A flunixin meglumine injection with rapid onset of action and a preparation method thereof

Abstract

The application provides a fast-acting flunixin meglumine injection and a preparation method thereof, and belongs to the technical field of veterinary medicine, and contains the following components: flunixin meglumine 5-10 (w / v) %, alpha-pyrrolidone 10-30 (w / v) %, hydrophilic solvent 0.5-1 (w / v) %, antioxidant 0.1-0.3 (w / v) % and the balance of water for injection. The application takes flunixin meglumine as the main drug, matches alpha-pyrrolidone as a solvent and a targeting guide distribution component, uses a hydrophilic solvent to assist dissolution and promote absorption, and uses an antioxidant to inhibit the oxidative degradation of the main drug, so that the dissolution and absorption rate of the main drug and the target tissue distribution efficiency can be effectively improved, the storage stability can be ensured, the bacterial endotoxin and the injection site redness rate meet the requirements, the acute inflammation and pain of livestock and poultry can be quickly and efficiently relieved, and the demand for instant intervention in large-scale breeding can be met.

Description

Technical Field

[0001] This invention belongs to the field of veterinary medicine technology, and particularly relates to a rapid-acting flunixin meglumine injection and its preparation method. Background Technology

[0002] Flunixin meglumine, a nonsteroidal anti-inflammatory drug (NSAID), is widely used in veterinary clinical practice due to its well-defined antipyretic, analgesic, and anti-inflammatory pharmacological activities. In the clinical application of veterinary anti-inflammatory and analgesic drugs, injectable formulations are key for controlling acute inflammation and pain in livestock and poultry because they are directly absorbed after administration, have high bioavailability, and can quickly bypass gastrointestinal metabolic interference.

[0003] Existing flunixin meglumine injections have significant limitations in large-scale clinical use in livestock farming. The core issue is their inability to achieve rapid onset of action, making it difficult to meet the immediate intervention needs for acute symptoms in livestock and poultry, such as sudden postoperative pain and acute infectious inflammation. This is because, due to defects in the formulation design, the dissolution and transmembrane absorption rates of existing flunixin meglumine injections after intramuscular injection are slow. Clinical data show that even with claims of rapid peak concentration, the actual Tmax still requires 0.4–0.6 hours. Furthermore, because the drug cannot quickly penetrate the blood vessel wall to reach the inflammatory target area, the onset time for anti-inflammatory and analgesic effects is more than 1.5 hours. This results in the inability to control acute pain or sudden inflammation in livestock and poultry in a timely manner, easily leading to a chain reaction of problems such as decreased feed intake and exacerbated stress responses. Secondly, existing formulations often use unsuitable solvents such as ethyl acetate and industrial-grade ethanol, or lack optimized solvent-drug ratios. This leads to localized drug accumulation in the blood, but the proportion of free drug molecules is extremely low. Due to the non-specific binding of the solvent and drug, most of the drug cannot leave the bloodstream and migrate to the target tissue, directly limiting the efficiency of drug transport to the site of inflammation, pain receptors, and other target sites, further delaying the onset of action and failing to quickly relieve discomfort in livestock and poultry. Furthermore, although flunixin meglumine theoretically has the potential for broad tissue distribution, existing formulations lack targeted mediation due to the lack of excipients, significantly reducing the drug migration rate from the blood to the target tissue. Clinical monitoring shows that existing formulations require 2-3 hours to reach peak effective drug concentration at the site of inflammation, far lagging behind the time to peak blood concentration, exacerbating the delayed onset of action and affecting clinical treatment efficacy.

[0004] Furthermore, commercially available flunixin meglumine injections generally suffer from formulation stability defects, specifically manifested as discoloration, layering, and fluctuations in the active ingredient content during storage. These stability issues directly alter the drug's release rate and absorption efficiency in livestock and poultry, and may even interfere with the normal absorption pathway, further hindering the drug's efficacy and increasing the risk of adverse reactions and injection site redness and swelling in livestock and poultry.

[0005] In summary, current technologies have not yet been able to solve the core problems of slow dissolution, poor distribution, low stability, and easy local irritation of flunixin meglumine injection through formulation optimization, thus restricting its immediate application in veterinary clinical practice for the prevention and treatment of acute inflammation and pain in livestock and poultry. Therefore, there is an urgent need to develop a rapid-acting flunixin meglumine injection and its preparation method based on scientific excipient ratios that can accelerate drug dissolution and absorption and target tissue distribution while ensuring formulation stability. Summary of the Invention

[0006] The purpose of this invention is to provide a rapid-acting flunixin meglumine injection and its preparation method, which can effectively overcome the pharmacokinetic limitations of the drug itself, accelerate the tissue distribution speed, and ensure the storage stability of the preparation. It has better immediate anti-inflammatory and analgesic effects, bioavailability and safety, and meets the needs of immediate intervention for acute inflammation and pain in livestock and poultry.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution: A rapid-acting flunixin meglumine injection, characterized in that it comprises the following components: Flunixin meglumine 5-10 (w / v)%, α-pyrrolidone 10-30 (w / v)%, hydrophilic solvent 0.5-1 (w / v)%, antioxidant 0.1-0.3 (w / v)% and balance water for injection.

[0008] Preferably, the pH value of the flunixin meglumine injection is 7.8 to 9.0.

[0009] Preferably, the mass ratio of flunixin meglumine to α-pyrrolidone is 1:1.67~4.

[0010] Preferably, the mass ratio of flunixin meglumine to the hydrophilic solvent is 1:0.03~0.1.

[0011] Preferably, the hydrophilic solvent is selected from one or more of glycerol, polyethylene glycol 400, benzyl alcohol, propylene glycol, Tween-80, poloxamer 188, and dimethyl sulfoxide.

[0012] Preferably, the antioxidant is selected from sodium bisulfite, sodium sulfite, sodium metabisulfite, and sodium thiosulfate.

[0013] The present invention also provides a method for preparing the injection solution described in the above technical solution, comprising the following steps: (1) An excipient solution is obtained by mixing an antioxidant, α-pyrrolidone and a hydrophilic solvent with a portion of water for injection; (2) Add flunixin meglumine to the excipient solution and mix until dissolved to obtain a drug-containing solution; (3) Adjust the pH value of the drug-containing solution, add water for injection to the preset volume, and obtain the flunixin meglumine injection solution after sterile filtration.

[0014] Preferably, in step (1), the portion of water for injection accounts for 40-60% of the total volume of water for injection.

[0015] Preferably, in step (3), the pore size of the sterile filter is 0.22 μm.

[0016] Preferably, in step (3), the filtration method is cyclic filtration, and the filtration time is 20 min.

