlet temperature 55℃) to obtain QUE-CMP-S-SNEDDS.

[0075] QUE-A200-S-SNEDDS were prepared using the preparation method described in Example 3, except that CMP was replaced with A200, and the performance was evaluated using the same efficacy evaluation experimental method as described in Example 1.

[0076] In terms of glucose metabolism, the fasting blood glucose level of mice in the QUE-CMP-S-SNEDDS group prepared in this embodiment decreased to 13.52±2.61 mmol / L, which was 48.7% lower than that of the control group (26.33±1.69 mmol / L) (p<0.01), and significantly better than that of the QUE-A200-S-SNEDDS group (16.94±2.56 mmol / L, a decrease of 35.7%) (p<0.01). Regarding pancreatic function, the insulin resistance index in the QUE-CMP-S-SNEDDS group decreased to 15.78±2.42, a 42.9% reduction compared to the control group (27.63±1.84) (p<0.01), significantly better than the QUE-A200-S-SNEDDS group (21.33±1.78, a 22.80% reduction) (p<0.01); the pancreatic sensitivity index increased to 0.0062±0.0009, which was 2 times that of the control group (0.0023±0.0007). The quercetin solid self-nanoemulsion drug delivery system prepared with CMP as a solid carrier was 7 times better than the QUE-A200-S-SNEDDS group (0.0041±0.0010, which was 1.78 times that of the control group) (p<0.01); the pancreatic β-cell function index increased to 39.16±1.87, which was 2.2 times that of the control group (17.58±2.44) (p<0.01), and was significantly better than the QUE-A200-S-SNEDDS group (26.56±2.10, which was 1.51 times that of the control group) (p<0.01). The results indicate that the quercetin solid self-nanoemulsion drug delivery system prepared with CMP as a solid carrier is superior to A-200 in improving hyperglycemic symptoms and restoring pancreatic function. The regulatory effect of CMP on T2DM further enhances the hypoglycemic efficacy of this drug delivery system.

[0077] Regarding hepatic lipid metabolism, the total cholesterol content in the liver of the QUE-CMP-S-SNEDDS group was 0.0376±0.0038 mg / g tissue, which was significantly lower than that of the control group (0.0906±0.0052) by 58.5% (p<0.01), and significantly better than that of the QUE-A200-S-SNEDDS group (0.0704±0.0045 mg / g tissue, a decrease of 22.30%) (p<0.01); the liver triglyceride content was 0.3245±0.0398 mg / g tissue, which was lower than that of the control group (0.5745±0.0319) by 43.5% (p<0.01), and significantly better than that of the QUE-A200-S-SNEDDS group (0.4577±0.0508). The liver low-density lipoprotein cholesterol content was 0.0245±0.0039 mg / g tissue, a decrease of 50.7% compared with the control group (0.0497±0.0063) (p<0.01), which was significantly better than the QUE-A200-S-SNEDDS group (0.0366±0.0071 mg / g tissue, a decrease of 26.36%) (p<0.01); the liver high-density lipoprotein cholesterol content increased to 0.0197±0.0048 mg / g tissue, which was 1.6 times that of the control group (0.0123±0.0075) (p<0.01), which was significantly better than the QUE-A200-S-SNEDDS group (0.0149±0.0084 mg / g tissue, which was 1.21 times that of the control group) (p<0.01). The results showed that the quercetin solid self-nanoemulsion drug delivery system prepared with CMP as a solid carrier was more effective than A-200 in regulating lipid metabolism disorders. The regulatory effect of CMP on lipid metabolism in T2DM further enhanced the lipid metabolism improvement efficacy of the drug delivery system.

[0078] This invention provides a quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsion drug delivery system, its preparation method, and its application. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsion drug delivery system, characterized in that, The drug delivery system is prepared by spray drying a mixture of Cordyceps militaris polysaccharide and liquid quercetin self-emulsifying precursor system; the solid-liquid ratio of the Cordyceps militaris polysaccharide and liquid quercetin self-emulsifying precursor system is 1 g:3 mL to 3 g:1 mL.

2. The drug delivery system according to claim 1, characterized in that, The liquid quercetin self-emulsifying precursor system comprises the following components in the following proportions: 20-40% by volume of oil phase, 30-60% by volume of emulsifier, 0-20% by volume of co-emulsifier, and 1-5% by mass of quercetin.

3. The preparation method of the quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsion drug delivery system according to claim 1 or 2, characterized in that, Includes the following steps: Step 1: Add quercetin to the oil phase and mix evenly. Then add emulsifier and co-emulsifier in sequence and continue stirring until the system forms a clear and transparent homogeneous liquid. After centrifugation, take the supernatant to obtain the liquid quercetin self-nanoemulsified precursor system. Step 2: Mix Cordyceps militaris polysaccharide and liquid quercetin from the nanoemulsion precursor system evenly and grind thoroughly until the two are fused together to form a uniform, lump-free mixture; Step 3: Suspend the mixture obtained in Step 2 in distilled water to fully disperse it into a homogeneous suspension. Spray dry the suspension to obtain the quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsion drug delivery system.

4. The preparation method according to claim 3, characterized in that, In step one, the oil phase is selected from any one or a combination of several of the following: polyoxyethylene castor oil glyceride, caprylic / capric triglyceride, propylene glycol monocaprylate, glyceryl oleate, and propylene glycol dicaprylate / dicaprylate.

5. The preparation method according to claim 3, characterized in that, In step one, the emulsifier is selected from any one or a combination of several of Tween 20, Tween 80, Span 80, polyethylene glycol 40 and polyoxyethylene castor oil.

6. The preparation method according to claim 3, characterized in that, In step one, the co-emulsifier is selected from any one or a combination of several of propylene glycol, Transcutol P, polyethylene glycol 200, polyethylene glycol 400 and polyethylene glycol 600.

7. The preparation method according to claim 3, characterized in that, In step three, the solid-liquid ratio of the mixture and distilled water is 1 g: 50 mL.

8. The preparation method according to claim 3, characterized in that, In step three, the spray drying process parameters are: inlet temperature 115 ℃ and outlet temperature 55 ℃.

9. The application of the quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsification drug delivery system according to claim 1 or 2 in the preparation of hypoglycemic food products.

10. The use of the quercetin-Cordyceps militaris polysaccharide solid self-nanoemulsion drug delivery system according to claim 1 or 2 in the preparation of drugs for the treatment and / or prevention of diabetes.

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