High-dispersity nosiheptide preparation and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a high-dispersity nosiheptide preparation and a preparation method thereof. The high-dispersity nosiheptide preparation is prepared from the following raw materials in parts by mass: 1 to 5 parts of nosiheptide, 1 to 3 parts of sodium alginate, 2 to 4 parts of solubilizer, 1 to 2 parts of carboxyl-terminated polyamidoamine, 1 to 2 parts of dispersant, 5 to 15 parts of absolute ethyl alcohol, 0.1 to 1 part of nonionic surfactant, 0.1 to 0.5 part of L-ascorbic acid, 0.1 to 0.5 part of sodium thiosulfate and 1 to 2 parts of compound stabilizer. According to the method, the solubility of nosiheptide is guaranteed, the risk of organic solvent residue is reduced, the safety standard of modern veterinary drugs is met, conventional production equipment can be adopted, raw materials are low in price and easy to obtain, industrial large-scale production can be achieved, and high economical efficiency and operability are achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a highly dispersible nosiheptide preparation and a preparation method thereof. BACKGROUND

[0002] Nosiheptide is a kind of sulfur-containing polypeptide antibiotic, which is produced by fermentation of Streptomyces actuosus and has inhibitory and killing effects on animal intestinal pathogenic bacteria. Streptomyces actuosus Nosiheptide is effective against most gram-positive bacteria, with the most significant effect on Clostridium perfringens, and has the lowest inhibitory effect on Clostridium perfringens among currently known antibiotics. The mechanism of action is to inhibit bacterial protein synthesis, which shows inhibitory effect at low concentration and killing effect at high concentration.

[0003] Nosiheptide is a non-absorptive drug with a large molecular weight (Mw = 1222.37D) and no residue in animal tissues and organs. Studies have shown that when broiler chickens are administered with 80 mg / kg of nosiheptide for 7 consecutive days, no residue is detected in muscle, kidney, liver, fat and other tissues 48 hours after drug withdrawal. Nosiheptide has low dosage, high safety and is not prone to drug resistance, and has no significant cross-resistance with other antibiotics. The target of nosiheptide is not crossed with common antibiotics (such as beta-lactams and macrolides), and the molecular structure is complex, making it difficult to transfer drug resistance genes through plasmids. In addition, nosiheptide is environmentally friendly and degrades rapidly in the environment, with a half-life of 20 days and 1 month in feces, and has no toxicity to soil microorganisms and aquatic organisms, which can avoid long-term pollution of antibiotics to the ecological chain from the source.

[0004] Nosiheptide is currently mainly in the form of traditional premix, and the technology is relatively primitive, mainly relying on physical mixing process, that is, adsorbing the raw drug on a simple carrier (such as calcium carbonate, corn starch) for use as a growth promoter, which can meet the demand, but there are still many problems as a clinical treatment drug: 1. It is found in the application process that the particle size of nosiheptide products is generally large, resulting in poor dispersibility, which leads to large dosage fluctuation in actual use and affects the stability of therapeutic effect; 2. The drug particles are rough and have strong hydrophobicity, which makes it difficult to administer by drinking water, and the feed addition method has a lag when the disease breaks out, which cannot quickly control the epidemic; 3. The low solubility of nosiheptide (almost insoluble in water) limits its dispersion and absorption in the intestinal tract, and a high dose is required in clinical practice to achieve an effective concentration, which not only increases the cost, but also may cause intestinal mucosa damage due to high local drug concentration. SUMMARY

[0005] The present application aims to solve the problems in the prior art and provides a highly dispersible nosiheptide preparation and a preparation method thereof.

[0006] A highly dispersed naxitide preparation, raw materials of which include, by mass fraction: naxitide 1-5 parts, sodium alginate 1-3 parts, solubilizer 2-4 parts, carboxy-terminated polyamide amine 1-2 parts, dispersant 1-2 parts, anhydrous ethanol 5-15 parts, non-ionic surfactant 0.1-1 part, L-ascorbic acid 0.1-0.5 part, sodium thiosulfate 0.1-0.5 part, and composite stabilizer 1-2 parts.

[0007] Preferably, the solubilizer is hydroxypropyl-beta-cyclodextrin.

[0008] Preferably, the dispersant is polyvinylpyrrolidone.

[0009] Preferably, the non-ionic surfactant is Tween-80.

[0010] Preferably, the composite stabilizer includes polyethylene glycol 400, trehalose, and mannitol.

