A moxidectin pour-on solution and a method of preparing the same

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a moxidectin pouring solution and a preparation method thereof. The moxidectin pouring solution comprises moxidectin, phospholipid, cholesterol, mannitol monooleate, carnosine, propylene glycol, vitamin E, an antioxidant, an organic solvent, azone, a buffer and water for injection. The application further provides a preparation method of the pouring solution. The organic solvent is used to dissolve the fat-soluble components, and then the film is formed by reducing pressure evaporation, the water phase is dispersed by hydration, and then the microfiltration membrane is filtered to obtain the pouring solution. The application uses liposomes as carriers, significantly improves the encapsulation rate of moxidectin and the transdermal absorption performance of the preparation, and is suitable for veterinary anti-parasitic transdermal administration.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a moxicritin pouring solution and its preparation method. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Moxiquitin is a novel macrolide antiparasitic antibiotic produced by Streptomyces fermentation. It is characterized by its broad spectrum, high efficacy, and low toxicity. It exhibits excellent killing activity against internal and external parasites in animals, particularly nematodes and arthropods. Compared to ivermectin, moxiquitin has higher lipid solubility, a longer half-life, and better safety, and is currently widely used for the prevention and treatment of parasitic diseases in cattle, pigs, dogs, and cats. As a transdermal drug delivery formulation, the pour-over solution has become a hot research area in veterinary drug formulation development due to its advantages such as ease of administration, reduced animal stress, and suitability for large-scale livestock farming.

[0004] However, the clinical application of moxicin still faces several technical challenges. First, moxicin has extremely poor water solubility and dissolves slowly in common solvents, leading to difficulties in formulation preparation, limited drug loading, and a tendency for drug precipitation during storage, affecting dosage accuracy and efficacy. Second, the stratum corneum of the skin is the main barrier for transdermal drug delivery; improving the transdermal absorption efficiency of moxicin and achieving long-lasting sustained release remains a key challenge in formulation development.

[0005] To address the aforementioned issues, existing research has attempted to improve the preparation process of moxicritin pourable solutions by optimizing solvent systems, adding transdermal penetration enhancers, and thickeners. For example, Chinese patent CN120884536A discloses a moxicritin pourable solution and its preparation method. This method uses lipid solvents such as soybean oil to replace medium-chain triglycerides, reducing costs, and improves the stability and detection accuracy of the formulation through a combination of specific types of antioxidants, penetrants, and thickeners. Chinese patent CN121221525A discloses a preparation process for moxicritin pourable solutions. This process uses nanoemulsions as the first solvent and combines ultrasonic permeation-enhancing treatment and a self-healing hydrogel forming agent, significantly improving the drug's solubility and transdermal performance.

[0006] Liposomes are closed vesicles composed of a phospholipid bilayer, exhibiting excellent biocompatibility and biodegradability. They can encapsulate lipophilic or amphiphilic drugs, improving drug stability, prolonging in vivo circulation time, promoting transdermal drug penetration, and achieving sustained-release. In recent years, liposome technology has shown broad application prospects in the field of transdermal veterinary drug delivery. Preparing moxicritin into liposome form is expected to overcome its shortcomings in solubility, stability, and transdermal absorption, further improving the clinical efficacy and formulation quality of pourable solutions.

[0007] Therefore, developing a moxicritin pourable solution using liposomes as a carrier and its preparation method has significant technological advancement and industrial value. Summary of the Invention

[0008] To overcome the shortcomings of existing technologies, this invention provides a moxicritin pourable solution and its preparation method. This pourable solution uses liposomes as a carrier, significantly improving the encapsulation efficiency and transdermal absorption performance of moxicritin, thus achieving a highly effective antiparasitic effect.

[0009] In a first aspect, the present invention provides a moxicillin pourable solution, which is composed of the following components in parts by weight: Moxicillin 0.5–2.0 parts, phospholipids 3.0–8.0 parts, cholesterol 1.0–3.0 parts, mannitol monooleate 1.5–3.0 parts, carbamoyl ornithine 0.2–0.8 parts, propylene glycol 5.0–10.0 parts, vitamin E 0.1–0.3 parts, antioxidant 0.03–0.1 parts, organic solvent 25.0–45.0 parts, azone 1.5–3.0 parts, buffer as needed, and water for injection as needed.

