A feline anti-stress oral formulation containing pregabalin and a method of preparing the same

Abstract

This application relates to the field of veterinary drug formulation technology, and discloses a cat anti-stress oral formulation containing pregabalin and its preparation method. The raw materials include: pregabalin-L-arginine co-ground micronized powder, isostearic acid, medium-chain triglycerides, hydrophobic fumed silica, and anhydrous yeast extract powder. The preparation method includes the following steps: weighing each raw material by mass; dissolving isostearic acid in medium-chain triglycerides by heating and stirring; starting high-speed dispersion under vacuum and constant temperature; introducing pregabalin-L-arginine co-ground micronized powder for reaction; introducing anhydrous yeast extract powder for dispersion; cooling and switching to low-speed stirring; adding hydrophobic fumed silica and running under vacuum; finally, static aging and packaging to obtain the finished product. This invention employs a technical solution of compounding pregabalin-L-arginine co-ground micronized powder, isostearic acid, and hydrophobic fumed silica in the oil phase, achieving the technical effect of thixotropic formulation and long-term static non-sedimentation.

Description

Technical Field

[0001] This invention relates to the field of veterinary drug formulation technology, specifically to an oral anti-stress formulation for cats containing pregabalin and its preparation method. Background Technology

[0002] Cats are highly susceptible to severe stress when faced with environmental changes such as veterinary visits, baths, or moving. Pregabalin is commonly used in veterinary clinics to alleviate this acute anxiety. Cats' taste buds are extremely sensitive to bitter substances. Pregabalin itself has a strong bitter taste. Forcing a cat to take a regular bitter medicine will cause it to resist violently. The process of administering the medication itself becomes a serious stressor.

[0003] Existing liquid pet medications typically contain high concentrations of sweeteners such as sucrose or sucralose to prepare aqueous solutions. These sweeteners, when dissolved in the aqueous phase, provide a strong sweet taste, thus masking the original odor of the medication. Another approach is to physically microencapsulate pregabalin using polymeric materials. This involves encapsulating the drug powder within a thin film to create microspheres, physically isolating the drug from the external environment. For ease of feeding, formulation developers also directly disperse the drug powder in vegetable oils such as medium-chain triglycerides. This is achieved by adding large amounts of fumed silica or polymeric resins to the system and then rapidly stirring. These thickeners can significantly increase the overall viscosity of the liquid in a short time. The increased viscosity and resulting fluid resistance effectively slows down the settling of powder particles initially.

[0004] Cats are born without sweet taste receptors. Sweeteners in aqueous solutions have no masking effect on their palates. Physically coated microparticles are easily crushed by a cat's sharp teeth when administered as a suspension. When the polymer film ruptures, bitter-tasting drugs are released directly into the mouth, causing the cat to immediately spit them out. Hydrophilic drug powders dispersed directly in a low-polarity oil phase will spontaneously agglomerate due to surface energy differences. Thickeners and drug particles added during routine stirring are dispersed separately in the oil phase. There are no intermolecular forces to maintain their dispersion. Over time, the agglomerated particles slowly settle to the bottom under gravity, forming hard clumps. Regular shaking is insufficient to resuspend these clumps evenly. Initially, the extracted drug concentration is too low to be effective; when the bottle is nearly empty, only highly concentrated residue remains. This greatly increases the risk of overdose and poisoning of the animal's nervous system. Simply increasing the viscosity of the liquid not only fails to solve the long-term physical clumping and stratification problem, but also makes the medicine too viscous, making it impossible to draw it smoothly with a regular syringe. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a pregabalin-containing oral anti-stress formulation for cats and its preparation method, which solves the problems of existing pregabalin-containing oral liquid formulations for cats, such as the easy sedimentation and clumping of solid drug particles leading to uneven dosage, poor physical stability of the system, and the bitter taste produced by direct contact of the solid drug with the oral cavity leading to low animal drug compliance.

[0006] To achieve the above objectives, the present invention provides the following technical solution: In a first aspect, the present invention provides an oral anti-stress formulation for cats containing pregabalin, employing the following technical solution: An oral anti-stress formulation for cats containing pregabalin, said oral formulation being made from the following raw materials in weight percentages: pregabalin-L-arginine co-ground micronized powder 8.75%–15.0%; isostearic acid 0.5%–1.5%; medium-chain triglycerides 77.5%–85.0%; hydrophobic fumed silica 1.5%–2.0%; and anhydrous yeast extract powder 3.0%–4.0%.

[0007] By adopting the above technical solution, the present invention utilizes a specific combination of pregabalin-L-arginine co-ground micro powder, isostearic acid, medium-chain triglycerides and hydrophobic fumed silica to enable in-situ heterogeneous interfacial reactions to occur in the system and construct a three-dimensional cross-linked network, thereby improving the physical stability of the formulation and effectively masking the bitterness of the drug.