[0011] More preferably, the mass ratio of polyethylene glycol 400, trehalose, and mannitol is 1-2:1-2:1-2.

[0012] The preparation method of the above-mentioned highly dispersed naxitide preparation includes the following steps: S1, dissolving naxitide in an organic solvent to form a naxitide solution; adding sodium alginate, solubilizer, carboxy-terminated polyamide amine, and dispersant to water, stirring uniformly at 40-50°C, adding the naxitide solution to it, homogenizing for 5-10 min, and spray drying; then vacuum drying until no organic solvent is left to obtain microencapsulated naxitide; S2, mixing anhydrous ethanol, non-ionic surfactant, and L-ascorbic acid, stirring uniformly at 40-50°C, adding the microencapsulated naxitide to it, and stirring for 10-30 min to obtain pretreated naxitide; S3, adding sodium thiosulfate and composite stabilizer to water, stirring uniformly, adjusting the pH of the system to 6-6.5, and adding the pretreated naxitide to it and stirring uniformly.

[0013] Preferably, in S1, the organic solvent is at least one of tetrahydrofuran, N,N'-dimethylformamide, N,N'-methylacetamide, and dimethyl sulfoxide.

[0014] Preferably, in S1, the homogenization pressure is 20-40 MPa.

[0015] Preferably, in S1, during the spray drying process, the inlet temperature is 120-130°C and the outlet temperature is 60-70°C.

[0016] Preferably, in S3, a citric acid-sodium citrate buffer with a pH of 3-4 is used to adjust the pH of the system to 6-6.5.

[0017] Beneficial effects: The present application adopts sodium alginate and solubilizer (hydroxypropyl-beta-cyclodextrin), carboxyl-terminated polyamide amine to compound onanaciptide microencapsulation treatment, and forms uniform coating structure through spray drying process, which can significantly improve the hydrophilicity of onanaciptide, effectively solve the problem of uneven distribution of active ingredients in traditional preparations, ensure the uniform dispersion of active ingredients during administration, and provide convenience for drinking water administration of livestock and poultry.

[0018] The trehalose in the composite stabilizer forms a stable matrix during storage to prevent degradation of the active ingredient, and cooperates with polyethylene glycol 400 and mannitol to effectively maintain the structural integrity of the active ingredient, and cooperates with the pH buffer system to avoid the inactivation caused by the acid and alkali environment.

[0019] The present application not only ensures the solubility of onanaciptide, but also reduces the risk of organic solvent residue, meets the safety standards of modern veterinary drugs, and can use conventional production equipment, raw materials are cheap and easy to obtain, and can realize industrial large-scale production, which has high economic efficiency and operability. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 The particle size and 4-hour sedimentation volume of the onanaciptide preparations obtained in Example 5 and Comparative Examples 1-3 are compared.

[0021] Figure 2 The cumulative dissolution rate curve of the onanaciptide preparations obtained in Example 5 and Comparative Examples 1-3 after treatment with digestive juice is shown in the following table. DETAILED DESCRIPTION

[0022] The present application will be further described below in conjunction with specific examples.

[0023] The raw materials used in the following can be purchased from the market. For example, carboxyl-terminated polyamide amine (PAMAM-COOH) with a generation number of 1.0 is purchased from a certain Joe Biotechnology Co., Ltd. in Hangzhou.

[0024] Example 1: A highly dispersible onanaciptide preparation, which comprises the following raw materials: onanaciptide 1g, sodium alginate 1g, hydroxypropyl-beta-cyclodextrin 2g, carboxyl-terminated polyamide amine 1g, PVP K30 1g, anhydrous ethanol 5g, Tween-80 0.1g, L-ascorbic acid 0.1g, sodium thiosulfate 0.1g, and composite stabilizer 1g. The composite stabilizer is composed of polyethylene glycol 400, trehalose and mannitol in a mass ratio of 1:1:2.

