Construction and application of oral gel drug delivery system based on yeast microcapsules

Abstract

The invention discloses construction and application of an oral gel drug delivery system based on a yeast microcapsule, and belongs to the field of new auxiliary materials and new dosage forms of pharmaceutical preparations, the drug delivery system is composed of budesonide nanoparticles, the yeast microcapsule and gel, budesonide nanoparticles are prepared from budesonide and a polylactic acid-glycolic acid copolymer through a water-in-oil emulsification evaporation technology, yeast cell wall microcapsules are formed after content of yeast powder is removed, and the budesonide-loaded yeast microcapsules are prepared from the yeast microcapsules and the budesonide nanoparticles through stirring, ultrasonic treatment and freeze drying methods. The yeast cell wall microcapsule without contents is used as a carrier, so that the medicine is protected from being degraded by gastric acid, and the intestinal immune response is regulated by targeting intestinal related lymphatic tissues (GALT). The gel prepared by combining pectin can prolong the residence time of the drug in the intestinal tract, realizes continuous release, reduces the whole-body side effect of budesonide, and improves the treatment efficiency.

Description

Technical Field

[0001] The invention belongs to the field of new excipients and new dosage forms of pharmaceutical preparations, and particularly relates to the construction of a yeast microcapsule oral gel-coated budesonide delivery system and its application in the preparation of a drug for treating IgA nephropathy. Background Art

[0002] IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world, characterized by abnormal deposition of IgA in the glomeruli, causing chronic renal inflammation and damage. Current treatment methods mainly rely on immunosuppressants, such as glucocorticoids (such as budesonide), however, these drugs may cause serious side effects and affect patient compliance. In recent years, studies have found that intestinal microbiota is closely related to the occurrence and development of IgAN. By regulating the gut-kidney axis, the production and deposition of abnormal IgA from the gut can be effectively reduced. Therefore, it is of great clinical significance to develop a drug delivery system targeting the intestine to reduce systemic side effects and improve the treatment efficiency of IgA nephropathy. Summary of the invention

[0003] In view of the defects of the prior art, the present invention intends to design and construct a yeast microcapsule gel drug delivery system (NYPs@Gel) loaded with budesonide. As a glucocorticoid, budesonide has an immunosuppressive effect, but its side effects and bioavailability may be limited, especially when administered orally or topically. The present invention uses yeast microcapsules as carriers to protect budesonide from gastric acid degradation, and regulates mucosal immunity through the gut associated lymphoid tissue (GALT) to reduce the systemic side effects of budesonide. The gel can prolong the retention time of the formula in the intestine and achieve sustained release. The NYPs@Gel of the present invention can enhance the anti-inflammatory ability of the intestinal mucosa, reduce the production of enterogenic IgA, alleviate the side effects of budesonide, and restore the balance of intestinal flora. In short, the present invention makes full use of the gut-kidney axis principle to alleviate IgAN. The present invention will provide a new, safe and effective drug delivery strategy for the treatment of IgAN through the gut-kidney axis.

[0004] The present invention achieves the above object through the following technical solutions:

[0005] The budesonide-loaded yeast microcapsule gel drug delivery system of the present invention is composed of budesonide nanoparticles (NPs), yeast microcapsules (YPs) and gel. The budesonide nanoparticles are prepared from budesonide and PLGA (polylactic acid-co-glycolic acid) by oil-in-water (O / W) emulsification evaporation technology.

[0006] The yeast microcapsule is a yeast cell wall microcapsule formed by removing the contents from yeast powder. The yeast microcapsule and budesonide nanoparticles are prepared into budesonide-loaded yeast microcapsules by stirring, ultrasonication and freeze drying.

[0007] The gel is pectin.

[0008] Among them, the mass ratio of budesonide to PLGA is 1:30 to form nanoparticles; the mass ratio of budesonide to yeast microcapsules is 1:5; and the mass ratio of yeast microcapsules to pectin is 1:16.

[0009] The yeast microcapsule oral gel drug delivery system of the present invention is prepared by the following method:

[0010] (1) Construction and confirmation of budesonide nanoparticles

[0011] ① Dissolve budesonide and PLGA-COOH (carboxyl-terminated poly(lactic acid-co-glycolic acid), or poly(lactic acid-co-glycolic acid-carboxyl) in an organic solvent and vortex until no particles are visible to the naked eye.