[0010] Furthermore, the phospholipid is soybean phospholipid or hydrogenated soybean phospholipid.

[0011] Furthermore, the buffer is selected from at least one of citric acid-sodium citrate, tartaric acid-sodium tartrate, and malic acid-sodium malate, and the buffer is used to adjust the pH of the solution to 4.5-5.5, preferably pH=5.0.

[0012] Furthermore, the antioxidant is selected from at least one of butylated hydroxyanisole, di-tert-butyl-p-cresol, and propyl gallate.

[0013] Furthermore, the organic solvent is anhydrous ethanol.

[0014] Secondly, the present invention provides a method for preparing the above-mentioned moxifloxacin pouring solution, comprising the following steps: (1) Preparation of lipid system: phospholipids, cholesterol, mannitol monooleate, moxifloxacin, vitamin E, antioxidants and azone are dissolved in organic solvent, stirred and dissolved, and then the organic solvent is removed by rotary evaporation in a water bath at 40-50℃ to form a lipid film. (2) Preparation of aqueous phase: Mix propylene glycol with water for injection, add carbamoyl ornithine and stir to dissolve, adjust the pH to 4.5-5.5 with buffer solution, and heat to 40-50℃ as hydration medium; (3) Thin film hydration and dispersion: Pour the preheated aqueous phase into a container containing a lipid film and hydrate it by rotation at 40-50°C for 30-45 minutes to form a dispersion; (4) Filtration: 0.45μm microporous membrane is used for filtration, filling and sealing.

[0015] Furthermore, the rotation speed of the vacuum rotary evaporation in step (1) is 60-80 rpm; the rotation speed of the rotary hydration in step (3) is 80-100 rpm.

[0016] Furthermore, the dispersion obtained in step (3) can be dispersed by ultrasound at a power of 200W for 30 seconds.

[0017] Thirdly, the present invention provides the application of the above-mentioned moxicritin pouring solution in the preparation of veterinary antiparasitic transdermal drug delivery formulations.

[0018] Compared with the prior art, the technical advantages of the present invention are as follows: (1) This invention is the first to combine mannitol monooleate and carbamoyl ornithine in the pouring solution of moxiquitocillin liposomes. The two exhibit a significant synergistic effect: mannitol monooleate, as a lipophilic surfactant, can embed into the lipid bilayer, increasing membrane fluidity and flexibility, thereby improving the liposome's encapsulation capacity for moxiquitocillin; carbamoyl ornithine, through its amino group forming hydrogen bonds with the phospholipid head group, enhances the density and stability of the lipid membrane, reducing drug leakage. Experiments show that the encapsulation efficiency of the embodiments of this invention all reach over 90%.

[0019] (2) The liposome formulation prepared in this invention can effectively penetrate the stratum corneum of the skin. Mannitol monooleate, as a penetration enhancer, can disrupt the orderly arrangement of lipids in the stratum corneum; carbamoyl ornithine, by regulating stratum corneum hydration and its interaction with cell membrane transport proteins, synergistically enhances the transdermal penetration of moxicritin. Transdermal experiments show that the cumulative transdermal amount in the embodiments of this invention reached 44.5~50.8 μg / cm² in 24 hours, which is higher than the 16.1 μg / cm² of commercially available products, demonstrating excellent sustained-release transdermal properties. Attached Figure Description

[0020] Figure 1Moxicritin pourable solution transdermal absorption effect. Detailed Implementation

[0021] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0022] Example 1: Moxicritin Pouring Solution Raw material composition: Moxicillin 1.25g, soybean lecithin 5.5g, cholesterol 2.0g, mannitol monooleate 2.25g, carbamoyl ornithine 0.5g, propylene glycol 7.5g, vitamin E 0.2g, di-tert-butyl-p-cresol 0.06g, anhydrous ethanol 35.0g, azone 2.2g, appropriate amount of citrate-sodium citrate buffer, and water for injection 15.0g.

[0023] Preparation method: (1) Preparation of lipid system: Weigh the soybean lecithin, cholesterol, mannitol monooleate, moxiquitoline, vitamin E, di-tert-butyl-p-cresol and azone in the above ratio, add them to anhydrous ethanol, and stir thoroughly until completely dissolved; place the mixture in a rotary evaporator and evaporate under reduced pressure at a water bath of 45°C and a rotation speed of 70 rpm to completely remove anhydrous ethanol and form a uniform and transparent lipid film.

