Attenuated artificial bear gall powder nano preparation as well as preparation method and application thereof

Abstract

The invention discloses an attenuated artificial bear gall powder nano preparation, the physical structure of which is a core-shell structure, the core is zinc oxide nanoparticles, the shell is mesoporous SiO2, and artificial bear gall powder is attached to the outer surface of the shell, through the design of the core-shell structure, the dissolution of zinc ions can be reduced while efficient loading and pH response release of the artificial bear gall powder can be realized, and the toxicity of the artificial bear gall powder can be reduced. The toxicity of the preparation is reduced; the invention further discloses a preparation method which has the characteristics of simple steps, low cost and suitability for industrial production. The invention further discloses a novel application range, namely, the compound has a wide clinical application prospect in the fields of inflammatory bowel diseases and the like needing targeted anti-inflammatory treatment.

Description

Technical Field

[0001] This invention relates to the field of artificial bear bile powder technology, specifically to a toxic artificial bear bile powder nano-formulation, its preparation method, and its application. Background Technology

[0002] Artificial bear bile powder is a commonly used traditional Chinese medicine compound preparation in clinical practice. It has multiple pharmacological effects, such as promoting bile secretion, regulating cholesterol metabolism, and protecting hepatocytes, playing an important role in the treatment of liver diseases and gallstones. However, the clinical application of artificial bear bile powder faces many challenges: the oral bioavailability of its main active ingredients (such as ursodeoxycholic acid, chenodeoxycholic acid, and other bile acids) is affected by various factors and may vary from person to person; some active ingredients may be unstable or degraded in the acidic environment of the stomach; traditional dosage forms lack targeting and controlled release capabilities, leading to rapid clearance of the drug from non-target sites and poor efficacy.

[0003] In existing technologies, researchers have developed various drug delivery systems. For example, enteric-coated formulations avoid gastric acid degradation, but the process is complex and release is uncontrollable; polymer nanoparticles (such as PLGA) can achieve sustained release, but they typically have low drug loading and slow degradation; liposome systems face challenges such as poor stability and high production costs. Recently, ZnO nanoparticles have been used as carriers for drug loading, utilizing their pH-responsive properties (acidic dissolution) to achieve targeted release, but they suffer from potential toxicity risks due to Zn ion dissolution and low loading efficiency. These drawbacks limit the clinical application of ZnO-based formulations in the delivery of multi-component drugs such as artificial bear bile powder. Summary of the Invention

[0004] In order to solve the technical problems existing in the prior art, the present invention provides a detoxified artificial bear bile powder nano-formulation, and also discloses its preparation method and application.

[0005] To achieve the above objectives, the present invention provides the following technical solution: A method for preparing an attenuated artificial bear bile powder nanoparticle formulation includes the following steps: Step S1: Preparation of zinc oxide nanoparticles Step S1.1: Dissolve the zinc salt precursor in deionized water, with a molar ratio of zinc salt to water of 1:(300~1000), and stir to obtain solution A; Step S1.2: Dissolve the alkaline compound in deionized water, with a molar ratio of alkaline compound to water of 1:(50~100), to obtain solution B; Step S1.3: Add solution B dropwise to solution A, with a solute molar ratio of 1:2 between solution B and solution A, and react at 60~80℃ for 1.5~3h to generate zinc oxide precipitate; Step S1.4: Precipitate zinc oxide, centrifuge, wash, and dry to obtain zinc oxide nanoparticles; Step S2: Constructing a ZnO@mesoporous SiO2 core-shell structure Step S2.1: Disperse zinc oxide nanoparticles in ethanol, add hexadecyltrimethylammonium bromide as a template agent, stir evenly, then add tetraethyl orthosilicate dropwise, and add ammonia water as a catalyst. React at room temperature for 5-8 hours to obtain ZnO@mesoporous SiO2 core-shell structure precursor. Step S2.2: After centrifuging and washing the ZnO@mesoporous SiO2 core-shell structure precursor, calcination is performed to remove hexadecyltrimethyl bromide, thus obtaining the ZnO@mesoporous SiO2 core-shell structure. Step S3: Loading with artificial bear bile powder Step S3.1: Disperse ZnO@mesoporous SiO2 core-shell structure and artificial bear bile powder in anhydrous ethanol at a mass ratio of (3~5):1, shake in the dark for 24 hours to obtain drug-loaded suspension; Step S3.2: After centrifuging, washing and drying the drug-loaded suspension, a toxic artificial bear bile powder nano-formulation is obtained.