[0012] ② Slowly drop 1% PVA (polyvinyl alcohol) aqueous solution and continue vortexing until a clear water-oil layer is formed.

[0013] ③ Treat with an ultrasonic cell disruptor at 400 W for 10-15 minutes, magnetically stir for 12-24 hours to remove the organic solvent, and dry at room temperature after centrifugation to obtain the budesonide-loaded nanoparticles.

[0014] ④ Use dynamic light scattering, transmission electron microscopy and other methods to characterize the particle size, potential and morphology of NPs.

[0015] (2) Construction and verification of yeast microcapsules

[0016] ① Disperse yeast powder in sodium hydroxide solution and stir at 70-80℃ for 1-2 hours.

[0017] ② After centrifuging the suspension at 3000 r / min for 5-8 minutes, the resulting precipitate was rinsed with deionized water 2-3 times and then resuspended in hydrochloric acid (pH = 4), and stirred at 60-80°C for 1-2 hours.

[0018] ③ Collect the yeast microcapsules by centrifugation, rinse them with deionized water for 2-3 times, then rinse them with isopropanol for 3-4 times, rinse them with acetone for 2-3 times, and dry them at room temperature to obtain hollow yeast cell wall microcapsules.

[0019] ④ Dynamic light scattering, transmission electron microscopy and other methods were used to characterize the particle size, potential and morphology of YPs.

[0020] (3) Construction and confirmation of budesonide-loaded yeast microcapsules

[0021] ① Take budesonide nanoparticles and prepare a 1 mg / mL suspension (based on budesonide content) with deionized water.

[0022] ② Separately, take yeast cell wall microcapsules and Na2CO3 (0.1 mol / L) aqueous solution to prepare a 5 mg / mL suspension.

[0023] ③ The two are mixed in a 1:1 (volume ratio), stirred for 12-24 hours, ultrasonically treated (100W, 20-30 minutes) and extruded, and finally freeze-dried.

[0024] ④ Dynamic light scattering, transmission electron microscopy and other methods were used to characterize the particle size, potential and morphology of NYPs.

[0025] (4) Construction and confirmation of yeast microcapsule gel loaded with budesonide

[0026] ① Prepare an 8% suspension of pectin powder and deionized water, add an equal volume of yeast cell wall microcapsules loaded with budesonide nanoparticles, and add CaCl2 solution dropwise under magnetic stirring to crosslink the suspension into a gel.

[0027] ② Drying at room temperature, thus completing the preparation of the yeast microcapsule-loaded budesonide oral gel.

[0028] ③ Dynamic light scattering, transmission electron microscopy and other methods were used to characterize the particle size, potential and morphology of YPs.

[0029] In the step (1), the mass ratio of budesonide to PLGA-COOH is 1:30. The organic solvent used is a mixed solution of methanol:dichloromethane=1:3 in volume ratio.

[0030] In the step (2), the concentration of the sodium hydroxide solution is 1 mol / L.

[0031] In the step (4), the mass concentration of the CaCl2 solution is 6%.

[0032] The yeast microcapsule oral gel drug delivery system of the present invention is used to regulate the intestinal mucosal immune response of IgA nephropathy mice, reduce the IgA produced in Peyer's lymph nodes, and reduce the levels of urine protein, serum urea nitrogen and serum creatinine. By regulating the intestinal-kidney axis, the abnormal IgA generation and deposition from the intestinal tract is reduced, and mesangial cell proliferation and IgA deposition are improved.

[0033] The present invention also provides application of the oral gel drug delivery system based on yeast microcapsules in preparing a drug delivery system.

[0034] The present invention also provides the use of the oral gel drug delivery system based on yeast microcapsules in the preparation of drugs for treating IgA nephropathy.

[0035] The present invention also provides application of the oral gel drug delivery system based on yeast microcapsules in preparing an oral drug delivery system.