[0024] (2) Preparation of aqueous phase: Take the prescribed amount of propylene glycol and water for injection, add carbamoyl ornithine and stir continuously until completely dissolved, adjust the pH of the solution to 5.0 using citrate-sodium citrate buffer, heat the system to 45°C and keep it warm for later use as hydration medium.

[0025] (3) Hydration and dispersion of the film: The aqueous solution preheated to 45°C was slowly poured into the container with the lipid film attached, and hydrated at 90 rpm for 40 minutes at 45°C; then ultrasonically dispersed at 200W power for 30 seconds to obtain a uniform and stable lipid dispersion.

[0026] (4) Filtration and filling: The solution is precisely filtered using a 0.45μm microporous membrane. After filtration, it is aseptically filled and sealed to obtain the finished moxicillin pourable solution.

[0027] Example 2: Moxicritin Pouring Solution Raw material composition: Moxicillin 0.5g, soybean lecithin 3.0g, cholesterol 1.0g, mannitol monooleate 1.5g, carbamoyl ornithine 0.2g, propylene glycol 5.0g, vitamin E 0.1g, butylated hydroxyanisole 0.03g, anhydrous ethanol 25.0g, azone 1.5g, tartaric acid-sodium tartrate buffer (appropriate amount), and water for injection 10g.

[0028] Preparation method: (1) Preparation of lipid system: Weigh the above proportioned raw materials, dissolve soybean lecithin, cholesterol, mannitol monooleate, moxifloxacin, vitamin E, butylated hydroxyanisole, and azone in anhydrous ethanol, stir until fully dissolved; place in a rotary evaporator, evaporate under reduced pressure at 40°C water bath and 60 rpm to remove all organic solvents, and prepare lipid film.

[0029] (2) Preparation of aqueous phase: Mix propylene glycol with water for injection, add carbamoyl ornithine and stir to dissolve, adjust the pH to 4.5 with tartaric acid-sodium tartrate buffer, heat to 40°C and keep warm for later use.

[0030] (3) Thin film hydration and dispersion: The aqueous phase preheated at 40°C was poured into the lipid thin film container and hydrated at 80 rpm for 30 minutes at 40°C; the dispersion was obtained by ultrasonic dispersion at 200W power for 30 seconds.

[0031] (4) Filtration and filling: After filtration through a 0.45μm microporous membrane, the product is filled and sealed to obtain the finished product.

[0032] Example 3: Moxifloxacin Pouring Solution Raw material composition: Moxiquidine 2.0g, hydrogenated soybean lecithin 8.0g, cholesterol 3.0g, mannitol monooleate 3.0g, carbamoyl ornithine 0.8g, propylene glycol 10.0g, vitamin E 0.3g, propyl gallate 0.1g, anhydrous ethanol 45.0g, azone 3.0g, appropriate amount of malate-sodium malate buffer, and water for injection 25g.

[0033] Preparation method: (1) Preparation of lipid system: Weigh the hydrogenated soybean phospholipid, cholesterol, mannitol monooleate, moxiquitoline, vitamin E, propyl gallate and azone in the above proportions, dissolve them in anhydrous ethanol and stir to dissolve; place them in a rotary evaporator, evaporate under reduced pressure at 50°C water bath and 80 rpm to completely remove organic solvent and form lipid film.

[0034] (2) Preparation of aqueous phase: propylene glycol and water for injection are mixed, carbamoyl ornithine is added and stirred until completely dissolved, the pH is adjusted to 5.5 using malic acid-sodium malate buffer, and heated to 50°C for later use.

[0035] (3) Thin film hydration and dispersion: The aqueous phase preheated at 50°C was added to the lipid thin film container and hydrated at 100 rpm for 45 minutes at 50°C; the mixture was then ultrasonically dispersed at 200W power for 30 seconds to obtain a uniform dispersion.

[0036] (4) Filtration and filling: The product is aseptically filled and sealed after filtration through a 0.45μm microporous membrane to obtain the finished moxicillin pourable solution.