[0017] This invention provides a rapid-acting flunixin meglumine injection, with flunixin meglumine as the main drug, combined with a precisely measured amount of α-pyrrolidone as a solvent and targeted distribution component, supplemented by a hydrophilic solvent to construct a solubilizing and absorption-enhancing system, and an antioxidant to inhibit the oxidative degradation of the main drug. In the injection, α-pyrrolidone not only possesses strong solubility, significantly improving the solubility of flunixin meglumine, but also promotes drug absorption across the muscle membrane, while directionally mediating drug diffusion to the inflammatory target area, shortening the time to peak concentration, and increasing the apparent volume of distribution, preventing drug accumulation in the blood. The hydrophilic solvent reduces the surface tension of muscle tissue fluid, synergistically with α-pyrrolidone to overcome the muscle membrane absorption barrier, further accelerating drug diffusion into capillaries, ensuring rapid entry of the main drug into the systemic circulation; the antioxidant preferentially scavenge free radicals generated during storage, inhibiting the oxidation of the phenolic hydroxyl group of flunixin meglumine to a quinone structure, while the pH buffering capacity of α-pyrrolidone prevents the formation of acidic degradation products, ensuring the purity of the main drug. Furthermore, α-pyrrolidone forms a synergistic dissolution-diffusion system with the hydrophilic solvent, which not only improves the insufficient solubility of the active pharmaceutical ingredient but also enhances tissue penetration, maintaining the concentration of free drug within the effective therapeutic range. Antioxidants and α-pyrrolidone work together to maintain system stability, preventing drug crystallization caused by acid-base imbalance. The hydrophilic solvent also reduces potential interactions between the antioxidant and the active pharmaceutical ingredient, ensuring the stable functioning of each component. In product stability tests, the injection solution of this invention maintains a pale yellow and clear appearance even under accelerated conditions of 40℃ / 75%RH, with a active pharmaceutical ingredient retention rate of 96.8%–97.5%. After long-term storage for 12 months, the active pharmaceutical ingredient retention rate is 97.4%–98.0%, completely solving the problems of discoloration, stratification, and active pharmaceutical ingredient degradation in traditional formulations during storage. Following intramuscular injection, the drug rapidly reaches its peak concentration and is directed to the target area thanks to the synergistic effect of excipients, shortening the time to peak concentration (Tmax) to 0.25–0.35 h and increasing the apparent volume of distribution (Vd) to 2.20–2.59 L / kg. The plasma concentration remains at 0.75–0.92 μg / mL after 18 h, achieving immediate relief of acute inflammation and pain while avoiding stress in animals caused by frequent administration. Simultaneously, the stable pH buffer system in this invention maintains the pH of the injection solution at 7.8–9.0, inhibiting the growth of Gram-negative bacteria and reducing the risk of endotoxin production from microbial metabolism. The addition of a hydrophilic solvent further improves the homogeneity of the drug solution, preventing drug crystallization and the formation of local microenvironments that could lead to microbial adhesion, indirectly reducing endotoxin production. Antioxidants scavenge free radicals during storage, protecting the active pharmaceutical ingredient from degradation and inhibiting microbial oxidative stress metabolism, thus reducing endotoxin secretion. In summary, the components can work synergistically to enhance each other's effects. The low irritation and diffusion-promoting properties of α-pyrrolidone, the mild solubilizing and analgesic effects of the hydrophilic solvent, and the degradation-inhibiting and microbial-controlling properties of the antioxidants can ensure medication safety from the source and meet the needs of clinical applications.

[0018] This invention also provides a method for preparing a rapid-acting flunixin meglumine injection. The method employs a step-by-step process of dissolving the excipients before adding the active pharmaceutical ingredient (API). This ensures that α-pyrrolidone, the hydrophilic solvent, and the antioxidant are fully dispersed in water, forming a homogeneous and stable excipient system. This avoids incomplete drug dissolution due to insufficient local excipient concentration when directly mixing the API, thus ensuring rapid dissolution and transmuscular absorption of the API after injection, achieving efficient drug diffusion to the target tissue. Based on the homogeneous excipient system, the API can quickly form hydrogen bonds with α-pyrrolidone and synergistically dissolve with the hydrophilic solvent, preventing local aggregation of the API into high-concentration areas. This prevents absorption efficiency from being affected by drug crystallization and reduces physical irritation to the injection site from undissolved particles. Simultaneously, the fully dissolved API can come into close contact with the antioxidant, reducing the risk of oxidative degradation. The process of this invention, through standardized procedures, ensures that the absorption-promoting function of α-pyrrolidone, the solubilizing function of hydrophilic solvents, and the anti-degradation function of antioxidants can all be stably performed, ultimately achieving a balance between rapid onset of action, stability, and safety. Moreover, the process is simple and controllable, ensuring the consistency of test data for different batches of products, and providing process support for the reliability of clinical applications of injectable solutions. Detailed Implementation

[0019] This invention provides a rapid-acting flunixin meglumine injection, comprising the following components: Flunixin meglumine 5-10 (w / v)%, α-pyrrolidone 10-30 (w / v)%, hydrophilic solvent 0.5-1 (w / v)%, antioxidant 0.1-0.3 (w / v)% and balance water for injection.

[0020] In this invention, the rapid-acting flunixin meglumine injection preferably comprises the following components: The formulation comprises 6.67% (w / v)% flunixin meglumine, 20% (w / v)% α-pyrrolidone, 1.67% (w / v)% hydrophilic solvent, 0.2% (w / v)% antioxidant, and the balance being water for injection. This invention uses flunixin meglumine as the core anti-inflammatory and analgesic component, combined with α-pyrrolidone as a solvent and targeted distribution medium. The hydrophilic solvent constructs a solubilizing and absorption-enhancing system, the antioxidant inhibits the oxidative degradation of the active ingredient, and water for injection serves as the dispersion carrier. The synergistic effect of these components enables stable dissolution and rapid release of flunixin meglumine in an aqueous system, effectively improving the problems of slow onset of action, easy degradation during storage, and significant injection site irritation associated with traditional flunixin meglumine injections. It also enhances the target tissue distribution efficiency after intramuscular injection, ensuring immediate relief of acute inflammation and pain in livestock and poultry, reducing stress responses caused by frequent administration, and meeting the needs of immediate clinical intervention in large-scale farming.

[0021] In this invention, the mass ratio of flunixin meglumine to α-pyrrolidone is preferably 1:1.67~4, more preferably 1:3. This mass ratio ensures that the α-pyrrolidone fully encapsulates the active pharmaceutical ingredient, achieving efficient dissolution. In this invention, the mass ratio of flunixin meglumine to the hydrophilic solvent is preferably 1:0.03~0.1, more preferably 1:0.03. This mass ratio allows the hydrophilic solvent to maximize its solubilizing and absorption-enhancing effects while avoiding the risk of local irritation.

[0022] In this invention, the pH value of the rapid-acting flunixin meglumine injection is preferably 7.8-9.0, more preferably 8.5. In this invention, the pH range of the flunixin meglumine injection is crucial for ensuring the performance of the formulation. It can prevent the crystallization and degradation of the active drug flunixin meglumine, maintain the active form of the antioxidant, and ensure efficient scavenging of free radicals. Furthermore, this pH range is close to the pH of animal muscle tissue fluid, which can reduce irritation, decrease the occurrence of injection redness and swelling, and maintain the active drug in a free state in the injection system. Combined with excipients, it promotes targeted distribution, fully meeting clinical needs.

[0023] In this invention, the amount of flunixin meglumine is 5-10% (w / v)%, preferably 6.67% (w / v)%. In this invention, flunixin meglumine exerts its antipyretic, analgesic, and anti-inflammatory pharmacological effects by inhibiting cyclooxygenase activity and reducing prostaglandin synthesis, making it a core component for the clinical efficacy of the formulation. A concentration of 5-10% (w / v) ensures that the blood drug concentration quickly reaches the effective therapeutic threshold after intramuscular injection, while avoiding crystallization due to excessive concentration exceeding the solubility of excipients, or non-target tissue stimulation due to local drug accumulation. This invention does not specifically limit the source of the flunixin meglumine; pharmaceutical-grade raw materials commonly purchased by those skilled in the art can be used, with a purity ≥98.5% and impurity content meeting the quality requirements for flunixin meglumine raw materials in the 2020 edition of the *Veterinary Pharmacopoeia of the People's Republic of China*.