[0036] Beneficial effects of the present invention:

[0037] The oral gel drug delivery system based on yeast microcapsules disclosed in the present invention is mainly used to treat IgA nephropathy (IgAN). The present invention prepares PLGA nanoparticles loaded with budesonide by innovative oil-in-water emulsification evaporation technology, and uses yeast cell wall microcapsules after removing the contents as carriers to protect the drug from gastric acid degradation and target the gut-associated lymphoid tissue (GALT) to regulate intestinal immune response. The gel prepared in combination with pectin can prolong the retention time of the drug in the intestine, achieve sustained release, reduce the systemic side effects of budesonide, and improve the treatment efficiency. Animal experiments show that the system can significantly reduce the amount of IgA secreted in the intestinal Peyer's lymph nodes of IgA nephropathy mice, reduce urine protein, serum urea nitrogen and serum creatinine levels, restore the balance of intestinal flora, and improve IgA nephropathy-related symptoms. The present invention provides a safe and effective new drug delivery strategy for the treatment of IgA nephropathy, and has important clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 These are the particle size results of budesonide nanoparticles (NPs), yeast microcapsules (YPs), and budesonide-loaded yeast microcapsules (NYPs) in Example 1 of the present invention.

[0039] Figure 2 These are the fluorescence confocal results of budesonide nanoparticles (NPs), yeast microcapsules (YPs), and budesonide-loaded yeast microcapsules (NYPs) in Example 1 of the present invention.

[0040] Figure 3 These are the transmission electron microscopy results of budesonide nanoparticles (NPs), yeast microcapsules (YPs), and budesonide-loaded yeast microcapsules (NYPs) in Example 1 of the present invention.

[0041] Figure 4 These are the surface potential results of budesonide nanoparticles (NPs), yeast microcapsules (YPs), and budesonide-loaded yeast microcapsules (NYPs) in Example 1 of the present invention.

[0042] Figure 5 These are the fluorescence confocal results of the uptake of C6 nanoparticles (NPs) and yeast microcapsules (NYPs) loaded with C6 nanoparticles by RAW264.7 cells in Example 2 of the present invention.

[0043] Figure 6 These are the fluorescence confocal results of the uptake of C6 nanoparticle yeast microcapsules (NYPs) loaded with laminarin by RAW264.7 cells in Example 2 of the present invention (not used).

[0044] Figure 7 This is a physical picture of the budesonide-loaded yeast microcapsule gel (NYPs@Gel) in Example 3 of the present invention.

[0045] Figure 8 This is a scanning electron micrograph of the budesonide-loaded yeast microcapsule gel (NYPs@Gel) in Example 3 of the present invention.

[0046] Fig. 9 The intestinal retention of budesonide-loaded yeast microcapsules (NYPs) and budesonide-loaded yeast microcapsule gel (NYPs@Gel) in Example 4 of the present invention.

[0047] Fig.10 This is a graph showing the release efficiency results of budesonide-loaded yeast microcapsules (NYPs) and budesonide-loaded yeast microcapsule gels (NYPs@Gel) in simulated intestinal fluid in Example 4 of the present invention.

[0048] Fig.11 This is a graph showing the results of in vitro safety assessment of budesonide-loaded yeast microcapsule gel (NYPs@Gel) on macrophage cell lines (RAW264.7) and small intestinal epithelial cell lines (IEC-6) in Example 5 of the present invention.

[0049] Fig.12 This is a graph showing the organ index results of the heart, liver, spleen, and lung of mice after treatment with budesonide-loaded yeast microcapsule gel (NYPs@Gel) in Example 6 of the present invention.

[0050] Fig.13 This is a graph showing the AST and ALT results of mice after treatment with budesonide-loaded yeast microcapsule gel (NYPs@Gel) in Example 6 of the present invention.

[0051] Fig.14 These are H&E photos of the heart, liver, spleen, and lungs of mice treated with budesonide-loaded yeast microcapsule gel (NYPs@Gel) in Example 6 of the present invention.

[0052] Fig.15 This is a graph showing the proportion of B cells capable of secreting IgA in the blank, budesonide nanoparticles (NPs), budesonide-loaded yeast microcapsules (NYPs), budesonide-loaded yeast microcapsule gels (NYPs@Gel), and Peyer's lymph nodes of IgA nephropathy (IgAN) mice in Example 7 of the present invention.