[0006] Preferably, in step S1.1, the zinc salt precursor is zinc nitrate hexahydrate, zinc acetate, or zinc chloride; in step S1.2, the alkaline compound is sodium hydroxide or potassium hydroxide.

[0007] Preferably, in step S2.1, the molar ratio of zinc oxide nanoparticles to hexadecyltrimethylammonium bromide is 1:(2~5), and the molar ratio of tetraethyl orthosilicate to CTAB is (4~6):1; in step S2.2, the calcination temperature is 500~600℃, and the calcination time is 3~5h.

[0008] Preferably, in step S3.1, the oscillation temperature is 25~35℃ and the oscillation speed is 150~200 rpm; in step S3.2, the drying temperature is 25~35℃ and the drying time is 1~3 hours.

[0009] A nano-formulation of attenuated artificial bear bile powder prepared by the above method.

[0010] Furthermore, the formulation has a core-shell structure, with zinc oxide nanoparticles as the core and mesoporous SiO2 as the shell, and artificial bear bile powder attached to the outer surface of the shell.

[0011] Preferably, the zinc ion dissolution rate of the formulation is <10% within 24 hours at pH 7.4.

[0012] Preferably, the drug loading of the formulation is 15-25%.

[0013] Preferably, in a phosphate buffer solution at pH 7.4, the release rate of the main active ingredient of the formulation is <40% within 24 hours; and in a phosphate buffer solution at pH 5.5, the release rate of the main active ingredient of the formulation is >60% within 24 hours.

[0014] Application of a toxic artificial bear bile powder preparation in the prevention or treatment of hepatobiliary diseases and inflammatory diseases.

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The attenuated artificial bear bile powder nano-formulation disclosed in this invention uses a ZnO@SiO2 core-shell structure as a carrier, which provides a physical barrier to protect ZnO nanoparticles while reducing the zinc ion dissolution rate by more than 50%, that is, significantly reducing the zinc ion dissolution rate, thereby reducing the potential toxic risks such as kidney damage caused by zinc ions, improving the safety of the formulation, reducing gastrointestinal side effects, and improving patient compliance.

[0016] (2) The attenuated artificial bear bile powder nano-preparation disclosed in this invention has a ZnO@SiO2 shell that can serve as a drug protection barrier, which can significantly reduce the dissolution and degradation of ZnO in neutral physiological environments such as blood and tissue fluid, thereby greatly reducing the potential systemic toxicity that may be caused by the ZnO carrier itself, and significantly improving the biosafety of the entire nano-preparation.

[0017] (3) The attenuated artificial bear bile powder nano-formulation disclosed in this invention has a ZnO@SiO2 pore structure that increases the surface area of ​​the formulation, enabling the artificial bear bile powder loading to be increased to 15-25%, and achieving precise pH-responsive release. In the inflammatory microenvironment, i.e. at pH 5.5, the release rate is >50% within 2 hours, and in the neutral environment, i.e. at pH 7.4, the release rate is <40% within 24 hours, exhibiting synergistic anti-inflammatory effects. At the same time, its bioavailability is also increased to 20-30%, enhancing the targeted therapeutic effect.

[0018] (4) The preparation method of the attenuated artificial bear bile powder nano-preparation disclosed in this invention is simple and low in cost, suitable for industrial production, and has a wide range of applications.

[0019] (5) The attenuated artificial bear bile powder nano-preparation disclosed in this invention has a wide range of applications. Its high safety, high drug loading and sensitive pH response release characteristics make it not only suitable for the treatment of hepatobiliary diseases such as cholestatic liver disease and gallstones, but also open up application scenarios in fields such as inflammatory bowel disease that require targeted anti-inflammatory treatment, and has broad clinical application prospects. Attached Figure Description

[0020] The disclosure of this invention is illustrated with reference to the accompanying drawings. It should be understood that the drawings are for illustrative purposes only and are not intended to limit the scope of protection of this invention. In the drawings, the same reference numerals are used to refer to the same parts. Wherein: Figure 1 This is a SEM image of the ZnO@SiO2 nanoparticles prepared in Example 1; Figure 2 This is a SEM image of the ZnO@SiO2 nanoparticles prepared in Example 2; Figure 3 Here is a SEM image of the ZnO@SiO2 nanoparticles prepared in Example 3; Figure 4 These are optical photographs of the attenuated artificial bear bile powder nanoparticles prepared in Examples 1-3; Figure 5 These are schematic diagrams of the structures of ZnO@SiO2 nanoparticles prepared in Examples 1-3; Figure 6 The images show the XRD patterns of the ZnO@SiO2 nanoparticles prepared in Examples 1-3. Detailed Implementation