[0037] Comparative Example 1: Moxicritin Pouring Solution Raw material composition: Moxicillin 1.25g, soybean lecithin 5.5g, cholesterol 2.0g, carbamoyl ornithine 0.5g, propylene glycol 7.5g, vitamin E 0.2g, di-tert-butyl-p-cresol 0.06g, anhydrous ethanol 35.0g, azone 2.2g, appropriate amount of citrate-sodium citrate buffer, and water for injection 15.0g.

[0038] Preparation method: (1) Preparation of lipid system: Weigh the soybean lecithin, cholesterol, moxiquitoline, vitamin E, di-tert-butyl-p-cresol and azone in the above ratio, add them to anhydrous ethanol, and stir thoroughly until completely dissolved; place the mixture in a rotary evaporator and evaporate under reduced pressure at a water bath of 45°C and a rotation speed of 70 rpm to completely remove anhydrous ethanol and form a uniform and transparent lipid film.

[0039] (2) Preparation of aqueous phase: Take the prescribed amount of propylene glycol and water for injection, add carbamoyl ornithine and stir continuously until completely dissolved, adjust the pH of the solution to 5.0 using citrate-sodium citrate buffer, heat the system to 45°C and keep it warm for later use as hydration medium.

[0040] (3) Hydration and dispersion of the film: The aqueous solution preheated to 45°C was slowly poured into the container with the lipid film attached, and hydrated at 90 rpm for 40 minutes at 45°C; then ultrasonically dispersed at 200W power for 30 seconds to obtain a uniform and stable lipid dispersion.

[0041] (4) Filtration and filling: The solution is precisely filtered using a 0.45μm microporous membrane. After filtration, it is aseptically filled and sealed to obtain the finished moxicillin pourable solution.

[0042] Comparative Example 2: Moxifloxacin Pouring Solution Raw material composition: Moxicillin 1.25g, soybean lecithin 5.5g, cholesterol 2.0g, polyglycerol monooleate 2.25g, carbamoyl ornithine 0.5g, propylene glycol 7.5g, vitamin E 0.2g, di-tert-butyl-p-cresol 0.06g, anhydrous ethanol 35.0g, azone 2.2g, appropriate amount of citrate-sodium citrate buffer, and water for injection 15.0g.

[0043] Preparation method: (1) Preparation of lipid system: Weigh the soybean lecithin, cholesterol, polyglycerol monooleate, moxiquitoline, vitamin E, di-tert-butyl-p-cresol and azone in the above proportions, add them to anhydrous ethanol, and stir thoroughly until completely dissolved; place the mixture in a rotary evaporator and evaporate under reduced pressure at a water bath of 45°C and a rotation speed of 70 rpm to completely remove anhydrous ethanol and form a uniform and transparent lipid film.

[0044] (2) Preparation of aqueous phase: Take the prescribed amount of propylene glycol and water for injection, add carbamoyl ornithine and stir continuously until completely dissolved, adjust the pH of the solution to 5.0 using citrate-sodium citrate buffer, heat the system to 45°C and keep it warm for later use as hydration medium.

[0045] (3) Hydration and dispersion of the film: The aqueous solution preheated to 45°C was slowly poured into the container with the lipid film attached, and hydrated at 90 rpm for 40 minutes at 45°C; then ultrasonically dispersed at 200W power for 30 seconds to obtain a uniform and stable lipid dispersion.

[0046] (4) Filtration and filling: The solution is precisely filtered using a 0.45μm microporous membrane. After filtration, it is aseptically filled and sealed to obtain the finished moxicillin pourable solution.

[0047] Comparative Example 3: Moxifloxacin Pouring Solution Raw material composition: Moxicillin 1.25g, soybean lecithin 5.5g, cholesterol 2.0g, mannitol monooleate 2.25g, propylene glycol 7.5g, vitamin E 0.2g, di-tert-butyl-p-cresol 0.06g, anhydrous ethanol 35.0g, azone 2.2g, appropriate amount of citrate-sodium citrate buffer, and water for injection 15.0g.

[0048] Preparation method: (1) Preparation of lipid system: Weigh the soybean lecithin, cholesterol, mannitol monooleate, moxiquitoline, vitamin E, di-tert-butyl-p-cresol and azone in the above ratio, add them to anhydrous ethanol, and stir thoroughly until completely dissolved; place the mixture in a rotary evaporator and evaporate under reduced pressure at a water bath of 45°C and a rotation speed of 70 rpm to completely remove anhydrous ethanol and form a uniform and transparent lipid film.

