Fluralan-moxidectin nano drop containing permeation enhancer and preparation method of fluralan-moxidectin nano drop

Abstract

The invention belongs to the technical field of veterinary drugs, and particularly discloses a permeation enhancer-containing fluralan-moxidectin nano drop and a preparation method thereof, the permeation enhancer-containing fluralan-moxidectin nano drop comprises the following components: fluralan, moxidectin, a permeation enhancer, glycosylglycerol, tocopheryl acetate, a cosolvent, modified chitosan, hydroxy acid salt, an antioxidant and the balance of a solvent; the permeation enhancer is prepared from phytosphingosine, beta-caryophyllene and caprylic / capric triglyceride according to the mass ratio of 1 to (0.2 to 2) to (0.2 to 1.8). According to the invention, the fluralan and the moxidectin are taken as active ingredients, and the permeation enhancer, the glycosylglycerol, the tocopheryl acetate, the modified chitosan, the hydroxy acid salt and the antioxidant are added, so that the permeation effect of the fluralan and the moxidectin is effectively improved, the transdermal absorption effect of the fluralan and the moxidectin is remarkably improved, and the stability of the drops is effectively improved.

Description

Technical Field

[0001] This invention relates to the field of veterinary drug technology, specifically to a permeation enhancer-containing flurana-moxiketine nanodrops and its preparation method. Background Technology

[0002] Fluranal is a novel isoxazoline insecticide that works by blocking the GABA and L-glutamate chloride channels of parasites, and has a highly effective killing effect on fleas, ticks and other ectoparasites. Moxiquidine is a macrolide compound that has both ectoparasitic and insecticidal activity, and can effectively control mites, nematodes and other parasites.

[0003] Combining flurana and moxicritin can achieve complementary anthelmintic spectrum and improve anthelmintic efficacy. However, flurana has poor water solubility, while moxicritin is highly lipid-soluble, resulting in low transdermal absorption efficiency and insufficient bioavailability when combined. In existing technologies, flurana-moxicritin combination formulations often use conventional penetration enhancers such as menthol. While these enhancers can temporarily increase the transdermal rate, they easily lead to skin dryness and itching, and are unlikely to fundamentally improve drug bioavailability.

[0004] Therefore, this application is submitted. Summary of the Invention

[0005] This invention provides a permeation enhancer-containing flurana-moxicritin nanodrop and its preparation method. The drop has excellent stability and transdermal absorption effect.

[0006] The present invention solves its technical problem by adopting the following technical solution: A permeation enhancer-containing flurana-moxicritin nanodroplet comprises the following components in weight percentage: 22-26% flurana, 1-1.5% moxicritin, 3-6% permeation enhancer, 0.5-2% glyceryl glucoside, 0.5-2% tocopheryl acetate, 15-20% cosolvent, 0.8-2% modified chitosan, 0.1-0.2% hydroxy acid salt, 0.2-0.6% antioxidant, and the balance being solvent; The penetration enhancer comprises phytosphingosine, β-caryophyllene, and caprylic / capric triglycerides in a mass ratio of 1:(0.2~2):(0.2~1.8).

[0007] As an embodiment of this application, the co-solvent includes diethyltoluamide.

[0008] As an embodiment of this application, the solvent includes at least one of acetone, dimethylacetamide, and 1,3-propanediol.

[0009] As an embodiment of this application, the penetration enhancer comprises phytosphingosine, β-caryophyllene, and caprylic / capric triglycerides in a mass ratio of 1:(0.6~1.5):(0.5~1.4).

[0010] As an embodiment of this application, the hydroxy acid salt includes at least one of sodium citrate, potassium sodium tartrate, and sodium malate.

[0011] As an embodiment of this application, the method for preparing the modified chitosan is as follows: (1) Add chitosan and citric acid to phosphate buffer, stir well, then add casein and stir well to obtain the precursor solution; (2) Chloroacetic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide were added to the precursor solution, the pH was adjusted to 5.6~6.2, the reaction was carried out, filtered and dried to obtain modified chitosan.

[0012] As an embodiment of this application, the mass ratio of chitosan, citric acid, phosphate buffer, and casein is 1:(0.01~0.02):(8~20):(0.08~0.15).

[0013] As an embodiment of this application, the mass ratio of chloroacetic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N-hydroxysuccinimide, and the precursor solution is 1:(0.8~2):(0.8~2):(20~50).