[0053] Fig.16 This is a graph showing the results of the content of sIgA in the feces and blood of blank, budesonide nanoparticles (NPs), budesonide-loaded yeast microcapsules (NYPs), budesonide-loaded yeast microcapsule gels (NYPs@Gel), and IgA nephropathy (IgAN) mice in Example 7 of the present invention.

[0054] Fig.17 The graphs show the results of proteinuria (urine albumin to creatinine ratio), serum creatinine, and serum urea nitrogen levels of blank, budesonide nanoparticles (NPs), budesonide-loaded yeast microcapsules (NYPs), budesonide-loaded yeast microcapsule gels (NYPs@Gel), and IgA nephropathy (IgAN) mice in Example 8 of the present invention.

[0055] Fig.18 This is a graph showing the PAS staining results of blank, budesonide nanoparticles (NPs), budesonide-loaded yeast microcapsules (NYPs), budesonide-loaded yeast microcapsule gel (NYPs@Gel), and IgA nephropathy (IgAN) mice in Example 8 of the present invention.

[0056] Fig.19 This is a graph showing the C3 immunofluorescence results of blank, budesonide nanoparticles (NPs), budesonide-loaded yeast microcapsules (NYPs), budesonide-loaded yeast microcapsule gel (NYPs@Gel), and IgA nephropathy (IgAN) mice in Example 8 of the present invention.

[0057] Fig. 20 This is a graph showing the results of IgA immunofluorescence of blank, budesonide nanoparticles (NPs), budesonide-loaded yeast microcapsules (NYPs), budesonide-loaded yeast microcapsule gels (NYPs@Gel), and IgA nephropathy (IgAN) mice in Example 8 of the present invention.

[0058] Fig.21 This is a graph showing the results of IL-6 content in the serum of blank, budesonide nanoparticles (NPs), budesonide-loaded yeast microcapsules (NYPs), budesonide-loaded yeast microcapsule gels (NYPs@Gel), and IgA nephropathy (IgAN) mice in Example 8 of the present invention.

[0059] Fig. 22 This is a graph showing the results of real-time fluorescence quantitative PCR analysis of gluconeogenesis genes in the liver and steroidogenesis genes in the adrenal gland of blank, budesonide nanoparticles (NPs), budesonide-loaded yeast microcapsules (NYPs), and budesonide-loaded yeast microcapsule gels (NYPs@Gel) in Example 9 of the present invention.

[0060] Fig.23The fasting (6 hours) blood glucose was measured for the blank mice, mice loaded with budesonide nanoparticles (NPs), mice loaded with budesonide yeast microcapsules (NYPs), and mice loaded with budesonide yeast microcapsule gel (NYPs@Gel) in Example 9 of the present invention. DETAILED DESCRIPTION

[0061] The above contents of the present invention are further described in detail through the following specific examples, but the examples do not limit the present invention.

[0062] Example 1: Preparation and characterization of budesonide-loaded yeast microcapsules

[0063] (1) Construction of budesonide nanoparticles: 2 mg of budesonide and 60 mg of PLGA-COOH (polylactic-co-glycolic acid) were dissolved in 4 mL of organic solvent (methanol: dichloromethane = 1:3, volume ratio) and vortexed until no particles were visible to the naked eye. 1% PVA (polyvinyl alcohol) aqueous solution was slowly added and continued to vortex until a clear water-oil layer was formed. The mixture was treated with an ultrasonic cell disruptor at a power of 400 W for 10 minutes, and the organic solvent was removed by magnetic stirring overnight. The mixture was centrifuged and dried at room temperature to obtain budesonide-loaded nanoparticles.

[0064] (2) Construction of yeast microcapsules: 50 g of yeast powder was dispersed in 1 L of sodium hydroxide solution (1 mol / L) and stirred at 80°C for 1 hour. The suspension was centrifuged at 3000 r / min for 5 minutes, and the resulting precipitate was rinsed twice with deionized water and resuspended in 1 L of hydrochloric acid (pH = 4) and stirred at 60°C for 1 hour. The yeast microcapsules were collected by centrifugation and rinsed twice with deionized water. Then, they were rinsed 4 times with 100 mL of isopropanol and 2 times with 100 mL of acetone, and dried at room temperature to obtain hollow yeast cell wall microcapsules.