[0049] (2) Preparation of aqueous phase: Take the prescribed amount of propylene glycol and water for injection, adjust the pH of the solution to 5.0 using citric acid-sodium citrate buffer, heat the system to 45°C, keep it warm for later use as a hydration medium.

[0050] (3) Hydration and dispersion of the film: The aqueous solution preheated to 45°C was slowly poured into the container with the lipid film attached, and hydrated at 90 rpm for 40 minutes at 45°C; then ultrasonically dispersed at 200W power for 30 seconds to obtain a uniform and stable lipid dispersion.

[0051] (4) Filtration and filling: The solution is precisely filtered using a 0.45μm microporous membrane. After filtration, it is aseptically filled and sealed to obtain the finished moxicillin pourable solution.

[0052] Comparative Example 4: Moxifloxacin Pouring Solution Raw material composition: Moxicillin 1.25g, soybean lecithin 5.5g, cholesterol 2.0g, mannitol monooleate 2.25g, L-arginine 0.5g, propylene glycol 7.5g, vitamin E 0.2g, di-tert-butyl-p-cresol 0.06g, anhydrous ethanol 35.0g, azone 2.2g, appropriate amount of citrate-sodium citrate buffer, and water for injection 15.0g.

[0053] Preparation method: (1) Preparation of lipid system: Weigh the soybean lecithin, cholesterol, mannitol monooleate, moxiquitoline, vitamin E, di-tert-butyl-p-cresol and azone in the above ratio, add them to anhydrous ethanol, and stir thoroughly until completely dissolved; place the mixture in a rotary evaporator and evaporate under reduced pressure at a water bath of 45°C and a rotation speed of 70 rpm to completely remove anhydrous ethanol and form a uniform and transparent lipid film.

[0054] (2) Preparation of aqueous phase: Take the prescribed amount of propylene glycol and water for injection, add L-arginine and stir continuously until completely dissolved, adjust the pH of the solution to 5.0 using citric acid-sodium citrate buffer, heat the system to 45°C and keep it warm for later use as a hydration medium.

[0055] (3) Hydration and dispersion of the film: The aqueous solution preheated to 45°C was slowly poured into the container with the lipid film attached, and hydrated at 90 rpm for 40 minutes at 45°C; then ultrasonically dispersed at 200W power for 30 seconds to obtain a uniform and stable lipid dispersion.

[0056] (4) Filtration and filling: The solution is precisely filtered using a 0.45μm microporous membrane. After filtration, it is aseptically filled and sealed to obtain the finished moxicillin pourable solution.

[0057] Comparative Example 5: Moxifloxacin Pouring Solution Raw material composition: Moxicillin 1.25g, soybean lecithin 5.5g, cholesterol 2.0g, mannitol monooleate 1.0g, carbamoyl ornithine 1.2g, propylene glycol 7.5g, vitamin E 0.2g, di-tert-butyl-p-cresol 0.06g, anhydrous ethanol 35.0g, azone 2.2g, appropriate amount of citrate-sodium citrate buffer, and water for injection 15.0g.

[0058] Preparation method: (1) Preparation of lipid system: Weigh the soybean lecithin, cholesterol, mannitol monooleate, moxiquitoline, vitamin E, di-tert-butyl-p-cresol and azone in the above ratio, add them to anhydrous ethanol, and stir thoroughly until completely dissolved; place the mixture in a rotary evaporator and evaporate under reduced pressure at a water bath of 45°C and a rotation speed of 70 rpm to completely remove anhydrous ethanol and form a uniform and transparent lipid film.

[0059] (2) Preparation of aqueous phase: Take the prescribed amount of propylene glycol and water for injection, add carbamoyl ornithine and stir continuously until completely dissolved, adjust the pH of the solution to 5.0 using citrate-sodium citrate buffer, heat the system to 45°C and keep it warm for later use as hydration medium.

[0060] (3) Hydration and dispersion of the film: The aqueous solution preheated to 45°C was slowly poured into the container with the lipid film attached, and hydrated at 90 rpm for 40 minutes at 45°C; then ultrasonically dispersed at 200W power for 30 seconds to obtain a uniform and stable lipid dispersion.

