A composite butyric acid nanoparticle, its preparation method and application

Abstract

The present invention belongs to the field of polymer composites, and relates to a composite butyric acid nanoparticle, a preparation method thereof and an application thereof. The composite butyric acid nanoparticle has a core-shell structure, wherein the core is a polyvinyl butyrate nanoparticle and the shell is a shellac gel. The composite butyric acid nanoparticle of the present invention can target the colon site to achieve sustained release of butyric acid, and compared with the current first-line drugs for colitis and other forms of butyrate preparations, can improve the effect and safety of relieving colitis. It can effectively regulate the intestinal microbial homeostasis, down-regulate the pro-inflammatory response, and can relieve secondary and primary osteoporosis.

Description

Technical Field

[0001] The present invention belongs to the field of polymer composites, and specifically, relates to a composite butyric acid nanoparticle, a preparation method thereof, and an application thereof. Background Art

[0002] Trillions of microorganisms inhabit the gastrointestinal tract and co-evolve with the host to form a mutually beneficial relationship. These symbiotic microorganisms are called the gut microbiota, which regulate the host's homeostasis in various ways. The gut microbiota affects the local immune response in the gut and contributes to the function of distal organs, including joints, liver, periodontal tissues, and the central nervous system, etc. Therefore, regulating the microbiome or its functional metabolites may provide opportunities for systemic diseases. Recent studies have confirmed that probiotics, functional microorganisms, and short-chain fatty acids have a positive impact on the host by altering the gut microbiota.

[0003] Some existing gut-derived bacterial metabolites, etc., are used to make dietary supplements, but their effectiveness in treating colitis is limited, and their safety is insufficient, and side effects such as gastrointestinal irritation may occur.

[0004] Butyrate is a short-chain fatty acid with anti-inflammatory properties. The gradual release of butyric acid helps to regulate the local intestinal environment, which plays a crucial role in regulating the activity and polarization of macrophages. However, it is difficult to obtain effective treatment results only using free butyrate because drug targeted delivery cannot be achieved for treatment, which may cause systemic toxicity. Nanotechnology has been used in oral drug delivery systems to further enhance the absorption of drugs by inflamed colon tissues. Some studies have tried to solve this problem through different formulations, such as polyvinyl alcohol butyrate and polymer micelles that release butyrate. However, the polyvinyl alcohol butyrate synthesized by Mu et al. was only tested for stability in a constant pH 7.4 solution and was not detected in gastric acid. Wang et al. synthesized two polymer micelles that released butyrate with neutral (NtL-ButM) or negative charges (Neg-ButM), but they only detected the alleviating effect on colitis and did not study the effects on other organs of the whole body. Summary of the Invention

[0005] The object of the present invention is to provide a composite butyric acid nanoparticle and a preparation method thereof. The composite butyric acid nanoparticle can target the colon site to achieve sustained release of butyric acid. Compared with the current first-line drugs for colitis and other forms of butyrate preparations, it can improve the effect and safety of alleviating colitis. It can effectively regulate the gut microbial homeostasis and down-regulate the pro-inflammatory response. In addition, the composite butyric acid nanoparticle can also alleviate secondary and primary osteoporosis.

[0006] To achieve the above object, a first aspect of the present invention provides a composite butyric acid nanoparticle, which is a core-shell structure, with a polyvinyl butyrate nanoparticle as the inner core and a shellac gel as the outer shell.

[0007] According to a preferred embodiment of the present invention, the weight ratio of the polyvinyl butyrate nanoparticle to the shellac gel is 0.3 - 0.6:1.

[0008] A second aspect of the present invention provides a method for preparing the above composite butyric acid nanoparticle, comprising the following steps: separately preparing a polyvinyl butyrate inner core and a shellac outer shell, and forming a core-shell structure by a double emulsion method.