[0025] The preparation method of the above-mentioned highly dispersible onanaciptide preparation comprises the following steps: S1, dissolve naxen in dimethyl sulfoxide to form a naxen solution; add sodium alginate, hydroxypropyl-β-cyclodextrin, carboxyl-terminated polyamide amine and PVP K30 to 40 g of deionized water, stir uniformly at a temperature of 40℃, add the naxen solution to it, homogenize at 20 MPa for 5 min, spray dry, the inlet temperature is 120℃, the outlet temperature is 60℃; then vacuum dry to dimethyl sulfoxide to obtain microencapsulated naxen; S2, mix anhydrous ethanol, Tween-80 and L-ascorbic acid, stir uniformly at a temperature of 40℃, add the microencapsulated naxen to it and stir for 10 min at a stirring speed of 100 r / min to obtain pretreated naxen; S3, add sodium thiosulfate and a composite stabilizer to 50 g of deionized water and stir uniformly, adjust the pH of the system to 6-6.5 using a citric acid-sodium citrate buffer with a pH of 3-4, and then add the pretreated naxen to it and stir uniformly.

[0026] Example 2 A highly dispersible naxen preparation, which comprises the following raw materials: naxen 5 g, sodium alginate 3 g, hydroxypropyl-β-cyclodextrin 4 g, carboxyl-terminated polyamide amine 2 g, PVP K30 2 g, anhydrous ethanol 15 g, Tween-80 1 g, L-ascorbic acid 0.5 g, sodium thiosulfate 0.5 g, and a composite stabilizer 2 g. The composite stabilizer is composed of polyethylene glycol 400, trehalose and mannitol in a mass ratio of 2:2:1.

[0027] The preparation method of the above-mentioned highly dispersible naxen preparation comprises the following steps: S1, dissolve naxen in N,N'-dimethylformamide to form a naxen solution; add sodium alginate, hydroxypropyl-β-cyclodextrin, carboxyl-terminated polyamide amine and PVP K30 to 50 g of deionized water, stir uniformly at a temperature of 50℃, add the naxen solution to it, homogenize at 40 MPa for 10 min, spray dry, the inlet temperature is 130℃, the outlet temperature is 70℃; then vacuum dry to N,N'-dimethylformamide to obtain microencapsulated naxen; S2, mix anhydrous ethanol, Tween-80 and L-ascorbic acid, stir uniformly at a temperature of 50℃, add the microencapsulated naxen to it and stir for 30 min at a stirring speed of 300 r / min to obtain pretreated naxen; S3, add sodium thiosulfate and a composite stabilizer to 100 g of deionized water and stir uniformly, adjust the pH of the system to 6-6.5 using a citric acid-sodium citrate buffer with a pH of 3-4, and then add the pretreated naxen to it and stir uniformly.

[0028] Example 3 A highly dispersed naxitide preparation, raw materials of which include: naxitide 2g, sodium alginate 2.5g, hydroxypropyl-beta-cyclodextrin 2.5g, carboxyl-terminated polyamide amine 1.8g, PVP K30 1.2g, anhydrous ethanol 12g, Tween-80 0.3g, L-ascorbic acid 0.4g, sodium thiosulfate 0.2g, and a composite stabilizer 1.8g. The composite stabilizer is composed of polyethylene glycol 400, trehalose, and mannitol in a mass ratio of 1:2:1.

[0029] The preparation method of the above-mentioned highly dispersed naxitide preparation includes the following steps: S1, dissolve naxitide in N,N'-dimethylformamide to form a naxitide solution; add sodium alginate, hydroxypropyl-beta-cyclodextrin, carboxyl-terminated polyamide amine, and PVP K30 to 48g of deionized water, stir uniformly at a temperature of 43℃, add the naxitide solution to it, homogenize at 25MPa for 7min, spray dry with an inlet temperature of 128℃ and an outlet temperature of 62℃; then vacuum dry the N,N'-dimethylformamide to obtain microencapsulated naxitide; S2, mix anhydrous ethanol, Tween-80, and L-ascorbic acid, stir uniformly at a temperature of 48℃, add the microencapsulated naxitide to it and stir for 15min at a stirring speed of 240r / min to obtain pretreated naxitide; S3, add sodium thiosulfate and a composite stabilizer to 70g of deionized water and stir uniformly, adjust the pH of the system to 6-6.5 using a citric acid-sodium citrate buffer with a pH of 3-4, and then add the pretreated naxitide to it and stir uniformly.

[0030] Example 4: A highly dispersed naxitide preparation, raw materials of which include: naxitide 2g, sodium alginate 2.5g, hydroxypropyl-beta-cyclodextrin 2.5g, carboxyl-terminated polyamide amine 1.8g, PVP K30 1.2g, anhydrous ethanol 12g, Tween-80 0.3g, L-ascorbic acid 0.4g, sodium thiosulfate 0.2g, and a composite stabilizer 1.8g. The composite stabilizer is composed of polyethylene glycol 400, trehalose, and mannitol in a mass ratio of 1:2:1.