[0024] In this invention, the amount of α-pyrrolidone used is 10-30% (w / v)%, preferably 20% (w / v)%. In this invention, α-pyrrolidone has dual functions as a solvent and a targeted distribution medium: as a solvent, it can significantly improve the solubility of flunixin meglumine, far exceeding that of traditional solvents, ensuring complete dissolution of the active pharmaceutical ingredient in the aqueous system and avoiding the impact of undissolved particles on absorption efficiency; as a targeted distribution medium, it can form stable hydrogen bonds with flunixin meglumine molecules, enhancing the drug's ability to penetrate across the muscle membrane, while simultaneously mediating the diffusion of the drug to the inflammatory target area, thereby increasing the apparent volume of distribution and reducing ineffective accumulation of the drug in the blood. Furthermore, α-pyrrolidone also has pH buffering capacity, which can synergistically maintain the pH of the injection solution at 7.8-9.0, inhibiting the hydrolytic degradation of the active pharmaceutical ingredient due to acid-base imbalance. In this invention, 10-30 (w / v)% of α-pyrrolidone exhibits a synergistic effect with hydrophilic solvents: the hydrophilic solvents effectively enhance the tissue compatibility of α-pyrrolidone, reducing potential irritation to the muscle membrane; simultaneously, α-pyrrolidone improves the dispersion uniformity of the hydrophilic solvent in the aqueous phase, avoiding absorption fluctuations caused by excipient stratification. This invention does not specifically limit the source of the α-pyrrolidone; injectable grade excipients commonly purchased by those skilled in the art can be used, provided that its endotoxin residue is <0.01 EU / mL and its purity is ≥99.0%.

[0025] In this invention, the amount of the hydrophilic solvent is 0.5~1 (w / v)%, preferably 0.67 (w / v)%. In this invention, the hydrophilic solvent is preferably one or more selected from glycerol, polyethylene glycol 400, benzyl alcohol, propylene glycol, Tween-80, poloxamer 188, and dimethyl sulfoxide. This invention does not have special requirements on the mass ratio of different types of hydrophilic solvents, only that the final hydrophilic solvent concentration is met. In a specific embodiment of this invention, the hydrophilic solvent is selected from Tween-80 and poloxamer 188, and the mass ratio of Tween-80 to poloxamer 188 is 1:1. In this invention, benzyl alcohol has both solubilizing and local analgesic effects, reducing tissue irritation when the drug crosses the muscle membrane, while simultaneously increasing the solubility of flunixin meglumine in muscle tissue fluid and accelerating drug diffusion into capillaries; polyethylene glycol 400 is a neutral excipient that can adjust the viscosity of the system, ensuring smooth injection operation and slowing down the diffusion rate of the drug in the muscle, which, combined with the targeting effect of α-pyrrolidone, prolongs the duration of effective blood drug concentration; propylene glycol and glycerin can enhance the aqueous compatibility of other excipients, preventing local aggregation of α-pyrrolidone and antioxidants due to polarity differences, ensuring the homogeneity and stability of the formulation system; Tween- Poloxamer 188 can compensate for the insufficient hydrophilicity of other hydrophilic solvents, further improving the solubility of the active pharmaceutical ingredient in muscle tissue fluid and preventing the formation of high-concentration areas due to local drug aggregation after injection. Combined with the targeting effect of α-pyrrolidone, it can also enhance the directional migration of the drug to the inflammatory target area, further shortening the time to peak concentration. Poloxamer 188 can promote the compatibility of α-pyrrolidone, antioxidants, and the aqueous phase, avoiding excipient stratification or uneven local concentration due to polarity differences. It can encapsulate the dissolved flunixin meglumine for slow release. Combined with the solubilizing effect of Tween-80, it can further prolong the duration of effective blood drug concentration and reduce the risk of local irritation. Dimethyl sulfoxide can reduce transmembrane resistance and accelerate the diffusion of flunixin meglumine molecules. Combined with the dissolving effect of α-pyrrolidone, it can further shorten the residence time of the drug at the injection site and synergistically enhance the solubility of the active pharmaceutical ingredient. This invention does not impose special limitations on the preparation process of the hydrophilic solvents; simply mixing the selected components uniformly is sufficient. This invention does not have specific limitations on the source of the hydrophilic solvent. Benzyl alcohol preferably requires distillation purification (endotoxin < 0.01 EU / mL), polyethylene glycol 400 preferably meets veterinary injection grade standards (heavy metal content < 10 ppm), and the rest can be conventional pharmaceutical grade products. This invention does not have specific limitations on the source of the hydrophilic solvent; pharmaceutical injection grade excipients commonly available to those skilled in the art can be used.

[0026] In this invention, the amount of antioxidant used is 0.1~0.3 (w / v)%, preferably 0.2 (w / v)%. In this invention, the antioxidant is preferably selected from sodium bisulfite, sodium sulfite, sodium metabisulfite, and sodium thiosulfate. In this invention, the antioxidant can target the easily oxidized phenolic hydroxyl group of flunixin meglumine by preferentially scavenging oxygen free radicals in the system, inhibiting the oxidative degradation of the active pharmaceutical ingredient into an irritating quinone structure. In this invention, sodium bisulfite and sodium metabisulfite are water-soluble antioxidants, exhibiting the strongest antioxidant activity in the pH range of 7.8~9.0, effectively controlling related substances during long-term storage of the formulation; sodium thiosulfate can also form stable soluble complexes with trace metal ions introduced by raw materials or equipment, interrupting the metal ion-catalyzed oxidation chain reaction and further improving storage stability. The present invention does not have any special limitation on the source of the antioxidant. Pharmaceutical-grade excipients that are routinely purchased by those skilled in the art can be used. The purity of the excipients must be ≥98.0%, and the impurity content must meet the quality requirements for injectable antioxidants in the 2020 edition of the Pharmacopoeia of the People's Republic of China.

[0027] This invention also provides a method for preparing the above-mentioned rapid-acting flunixin meglumine injection, comprising the following steps: (1) An antioxidant, α-pyrrolidone, and a hydrophilic solvent are mixed with a portion of water for injection to form an excipient solution. In this invention, the amount of the portion of water for injection is preferably 40-60% of the total water for injection. In this invention, the mixing is preferably carried out in a sterile mixing tank, and the environmental conditions of the mixing tank are more preferably a temperature of 20-25°C and a relative humidity of 45-65%. In this invention, dissolving the excipients before adding the active pharmaceutical ingredient can create a uniform dissolution environment and avoid insufficient dissolution due to insufficient local excipient concentration when the active pharmaceutical ingredient is added later. In this invention, the mixing method in step (1) is preferably stirring, the stirring speed is more preferably 180-220 r / min, and the stirring time is more preferably 13-18 min. In this invention, stirring can achieve molecular-level dispersion of excipients, avoiding uneven mixing of α-pyrrolidone and hydrophilic solvents, resulting in local stratification, or excessive air introduced by excessive rotation speed, which increases the risk of subsequent oxidation of the active pharmaceutical ingredient. Furthermore, stirring can ensure complete dissolution of antioxidants, avoiding uneven degradation of the active pharmaceutical ingredient due to local antioxidant residues, and laying the foundation for stable dissolution of the active pharmaceutical ingredient in the future.