[0009] According to a preferred embodiment of the present invention, the method comprises the following steps:

[0010] (1) Under the protection of an inert gas, vinyl butyrate, an initiator and a solvent are mixed and subjected to a polymerization reaction to obtain polyvinyl butyrate; the toluene solution of polyvinyl butyrate is mixed with an aqueous liquid of a polyoxyethylene-polyoxypropylene ether triblock copolymer and ascorbic acid, and the mixed two phases are stirred at high speed, ultrasonically treated, and then stirred overnight to obtain polyvinyl butyrate nanoparticles;

[0011] (2) The sodium carbonate solution of shellac is mixed with glucono-delta-lactone to gel it, and stirring is stopped when the liquid becomes completely opaque, the supernatant is discarded by centrifugation, and the gelled shellac is collected and freeze-dried;

[0012] (3) The freeze-dried shellac is dissolved in a mixed liquid of dichloromethane and methanol to obtain a shellac solution, the shellac solution is mixed with the polyvinyl butyrate nanoparticle solution, and the obtained mixture is ultrasonically emulsified in an ice bath to obtain suspension A; suspension A is mixed with a sodium cholate solution, and the obtained mixture is ultrasonically emulsified in an ice bath to obtain suspension B; suspension B is added dropwise to the sodium cholate solution and stirred at room temperature to obtain suspension C; suspension C is rotary evaporated to remove dichloromethane to obtain suspension D; suspension D is centrifuged at room temperature, the supernatant is discarded and then redispersed to obtain the composite butyric acid nanoparticle.

[0013] According to a preferred embodiment of the present invention, in step (1), the molar ratio of vinyl butyrate, the initiator and the solvent is 100 - 105:1:800 - 1000; the initiator is azobisisobutyronitrile, and the solvent is acetone; the conditions of the polymerization reaction include: the temperature is 40 - 60 °C, and the time is 36 - 64 h; after the polymerization reaction is completed, the reaction solution is dialyzed, rotary evaporated and freeze-dried; the concentration of the toluene solution of polyvinyl butyrate is 0.3 - 0.5 g / mL, the concentration of the polyoxyethylene-polyoxypropylene ether triblock copolymer in the aqueous phase system is 4 - 6% (w / v), and the concentration of ascorbic acid is 4 - 6 mg / mL.

[0014] According to a preferred embodiment of the present invention, in step (1), the conditions for high-speed stirring include: a rotation speed of 600 - 1000 rpm and a stirring time of 8 - 12 min; the conditions for ultrasonic treatment include: a frequency of 10 - 30 kHz, a power of 10 - 30 W, and a treatment time of 4 - 6 min; the conditions for overnight stirring include: a rotation speed of 200 - 400 rpm.

[0015] According to a preferred embodiment of the present invention, in step (2), the concentration of the sodium carbonate solution of shellac is 70 - 90 mg / mL; the mass ratio of shellac to glucono - δ - lactone in the sodium carbonate solution of shellac is 1:0.6 - 0.8.

[0016] According to a preferred embodiment of the present invention, in step (3), the concentration of the shellac solution is 4 - 8 mg / mL; the volume ratio of dichloromethane to methanol in the mixed liquid is 1.5 - 2.5:1; the volume ratio of the shellac solution to the polyvinyl butyrate nanoparticle solution is 8 - 12:1; the concentration of the sodium cholate solution is 0.5 - 1%.

[0017] The third aspect of the present invention provides the application of the above - mentioned composite butyric acid nanoparticles in the preparation of oral bacterial metabolite preparations.

[0018] The fourth aspect of the present invention provides the application of the above - mentioned composite butyric acid nanoparticles in the preparation of drugs for colitis or osteoporosis drugs. The osteoporosis includes both secondary osteoporosis and primary osteoporosis.

[0019] Compared with the prior art, the technical advantages of the present invention include:

[0020] (1) Existing oral bacterial metabolite preparations are absorbed in the upper digestive tract, with poor targeting and unable to reach sites such as the colon where they need to exert their effects. The composite butyric acid nanoparticles of the present invention can effectively target the colon and relieve colitis.

[0021] (2) Existing oral bacterial metabolite preparations may cause side effects such as intestinal inflammation after rapid release in a short time in the digestive tract. The composite butyric acid nanoparticles of the present invention can stay in the colon for a longer time to achieve slow release of butyric acid.

[0022] (3) Existing oral bacterial metabolite preparations will enter the circulatory system after being absorbed in the intestine, which may have an adverse impact on other organ systems of the whole body and cause side effects. The composite butyric acid nanoparticles of the present invention do not affect the level of butyric acid in the circulation and ensure the biosafety of the material.

[0023] (4) The composite butyric acid nanoparticles of the present invention can also relieve secondary and primary osteoporosis.

[0024] Other features and advantages of the present invention will be described in detail in the following specific implementation section. Brief Description of the Drawings

[0025] By describing the exemplary embodiments of the present invention in more detail in conjunction with the accompanying drawings, the above and other objects, features, and advantages of the present invention will become more apparent.