[0031] The preparation method of the above-mentioned highly dispersed naxitide preparation includes the following steps: S1, dissolve naxitide in N,N'-dimethylformamide to form a naxitide solution; add sodium alginate, hydroxypropyl-beta-cyclodextrin, carboxyl-terminated polyamide amine, and PVP K30 to 48g of deionized water, stir uniformly at a temperature of 43℃, add the naxitide solution to it, homogenize at 25MPa for 7min, spray dry with an inlet temperature of 128℃ and an outlet temperature of 62℃; then vacuum dry the N,N'-dimethylformamide to obtain microencapsulated naxitide; S2. Mix anhydrous ethanol, Tween-80 and L-ascorbic acid, stir at 42°C until homogeneous, add microencapsulated nascetide and stir for 25 min at a stirring speed of 150 r / min to obtain pretreated nascetide. S3. Add sodium thiosulfate and composite stabilizer to 90g of deionized water and stir well. Adjust the pH of the system to 6-6.5 using a citrate-sodium citrate buffer solution with a pH of 3-4. Add pretreated nasitide and stir well.

[0032] Example 5: A highly dispersible nasitide formulation comprises the following raw materials: 3g nasitide, 2g sodium alginate, 3g hydroxypropyl-β-cyclodextrin, 1.5g carboxyl-terminated polyamide amine, 1.5g PVP K30, 10g anhydrous ethanol, 0.5g Tween-80, 0.3g L-ascorbic acid, 0.3g sodium thiosulfate, and 1.5g composite stabilizer. The composite stabilizer is composed of polyethylene glycol 400, trehalose, and mannitol in a mass ratio of 2:1.5:1.

[0033] The preparation method of the above-mentioned highly dispersible nascetide formulation includes the following steps: S1. Dissolve nascetin in N,N'-dimethylformamide to form a nascetin solution; add sodium alginate, hydroxypropyl-β-cyclodextrin, carboxyl-terminated polyamide amine, and PVP K30 to 45g of deionized water, stir evenly at 45℃, add the nascetin solution, homogenize at 30MPa for 8min, spray dry at an inlet temperature of 125℃ and an outlet temperature of 65℃; then vacuum dry to N,N'-dimethylformamide to obtain microencapsulated nascetin. S2. Mix anhydrous ethanol, Tween-80 and L-ascorbic acid, stir at 45°C until homogeneous, add microencapsulated nascetide and stir for 20 min at a stirring speed of 200 r / min to obtain pretreated nascetide. S3. Add sodium thiosulfate and composite stabilizer to 80g of deionized water and stir well. Adjust the pH of the system to 6-6.5 using a citrate-sodium citrate buffer solution with a pH of 3-4. Add pretreated nasitide and stir well.

[0034] Comparative Example 1: A highly dispersible nascetide formulation comprises the following raw materials: 3g nascetide, 3.5g sodium alginate, 3g hydroxypropyl-β-cyclodextrin, 1.5g PVP K30, 10g anhydrous ethanol, 0.5g Tween-80, 0.3g L-ascorbic acid, 0.3g sodium thiosulfate, and 1.5g composite stabilizer. The composite stabilizer is composed of polyethylene glycol 400, trehalose, and mannitol in a mass ratio of 2:1.5:1.

[0035] The preparation method of the above-mentioned highly dispersible nascetide formulation includes the following steps: S1. Dissolve nascetin in N,N'-dimethylformamide to form a nascetin solution; add sodium alginate, hydroxypropyl-β-cyclodextrin, and PVP K30 to 45g of deionized water, stir evenly at 45℃, add the nascetin solution, homogenize at 30MPa for 8min, spray dry at an inlet temperature of 125℃ and an outlet temperature of 65℃; then vacuum dry to N,N'-dimethylformamide to obtain microencapsulated nascetin. S2. Mix anhydrous ethanol, Tween-80 and L-ascorbic acid, stir at 45°C until homogeneous, add microencapsulated nascetide and stir for 20 min at a stirring speed of 200 r / min to obtain pretreated nascetide. S3. Add sodium thiosulfate and composite stabilizer to 80g of deionized water and stir well. Adjust the pH of the system to 6-6.5 using a citrate-sodium citrate buffer solution with a pH of 3-4. Add pretreated nasitide and stir well.