[0065] (3) Construction of budesonide-loaded yeast microcapsules: Budesonide nanoparticles were prepared into a 1 mg / mL suspension (based on budesonide content) with deionized water. Yeast cell wall microcapsules and Na2CO3 (0.1 mol / L) aqueous solution were prepared into a 5 mg / mL suspension. The two were mixed in a 1:1 (volume ratio), stirred overnight, ultrasonicated (100 W, 20 minutes) and extruded by an extruder, and finally freeze-dried.

[0066] The particle size and potential of PLGA-modified budesonide nanoparticles were determined by dynamic light scattering. Figure 1 , the surface potential is Figure 4 The particle size and morphology of the budesonide nanoparticles, yeast empty capsules and budesonide-loaded yeast microcapsules prepared in Example 1 were observed using a transmission electron microscope. Figure 3 Fluorescence confocal microscopy also confirmed that budesonide nanoparticles were effectively loaded into yeast microcapsules, as shown in Figure 2. Figure 2 shown.

[0067] Example 2: Targeting of budesonide-loaded yeast microcapsules

[0068] Mouse mononuclear macrophages (RAW264.7) were cultured in a 12-well cell culture plate. After the cells grew to 80% confluence, they were incubated with nanoparticles (NPs) containing coumarin-6 (C6) and yeast microcapsules (NYPs) loaded with C6 nanoparticles for 2 hours. After 2 hours, the culture medium was removed and the cells were rinsed twice with PBS. The uptake efficiency of NPs and NYPs by RAW264.7 was observed using a fluorescence confocal microscope. Figure 5 As shown, the use of yeast microcapsules as carriers improves the uptake efficiency of nanoparticles by macrophages. RAW264.7 was cultured in a 12-well cell culture plate. After the cells grew to 80% confluence, NYPs, laminarin (dectin-1 receptor blocker) and NYPs were given and incubated for 2 hours. After 2 hours, the culture medium was removed and washed twice with PBS. An appropriate volume of fluorescent dye DAPI was added and incubated for 10 minutes and washed twice with PBS. The uptake efficiency of RAW264.7 for NYPs was observed using a fluorescent confocal microscope, as shown in Figure 6 As shown, the uptake efficiency of yeast microcapsules by RAW264.7 was reduced when receptor blockers were used, proving that yeast microcapsules exerted their targeting ability by binding of surface β-glucan to the dectin-1 receptor of RAW264.7.

[0069] Example 3: Construction and characterization of budesonide-loaded yeast microcapsule gel

[0070] Pectin powder and deionized water were mixed to prepare an 8% suspension, and an equal volume of yeast cell wall microcapsule solution loaded with budesonide nanoparticles (0.25 mg / mL of budesonide, water as solvent) was added. Under magnetic stirring, 6% CaCl2 solution was added dropwise to crosslink the suspension into a gel. Figure 7 As shown in the figure, the fluidity of the preparation decreased after adding pectin. Drying at room temperature completed the preparation of the oral gel with yeast microcapsules loaded with budesonide. Figure 8 Scanning electron microscopy showed that NYPs@Gel exhibited a fibrous structure with a large number of pores. After magnification, protruding NYPs were seen on the surface, further confirming the successful preparation of NYPs@Gel.

[0071] Example 4: Viscosity and sustained release of budesonide-loaded yeast microcapsule gel

[0072] The mice were fasted for 12 hours and given an equal amount (in terms of budesonide) of DiR-labeled budesonide-loaded yeast microcapsules and budesonide-loaded yeast microcapsule gels. After administration, the complete intestinal tissues from the duodenum-rectum of the mice were collected at 1h, 2h, 4h, 6h, and 9h, and the changes in the fluorescence intensity of the intestinal tissues over time were observed under the small animal imaging system. Fig. 9 As shown in the figure, NYPs@Gel has a longer retention time in the intestine than NYPs, which highlights its viscosity. In order to evaluate the sustained-release properties of the formulation, the present invention observed the sustained-release properties of budesonide under in vitro simulated intestinal conditions. Fig.10 As shown, NYPs@Gel was completely released within 12 h, showing a significant sustained-release function compared with NYPs.