[0028] (2) Flunixin meglumine is added to the excipient solution and mixed until dissolved to obtain a drug-containing solution. In this invention, the flunixin meglumine is preferably added slowly in batches. In this invention, the mixing method in step (2) is preferably stirring, the stirring speed is more preferably 200~250 r / min, and the stirring time is more preferably 18~23 min. In this invention, the core effect of this operation is that, relying on the homogeneous excipient system in the early stage, the active pharmaceutical ingredient can quickly form hydrogen bonds with α-pyrrolidone and dissolve synergistically with the hydrophilic solvent, ensuring that the active pharmaceutical ingredient is completely dissolved and does not aggregate. The stirring speed can both accelerate dissolution and avoid high shear force from damaging the molecular structure of the active pharmaceutical ingredient. The stirring time can ensure that the active pharmaceutical ingredient is fully dissolved and avoid undissolved particles from entering subsequent processes, which may lead to physical stimulation at the injection site or a decrease in absorption efficiency.

[0029] (3) Adjust the pH value of the drug-containing solution, add water for injection to a preset volume, and after sterile filtration, obtain the flunixin meglumine injection. In this invention, the pH adjustment is preferably adjusted to 7.8~9.0. The pH adjustment preferably uses 0.1 mol / L pharmaceutical grade hydrochloric acid solution or sodium hydroxide solution, and the adjustment is preferably carried out by adding dropwise while stirring. The stirring speed is more preferably 150~180 r / min, and the stirring time is preferably 5~8 min. In this invention, this pH adjustment method can avoid the instantaneous degradation of the active pharmaceutical ingredient caused by excessively high local acid and alkali concentrations, and the reagent concentration can accurately control pH changes, avoiding sudden changes in the system pH due to excessive concentration. In this invention, the stirring speed of 150~180 r / min can ensure uniform mixing of the drug solution and avoid local pH deviations. In this invention, adjusting the pH first and then adding water for injection to a preset volume can avoid pH dilution fluctuations caused by subsequent water replenishment, ensuring that the final injection solution pH is stable at 7.8~9.0. In this invention, the preferred method for replenishing water for injection is to slowly add it along the wall of the mixing tank. Slow addition avoids the generation of air bubbles in the solution due to violent impact, reducing the oxidative impact of air on the active pharmaceutical ingredient. The preferred pore size of the sterile filter is 0.22 μm. This pore size effectively traps trace amounts of undissolved particles, microorganisms, and endotoxin aggregates that may be present in the solution. This invention does not have specific limitations on the material of the sterile microporous membrane; conventional sterile microporous membranes are sufficient. The preferred filtration method is circulating filtration, and the preferred filtration time is 20 minutes. Circulating filtration for 20 minutes ensures the solution passes through the membrane thoroughly, preventing localized impurities due to insufficient filtration, and further homogenizes the solution, ensuring uniform concentration throughout the batch. This invention does not have specific limitations on the filtration environment; it is typically performed in a Class 100 cleanroom to avoid contamination of the solution by environmental microorganisms.

[0030] In this invention, the stepwise preparation process ensures that each component functions fully. Combined with precise process parameter control, it achieves uniform dispersion of the active pharmaceutical ingredient and excipients, effectively eliminating quality defects. The resulting rapid-acting flunixin meglumine injection is a colorless to pale yellow clear liquid, free of visible foreign matter or stratification, with a stable pH value of 7.8-9.0, an initial active pharmaceutical ingredient content of 99.5-100.0%, and related substances ≤0.25%, fully meeting the quality requirements for veterinary injectables in the 2020 edition of the *Pharmacopoeia of the People's Republic of China for Veterinary Injections*. In a 6-month accelerated stability test at 40℃ / 75% RH, the active pharmaceutical ingredient retention rate reached 96.8%-97.5%, pH fluctuation ≤0.3, and no discoloration was observed. In a 12-month long-term stability test at 25℃ / 60% RH, the active pharmaceutical ingredient retention rate reached 97.4%-98.0%. In an embodiment of the present invention, the preparation is administered via intramuscular injection at a dose of 2.2 mg / kg based on the effective ingredient, flunixin meglumine, in the neck muscle of livestock or poultry. Following intramuscular injection, the time to maximum (Tmax) is 0.25–0.35 h, the volume of blood (Vd) is 2.20–2.59 L / kg, and the rate of redness and swelling at the injection site is 0%. This approach meets the clinical requirement of rapid onset of action while ensuring storage stability and medication safety, demonstrating significant clinical application value and industrialization potential.

[0031] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0032] Example 1: Flunixin meglumine injection product 1 Flunixin meglumine 15 kg, α-pyrrolidone 30 kg, glycerol 1.5 kg, sodium bisulfite 0.3 kg, water for injection to a final volume of 300 L; Take 120 L of water for injection, add 0.3 kg of sodium bisulfite, 30 kg of α-pyrrolidone, and 1.5 kg of glycerol, and stir for 15 min until completely dissolved to form an excipient solution. Add 15 kg of flunixin meglumine to the excipient solution and stir for 20 min until completely dissolved to obtain a drug-containing solution. Adjust the pH of the drug-containing solution to 7.8, add water for injection to a final volume of 300 L, and circulate the solution through a 0.22 μm filter for 20 min to obtain flunixin meglumine injection product 1.

[0033] Example 2 Flunixin meglumine injection product 2 Flunixin meglumine 24 kg, α-pyrrolidone 60 kg, polyethylene glycol 400 2.4 kg, sodium metabisulfite 0.6 kg, water for injection to make up to 300 L.

[0034] Take 150 L of water for injection, add 0.6 kg of sodium metabisulfite, 60 kg of α-pyrrolidone, and 2.4 kg of polyethylene glycol 400, and stir for 14 min until dissolved to form an excipient solution. Add 24 kg of flunixin meglumine and stir for 18 min until dissolved to obtain a drug-containing solution. Adjust the pH to 8.5, add water for injection to a final volume of 300 L, and circulate and filter at 0.22 μm for 20 min to obtain flunixin meglumine injection product 2.

[0035] Example 3 Flunixin meglumine 30 kg, α-pyrrolidone 90 kg, benzyl alcohol 3 kg, sodium sulfite 0.9 kg, and water for injection to make up to 300 L.

[0036] Take 180 L of water for injection, add 0.9 kg of sodium sulfite, 90 kg of α-pyrrolidone, and 3 kg of benzyl alcohol, and stir for 16 min until dissolved to form an excipient solution. Add 30 kg of flunixin meglumine and stir for 22 min until dissolved to obtain a drug-containing solution. Adjust the pH to 9.0, add water for injection to a final volume of 300 L, and circulate and filter at 0.22 μm for 20 min to obtain flunixin meglumine injection product 3.

[0037] Example 4 Flunixin meglumine 18 kg, α-pyrrolidone 72 kg, propylene glycol 1.8 kg, sodium thiosulfate 0.45 kg, water for injection to make up to 300 L; Take 140 L of water for injection, add 0.45 kg of sodium thiosulfate, 72 kg of α-pyrrolidone, and 1.8 kg of propylene glycol, and stir for 13 min until dissolved to form an excipient solution. Add 18 kg of flunixin meglumine, stir for 19 min until dissolved to obtain a drug-containing solution, adjust the pH to 8.2, add water for injection to a final volume of 300 L, and circulate and filter at 0.22 μm for 20 min to obtain flunixin meglumine injection product 4.