[0036] Comparative Example 2: A highly dispersible nascetide formulation comprises the following raw materials: 3g nascetide, 16.35g anhydrous ethanol, 0.82g Tween-80, 0.49g L-ascorbic acid, 0.49g sodium thiosulfate, and 2.45g composite stabilizer. The composite stabilizer is composed of polyethylene glycol 400, trehalose, and mannitol in a mass ratio of 2:1.5:1.

[0037] The preparation method of the above-mentioned highly dispersible nascetide formulation includes the following steps: S1. Mix anhydrous ethanol, Tween-80 and L-ascorbic acid, stir at 45°C until homogeneous, add nascetide and stir for 20 min at a stirring speed of 200 r / min to obtain pretreated nascetide. S2. Add sodium thiosulfate and the composite stabilizer to 80g of deionized water and stir well. Adjust the pH of the system to 6-6.5 using a citrate-sodium citrate buffer solution with a pH of 3-4. Add the pretreated nasitide and stir well.

[0038] Comparative Example 3: A highly dispersible nasitide formulation comprises the following raw materials: 3g nasitide, 2g sodium alginate, 3g hydroxypropyl-β-cyclodextrin, 1.5g carboxyl-terminated polyamide amine, 1.5g PVP K30, 10g anhydrous ethanol, 0.5g Tween-80, 0.3g L-ascorbic acid, 0.3g sodium thiosulfate, and 1.5g composite stabilizer. The composite stabilizer is composed of polyethylene glycol 400 and mannitol in a mass ratio of 2:1.

[0039] The preparation method of the above-mentioned highly dispersible nascetide formulation includes the following steps: S1. Dissolve nascetin in N,N'-dimethylformamide to form a nascetin solution; add sodium alginate, hydroxypropyl-β-cyclodextrin, carboxyl-terminated polyamide amine, and PVP K30 to 45g of deionized water, stir evenly at 45℃, add the nascetin solution, homogenize at 30MPa for 8min, spray dry at an inlet temperature of 125℃ and an outlet temperature of 65℃; then vacuum dry to N,N'-dimethylformamide to obtain microencapsulated nascetin. S2. Mix anhydrous ethanol, Tween-80 and L-ascorbic acid, stir at 45°C until homogeneous, add microencapsulated nascetide and stir for 20 min at a stirring speed of 200 r / min to obtain pretreated nascetide. S3. Add sodium thiosulfate and composite stabilizer to 80g of deionized water and stir well. Adjust the pH of the system to 6-6.5 using a citrate-sodium citrate buffer solution with a pH of 3-4. Add pretreated nasitide and stir well.

[0040] The nasitide formulations obtained in Example 5 and Comparative Examples 1-3 were added to purified water at 25°C and stirred until homogeneous. The particle size of the dispersion was measured using a particle size analyzer. The sedimentation volume ratio of the nasitide formulations obtained in Example 5 and Comparative Examples 1-3 in water was determined after 4 hours.

[0041] like Figure 1 As shown, the nosine peptide formulations obtained in Example 5 and Comparative Example 3 had the smallest particle size, significantly better than those in Comparative Examples 1-2, with no significant difference between the two. Conversely, the nosine peptide formulations obtained in Example 5 and Comparative Example 3 had the highest sedimentation volume ratio, significantly better than those in Comparative Examples 1-2, with no significant difference between the two. This confirms that the nosine peptide formulations obtained in Example 5 and Comparative Example 3 have the best dispersibility and stability in water.

[0042] The nasitide preparations obtained in Example 5 and Comparative Examples 1-3 were placed in artificial gastric fluid at 37°C and shaken for 90 min, and then added to artificial intestinal fluid at 37°C and shaken for 0-90 min. Samples were taken at regular intervals (an equal amount of fresh artificial intestinal fluid was added after each sample). The nasitide content was determined by HPLC and the cumulative dissolution rate was calculated.

[0043] like Figure 2 As shown, the cumulative dissolution rate of each group of nasitide preparations was higher than 60% within half an hour, ensuring that a high concentration environment could be formed in the intestine after animal ingestion to achieve sterilization. However, the cumulative dissolution rate of the nasitide preparation obtained in Example 5 was consistently lower than that of the other groups within 90 minutes, confirming that the nasitide preparation obtained by the present invention effectively maintains the stability of the active ingredient in acidic or alkaline environments, forming a sustained-release effect. This avoids damage to the intestinal mucosa caused by excessively high nasitide concentrations and maintains the duration of nasitide in the intestine, achieving a long-term therapeutic effect.