[0026] Figure 1 Shows the butyric acid release amount in the supernatant after the composite butyric acid nanoparticles are immersed in the gastric juice simulation solution (pH 1.5) and the intestinal juice simulation solution (pH 7.4) for different times.

[0027] Figure 2 Shows the zeta potential of polyvinyl butyrate nanoparticles (BuNP), shellac, and composite butyric acid nanoparticles (B@S).

[0028] Figure 3 Shows the residence situation of polyvinyl butyrate nanoparticles (BuNP) and composite butyric acid nanoparticles (B@S) in the colon after intragastric administration to mice.

[0029] Figure 4 Shows the disease activity index (DAI) of the colitis scores of the blank group (Ctrl group), the disease group (DSS group), and the treatment groups: orally administered 5-aminosalicylic acid (5-ASA), free butyrate (Bu), polyvinyl butyrate nanoparticles (BuNP), and composite butyric acid nanoparticles (B@S) after inducing colitis in mice with dextran sulfate sodium (DSS).

[0030] Figure 5 Shows the high-throughput sequencing results of 16S rRNA of the cecal feces of mice in the blank group (Ctrl group), the disease group (DSS group), and the treatment groups: orally administered 5-aminosalicylic acid (5-ASA), free butyrate (Bu), polyvinyl butyrate nanoparticles (BuNP), and composite butyric acid nanoparticles (B@S) after inducing colitis in mice with dextran sulfate sodium (DSS).

[0031] Figure 6 Shows the test results of the butyric acid content in the sera of mice in the disease group (DSS group) and the composite butyric acid nanoparticle treatment group (B@S group) after inducing colitis in mice with dextran sulfate sodium (DSS).

[0032] Figure 7Shows the bone mass of the blank group (Ctrl group), disease group (DSS group), treatment groups: orally administered 5-aminosalicylic acid (5-ASA), free butyrate (Bu), polyvinyl butyrate nanoparticles (BuNP), and composite butyric acid nanoparticles (B@S) after inducing secondary osteoporosis in mice with dextran sulfate sodium (DSS): (a) micro-CT scan images; (b) quantitative bar graphs.

[0033] Figure 8 Shows the bone mass of the sham operation group (Sham group), disease group (OVX group), treatment groups: free butyrate (Bu) and composite butyric acid nanoparticles (B@S) after inducing postmenopausal primary osteoporosis in mice with bilateral ovariectomy (OVX): (a) micro-CT scan images; (b) quantitative bar graphs. Detailed implementation mode

[0034] The preferred embodiments of the present invention will be described in more detail below. Although the preferred embodiments of the present invention are described below, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments set forth herein. Examples

[0035] Prepare polyvinyl butyrate cores and shellac shells respectively, and form a core-shell structure by the double emulsion method.

[0036] (1) Preparation of polyvinyl butyrate nanoparticles

[0037] 1) Add vinyl butyrate, azobisisobutyronitrile (AIBN), and acetone (molar ratio 103:1:810) to a three-necked flask, seal it, and blow nitrogen for 30 min.

[0038] 2) After blowing nitrogen, transfer the flask to a 50°C water bath for polymerization reaction for 48 h.

[0039] 3) Dialyze the polymerization solution with methanol for 48 h, and after dialysis, perform rotary evaporation and freeze-drying to obtain polyvinyl butyrate.

[0040] 4) Dissolve the prepared polyvinyl butyrate with toluene until the solution concentration is 0.4 g / mL.

[0041] 5) Add the obtained solution to an aqueous liquid containing 5% (w / v) Pluronic F-127 and 5 mg / mL ascorbic acid, stir the two mixed phases with a high-speed stirrer at 800 rpm for 10 min, and then ultrasonicate with an ultrasonic probe (20% power, 20 kHz, 20 W) for 5 min.

[0042] 6) Stir (300 rpm / min) overnight to obtain polyvinyl butyrate nanoparticles (BuNP).

[0043] (2)Preparation of Shellac

[0044] 1) Add 8 g of shellac (concentration 80 mg / mL) to 100 mL of sodium carbonate solution, and stir until the solution turns dark purple-black.

[0045] 2) Then add 11.5 g of glucono-delta-lactone (concentration 115 mg / mL), mix well, and gelify it.

[0046] 3) Stop stirring after the liquid becomes completely opaque, centrifuge at 4000 rpm for 15 min, discard the supernatant, collect the gelled shellac, and freeze-dry for later use.