[0021] It is readily understood that, based on the technical solution of this invention, those skilled in the art can propose various interchangeable structural methods and implementations without altering the essential spirit of the invention. Therefore, the following detailed embodiments and accompanying drawings are merely illustrative examples of the technical solution of this invention and should not be considered as the entirety of the invention or as limitations or restrictions on the technical solution of this invention.

[0022] The technical solution of this application will now be described in detail with reference to the accompanying drawings. The description of exemplary embodiments is merely for illustrative purposes and is by no means a limitation on the invention or its application or use.

[0023] Example 1 (1) Preparation of ZnO nanoparticles Solution A: Weigh 2.97 g of zinc nitrate hexahydrate (Zn(NO3)2·6H2O, about 10 mmol) and dissolve it in 100 mL of deionized water (the molar ratio of zinc salt to water is about 1:500), and stir until completely dissolved.

[0024] Solution B: Weigh out sodium hydroxide (NaOH, 0.8 g, about 20 mmol) and dissolve it in 50 mL of deionized water (the molar ratio of alkali to water is about 1:100). Stir to dissolve.

[0025] Reaction: Under vigorous stirring, solution B is added dropwise to solution A (Zn). 2+The reaction mixture (with OH⁻ in a molar ratio of approximately 1:2) was reacted at 60°C for 2 hours to produce a white ZnO precipitate.

[0026] Post-processing: After the reaction was completed, the precipitate was collected by centrifugation (10,000 rpm, 10 minutes), washed three times with deionized water, then washed three times with ethanol, and dried in a 60℃ forced-air drying oven for 4 hours to obtain ZnO nanoparticles.

[0027] (2) Construction of ZnO@mesoporous SiO2 core-shell structure 0.1 g of the ZnO nanoparticles prepared above were dispersed in 40 mL of ethanol and sonicated for 30 minutes to ensure uniform dispersion. 0.896 g of cetyltrimethylammonium bromide (CTAB) was added, with a ZnO to CTAB molar ratio of 1:2, and the mixture was stirred for 30 minutes. 2.05 g of tetraethyl orthosilicate (TEOS) was added dropwise, with a TEOS to CTAB molar ratio of 4:1, followed by the addition of 1 mL of ammonia (25%) as a catalyst. The reaction was carried out at room temperature (approximately 25°C) for 6 hours.

[0028] After the reaction was complete, the product was collected by centrifugation (10,000 rpm, 10 min), and washed three times with ethanol to remove unreacted substances and byproducts. The washed precipitate was dried at 80 °C overnight, then placed in a muffle furnace and calcined at 550 °C for 4 hours in air at a rate of 2 °C / min to remove the CTAB template agent, yielding ZnO@mesoporous silica core-shell structured nanoparticles, such as... Figure 1 As shown. Simultaneously combined with Figure 5 It can be seen that the material surface exhibits a distinctly rough and porous structure with irregularly distributed clusters, indicating that the framework structure of mesoporous silica has been formed.

[0029] The X-ray diffraction pattern of the prepared material is as follows: Figure 6 As shown, the material preparation was successful based on the phase retrieval results.

[0030] (3) Loading of artificial bear bile powder 60 mg ZnO@SiO2 and 12 mg artificial bear bile powder were mixed in 10 mL of anhydrous ethanol and shaken at 25°C in the dark for 24 hours (150 rpm). After the reaction, the precipitate was collected by centrifugation (12,000 rpm, 15 minutes) and washed twice with a small amount of anhydrous ethanol to remove unloaded artificial bear bile powder. The washed precipitate was dried at 25°C for 1 hour to obtain a reduced-toxicity artificial bear bile powder nanoparticle formulation. It should be noted that the physical structure of this formulation is a core-shell structure, with zinc oxide nanoparticles as the core and mesoporous SiO2 as the shell, with artificial bear bile powder adhering to the outer surface of the shell. Figure 4 As shown in (b) of the diagram.