[0014] As an embodiment of this application, the reaction temperature is 25~35℃ and the time is 2~6h.

[0015] This invention also provides a method for preparing a permeation-enhancing agent-containing flurana-moxicritin nanodroplet, comprising the following steps: Add the solubilizer to the solvent and stir until homogeneous. Then add glyceryl glucoside, tocopheryl acetate, and a penetration enhancer, and stir until homogeneous. Next, add flurranal, moxicritin, modified chitosan, hydroxy acid salt, and an antioxidant, and stir until homogeneous to obtain flurranal-moxicritin nanodrops containing a penetration enhancer.

[0016] The beneficial effects of this invention are as follows: This invention uses freranal and moxicritin as active ingredients, and by adding penetration enhancers, glyceryl glucoside, tocopheryl acetate, modified chitosan, hydroxy acid salts, and antioxidants, it effectively improves the penetration effect of freranal and moxicritin, significantly improves the transdermal absorption effect of freranal and moxicritin, and effectively improves the stability of the drops. Detailed Implementation

[0017] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0018] In this invention, the technical features described in an open-ended manner include both closed-ended technical solutions composed of the listed features and open-ended technical solutions that include the listed features.

[0019] In this invention, numerical ranges are involved. Unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe features or characteristics, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0020] In this invention, there are no particular limitations on the specific dispersion and stirring methods.

[0021] Unless otherwise specified, all reagents or instruments used in this invention are commercially available conventional products. Unless otherwise specified, the raw materials used in each comparative example and the parallel experiments of each embodiment are the same commercially available products.

[0022] This application provides a permeation enhancer-containing flurana-moxicamin nanodroplet, comprising the following components by mass percentage: 22-26% flurana, 1-1.5% moxicamin, 3-6% permeation enhancer, 0.5-2% glyceryl glucoside, 0.5-2% tocopheryl acetate, 15-20% cosolvent, 0.8-2% modified chitosan, 0.1-0.2% hydroxy acid salt, 0.2-0.6% antioxidant, and the balance being solvent; The penetration enhancer comprises phytosphingosine, β-caryophyllene, and caprylic / capric triglycerides in a mass ratio of 1:(0.2~2):(0.2~1.8).

[0023] This invention uses freranil and moxicritin as active ingredients. By adding penetration enhancers, glyceryl glucoside, tocopheryl acetate, modified chitosan, hydroxy acid salts, and antioxidants, the permeation effect of freranil and moxicritin is effectively improved, significantly enhancing the transdermal absorption of freranil and moxicritin, and effectively improving the stability of the drops.

[0024] The phytosphingosine mentioned above is a homologous component of stratum corneum lipids and has good compatibility with the skin. It can be embedded into the lipid bilayer structure of the stratum corneum through hydrogen bonding and lipid intercalation, increasing the hydrophilic channels and lipid gaps of the stratum corneum without disrupting the normal barrier function of the skin, thus providing physical space for the penetration of frerana-moxicillin. The β-caryophyllene mentioned above can reduce the diffusion resistance of the drug in the stratum corneum, allowing it to remain in the stratum corneum and continuously interfere with its barrier function. The caprylic / capric triglyceride mentioned above can effectively improve the solubility of frerana-moxicillin, while also improving the stability of the system and preventing the release of active ingredients. It can also be integrated into the hydrophobic regions of the lipid bilayer through hydrophobic interactions, reducing the van der Waals forces between lipid molecules and breaking the tight and orderly arrangement of the lipid bilayer. Through the synergistic effect of phytosphingosine, β-caryophyllene, and caprylic / capric triglyceride, the transdermal absorption of frerana and moxicillin is effectively improved, and the stability of the drops is also effectively enhanced.

[0025] The amount of the fluranar is 22-26%, for example, it can be 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26% or any two of these values.

[0026] The dosage of moxifloxacin is 1 to 1.5%, for example, it can be 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, or any two of these values.

[0027] The amount of the penetration enhancer is 0.5-2%, for example, it can be 0.5%, 0.6%, 0.8%, 1%, 1.2%, 1.5%, 1.8%, 2% or any two of these values.

[0028] The amount of glycerol glucoside used is 0.5-2%, for example, it can be 0.5%, 0.6%, 0.8%, 1%, 1.2%, 1.5%, 1.8%, 2% or any two of these values.