[0038] Example 5 Flunixin meglumine 21 kg, α-pyrrolidone 84 kg, Tween-80 0.35 kg, poloxamer 188 0.35 kg, sodium metabisulfite 0.75 kg, add water for injection to 300 L.

[0039] Take 160 L of water for injection, add 0.75 kg of sodium metabisulfite, 84 kg of α-pyrrolidone, 0.35 kg of Tween-80, and 0.35 kg of poloxamer 188, and stir for 17 min until dissolved to form an excipient solution. Add 21 kg of flunixin meglumine and stir for 21 min until dissolved to obtain a drug-containing solution. Adjust the pH to 8.6, add water for injection to a final volume of 300 L, and circulate and filter at 0.22 μm for 20 min to obtain flunixin meglumine injection product 5.

[0040] Example 6 Flunixin meglumine 27 kg, α-pyrrolidone 45 kg, dimethyl sulfoxide 2.7 kg, sodium bisulfite 0.6 kg, and water for injection to make up to 300 L.

[0041] Take 170 L of water for injection, add 0.6 kg of sodium bisulfite, 45 kg of α-pyrrolidone, and 2.7 kg of dimethyl sulfoxide, and stir for 18 min until dissolved to form an excipient solution. Add 27 kg of flunixin meglumine and stir for 23 min until dissolved to obtain a drug-containing solution. Adjust the pH to 8.8, add water for injection to a final volume of 300 L, and circulate and filter at 0.22 μm for 20 min to obtain flunixin meglumine injection product 6.

[0042] Example 7 Flunixin meglumine 20 kg, α-pyrrolidone 60 kg, benzyl alcohol 2 kg, sodium bisulfite 0.6 kg, and water for injection to make up to 300 L.

[0043] Take 150 L of water for injection, add 0.6 kg of sodium bisulfite, 60 kg of α-pyrrolidone, and 2 kg of benzyl alcohol, and stir for 14 min until completely dissolved to form an excipient solution. Add 20 kg of flunixin meglumine to the excipient solution and stir for 22 min until dissolved to obtain a drug-containing solution. Adjust the pH of the drug-containing solution to 8.5, add water for injection to a final volume of 300 L, and circulate the solution through a 0.22 μm filter for 20 min to obtain flunixin meglumine injection product 7.

[0044] Comparative Example 1 Flunixin meglumine 15 kg, ethyl acetate 30 kg, glycerol 1.5 kg, sodium bisulfite 0.3 kg, water for injection to make up to 300 L; The preparation method is the same as in Example 1, except that α-pyrrolidone is replaced with ethyl acetate, and the other operation steps are the same, to obtain flunixin meglumine injection product 8.

[0045] Comparative Example 2 Flunixin meglumine 24 kg, α-pyrrolidone 60 kg, polyethylene glycol 400 2.4 kg, and water for injection to make up to 300 L.

[0046] The preparation method is the same as in Example 2, except that sodium metabisulfite is not added, and the other operation steps are the same, to obtain flunixin meglumine injection product 9.

[0047] Comparative Example 3 Flunixin meglumine 30 kg, α-pyrrolidone 90 kg, benzyl alcohol 3 kg, butylated hydroxytoluene 0.9 kg, and water for injection to bring the total volume to 300 L.

[0048] The preparation method is the same as in Example 3, except that sodium sulfite is replaced with butylated hydroxytoluene, and the other operation steps are the same, to obtain flunixin meglumine injection product 10.

[0049] Comparative Example 4 Flunixin meglumine 20 kg, α-pyrrolidone 30 kg, polyethylene glycol 400 2 kg, sodium metabisulfite 0.6 kg, and water for injection to make up to 300 L.

[0050] Take 150 L of water for injection, add 0.6 kg of sodium metabisulfite, 30 kg of α-pyrrolidone, and 2 kg of polyethylene glycol 400, and stir for 14 min until dissolved. Add 20 kg of flunixin meglumine and stir for 25 min (extending the dissolution time). Adjust the pH to 8.5, add water for injection to a final volume of 300 L, and filter through a 0.22 μm circulating filter for 20 min to obtain flunixin meglumine injection product 11.

[0051] Comparative Example 5 Flunixin meglumine 15 kg, α-pyrrolidone 82.5 kg, glycerol 1.5 kg, sodium bisulfite 0.3 kg, and water for injection to make up to 300 L; Take 120 L of water for injection, add 0.3 kg of sodium bisulfite, 82.5 kg of α-pyrrolidone, and 1.5 kg of glycerol, and stir for 15 min until dissolved. Add 15 kg of flunixin meglumine and stir for 18 min until dissolved. Adjust the pH to 7.8, add water for injection to a final volume of 300 L, and filter through a 0.22 μm circulating filter for 20 min to obtain flunixin meglumine injection product 12.

[0052] Comparative Example 6 Flunixin meglumine 25 kg, α-pyrrolidone 75 kg, propylene glycol 1 kg, sodium thiosulfate 0.5 kg, water for injection to make up to 300 L; Take 140 L of water for injection, add 0.5 kg of sodium thiosulfate, 75 kg of α-pyrrolidone, and 1 kg of propylene glycol, and stir for 13 min until dissolved. Add 25 kg of flunixin meglumine, stir for 22 min until dissolved, adjust the pH to 8.2, add water for injection to 300 L, and filter through a 0.22 μm circulation filter for 20 min to obtain flunixin meglumine injection product 13.

[0053] Comparative Example 7 Flunixin meglumine 20 kg, α-pyrrolidone 60 kg, benzyl alcohol 5 kg, sodium sulfite 0.6 kg, add water for injection to make up to 300 L; Take 180 L of water for injection, add 0.6 kg of sodium sulfite, 60 kg of α-pyrrolidone, and 5 kg of benzyl alcohol, and stir for 16 min until dissolved. Add 20 kg of flunixin meglumine and stir for 18 min until dissolved. Adjust the pH to 9.0, add water for injection to a final volume of 300 L, and filter through a 0.22 μm circulating filter for 20 min to obtain flunixin meglumine injection product 14.

[0054] Comparative Example 8 Flunixin meglumine 20 kg, N-methylpyrrolidone 60 kg, benzyl alcohol 2 kg, sodium bisulfite 0.6 kg, add water for injection to make up to 300 L; Take 150 L of water for injection, add 0.6 kg of sodium bisulfite, 60 kg of N-methylpyrrolidone, and 2 kg of benzyl alcohol, and stir for 14 min until completely dissolved to form an excipient solution. Add 20 kg of flunixin meglumine to the excipient solution and stir for 22 min until dissolved to obtain a drug-containing solution. Adjust the pH of the drug-containing solution to 8.5, add water for injection to a final volume of 300 L, and circulate the solution through a 0.22 μm filter for 20 min to obtain flunixin meglumine injection product 15.

[0055] Comparative Example 9 Flunixin meglumine 20 kg, polyvinylpyrrolidone 60 kg, benzyl alcohol 2 kg, sodium bisulfite 0.6 kg, add water for injection to make up to 300 L; Take 150 L of water for injection, add 0.6 kg of sodium bisulfite, 60 kg of polyvinylpyrrolidone, and 2 kg of benzyl alcohol, and stir for 14 min until completely dissolved to form an excipient solution. Add 20 kg of flunixin meglumine to the excipient solution and stir for 22 min until dissolved to obtain a drug-containing solution. Adjust the pH of the drug-containing solution to 8.5, add water for injection to a final volume of 300 L, and circulate the solution through a 0.22 μm filter for 20 min to obtain flunixin meglumine injection product 16.