[0047] (3)Preparation of Engineered Complex Postbiotics Nanoparticles

[0048] 1) Weigh 50 mg of freeze-dried shellac and dissolve it in a mixture of dichloromethane and methanol (volume ratio 5:3) to a final concentration of 6 mg / mL.

[0049] 2) Take 2 mL of the shellac solution and mix it with 200 μL of polyvinyl butyrate nanoparticle solution (volume ratio 10:1). Place the mixture in an ice bath and ultrasonically emulsify it with a 25 W cell disruptor for 3 min to obtain suspension A.

[0050] 3) Mix suspension A with 1% sodium cholate solution (volume ratio 1:1), place the mixture in an ice bath and ultrasonically emulsify it with a 30 W cell disruptor for 5 min to obtain suspension B.

[0051] 4) Slowly add suspension B dropwise to 0.5% sodium cholate solution (volume ratio 2:5), and stir at room temperature for 10 min to obtain suspension C.

[0052] 5) Rotate and evaporate suspension C for 10 min using a rotary evaporator to remove dichloromethane and obtain suspension D.

[0053] 6) Centrifuge suspension D at 11,000 g for 15 min at room temperature, discard the supernatant, and resuspend it with triple-distilled water to obtain engineered complex postbiotics nanoparticles (BuNP@Shellac, B@S).

[0054] Detect the butyric acid release amount in the supernatant after the composite nanoparticles are immersed in simulated gastric fluid (pH 1.5) and simulated intestinal fluid (pH 7.4) for different times. As Figure 1 shown, the material releases less butyric acid in an acidic environment and can release most of the butyric acid in a weakly alkaline environment, achieving good colon targeting and avoiding extensive decomposition in gastric acid.

[0055] It can be seen that forming a core-shell structure can improve the colonic targeting of the material (the colon has a weakly alkaline pH), avoid the massive disintegration and release of butyric acid of the material in the acidic environment of the stomach, which can not only improve the targeting of the material, but also enhance the safety of the material.

[0056] Test the zeta potential of polyvinyl butyrate nanoparticles (BuNP), shellac, and composite butyric acid nanoparticles (B@S).

[0057] The results are as Figure 2 shown: Polyvinyl butyrate nanoparticles (BuNP) are positively charged, shellac is negatively charged, and the zeta potential of the composite butyric acid nanoparticles (B@S) after forming the core-shell structure changes from positive to negative. According to previous research reports, negatively charged drugs are more conducive to alleviating intestinal inflammation because there is often an enrichment of positively charged proteins at the site of intestinal inflammation, and negatively charged materials are more likely to target the inflamed site.

[0058] Use a gavage needle to gavages mice with fluorescently labeled polyvinyl butyrate nanoparticles (BuNP) and composite butyric acid nanoparticles (B@S). After 48 h of gavage, dissect and isolate the digestive tract of the mice, and use a small animal imaging system to take images of the digestive tract.

[0059] The results are as Figure 3 shown: When only polyvinyl butyrate nanoparticles (BuNP) are used, its residence time in the intestine is short, and only a small amount of the material remains in the drug action site - the colon after 48 h, and it cannot continuously release butyric acid to relieve colonic inflammation. After forming the core-shell structure, the composite butyric acid nanoparticles (BuNP@Shellac) have a longer residence time in the colon of mice. The right figure is a photo of BuNP@Shellac 48 h after gavage, and a large number of composite butyric acid nanoparticles can still be observed remaining in the colon, which is beneficial for the continuous release of butyric acid to play a role.

[0060] The colitis score DAI is comprehensively evaluated by the changes in body weight, diarrhea, and the severity of bloody stools, and is used to evaluate the severity of colitis. The higher the score, the more severe the disease. As Figure 4 shown, dextran sulfate sodium (DSS) is used to induce colitis in mice. It can be observed that the DAI score of the disease group (DSS group) is significantly higher than that of the blank group (Ctrl group). After orally administering 5-aminosalicylic acid (5-ASA, the first-line drug for clinical treatment of colitis), free butyrate (Bu), polyvinyl butyrate nanoparticles (BuNP), and composite butyric acid nanoparticles (B@S) to DSS-induced colitis mice, the severity of colitis is evaluated. It can be found that the B@S material with a core-shell structure formed in the present invention can effectively relieve colitis in mice, and its effect is better than that of the first-line drug 5-ASA and other forms of butyric acid materials (Bu, BuNP) in clinical practice.