[0073] Example 5: In vitro cytotoxicity evaluation of budesonide-loaded yeast microcapsule gel

[0074] Take cells (RAW264.7 and IEC-6) with good growth status, digest and centrifuge them, discard the upper culture medium, resuspend the cells with 1mL of culture medium, take 10μL of cell suspension and add it to the cell counting plate, and count under a microscope. Dilute the cell suspension to a density of 1×10 4 cells / mL, inoculated into 96-well plates respectively, and 100 to 150 μL of cell suspension was added to each well. Cultured in an incubator, wait for the cells to completely adhere to the wall, discard the old culture medium, add PBS and NYPs@Gel (40, 20, 10, 5, 2 μM based on the dosage of budesonide) solutions prepared with serum-free culture medium, 100 μL per well, and set up 3 parallel wells for each group, among which the zeroing well is a well without cells, and an equal amount of cell culture medium is added to the zeroing well. After 24 hours of culture, 100 μL of 10% CCK-8 culture medium was added to each well in the form of liquid replacement under light-proof conditions. After incubation for 1 hour, the absorbance value of each well was measured at a wavelength of 450 nm using an enzyme reader, and the corresponding cell survival percentage was obtained by calculation. The results are as follows Fig.11 shown.

[0075] Example 6: Safety evaluation of budesonide-loaded yeast microcapsule gel

[0076] SPF-grade balb / c male mice aged 8-12 weeks were selected as model mice. After one week of adaptive feeding of mice, the modeling group was gavaged with 800 mg / kg of BSA acidified water every other day; 0.10 mL of castor oil and CCl4 mixed in a ratio of 5:1 was injected subcutaneously once a week, and 0.06 mL was injected intraperitoneally once every two weeks; LPS 50 μg / mouse / time was injected into the tail vein at the 6th and 8th weeks, respectively. After successful modeling, an equal amount of NYPs@Gel (3.125 mg / kg / d of budesonide) was given. The drug was administered once a day for 4 consecutive weeks. After 4 weeks, the heart, liver, spleen, and lung weights of the mice were weighed, and the body mass index was calculated, as shown in Figure 2. Fig.12 As shown in the figure, there was no significant difference between NYPs@Gel and blank mice. The relevant kits were used to detect transaminases before and after administration. The AST and ALT of mice treated with NYPs@Gel showed no obvious liver toxicity. Fig.13 H&E technology was used to stain the five main organs of heart, liver, spleen, and lung. After NYPs@Gel treatment, there was no obvious pathological change in cell morphology and tissue structure. Fig.14 .

[0077] Example 7: The ability of budesonide-loaded yeast microcapsule gel to regulate intestinal mucosal immunity in IgAN mice

[0078] As in the modeling method of Example 6, model mice were constructed and divided into 5 groups, namely, blank group, IgAN group, NPs, NYPs, and NYPs@Gel (3.125 mg / kg / d of budesonide), once a day for 4 consecutive weeks. After four weeks, Peyer's lymph nodes were dissected out and flow cytometry was performed. Fig.15 As shown, mature IgA-secreting B cells (IgA + B220 + The number of B cells decreased in the NYPs@Gel group, but it was particularly significant in the NYPs@Gel group. This suggests that NYPs@Gel can reduce the IgA produced in the intestinal Peyer's lymph nodes, which is further secreted into the blood and small intestine. Therefore, due to the reduction of intestinal IgA, this study confirmed that sIgA secreted by the small intestine and in the blood may also be reduced accordingly, such as Fig.16 .

[0079] Example 8: Pharmacodynamic evaluation of budesonide-loaded yeast microcapsule gel

[0080] After the IgAN model was established, this study gave NPs, NYPs, and NYPs@Gel treatment for 4 weeks. After treatment, mice treated with NPs, NYPs, and NYPs@Gel showed varying degrees of reduction in urine protein. Compared with NPs and NYPs, NYPs@Gel treatment could more significantly reduce proteinuria, serum urea nitrogen, and serum creatinine. Fig.17 Compared with IgAN mice, mice treated with NYPs@Gel showed significant improvements in mesangial cell proliferation, IgA and C3 deposition in the mesangial region, such as Fig.18 , 19 , 20. In addition, NYPs@Gel treatment can also improve systemic inflammatory response. By detecting the IL-6 levels in the serum of different groups of mice by Elisa method, this study observed significant results, such as Fig.21 .