[0031] (4) Performance testing Loading effect: drug loading 15% (detection error controlled within ±0.5%); Zn 2+ Dissolution rate: In PBS buffer solution at pH 7.4 and 37°C, the cumulative zinc ion dissolution rate of the attenuated artificial bear bile powder nanoparticles was 7.65% over 24 hours. Under the same conditions, the dissolution rate of zinc ions from pure ZnO nanoparticles (without SiO2 coating) was significantly higher. 2+ The dissolution rate was 18.7%, which is the Zn content of the attenuated artificial bear bile powder nanoparticles prepared in this embodiment. 2+ The dissolution rate decreased by 59%.

[0032] Sustained release of artificial bear bile powder: The release rates of the attenuated artificial bear bile powder nano-formulation in PBS buffer solution at 37°C and 100 rpm are as follows: pH 7.4: 0.5h release rate 4.5±0.7%, 24h release rate 35.2±2.5%.

[0033] pH 5.5: 0.5h release rate 15.3±1.2%, 24h release rate 65.7±3.0%.

[0034] Example 2 (1) Preparation of ZnO nanoparticles Solution A: Weigh zinc acetate dihydrate (Zn(CH3COO)2·2H2O, 2.195 g, about 10 mmol) and dissolve it in 60 mL of deionized water (the molar ratio of zinc salt to water is about 1:300), and stir until completely dissolved.

[0035] Solution B: Weigh potassium hydroxide (KOH, 1.122 g, about 20 mmol) and dissolve it in 40 mL of deionized water (the molar ratio of alkali to water is about 1:80). Stir to dissolve.

[0036] Reaction: Under vigorous stirring, solution B is added dropwise to solution A (Zn). 2+ The reaction mixture (with OH⁻ in a molar ratio of approximately 1:2) was reacted at 70°C for 1.5 hours to produce a white ZnO precipitate.

[0037] Post-treatment: centrifugation (10,000 rpm, 10 min), washing, and drying (65℃, 5 h) to obtain ZnO nanoparticles.

[0038] (2) Construction of ZnO@mesoporous SiO2 core-shell structure 0.1 g of the ZnO nanoparticles prepared above were dispersed in 40 mL of ethanol and sonicated for 30 min. 1.344 g of CTAB was added, with a ZnO to CTAB molar ratio of 1:3, and the mixture was stirred for 30 min. 3.84 g of TEOS was added dropwise, with a TEOS to CTAB molar ratio of 5:1, followed by 2 mL of 25% ammonia solution, and the reaction was carried out at room temperature for 5 h. After centrifugation (10,000 rpm, 10 min), washing, and calcination at 500 °C for 5 h, a ZnO@SiO2 core-shell structure was obtained, as shown below. Figure 2 As shown. Simultaneously combined with Figure 5 It is known that the material surface is formed by the accumulation of a large number of smaller particles or aggregates, forming a relatively continuous but uneven structure, which is a typical manifestation of the formation of particulate composite materials.

[0039] X-ray diffraction pattern of the prepared material, such as Figure 6 As shown, the material preparation was successful based on the phase retrieval results.

[0040] (3) Loading of artificial bear bile powder 60 mg ZnO@SiO2 and 15 mg artificial bear bile powder were mixed in 10 mL of anhydrous ethanol and shaken at 30°C in the dark for 24 hours (180 rpm). After the reaction, the precipitate was collected by centrifugation (12,000 rpm, 15 minutes) and washed twice with a small amount of anhydrous ethanol to remove unloaded artificial bear bile powder. The washed precipitate was dried at 30°C for 2 hours to obtain a reduced-toxicity artificial bear bile powder nanoparticle formulation. It should be noted that the physical structure of this formulation is a core-shell structure, with zinc oxide nanoparticles as the core and mesoporous SiO2 as the shell layer, with artificial bear bile powder adhering to the outer surface of the shell. Figure 4 As shown in (b) of the diagram.

[0041] (4) Performance testing Loading effect: drug loading 19% (detection error controlled within ±0.5%); Zn²⁺ dissolution rate: In PBS buffer solution at pH 7.4 and 37°C, the cumulative zinc ion dissolution rate of the attenuated artificial bear bile powder nanoparticles was 6.45% over 24 hours. Under the same conditions, the zinc ion dissolution rate of pure ZnO nanoparticles was significantly higher. 2+ The dissolution rate was 19.1%, which is the Zn content of the attenuated artificial bear bile powder nanoparticles prepared in this embodiment. 2+ The dissolution rate decreased by 66%.