[0029] The amount of tocopherol acetate used is 0.5-2%, for example, it can be 0.5%, 0.6%, 0.8%, 1%, 1.2%, 1.5%, 1.8%, 2% or any two of these values.

[0030] The amount of the co-solvent used is 15-20%, for example, it can be 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20% or any two of these values.

[0031] The modified chitosan is used in an amount of 0.8-2%, for example, it can be 0.8%, 1%, 1.2%, 1.5%, 1.8%, 2% or any two of these values.

[0032] The amount of antioxidant used is 0.2-0.6%, for example, it can be 0.2%, 0.3%, 0.4%, 0.5%, 0.6% or any two of these values.

[0033] In some embodiments, the co-solvent includes at least one of N,N-dimethylacetamide and diethyltoluamide.

[0034] In some embodiments, the solvent includes at least one of acetone, dimethylacetamide, and 1,3-propanediol.

[0035] In some embodiments, the penetration enhancer comprises phytosphingosine, β-caryophyllene, and caprylic / capric triglycerides in a mass ratio of 1:(0.6~1.5):(0.5~1.4).

[0036] In some embodiments, the hydroxy acid salt includes at least one of sodium citrate, potassium sodium tartrate, and sodium malate.

[0037] In some embodiments, the modified chitosan is prepared by: (1) Add chitosan and citric acid to phosphate buffer and stir evenly (stirring speed is 200~600 rpm, time is 0.2~1h), then add casein and stir evenly (stirring speed is 200~600 rpm, time is 0.5~2h) to obtain the precursor solution; (2) Chloroacetic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide were added to the precursor solution, the pH was adjusted to 5.6~6.2, the reaction was carried out, filtered and dried to obtain modified chitosan.

[0038] This application modifies chitosan using a two-step method. First, chitosan is treated with citric acid and casein, with the casein uniformly adsorbed onto the chitosan surface. Then, it is reacted with 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide. The modified chitosan inhibits aggregation and steric hindrance through electrostatic repulsion and reduces interfacial tension, effectively improving the stability of fluranar and moxidectin. At the same time, the casein binds to the active ingredients through secondary bonds such as van der Waals forces, hydrogen bonds, hydrophobic interactions, and electrostatic interactions, effectively improving the stability and penetration of the drops.

[0039] In some embodiments, the mass ratio of chitosan, citric acid, phosphate buffer, and casein is 1:(0.01~0.02):(8~20):(0.08~0.15).

[0040] In some embodiments, the mass ratio of chloroacetic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N-hydroxysuccinimide, and the precursor solution is 1:(0.8~2):(0.8~2):(20~50).

[0041] In some embodiments, the reaction is carried out at a temperature of 25-35°C for 2-6 hours.

[0042] In some embodiments, the antioxidant includes butylated hydroxytoluene (antioxidant BHT).

[0043] This invention also provides a method for preparing a permeation-enhancing agent-containing flurana-moxicritin nanodroplet, comprising the following steps: Add the solubilizer to the solvent and stir until homogeneous. Then add glyceryl glucoside, tocopheryl acetate, and a penetration enhancer, and stir until homogeneous. Next, add flurranal, moxicritin, modified chitosan, hydroxy acid salt, and an antioxidant, and stir until homogeneous to obtain flurranal-moxicritin nanodrops containing a penetration enhancer.

[0044] The present application is further illustrated below with specific embodiments:

[0045] Example 1 A permeation enhancer-containing flurana-moxiketine nanodroplet comprises the following components by weight percentage: 25% flurana, 1.2% moxiketine, 5% permeation enhancer, 1.2% glyceryl glucoside, 1% tocopheryl acetate, 18% diethyltoluamide, 1.5% modified chitosan, 0.15% sodium citrate, 0.5% antioxidant BHT, and the balance being solvent.

[0046] The penetration enhancer comprises phytosphingosine, β-caryophyllene, and caprylic / capric triglycerides in a mass ratio of 1:1.2:0.8.

[0047] The solvent comprises acetone and dimethylacetamide in a mass ratio of 1:2.

[0048] The method for preparing the modified chitosan is as follows: (1) Chitosan and citric acid were added to phosphate buffer (pH 7.4) and stirred at 300 rpm for 0.5 h. Casein was then added and stirred at 300 rpm for 1 h to obtain the precursor solution. The mass ratio of chitosan, citric acid, phosphate buffer and casein was 1:0.015:15:0.12.