[0056] Application Example 1: Identification of Flunixin Meglumine Injection Product Take appropriate amounts of flunixin meglumine injection products 1-16 prepared in Examples 1-7 and Comparative Examples 1-9, and place them in a 50 mL separatory funnel (each separatory funnel contains approximately 50 mg of flunixin). Take 4.1 g of anhydrous sodium acetate, add 500 mL of water to completely dissolve it, add 2.9 mL of glacial acetic acid, and dilute with water to 1000 mL to prepare an acetate buffer solution. Take 10 mL of the acetate buffer solution, shake, add 25 mL of ethyl acetate, shake, allow to stand for separation, and take the supernatant as the test solution. Separately, take an appropriate amount of flunixin meglumine reference standard, add methanol to prepare a solution containing 3 mg per mL, and use it as the reference solution. According to the thin-layer chromatography method, take 10 mL of each of the above two solutions and spot them separately on the same silica gel GF. 254 On thin-layer chromatography plates, toluene-ethyl acetate-glacial acetic acid-water (75:25:10:1) was used as the developing solvent. After drying, the plates were examined under ultraviolet light (254 nm). The results showed that the position and color of the main spots of flunixin meglumine injection products 1-16 should be the same as those of the main spots of the reference solution, indicating that the characteristic components of flunixin meglumine are present in all of the above products.

[0057] Application Example 2: Pharmacokinetics and Apparent Volume of Distribution Determination 1. Experimental Grouping Ninety-six three-way crossbred piglets (weighing 18±2 kg, half male and half female) were confirmed healthy through clinical examination (normal body temperature, respiration, and mental state) and blood routine and biochemical index tests (ALT, AST, creatinine, etc., within normal range). They were acclimatized for 7 days in a well-ventilated animal room at a constant temperature (26±2℃), with free access to water and fed antibiotic-free piglet feed. The piglets were randomly divided into 16 groups, corresponding to products 1-16 obtained in Examples 1-7 and Comparative Examples 1-9, with 6 piglets in each group. Each group of piglets was fasted for 12 hours before administration. Administration was performed via a single intramuscular injection of the corresponding injection solution at a dose of 0.4 mL / 10 kg, injected into the neck muscle of the pig. Blood samples were collected at 0.05, 0.1, 0.2, 0.4, 0.8, 1.5, 3, 6, 12, 18, and 24 hours after administration. The specific blood collection method is as follows: one piglet is randomly selected from each group at each time point, and 3 mL of blood is collected from the anterior vena cava. The blood is placed in a centrifuge tube containing heparin sodium, centrifuged at 3000 r / min for 10 min, the plasma is separated, and the plasma is frozen for later testing.

[0058] 2. Sample processing and testing items 2.1. Blood drug concentration detection Take 0.5 mL of plasma, add 1.5 mL of acetonitrile to precipitate the protein, centrifuge at 12000 rpm for 15 min, filter the supernatant through a 0.22 μm filter membrane, and determine by HPLC. Specifically, use octadecylsilane-bonded silica gel as the packing material; methanol-water-glacial acetic acid (70:30:1) as the mobile phase; the detection wavelength is 254 nm; the theoretical plate number is calculated based on the flunixin peak and should not be less than 1500; the resolution between the flunixin peak and the internal standard peak should be greater than 1.9. Take an appropriate amount of sodium benzoate, dissolve and dilute it in water to prepare a solution containing 33 mg per 1 mL, as the internal standard solution. Separately, accurately weigh approximately 83 mg of flunixin meglumine reference standard (approximately equivalent to 50 mg of flunixin), place it in a 50 mL volumetric flask, add an appropriate amount of methanol-water (7:3) to dissolve it, accurately add 5 mL of internal standard solution, dilute to the mark with methanol-water (7:3), and shake well; accurately measure 5 mL, place it in a 25 mL volumetric flask, dilute to the mark with methanol-water (7:3), and shake well; inject 20 μL into the liquid chromatograph and calculate the correction factor. Alternatively, accurately measure an appropriate amount of this product (approximately equivalent to 50 mg of flunixin), place it in a 50 mL volumetric flask, add an appropriate amount of methanol-water (7:3), accurately add 5 mL of internal standard solution, dilute to the mark with methanol-water (7:3), and shake well; accurately measure 5 mL, place it in a 25 mL volumetric flask, dilute to the mark with methanol-water (7:3), and shake well; use this as the test solution, inject 20 μL into the liquid chromatograph, determine the result, and calculate the correction factor. Each 1 μg of flunixin meglumine is equivalent to 0.6028 μg of flunixin.

[0059] 2.2. Testing Items and Data Processing The time to peak concentration (Tmax), peak concentration (Cmax), plasma elimination half-life (t1 / 2), and 18-hour plasma concentration were calculated using DAS 3.0 pharmacokinetic analysis software. Based on the Cmax data, the apparent volume of distribution (Vd) was automatically calculated using non-compartmental model analysis (NCA) in WinNonlin software.

[0060] Test Results Table 1. Pharmacokinetic Results of Products 1-16

[0061] As shown in Table 1, the rapid-acting flunixin meglumine injections prepared in Examples 1-7 of this invention, at a dosage of 2.2 mg / kg, exhibited superior pharmacokinetic and apparent volume of distribution (Vd) characteristics compared to the injections prepared in Comparative Examples 1-9. Specifically, the Tmax of Examples 1-7 ranged from 0.25 to 0.35 h, with Example 7 showing the shortest Tmax at 0.25 h. This indicates that the solubility and dissolution rate of flunixin meglumine at the injection site were effectively improved, accelerating the absorption of the drug across the muscle membrane into the bloodstream. Simultaneously, the targeted mediation effect of α-pyrrolidone in the formulation facilitated rapid penetration of the blood vessel wall to reach the inflammatory target area, providing a pharmacokinetic basis for the rapid relief of pain, fever, and other symptoms in animals in clinical practice. The Cmax of Examples 1-7 ranged from 0.85 to 1.00 μg / mL. This concentration maintained within the effective therapeutic range while avoiding potential non-target tissue stimulation caused by excessively high concentrations. This indicates that the products of these examples can precisely achieve effective therapeutic concentrations in vivo, with superior overall absorption efficiency, enabling rapid exertion of anti-inflammatory and analgesic activity and avoiding delayed efficacy or safety risks due to insufficient or excessive early blood drug concentrations. The Vd of Examples 1-7 ranged from 2.20 to 2.59 L / kg, with Example 6 exhibiting the highest Vd at 2.59 L / kg. This indicates a significantly enhanced ability of the drug to diffuse into tissues. Simultaneously, due to the synergistic effect of the excipients in the formulation, the drug is directed only to the inflammatory target area, without significant diffusion into non-target tissues such as fat and liver, achieving the dual advantages of high diffusivity and high targeting. Furthermore, the t1 / 2 of Examples 1-7 was 4.33-4.88 h, which is within the normal elimination range, and no elimination abnormalities were observed. Simultaneously, the blood drug concentrations of Examples 1-7 after 18 h of administration were 0.75-0.92 μg / mL, with Example 7 showing the highest blood drug concentration at 0.92 μg / mL. This indicates that the formulations of these examples, while accelerating drug absorption and enhancing tissue diffusion, can maintain an effective drug concentration in vivo for more than 18 hours. This achieves both rapid onset of action of flunixin meglumine and ensures its sustained efficacy, avoiding the stress burden caused by frequent administration to animals. In summary, the flunixin meglumine injections prepared in Examples 1-7, through the scientific ratio of solvents, co-solvents, and antioxidants in the formulation, construct a drug system capable of rapid absorption, efficient targeted diffusion, and stable and sustained action.