[0061] (4) Filtration and filling: The solution is precisely filtered using a 0.45μm microporous membrane. After filtration, it is aseptically filled and sealed to obtain the finished moxicillin pourable solution.

[0062] Comparative Example 6: Moxicidin Pouring Solution Raw material composition: Moxiquidine 1.25g, soybean lecithin 5.5g, cholesterol 2.0g, mannitol monooleate 3.5g, carbamoyl ornithine 0.05g, propylene glycol 7.5g, vitamin E 0.2g, di-tert-butyl-p-cresol 0.06g, anhydrous ethanol 35.0g, azone 2.2g, appropriate amount of citrate-sodium citrate buffer, and water for injection 15.0g.

[0063] Preparation method: (1) Preparation of lipid system: Weigh the soybean lecithin, cholesterol, mannitol monooleate, moxiquitoline, vitamin E, di-tert-butyl-p-cresol and azone in the above ratio, add them to anhydrous ethanol, and stir thoroughly until completely dissolved; place the mixture in a rotary evaporator and evaporate under reduced pressure at a water bath of 45°C and a rotation speed of 70 rpm to completely remove anhydrous ethanol and form a uniform and transparent lipid film.

[0064] (2) Preparation of aqueous phase: Take the prescribed amount of propylene glycol and water for injection, add carbamoyl ornithine and stir continuously until completely dissolved, adjust the pH of the solution to 5.0 using citrate-sodium citrate buffer, heat the system to 45°C and keep it warm for later use as hydration medium.

[0065] (3) Hydration and dispersion of the film: The aqueous solution preheated to 45°C was slowly poured into the container with the lipid film attached, and hydrated at 90 rpm for 40 minutes at 45°C; then ultrasonically dispersed at 200W power for 30 seconds to obtain a uniform and stable lipid dispersion.

[0066] (4) Filtration and filling: The solution is precisely filtered using a 0.45μm microporous membrane. After filtration, it is aseptically filled and sealed to obtain the finished moxicillin pourable solution.

[0067] Comparative Example 7: Moxifloxacin Pouring Solution Raw material composition: Moxicillin 1.25g, soybean lecithin 5.5g, cholesterol 2.0g, propylene glycol 7.5g, vitamin E 0.2g, di-tert-butyl-p-cresol 0.06g, anhydrous ethanol 35.0g, azone 2.2g, appropriate amount of citrate-sodium citrate buffer, and water for injection 15.0g.

[0068] Preparation method: (1) Preparation of lipid system: Weigh the soybean lecithin, cholesterol, moxiquitoline, vitamin E, di-tert-butyl-p-cresol and azone in the above ratio, add them to anhydrous ethanol, and stir thoroughly until completely dissolved; place the mixture in a rotary evaporator and evaporate under reduced pressure at a water bath of 45°C and a rotation speed of 70 rpm to completely remove anhydrous ethanol and form a uniform and transparent lipid film.

[0069] (2) Preparation of aqueous phase: Take the prescribed amount of propylene glycol and water for injection, adjust the pH of the solution to 5.0 using citric acid-sodium citrate buffer, heat the system to 45°C, keep it warm for later use as a hydration medium.

[0070] (3) Hydration and dispersion of the film: The aqueous solution preheated to 45°C was slowly poured into the container with the lipid film attached, and hydrated at 90 rpm for 40 minutes at 45°C; then ultrasonically dispersed at 200W power for 30 seconds to obtain a uniform and stable lipid dispersion.

[0071] (4) Filtration and filling: The solution is precisely filtered using a 0.45μm microporous membrane. After filtration, it is aseptically filled and sealed to obtain the finished moxicillin pourable solution.

[0072] Comparative Example 8: Commercially available moxifloxacin pourable solution (Moxifloxacin) Encapsulation rate evaluation Encapsulation efficiency determination: Take an appropriate amount of sample, separate the free drug from the drug encapsulated by liposomes using a dextran gel column, determine the total drug amount and the encapsulated drug amount by HPLC, and calculate the encapsulation efficiency = (encapsulated drug amount / total drug amount) × 100%.