[0061] The cecal feces of each group of mice in Test Example 4 were subjected to high-throughput sequencing of the 16S rRNA microbiome. The results were as follows Figure 5 shown. In the diseased group (DSS group), significant changes occurred in the intestinal microbiota compared with the blank group (Ctrl group). The beneficial microbiota decreased, and the harmful microbiota increased. After treatment with different drugs, the use of composite butyric acid nanoparticles (BuNP@Shellac) could more effectively regulate the balance of the intestinal flora than other treatment groups, restoring the intestinal flora composition to be closest to the blank group.

[0062] The butyric acid content in the serum of mice in the diseased group (DSS group) and the composite butyric acid nanoparticle treatment group (B@S group) in Test Example 4 was measured. The results were as follows Figure 6 shown. It was found that after treatment with B@S, there was no significant difference in the butyric acid content in the serum of mice compared with the diseased group, indicating that the formation of the core-shell structure did not affect the butyric acid level in the circulation (serum), that is, the butyric acid released by the B@S material only played a role in the colon and did not enter the circulation to directly affect the functions of other organs, ensuring the safety of the material.

[0063] The femurs of each group of mice in Test Example 4 were scanned using micro-computed tomography (micro-CT) technology and subjected to femur bone mass analysis. The results were as follows Figure 7 shown. The use of dextran sulfate sodium (DSS) could not only induce colitis in mice but also cause secondary osteoporosis in enteritis, manifested as a decrease in the percentage of femoral trabeculae (BV / TV), and the three-dimensional reconstruction images of micro-CT also showed sparse trabeculae. After orally administering 5-aminosalicylic acid (5-ASA, a first-line drug for the clinical treatment of colitis), free butyrate (Bu), polyvinyl butyrate nanoparticles (BuNP), and composite butyric acid nanoparticles (B@S) to mice with DSS-induced secondary osteoporosis in colitis, the femoral bone mass was evaluated. It was found that the B@S material with a core-shell structure formed in the present invention could effectively relieve secondary osteoporosis in mice, and its effect was better than that of 5-ASA and other forms of butyric acid materials (Bu, BuNP).

[0064] Bilateral ovariectomy (OVX) was performed on mice to induce postmenopausal osteoporosis (primary osteoporosis). The femurs of mice in the sham operation control group (Sham), diseased group (OVX), free butyrate treatment group (Bu), and composite butyric acid nanoparticle treatment group (B@S) were scanned using micro-computed tomography (micro-CT) technology and subjected to femur bone mass analysis. The results were as follows Figure 8As shown, bilateral ovariectomy (OVX) can induce osteoporosis in mice, manifested as a decrease in the percentage of femoral trabecular bone (BV / TV), and the three-dimensional reconstruction images of micro-CT also show sparse trabecular bone. After orally administering free butyrate (Bu) and composite butyric acid nanoparticles (B@S) to OVX primary osteoporosis mice, the femoral bone mass was evaluated. It was found that the B@S material with a core-shell structure formed in the present invention can effectively alleviate primary osteoporosis in mice, and its effect is better than that of free butyrate.

[0065] The embodiments of the present invention have been described above. The above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations are obvious to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.