[0049] (2) Chloroacetic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and N-hydroxysuccinimide were added to the precursor solution, the pH was adjusted to 5.8, and the reaction was carried out at 30°C for 4 hours. The mixture was then filtered and dried to obtain modified chitosan. The mass ratio of chloroacetic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N-hydroxysuccinimide, and the precursor solution was 1:1:1:45.

[0050] The preparation method of the permeation-enhancing agent-containing flurana-moxicritin nanodrops includes the following steps: Add the solubilizer to the solvent and stir until homogeneous. Then add glyceryl glucoside, tocopheryl acetate, and a penetration enhancer, and stir until homogeneous. Next, add flurranal, moxicritin, modified chitosan, hydroxy acid salt, and an antioxidant, and stir until homogeneous to obtain flurranal-moxicritin nanodrops containing a penetration enhancer.

[0051] Example 2 The difference between Example 2 and Example 1 is that the penetration enhancer is different, but everything else is the same.

[0052] The penetration enhancer in this embodiment includes phytosphingosine, β-caryophyllene, and caprylic / capric triglycerides in a mass ratio of 1:0.6:1.4.

[0053] Example 3 The difference between Example 3 and Example 1 is that the penetration enhancer is different, but everything else is the same.

[0054] The penetration enhancer in this embodiment includes phytosphingosine, β-caryophyllene, and caprylic / capric triglycerides in a mass ratio of 1:1.5:0.5.

[0055] Example 4 The difference between Example 4 and Example 1 is that the penetration enhancer is different, but everything else is the same.

[0056] The penetration enhancer in this embodiment includes phytosphingosine, β-caryophyllene, and caprylic / capric triglycerides in a mass ratio of 1:2:0.2.

[0057] Example 5 The difference between Example 5 and Example 1 is that the penetration enhancer is different, but everything else is the same.

[0058] The penetration enhancer in this embodiment includes phytosphingosine, β-caryophyllene, and caprylic / capric triglycerides in a mass ratio of 1:0.2:1.8.

[0059] Example 6 The difference between Example 6 and Example 1 is that the amount of drops used is different, but everything else is the same.

[0060] The permeation enhancer-containing flurana-moxiketine nanodrops of this embodiment comprise the following components by weight percentage: 22% flurana, 1.5% moxiketine, 6% permeation enhancer, 0.5% glyceryl glucoside, 2% tocopheryl acetate, 15% diethyltoluamide, 2% modified chitosan, 0.1% sodium citrate, 0.2% antioxidant BHT, and the balance being solvent.

[0061] Example 7 The difference between Example 7 and Example 1 is that the amount of drops used is different, but everything else is the same.

[0062] The permeation enhancer-containing flurana-moxiketine nanodrops of this embodiment comprise the following components by weight percentage: 26% flurana, 1% moxiketine, 3% permeation enhancer, 2% glyceryl glucoside, 0.5% tocopheryl acetate, 20% diethyltoluamide, 0.8% modified chitosan, 0.2% sodium citrate, 0.6% antioxidant BHT, and the balance being solvent.

[0063] Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that the penetration enhancer is different, but everything else is the same.

[0064] A permeation enhancer-containing flurana-moxiketine nanodroplet comprises the following components by weight percentage: 25% flurana, 1.2% moxiketine, 5% permeation enhancer, 1.2% glyceryl glucoside, 1% tocopheryl acetate, 18% diethyltoluamide, 1.5% modified chitosan, 0.15% sodium citrate, 0.5% antioxidant BHT, and the balance being solvent.

[0065] The penetration enhancer comprises β-caryophyllene and caprylic / capric triglycerides in a mass ratio of 1.2:0.8.

[0066] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that the penetration enhancer is different, but everything else is the same.

[0067] A permeation enhancer-containing flurana-moxiketine nanodroplet comprises the following components by weight percentage: 25% flurana, 1.2% moxiketine, 5% permeation enhancer, 1.2% glyceryl glucoside, 1% tocopheryl acetate, 18% diethyltoluamide, 1.5% modified chitosan, 0.15% sodium citrate, 0.5% antioxidant BHT, and the balance being solvent.

[0068] The penetration enhancer comprises phytosphingosine and caprylic / capric triglycerides in a mass ratio of 1:0.8.

[0069] Comparative Example 3 The difference between Comparative Example 3 and Example 1 is that the penetration enhancer is different, but everything else is the same.