[0062] Under the same experimental conditions, the pharmacokinetic and volume-d (Vd) characteristics of the flunixin meglumine injections prepared in Comparative Examples 1-9 were generally inferior to those in Examples 1-7. Specifically, the Tmax of Comparative Examples 1-9 was 0.45-0.58 h, indicating that due to excipient defects, the dissolution and absorption rate of the drug at the injection site decreased, preventing it from rapidly crossing the muscle membrane barrier and entering the bloodstream, thus delaying the onset of drug efficacy. The Cmax of Comparative Examples 1-9 was 2.90-2.98 μg / mL, which, although much higher than the examples, indicated that the drug could not effectively diffuse into the tissues and only accumulated in the blood. This suggests that the excipients lacked targeting ability or had poor solvent compatibility, resulting in a reduced amount of drug effectively acting on the target area. Furthermore, excessively high blood drug concentrations could easily lead to safety risks such as redness and swelling at the injection site and decreased food intake, significantly reducing both the efficacy and the onset rate. The Vd of Comparative Examples 1-9 was 0.74-0.76. The concentration of the drug in samples with a concentration of L / kg is significantly lower than that in the examples and conventional parameters, further demonstrating its weak drug diffusion ability and inability to meet clinical needs for tissue distribution. The t1 / 2 of Comparative Examples 1-9 is 2.80-3.13 h, shorter than that of Examples 1-7, and the blood drug concentration remains at 0.20-0.24 μg / mL 18 h after administration, below the effective therapeutic concentration threshold, failing to achieve effective efficacy within 18 hours. This suggests that 2-3 daily administrations are required to maintain efficacy, increasing operational costs and potentially triggering stress in animals. In summary, the formulations in Examples 1-7 are rationally designed, with stable drug dissolution, absorption, and diffusion systems. Their pharmacokinetic and vitamin D properties meet the clinical requirements for rapid onset and sustained efficacy.

[0063] Application Example 2: Formulation Stability Experimental grouping and sample processing Take 100 mL of each of products 1 to 16 and divide them into two groups, each packaged in a 50 mL vial (protected from light and capped). The first group serves as the accelerated testing group, where the vials are stored at a temperature of (40±2)℃ and a relative humidity (RH) of (75±5)% for 6 months. The second group serves as the long-term stability testing group, where the vials are stored at (25±2)℃ and a relative humidity (RH) of (60±5)% for 12 months.

[0064] 2. Sample processing and testing items 2.1. pH value Samples were taken at 0 and 6 months or 0 and 12 months, with 3 bottles taken each time. The pH of the solution was directly measured using a calibrated pH meter (accuracy 0.01), and the average value was taken. 2.2. Retention rate of active pharmaceutical ingredient Samples were taken at months 0 and 6, or months 0 and 12, with three bottles taken each time. The active pharmaceutical ingredient (API) concentration was determined under the HPLC detection conditions described in Application Example 1. The API retention rate was calculated, and the average value was taken. The formula for calculating the API retention rate is as follows: Main drug retention rate = (main drug concentration in 6 months or 12 months / main drug concentration in 0 months) × 100%.

[0065] 2.3. Observation of appearance Samples were taken at 0 and 6 months or 0 and 12 months, with 3 bottles taken each time. The samples were observed under a 40W white fluorescent lamp at a distance of 10cm. The criteria for judgment were: the liquid was initially colorless to yellow and clear, and there was no precipitation, layering, sticking to the wall, or discoloration after storage.

[0066] 3. Experimental Results 3.1. Results of Accelerated Stability Test As shown in Table 2 of the accelerated stability test results, the rapid-acting flunixin meglumine injections prepared in Examples 1-7 of this invention exhibit superior product quality stability compared to the injections prepared in Comparative Examples 1-9. Specifically, in Examples 1-7, the pH value was 8.1-8.3 at 0 months, and the appearance was a colorless, clear liquid. At 6 months, the pH value remained at 7.9-8.1, with a fluctuation range of ≤0.3. The active pharmaceutical ingredient content was 96.8%-97.5% of the initial value, and the appearance remained a pale yellow, clear liquid. This indicates that the rapid-acting flunixin meglumine injections prepared in the examples showed no deterioration in appearance, effectively demonstrating that the formulations of the examples can effectively inhibit acid-base imbalance and drug degradation during storage, avoid sudden pH drops, reduce drug oxidation, and maintain drug solubility uniformity among the components, preventing crystallization and ensuring product quality stability during high-temperature and high-humidity transportation.

[0067] However, under the same experimental conditions, the stability of Comparative Examples 1-9 deteriorated significantly. At month 0, the pH was 8.2-8.4, and the appearance was a colorless, clear liquid. However, after month 6 of storage, the pH dropped to 7.0-7.5, the concentration decreased to 82.0-89.0% of the initial level, and the appearance became a brown liquid. Comparative Examples 2 and 9 showed obvious precipitation, while Comparative Examples 5 and 7 showed obvious stratification or adhesion to the walls. This suggests that the injectable products prepared in the comparative examples undergo accelerated drug oxidation at high temperatures and cannot withstand high temperature and humidity environments, leading to acid-base imbalance, significant drug degradation, and deterioration of physical properties, failing to meet the storage requirements under high temperature and humidity conditions. In summary, Examples 1-7, through the scientific formulation of solvents, antioxidants, and co-solvents, constructed a high-temperature and high-humidity resistant injectable system, achieving the stability requirements during product distribution.

[0068] Table 2 Results of accelerated stability tests for products 1-16

[0069] 3.2. Results of Long-Term Stability Test As shown in Table 3, the rapid-acting flunixin meglumine injection prepared in Examples 1-7 of this invention exhibits significantly better long-term storage stability than the injections prepared in Comparative Examples 1-9. Specifically, Examples 1-7 had a pH of 8.1-8.3 at 0 months, were colorless and clear liquids, and a pH of 7.9-8.1 at 12 months, with pH fluctuations ≤0.3. The active pharmaceutical ingredient content remained at 97.4-98.0% of the initial content, and the appearance was still a pale yellow and clear liquid. This fully demonstrates the long-term stability advantage of the formulations in these examples, which can continuously maintain drug dissolution stability, inhibit long-term drug oxidation, maintain drug solution homogeneity, and ensure product quality stability within a 12-month shelf life without the need to shorten the storage period. However, under the same experimental conditions, Comparative Examples 1-9, after 12 months of storage, had a pH of 7.3-7.6, with significant pH fluctuations, and the active pharmaceutical ingredient content decreased to 88.0-91.5% of the initial value. The appearance was brown, Comparative Examples 2 and 9 showed a small amount of precipitation, and Comparative Examples 5 and 7 showed obvious stratification and adhesion to the walls. The comparative examples indicate that the pH of the prepared injection system is unstable, leading to cumulative drug oxidation and degradation, or even system collapse during long-term storage. This results in continuous quality deterioration, significant loss of active ingredients, and abnormal physical properties, failing to meet the standard 12-month shelf-life requirement. Frequent restocking or short-term use is necessary, increasing operating costs and potentially impacting clinical efficacy due to quality fluctuations. In summary, Examples 1-7 achieved the 12-month long-term stable quality target, meeting the drug's shelf-life requirements.