[0042] Sustained release of artificial bear bile powder: The release rates of the attenuated artificial bear bile powder nano-formulation in PBS buffer solution at 37°C and 100 rpm are as follows: pH 7.4: 0.5h release rate 5.2±0.6%, 24h release rate 37.4±2.1%.

[0043] At pH 5.5, the release rate was 18.3±1.5% at 0.5h and 68.7±3.2% at 24h.

[0044] Example 3 Solution A: Weigh zinc chloride (ZnCl2, 1.36 g, about 10 mmol) and dissolve it in 200 mL of deionized water (the molar ratio of zinc salt to water is about 1:1000), and stir until completely dissolved.

[0045] Solution B: Weigh sodium hydroxide (NaOH, 0.8 g, 20 mmol) and dissolve it in 50 mL of deionized water (molar ratio 1:100), and stir well.

[0046] Reaction: Under vigorous stirring, solution B was added dropwise to solution A, and the reaction was carried out at 80°C for 3 hours to produce a white ZnO precipitate.

[0047] Post-processing: After the reaction was completed, the precipitate was collected by centrifugation (10,000 rpm, 10 minutes), washed three times with deionized water, then washed three times with ethanol, and dried in a 70℃ forced-air drying oven for 6 hours to obtain ZnO nanoparticles.

[0048] (2) Construction of ZnO@mesoporous SiO2 core-shell structure: 0.1 g of the ZnO nanoparticles prepared above were dispersed in 40 mL of ethanol and ultrasonically treated for 30 minutes to ensure uniform dispersion.

[0049] Add 2.24 g of hexadecyltrimethylammonium bromide (CTAB), with a ZnO to CTAB molar ratio of 1:5, and stir for 30 minutes. Add 7.68 g of tetraethyl orthosilicate (TEOS), with a TEOS to CTAB molar ratio of 6:1, followed by 3 mL of ammonia (25%) as a catalyst. React at room temperature (approximately 25°C) for 8 hours. After the reaction, collect the product by centrifugation (10,000 rpm, 10 minutes) and wash three times with ethanol. Dry the washed precipitate overnight at 80°C, then place it in a muffle furnace and calcine it at 600°C for 3 hours under air atmosphere at a rate of 2°C / min to remove the CTAB template agent, yielding a ZnO@mesoporous SiO2 core-shell structure, as shown below. Figure 3 As shown. Simultaneously combined with Figure 5 It can be seen that the composite material is a porous network structure formed by the aggregation of nano- to submicron-sized particles. This porous packing morphology is highly consistent with the composite structure characteristics of mesoporous silica carriers and their loaded ZnO.

[0050] The X-ray diffraction pattern of the prepared material is attached. Figure 6 As shown, the material preparation was successful based on the phase retrieval results.

[0051] (3) Loading of artificial bear bile powder: 60 mg ZnO@SiO2 and 20 mg artificial bear bile powder were mixed in 10 mL of anhydrous ethanol and shaken at 35°C in the dark for 24 hours (200 rpm). After the reaction, the precipitate was collected by centrifugation (12,000 rpm, 15 minutes) and washed twice with a small amount of anhydrous ethanol to remove unloaded artificial bear bile powder. The washed precipitate was dried at 35°C for 3 hours to obtain a reduced-toxicity artificial bear bile powder nanoparticle formulation. It should be noted that the physical structure of this formulation is a core-shell structure, with zinc oxide nanoparticles as the core and mesoporous SiO2 as the shell layer, with artificial bear bile powder adhering to the outer surface of the shell. Figure 4 As shown in (c) in the figure.

[0052] (4) Performance testing: Loading effect: drug loading 24.2% (detection error controlled within ±0.5%); Zn 2+ Dissolution rate: In PBS buffer solution at pH 7.4 and 37°C, the cumulative zinc ion dissolution rate of the attenuated artificial bear bile powder nanoparticles was 5.2% over 24 hours. Under the same conditions, the zinc ion dissolution rate of pure ZnO nanoparticles was significantly higher. 2+ The dissolution rate was 19.8%, which is the Zn content of the attenuated artificial bear bile powder nanoparticles prepared in this embodiment. 2+ The dissolution rate decreased by 74%.

[0053] Sustained release of artificial bear bile powder: The release rates of the attenuated artificial bear bile powder nano-formulation in PBS buffer solution at 37°C and 100 rpm are as follows: pH 7.4: 0.5h release rate 4.2±0.5%, 24h release rate 39.9±2.3%.