[0070] A permeation enhancer-containing flurana-moxiketine nanodroplet comprises the following components by weight percentage: 25% flurana, 1.2% moxiketine, 5% permeation enhancer, 1.2% glyceryl glucoside, 1% tocopheryl acetate, 18% diethyltoluamide, 1.5% modified chitosan, 0.15% sodium citrate, 0.5% antioxidant BHT, and the balance being solvent.

[0071] The penetration enhancer comprises phytosphingosine and β-caryophyllene in a mass ratio of 1:1.2.

[0072] Comparative Example 4 The difference between Comparative Example 4 and Example 1 is that β-caryophyllene was replaced with an equal amount of menthol, and caprylic / capric triglyceride was replaced with an equal amount of propylene glycol laurate. All other aspects are the same.

[0073] A permeation enhancer-containing flurana-moxiketine nanodroplet comprises the following components by weight percentage: 25% flurana, 1.2% moxiketine, 5% permeation enhancer, 1.2% glyceryl glucoside, 1% tocopheryl acetate, 18% diethyltoluamide, 1.5% modified chitosan, 0.15% sodium citrate, 0.5% antioxidant BHT, and the balance being solvent.

[0074] The penetration enhancer comprises phytosphingosine, menthol, and propylene glycol laurate in a mass ratio of 1:1.2:0.8.

[0075] Comparative Example 5 The difference between Comparative Example 5 and Example 1 is that an equal amount of chitosan was used to replace the modified chitosan, while everything else is the same.

[0076] Test case 1. Stability test: The drops of the examples and comparative examples were placed at -18°C, 25°C and 45°C for 30 days respectively, and the stability was observed.

[0077] Table 1

[0078] 2. Permeation enhancement effect test: The permeation diffusion cell test formulation of pig skin-Franz cell was used, with fluranal and moxicritin as target substances.

[0079] Test steps: S1. Preparation of isolated piglet skin: Thaw the back skin of 1-month-old piglets stored at -20℃ with deionized water at room temperature and rinse repeatedly with PBS buffer.

[0080] S2, Transdermal Absorption Test (1) First, fix the pig skin between the supply chamber and the receiving chamber of the Franz diffusion cell, with the stratum corneum of the skin facing the supply chamber and the dermis facing the receiving chamber. (2) Add 7.0 mL of receiving solution to the receiving chamber, tighten and fix the piglet skin, add 1.0 mL of receiving solution (PBS) to the receiving chamber through the sampler, remove the air, and make the dermal layer of the skin in close contact with the receiving solution; (3) The sample was added to the skin surface in the supply chamber, and the effective penetration area S was approximately 3.14 cm². 2 Apply the sample to the surface of the pigskin, spreading it evenly radially from the center outwards. Perform three replicates and parallels for each sample. (4) Penetration: After application, place the product in a pre-set (32±1)℃ receiving tank for constant temperature water bath. Turn on the electromagnetic stirrer at 300rpm to ensure that there are no air bubbles in the water bath jacket; (5) Take the sample solution at 24h time point, use a sampler to extract 2.0mL of receiving solution through the sampling tube, and then put it into a 2mL EP tube. In addition, add an equal amount of receiving solution after each sampling.

[0081] S3, Transdermal Content Test (1) The content of the test sample contained in the epidermis, epidermis, and subcutaneous tissue of the experimental group was detected. The specific processing method is as follows: (2) Detection of non-penetrating part on the skin: Use a 1mL pipette to repeatedly blow and clean the skin surface, wash the receiving liquid 5 times to a total of 5mL, and place it in a 5mL EP tube for testing; (3) Detection of the skin part: Use a sterile scalpel to cut the skin along the edge of the supply chamber, cut the skin into pieces, add 10 mL of receiving solution and sonicate for 60 min. After sonication, aspirate the supernatant and wait for testing. (4) Subcutaneous part detection: At each time point, 2.0 mL of receiving liquid was drawn from the receiving chamber and placed into a 2 mL EP tube for testing.

[0082] The concentrations of fluranazine and moxicritin were determined by HPLC. The test parameters are shown in Tables 2 and 3.

[0083] Table 2

[0084] Table 3

[0085] S4. Statistics and Analysis (1) Cumulative infiltration: Q = Cn × V + ∑Ci × V0 (i = 1···n-1).

[0086] Where: Q: cumulative permeation volume; V: volume of receiving liquid in the receiving chamber; V0: volume of each sampling; Ci: sample concentration in the receiving liquid from the first to the (n-1)th sampling; Cn: sample concentration measured at the nth sampling point.