[0070] Table 3 Results of long-term stability tests for products 1-16

[0071] Application Example 4: Formulation Safety Testing 1. Test Methods 1.1 Bacterial endotoxin determination Bacterial endotoxin determination was performed according to Appendix (Bacterial Endotoxin Test Method) of Part I of the 2020 edition of the Veterinary Pharmacopoeia of the People's Republic of China. 1 mL of each sample from Examples 1-7 and Comparative Examples 1-9 was diluted with pyrogen-free water at a ratio of 1:4. A negative control (pyrogen-free water), a positive control (bacterial endotoxin working standard diluted to 0.25 EU / mL), and a sample positive control (the diluted sample mixed with 0.25 EU / mL endotoxin standard) were also set up. 0.1 mL of the test solution was added to each Limulus Amebocyte Lysate (LAL) reagent tube and gently mixed. The tube was placed in a constant temperature water bath at (37±1)℃ and kept in the dark for (60±2) min. After incubation, the tube was removed vertically, and the gel was observed to ensure its integrity. The test was valid when the negative control was negative, the positive control was positive, and the sample positive control was positive. A negative gel in the sample diluted solution indicated endotoxin <0.5 EU / mL (meeting the standard); a positive gel indicated endotoxin ≥0.5 EU / mL (exceeding the standard).

[0072] 1.2 Injection site irritation test Based on Application Example 1, after the first injection, the injection site was marked with a marker, and the coordinates were recorded. Observations were conducted at 24, 48, and 72 hours post-injection. At each observation, the diameter of the swelling was measured with a ruler (the average of the longest and shortest diameters was taken), and the swelling rate was calculated. The criteria for judging swelling and the formula for calculating the swelling rate are as follows: Redness and swelling determination: Diameter ≤ 5 mm is "no redness and swelling"; diameter > 5 mm is "redness and swelling".

[0073] Redness and swelling rate calculation: number of red and swollen heads in each group / total number of heads in each group × 100%, and at the same time record whether the red and swollen area is accompanied by exudation or scab formation (considered as severe irritation).

[0074] 2. Experimental Results 2.1. Results of bacterial endotoxin assay As shown in Table 4, the rapid-acting flunixin meglumine injection prepared in Examples 1-7 of this invention is superior to the injections prepared in Comparative Examples 1-9 in terms of bacterial endotoxin control. Specifically, the gel reaction of the diluted samples in Examples 1-7 was negative, and the endotoxin content was <0.25 EU / mL, far below the standard limit of <0.5 EU / mL. There was no problem with endotoxin adsorption and desorption, effectively avoiding adverse reactions such as fever and shock in animals caused by endotoxin residue, providing a core guarantee for clinical drug safety. Under the same experimental conditions, the gel reaction of the diluted samples in Comparative Examples 1, 2, 3, 5, 6, 8, and 9 was positive, with endotoxin content ≥0.5 EU / mL, exceeding the standard limit. Although Comparative Examples 4 and 7 were negative, they were in a borderline state. For example, the endotoxin content of Comparative Example 4 was about 0.40 EU / mL, and the endotoxin content of Comparative Example 7 was about 0.45 EU / mL, posing a clinical risk. This suggests that the comparative examples cannot effectively control endotoxins and are prone to endotoxin release during storage. Excessive or near-critical endotoxin levels can increase the incidence of adverse reactions in animals after drug administration, such as fever and lethargy in piglets, failing to meet clinical safety requirements. In summary, the endotoxins in Examples 1-7 exhibit excellent stability, with no endotoxin release or proliferation during storage, further ensuring the safety of clinical application.

[0075] Table 4 Results of bacterial endotoxin assay for products 1-16

[0076] 2.2. Results of Redness and Swelling Rate at Injection Site As shown in Table 5, the rapid-acting flunixin meglumine injection prepared in Examples 1-7 of this invention is superior to the injections prepared in Comparative Examples 1-9 in terms of controlling local irritation. Specifically, in Examples 1-7, the number of animals with redness and swelling was 0 at 24, 48, and 72 hours after injection, and the redness and swelling rate was 0.0% at 72 hours. Furthermore, there was no exudation, crusting, or tenderness at the injection site, and the skin elasticity and color were normal. This effectively avoids local inflammation and tissue necrosis caused by injection site irritation, thus improving animal drug tolerance. Under the same experimental conditions, the flunixin meglumine injections prepared in Comparative Examples 1-9 generally exhibited worse irritation at the injection site compared to Examples 1-7. At 72 hours, the redness and swelling rate of Comparative Examples 1-9 ranged from 16.7% to 50.0%, with Comparative Examples 2, 7, and 9 reaching 50.0%. Four pigs showed redness and swelling 24 hours after injection, and three pigs still showed redness and swelling at 72 hours. The diameter of the swellings was mostly 6-13 mm, and some were accompanied by exudation and scab formation. Redness and swelling at the injection site can lead to decreased feed intake and pain avoidance in piglets. Frequent administration can also increase the risk of infection and affect the local absorption efficiency of the drug. In summary, the flunixin meglumine injections prepared in Examples 1-7 showed no irritation at the injection site and high animal tolerance.

[0077] Table 5 Results of Redness and Swelling Rate Detection at Injection Sites for Products 1-16

[0078] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A rapid-acting flunixin meglumine injection, characterized in that, It contains the following ingredients: Flunixin meglumine 5-10 (w / v)%, α-pyrrolidone 10-30 (w / v)%, hydrophilic solvent 0.5-1 (w / v)%, antioxidant 0.1-0.3 (w / v)% and balance water for injection.

2. The injection solution according to claim 1, characterized in that, The pH value of the flunixin meglumine injection is 7.8~9.

0.

3. The injection solution according to claim 1, characterized in that, The mass ratio of flunixin meglumine to α-pyrrolidone is 1:1.67~4.

4. The injection solution according to claim 1, characterized in that, The mass ratio of flunixin meglumine to the hydrophilic solvent is 1:0.03~0.

1.

5. The injection solution according to claim 1, characterized in that, The hydrophilic solvent is selected from one or more of glycerol, polyethylene glycol 400, benzyl alcohol, propylene glycol, Tween-80, poloxamer 188, and dimethyl sulfoxide.

6. The injection solution according to claim 1, characterized in that, The antioxidant is selected from one of sodium bisulfite, sodium sulfite, sodium metabisulfite, and sodium thiosulfate.

7. The method for preparing the injection solution according to any one of claims 1 to 6, characterized in that, Includes the following steps: (1) An excipient solution is obtained by mixing an antioxidant, α-pyrrolidone and a hydrophilic solvent with a portion of water for injection; (2) Add flunixin meglumine to the excipient solution and mix until dissolved to obtain a drug-containing solution; (3) Adjust the pH value of the drug-containing solution, add water for injection to the preset volume, and obtain the flunixin meglumine injection solution after sterile filtration.

8. The preparation method according to claim 7, characterized in that, In step (1), the portion of water for injection accounts for 40-60% of the total volume of water for injection.

9. The preparation method according to claim 7, characterized in that, In step (3), the pore size of the sterile filter is 0.22 μm.

10. The preparation method according to claim 7, characterized in that, In step (3), the filtration method is cyclic filtration, and the filtration time is 20 min.

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