[0081] Example 9: Attenuation of budesonide-loaded yeast microcapsule gel

[0082] Long-term treatment with glucocorticoids may lead to a variety of adverse effects, such as hyperglycemia, infection, osteoporosis, and suppression of the hypothalamic-pituitary-adrenal (HPA) axis. To determine whether NYPs@Gel reduces these side effects, this study investigated its effects on the liver and adrenal glands. Compared with mice treated with NPs alone, NYPs@Gel treatment significantly reduced fasting blood glucose levels, such as Fig.23 , and reduced the expression of gluconeogenesis markers G6pc and Pck1 in the liver, such as Fig. 22 This may be because NYPs@Gel reduced the drug concentration in the liver. NPs treatment alone suppressed the expression of steroidogenic genes in the adrenal gland, while NYPs@Gel treatment had less effect on these transcription factors.

Claims

1. A yeast microcapsule oral gel drug delivery system, characterized in that: The invention is composed of budesonide nanoparticles, yeast microcapsules and gel; wherein the budesonide nanoparticles are prepared from budesonide and polylactic acid-glycolic acid copolymer by oil-in-water emulsification evaporation technology.

2. The yeast microcapsule oral gel drug delivery system according to claim 1, characterized in that: The yeast microcapsules are yeast cell wall microcapsules formed after removing the contents from yeast powder; the yeast microcapsules and budesonide nanoparticles are prepared into budesonide-loaded yeast microcapsules by stirring, ultrasonication and freeze-drying.

3. The yeast microcapsule oral gel drug delivery system according to claim 1, characterized in that: The gel is pectin.

4. The yeast microcapsule oral gel drug delivery system according to claim 1, characterized in that: The mass ratio of budesonide to poly(lactic acid-co-glycolic acid) was 1:30 to form nanoparticles; the mass ratio of budesonide to yeast microcapsules was 1:5; and the mass ratio of yeast microcapsules to pectin was 1:

16.

5. A method for preparing the yeast microcapsule oral gel drug delivery system according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) Construction of budesonide nanoparticles: budesonide and poly(lactic-co-glycolic acid)-carboxyl were dissolved in an organic solvent, vortexed, and 1% PVA aqueous solution was slowly added dropwise, vortexed, and sonicated to obtain budesonide-loaded nanoparticles; (2) Construction of yeast microcapsules: yeast cell wall microcapsules were obtained by removing the contents of yeast powder; (3) Construction of budesonide-loaded yeast microcapsules: mixing budesonide nanoparticles with yeast cell wall microcapsules, stirring, sonicating, and extruding; (4) Construction of budesonide-loaded yeast microcapsule gel: Pectin powder and deionized water were prepared into a suspension, yeast cell wall microcapsules loaded with budesonide nanoparticles were added, stirred, CaCl2 solution was added to cross-link the suspension into a gel, and dried at room temperature to obtain budesonide-loaded yeast microcapsule gel.

6. The method for preparing the yeast microcapsule oral gel drug delivery system according to claim 5, characterized in that: In the step (1), the mass ratio of budesonide to poly(lactic acid-co-glycolic acid)-carboxyl is 1:30; and the organic solvent used is a mixed solution of methanol:dichloromethane=1:3 by volume.

7. The method for preparing the yeast microcapsule oral gel drug delivery system according to claim 5, characterized in that: In the step (4), the concentration of the CaCl2 solution is 6%.

8. Use of the yeast microcapsule oral gel drug delivery system according to any one of claims 1 to 4 in the preparation of a drug delivery system.

9. Use of the yeast microcapsule oral gel drug delivery system according to any one of claims 1 to 4 in the preparation of drugs for treating IgA nephropathy.

10. Use of the yeast microcapsule oral gel drug delivery system according to any one of claims 1 to 4 in the preparation of an oral drug delivery system.

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