[0044] The minimum inhibitory concentration of the nasitide preparations obtained in Example 5 and Comparative Examples 1-3 against Clostridium perfringens (CVCC2027) was determined, with the applicant's previous patent application (A water-soluble nasitide and its preparation method and application, application number: 202410073369.9, application date: 2024-01-18, publication date: 2024-05-28) as a control.

[0045] Referring to the minimum inhibitory concentration determination method in the previously filed patent application, the minimum inhibitory concentration of the nasitide preparations obtained in Example 5 and Comparative Examples 1-3 against Clostridium perfringens (CVCC2027) was determined.

[0046] The results showed that the minimum inhibitory concentration (MIC) of the nasitide preparation obtained in Comparative Example 1 against Clostridium perfringens was 10 ppb, the MIC of the nasitide preparation obtained in Comparative Example 2 against Clostridium perfringens was 20 ppb, the MIC of the nasitide preparation obtained in Comparative Example 3 against Clostridium perfringens was 7.5 ppb, and the MIC of the nasitide preparation obtained in Example 5 against Clostridium perfringens was 5 ppb.

[0047] Although the minimum inhibitory concentration of the nasitide preparation obtained in Example 5 is higher than that of amorphous nasitide (1 ppb) in the previous patent application, the nasitide content of amorphous nasitide in the previous patent application was 98.53-99.23 wt%, while the nasitide content of the nasitide preparation obtained in Example 5 was only 12.75 ± 1.28 wt%, which confirms that the nasitide preparation obtained in this invention can further reduce the clinical dosage.

[0048] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A highly dispersed formulation of naxartide, characterized in that, The raw materials include, by mass fraction: naxitide 1-5 parts, sodium alginate 1-3 parts, solubilizer 2-4 parts, carboxyl-terminated polyamide amine 1-2 parts, dispersant 1-2 parts, anhydrous ethanol 5-15 parts, non-ionic surfactant 0.1-1 part, L-ascorbic acid 0.1-0.5 part, sodium thiosulfate 0.1-0.5 part, and composite stabilizer 1-2 parts.

2. The highly dispersed naxivide formulation of claim 1, wherein, The solubilizer is hydroxypropyl-beta-cyclodextrin.

3. The highly dispersed naxivide formulation of claim 1, wherein, The dispersant is polyvinylpyrrolidone.

4. The highly dispersed naxivide formulation of claim 1, wherein, The non-ionic surfactant is Tween-80.

5. The highly dispersed naxivide formulation of claim 1, wherein, The composite stabilizer includes polyethylene glycol 400, trehalose, and mannitol.

6. The highly dispersed naxivide formulation of claim 5, wherein, The mass ratio of polyethylene glycol 400, trehalose, and mannitol is 1-2:1-2:1-2.

7. A process for the preparation of a highly dispersed naxartide formulation according to any one of claims 1 to 6, characterized in that, The method includes the following steps: S1, dissolving naxitide in an organic solvent to form a naxitide solution; adding sodium alginate, solubilizer, carboxyl-terminated polyamide amine, and dispersant to water, stirring uniformly at 40-50°C, adding the naxitide solution to the mixture, homogenizing for 5-10 min, and spray drying; then vacuum drying until no organic solvent is left to obtain microencapsulated naxitide; S2, mixing anhydrous ethanol, non-ionic surfactant, and L-ascorbic acid, stirring uniformly at 40-50°C, adding the microencapsulated naxitide to the mixture, and stirring for 10-30 min to obtain pretreated naxitide; S3, adding sodium thiosulfate and composite stabilizer to water, stirring uniformly, adjusting the pH of the system to 6-6.5, and adding the pretreated naxitide to the mixture and stirring uniformly.

8. The method of claim 7, wherein the highly dispersed nanatin formulation is prepared by, In S1, the organic solvent is at least one of tetrahydrofuran, N,N'-dimethylformamide, N,N'-methylacetamide, and dimethyl sulfoxide; and the homogenization pressure is 20-40 MPa.

9. The method of claim 7, wherein the highly dispersed nanatin formulation is prepared by, In S1, during the spray drying process, the inlet temperature is 120-130°C, and the outlet temperature is 60-70°C.

10. The method of claim 7, wherein the preparation of the highly dispersed nanatin formulation is characterized by, In S3, a citric acid-sodium citrate buffer with a pH of 3-4 is used to adjust the pH of the system to 6-6.5.

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