Claims

1. A composite butyric acid nanoparticle, characterized in that, The composite butyric acid nanoparticles have a core-shell structure, with a poly(vinyl butyrate) nanoparticle as the core and shellac gel as the shell; The weight ratio of the poly(vinyl butyrate) nanoparticles to the shellac gel is 0.3 - 0.6:1; The preparation method of the composite butyric acid nanoparticles comprises the following steps: (1) Under the protection of an inert gas, vinyl butyrate, an initiator and a solvent are mixed and subjected to a polymerization reaction to obtain poly(vinyl butyrate); the toluene solution of poly(vinyl butyrate) is mixed with the aqueous liquid of poly(oxyethylene poly(oxypropylene) ether triblock copolymer) and ascorbic acid, and the two mixed phases are subjected to high-speed stirring, ultrasonic treatment, and then stirred overnight to obtain poly(vinyl butyrate) nanoparticles; (2) The sodium carbonate solution of shellac is mixed with glucono-δ-lactone to gel it. When the liquid becomes completely opaque, stirring is stopped, the supernatant is discarded by centrifugation, and the gelled shellac is collected and freeze-dried; (3) The freeze-dried shellac is dissolved in a mixed liquid of dichloromethane and methanol to obtain a shellac solution. The shellac solution is mixed with the poly(vinyl butyrate) nanoparticle solution, and the obtained mixture is subjected to ice-bath ultrasonic emulsification to obtain suspension A; suspension A is mixed with a sodium cholate solution, and the obtained mixture is subjected to ice-bath ultrasonic emulsification to obtain suspension B; suspension B is added dropwise to the sodium cholate solution, and stirred at room temperature to obtain suspension C; suspension C is rotary evaporated to remove dichloromethane to obtain suspension D; suspension D is centrifuged at room temperature, the supernatant is discarded and then resuspended to obtain the composite butyric acid nanoparticles; The molar ratio of the vinyl butyrate, the initiator and the solvent is 100 - 105:1:800 - 1000; The initiator is azobisisobutyronitrile, and the solvent is acetone; The conditions of the polymerization reaction include: the temperature is 40 - 60 °C, and the time is 36 - 64 h; After the polymerization reaction is completed, the reaction solution is dialyzed, rotary evaporated, and freeze-dried.

2. The preparation method of the composite butyric acid nanoparticles according to claim 1, comprising the following steps: (1) Under the protection of an inert gas, vinyl butyrate, an initiator and a solvent are mixed and subjected to a polymerization reaction to obtain poly(vinyl butyrate); the toluene solution of poly(vinyl butyrate) is mixed with the aqueous liquid of poly(oxyethylene poly(oxypropylene) ether triblock copolymer) and ascorbic acid, and the two mixed phases are subjected to high-speed stirring, ultrasonic treatment, and then stirred overnight to obtain poly(vinyl butyrate) nanoparticles; (2) The sodium carbonate solution of shellac is mixed with glucono-δ-lactone to gel it. When the liquid becomes completely opaque, stirring is stopped, the supernatant is discarded by centrifugation, and the gelled shellac is collected and freeze-dried; (3) The freeze-dried shellac is dissolved in a mixed liquid of dichloromethane and methanol to obtain a shellac solution. The shellac solution is mixed with the poly(vinyl butyrate) nanoparticle solution, and the obtained mixture is subjected to ice-bath ultrasonic emulsification to obtain suspension A; suspension A is mixed with a sodium cholate solution, and the obtained mixture is subjected to ice-bath ultrasonic emulsification to obtain suspension B; suspension B is added dropwise to the sodium cholate solution, and stirred at room temperature to obtain suspension C; suspension C is rotary evaporated to remove dichloromethane to obtain suspension D; suspension D is centrifuged at room temperature, the supernatant is discarded and then resuspended to obtain the composite butyric acid nanoparticles; The molar ratio of vinyl butyrate, initiator and solvent is 100-105:1:800-1000; The initiator is azobisisobutyronitrile and the solvent is acetone; The conditions for the polymerization reaction include: temperature 40-60 °C, time 36-64 h; After the polymerization reaction is completed, the reaction solution is dialyzed, rotary evaporated and freeze-dried.

3. The preparation method according to claim 2, wherein, In step (1), the concentration of the toluene solution of polyvinyl butyrate is 0.3-0.5 g / mL, the concentration of the polyoxyethylene polyoxypropylene ether triblock copolymer in the aqueous phase system is 4-6% (w / v), and the concentration of ascorbic acid is 4-6 mg / mL.

4. The preparation method according to claim 2, wherein, In step (1), The conditions for the high-speed stirring include: rotation speed 600-1000 rpm, stirring time 8-12 min; The conditions for the ultrasonic treatment include: frequency 10-30 kHz, power 10-30 W, treatment time 4-6 min; The conditions for the overnight stirring include: rotation speed 200-400 rpm.

5. The preparation method according to claim 2, wherein, In step (2), the concentration of the sodium carbonate solution of shellac is 70-90 mg / mL.

6. The preparation method according to claim 2, wherein, In step (3), the concentration of the shellac solution is 4-8 mg / mL; the volume ratio of dichloromethane and methanol in the mixed liquid is 1.5-2.5:1; The volume ratio of the shellac solution to the polyvinyl butyrate nanoparticle solution is 8-12:1; The concentration of the sodium cholate solution is 0.5-1%.

7. Use of the composite butyric acid nanoparticles according to claim 1 in the preparation of drugs for colitis or osteoporosis.

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