[0054] pH 5.5: 0.5h release rate 22.1±1.8%, 24h release rate 72.5±3.5%.

[0055] The technical scope of this invention is not limited to the content described above. Those skilled in the art can make various modifications and variations to the above embodiments without departing from the technical concept of this invention, and all such modifications and variations should fall within the protection scope of this invention.

Claims

1. A method for preparing a toxic artificial bear bile powder nanoparticle formulation, characterized in that, Includes the following steps: Step S1: Preparation of zinc oxide nanoparticles Step S1.1: Dissolve the zinc salt precursor in deionized water, with a molar ratio of zinc salt to water of 1:(300~1000), and stir to obtain solution A; Step S1.2: Dissolve the alkaline compound in deionized water, with a molar ratio of alkaline compound to water of 1:(50~100), to obtain solution B; Step S1.3: Add solution B dropwise to solution A, wherein the molar ratio of solute in solution B to solution A is 1:2, and react at 60~80℃ for 1.5~3h to generate zinc oxide precipitate; Step S1.4: The zinc oxide precipitate is centrifuged, washed, and dried to obtain zinc oxide nanoparticles; Step S2: Constructing a ZnO@mesoporous SiO2 core-shell structure Step S2.1: Disperse the zinc oxide nanoparticles in ethanol, add hexadecyltrimethylammonium bromide as a template agent, stir evenly, then add tetraethyl orthosilicate dropwise, and add ammonia water as a catalyst. React at room temperature for 5-8 hours to obtain the ZnO@mesoporous SiO2 core-shell structure precursor. Step S2.2: After centrifuging and washing the ZnO@mesoporous SiO2 core-shell structure precursor, calcination is performed to remove hexadecyltrimethyl bromide to obtain the ZnO@mesoporous SiO2 core-shell structure. Step S3: Loading with artificial bear bile powder Step S3.1: Disperse the ZnO@mesoporous SiO2 core-shell structure and artificial bear bile powder in anhydrous ethanol at a mass ratio of (3~5):1, shake in the dark for 24 hours to obtain a drug-loaded suspension; Step S3.2: After centrifuging, washing and drying the drug-loaded suspension, a toxic artificial bear bile powder nano-formulation is obtained.

2. The preparation method of the attenuated artificial bear bile powder nanoparticle formulation according to claim 1, characterized in that, In step S1.1, the zinc salt precursor is zinc nitrate hexahydrate, zinc acetate, or zinc chloride; in step S1.2, the alkaline compound is sodium hydroxide or potassium hydroxide.

3. The preparation method of the attenuated artificial bear bile powder nanoparticle formulation according to claim 1, characterized in that, In step S2.1, the molar ratio of zinc oxide nanoparticles to hexadecyltrimethylammonium bromide is 1:(2~5), and the molar ratio of tetraethyl orthosilicate to CTAB is (4~6):1; in step S2.2, the calcination temperature is 500~600℃, and the calcination time is 3~5h.

4. The method for preparing the attenuated artificial bear bile powder nanoparticle formulation according to claim 1, characterized in that, In step S3.1, the oscillation temperature is 25~35℃ and the oscillation speed is 150~200 rpm; in step S3.2, the drying temperature is 25~35℃ and the drying time is 1~3 hours.

5. A nano-formulation of attenuated artificial bear bile powder prepared by the method described in any one of claims 1 to 4.

6. The attenuated artificial bear bile powder nanoformulation according to claim 5, characterized in that, The formulation has a core-shell structure, with zinc oxide nanoparticles as the core and mesoporous SiO2 as the shell, and artificial bear bile powder attached to the outer surface of the shell.

7. The attenuated artificial bear bile powder nanoformulation according to claim 5, characterized in that, The zinc ion dissolution rate of the formulation is <10% within 24 hours at pH 7.

4.

8. The attenuated artificial bear bile powder nanoformulation according to claim 5, characterized in that, The drug loading of the formulation is 15-25%.

9. The attenuated artificial bear bile powder nanoformulation according to claim 5, characterized in that, In a phosphate buffer solution at pH 7.4, the release rate of the main active ingredient of the formulation is <40% within 24 hours; in a phosphate buffer solution at pH 5.5, the release rate of the main active ingredient of the formulation is >60% within 24 hours.

10. The application of the attenuated artificial bear bile powder nano-formulation according to any one of claims 1-4 in the prevention or treatment of hepatobiliary system diseases and inflammatory diseases.

Images