[0087] (2) Diffusion percentage: P = Q / Po × 100%.

[0088] Where: P: diffusion percentage; Q: cumulative permeation of the sample at each time point in the receiving chamber; Po: theoretical content of the sample in the release chamber.

[0089] Table 4

[0090] As can be seen from Tables 1 and 4 above, the drops described in this application have excellent stability and transdermal absorption effect.

[0091] Comparing Examples 1-3 with Examples 4-5, it can be seen that by controlling the mass ratio of phytosphingosine, β-caryophyllene, and caprylic / capric triglycerides to 1:(0.6-1.5):(0.5-1.4), this application can further improve stability and transdermal absorption.

[0092] As can be seen from the comparison of Example 1 with Comparative Examples 1-4, the penetration enhancer described in this application can effectively improve stability and transdermal absorption.

[0093] Comparing Example 1 and Comparative Example 5, it can be seen that the modified chitosan described in this application can effectively improve stability and transdermal absorption.

[0094] Finally, it should be noted that the above embodiments are used to illustrate the technical solutions of the present invention and not to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A permeation-enhancing agent-containing flurana-moxicritin nanodroplet, characterized in that, It comprises the following components by weight percentage: 22-26% Freranal, 1-1.5% Moxifloxacin, 3-6% Penetration Enhancer, 0.5-2% Glyceryl Glucoside, 0.5-2% Tocopheryl Acetate, 15-20% Cosolvent, 0.8-2% Modified Chitosan, 0.1-0.2% Hydroxy Acid Salt, 0.2-0.6% Antioxidant, and the balance being solvent; The penetration enhancer comprises phytosphingosine, β-caryophyllene, and caprylic / capric triglycerides in a mass ratio of 1:(0.2~2):(0.2~1.8).

2. The permeation-enhancing agent-containing flurana-moxicritin nanodrops according to claim 1, characterized in that, The co-solvent includes diethyltoluamide.

3. The permeation-enhancing agent-containing flurana-moxicritin nanodrops according to claim 1, characterized in that, The solvent includes at least one of acetone, dimethylacetamide, and 1,3-propanediol.

4. The permeation-enhancing agent-containing flurana-moxicritin nanodrops according to claim 1, characterized in that, The penetration enhancer comprises phytosphingosine, β-caryophyllene, and caprylic / capric triglycerides in a mass ratio of 1:(0.6~1.5):(0.5~1.4).

5. The permeation-enhancing agent-containing flurana-moxicritin nanodrops according to claim 1, characterized in that, The hydroxy acid salt includes at least one of sodium citrate, potassium sodium tartrate, and sodium malate.

6. The permeation-enhancing agent-containing flurana-moxicritin nanodrops according to claim 1, characterized in that, The method for preparing the modified chitosan is as follows: (1) Add chitosan and citric acid to phosphate buffer, stir well, then add casein and stir well to obtain the precursor solution; (2) Chloroacetic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide were added to the precursor solution, the pH was adjusted to 5.6~6.2, the reaction was carried out, filtered and dried to obtain modified chitosan.

7. The permeation-enhancing agent-containing flurana-moxicritin nanodrops according to claim 6, characterized in that, The mass ratio of chitosan, citric acid, phosphate buffer, and casein is 1:(0.01~0.02):(8~20):(0.08~0.15).

8. The permeation-enhancing agent-containing flurana-moxicritin nanodrops according to claim 6, characterized in that, The mass ratio of chloroacetic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N-hydroxysuccinimide, and the precursor solution is 1:(0.8~2):(0.8~2):(20~50).

9. The permeation-enhancing agent-containing flurana-moxicritin nanodrops according to claim 6, characterized in that, The reaction is carried out at a temperature of 25-35°C for 2-6 hours.

10. A method for preparing the permeation-enhancing agent-containing fluranar-moxicritin nanodrops according to any one of claims 1 to 9, characterized in that, Includes the following steps: Add the solubilizer to the solvent and stir until homogeneous. Then add glyceryl glucoside, tocopheryl acetate, and a penetration enhancer, and stir until homogeneous. Next, add flurranal, moxicritin, modified chitosan, hydroxy acid salt, and an antioxidant, and stir until homogeneous to obtain flurranal-moxicritin nanodrops containing a penetration enhancer.

Images