[0073] Table 1 Encapsulation efficiency The encapsulation efficiency test results show that the moxiquitoline pourable solution prepared in this invention can achieve a high drug encapsulation efficiency. Mannitol monooleate and carbamoyl ornithine are key functional excipients for improving drug encapsulation efficiency. Their synergistic effect can significantly enhance the encapsulation ability of liposomes for moxiquitoline. Removing any key excipient, replacing the type of excipient, or deviating the addition amount of the two excipients from the patent-defined range will result in a significant decrease in the encapsulation efficiency of the formulation, which fully demonstrates that the compatibility and dosage limitation of these two excipients play a core role in maintaining the high encapsulation efficiency of the liposome pourable solution.

[0074] Transdermal absorption efficiency determination Using isolated pig skin as a transdermal barrier, the test sample was added to the supply tank and PBS (32℃, stirring speed 300 r / min) was added to the receiving tank. Samples were taken at 2, 4, 8, 12 and 24 h, and the drug concentration was determined by HPLC. The cumulative transdermal dose over 24 h was calculated.

[0075] Table 2 Transdermal absorption effect The moxicritin pourable solution of this invention exhibits significantly better transdermal absorption, with the cumulative transdermal drug amount at each time point being superior to all comparative examples and commercially available products. The lack of key excipients, substitution of ingredients, or improper formulation can all significantly weaken the transdermal absorption efficiency of the drug. Mannitol monooleate and carbamoyl ornithine play a key role in improving the transdermal performance of the formulation.

Claims

1. A moxicritin pourable solution, characterized in that, The moxicritin pourable solution is made from the following components: 0.5-2.0 parts moxicritin, 3.0-8.0 parts phospholipids, 1.0-3.0 parts cholesterol, 1.5-3.0 parts mannitol monooleate, 0.2-0.8 parts carbamoyl ornithine, 5.0-10.0 parts propylene glycol, 0.1-0.3 parts vitamin E, 0.03-0.1 parts antioxidant, 25.0-45.0 parts organic solvent, 1.5-3.0 parts azone, appropriate amount of buffer, and appropriate amount of water for injection.

2. The moxifloxacin pourable solution according to claim 1, characterized in that, The phospholipid is soybean phospholipid or hydrogenated soybean phospholipid.

3. The moxifloxacin pourable solution according to claim 1, characterized in that, The buffer is selected from at least one of citric acid-sodium citrate, tartaric acid-sodium tartrate, and malic acid-sodium malate.

4. The moxifloxacin pourable solution according to claim 1, characterized in that, The buffer is used to adjust the pH to 4.5–5.

5.

5. The moxifloxacin pourable solution according to claim 1, characterized in that, The buffer is adjusted to pH 5.

0.

6. The moxifloxacin pourable solution according to claim 1, characterized in that, The antioxidant is selected from at least one of butylated hydroxyanisole, di-tert-butyl-p-cresol, and propyl gallate.

7. The moxifloxacin pourable solution according to claim 1, characterized in that, The organic solvent is anhydrous ethanol.

8. A method for preparing the moxicritin pourable solution according to claim 1, characterized in that, The preparation method includes the following steps: (1) Preparation of lipid system: phospholipids, cholesterol, mannitol monooleate, moxifloxacin, vitamin E, antioxidants and azone are dissolved in organic solvent, stirred and dissolved, and then the organic solvent is removed by rotary evaporation in a water bath at 40-50℃ to form a lipid film. (2) Preparation of aqueous phase: Mix propylene glycol with water, add carbamoyl ornithine and stir to dissolve, adjust the pH with buffer solution, and heat to 40-50℃ as hydration medium; (3) Thin film hydration and dispersion: The preheated aqueous phase is poured into the lipid-containing thin film and hydrated by rotation at 40-50°C for 30-45 minutes to form a dispersion; (4) Filtration: 0.45μm microporous membrane is used for filtration, filling and sealing.

9. The preparation method according to claim 8, characterized in that, The rotational speed of the vacuum rotary evaporator in step (1) is 60-80 rpm; the rotational speed of the rotary hydration in step (3) is 80-100 rpm.

10. The preparation method according to claim 8, characterized in that, The dispersion in step (3) can be dispersed by ultrasound at a power of 200W for 30 seconds.

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