[0008] Its reaction and mechanism of action mainly involve the in-situ transformation of particle surface properties and the construction of a physical cross-linking network. When pregabalin is co-ground with L-arginine, the basic guanidine group of L-arginine and the carboxyl group of pregabalin undergo intermolecular hydrogen bonding and even partial proton transfer, resulting in a layer of L-arginine adhering to the surface of the pregabalin crystals, thus forming co-ground microparticles. This physical barrier can, to some extent, reduce the dissolution rate of pregabalin in oral saliva, reduce its contact with taste receptors, and play a preliminary role in masking taste.

[0009] After the co-ground micropowder is dispersed into a continuous phase containing isostearic acid and medium-chain triglycerides, further interfacial reactions occur within the system. Specifically, isostearic acid diffuses to the solid-liquid interface, and its free carboxyl groups react with the free amino or guanidinyl groups of L-arginine on the surface of the micropowder to form a heterogeneous salt. The main reaction formula is: R − COOH + R′ − NH2 → R − COO - + R′ − NH3 +The isostearate arginine salt generated by the reaction forms a coating layer on the surface of the micropowder. Because the salt structure has amphiphilic and hydrophobic 18-carbon branches that extend toward the oil phase, the surface of the micropowder changes from a hydrophilic state to an oleophilic state. This reduces the interfacial tension between the particles and the oil phase and prevents direct aggregation between particles.

[0010] After the microparticles undergo surface hydrophobic modification, the dispersed hydrophobic fumed silica in the system immediately plays a cross-linking role. The unsubstituted free silanol groups retained on its surface can form hydrogen bonds with the polar groups of isostearate arginine salt on the microparticle surface. Through the three-dimensional chain-like structure of fumed silica, bridges are formed between particles, ultimately constructing a three-dimensional physical cross-linked network with dynamic yield stress in the continuous phase. This network endows the system with necessary thixotropy; the high viscosity exhibited in the static state hinders the sedimentation of microparticles under gravity, while the hydrogen bonds reversibly dissociate under shear force during extraction and administration, thinning the system. Furthermore, the anhydrous yeast extract powder dispersed in this system provides animals with a specific flavor preference, working in conjunction with the aforementioned taste-masking structure to improve overall palatability.

[0011] Preferably, the oral formulation is made from the following raw materials in the indicated weight percentages: pregabalin-L-arginine co-ground micronized powder 11.0%; isostearic acid 1.0%; medium-chain triglycerides 83.5%; hydrophobic fumed silica 1.5%; and anhydrous yeast extract powder 3.0%.

[0012] By adopting the above technical solution, the above ratio maintains a good balance between the amount of isostearic acid in the system and the number of reactive sites on the surface of the micronized powder, and the generated interfacial salt can meet the requirements of silica for three-dimensional network bridging. At the same time, it avoids the rancidity of the formulation caused by the introduction of excessive free fatty acids, and takes into account the physicochemical stability and rheological reproducibility of the formulation during long-term storage.

[0013] Preferably, in the pregabalin-L-arginine co-ground micro powder, the mass ratio of pregabalin to L-arginine is 2:1 to 8:3.

[0014] By adopting the above technical solution and controlling the material mass ratio within this range, the amount of L-arginine can effectively cover the surface of pregabalin crystals. A low proportion of L-arginine often leads to the exposure of the pregabalin crystal face, affecting the masking effect and causing insufficient surface salt-forming reaction sites; if the proportion is too high, it easily increases the overall hygroscopicity of the powder, causing water to mix into the oil phase system and thus destroying its physical stability.

[0015] Preferably, the pregabalin-L-arginine co-ground micro powder is prepared by a method including the following steps: pregabalin and L-arginine are mixed evenly and then fed into a fluidized bed air jet mill. Dehumidified and cooled compressed air is introduced, the working temperature in the grinding chamber is controlled to be constant at 10-15℃, and the grinding gas pressure is set to 0.6-0.8MPa for high-energy grinding until the particle size distribution of the collected co-ground micro powder meets the requirement that D90 is less than 15μm.

[0016] By employing the above technical solution, high-speed compressed airflow causes material particles to collide and cleave together. Simultaneously, dehumidification and cooling treatment, along with controlling the grinding chamber temperature at 10–15°C, removes the mechanical heat generated by the collisions, preventing the two organic compounds from melting and bonding or chemically degrading under heat. This mechanochemical action promotes the bonding of the two powders at the newly formed fracture surfaces. Furthermore, controlling the particle size distribution to D90 less than 15 μm increases the specific surface area of ​​the micro-powder, providing the necessary reaction contact surface for the subsequent interfacial salt-forming reaction in the continuous phase.

[0017] Preferably, the characteristic parameters of the raw materials meet the following conditions: the isostearic acid is a mixture of saturated octadecano fatty acids with multiple methyl branched structures, is liquid at room temperature, has an acid value ranging from 180 to 195 mg KOH / g, and an iodine value ≤ 3.0 g I2 / 100 g; the hydrophobic fumed silica is fumed silica surface-modified with dimethyldichlorosilane, with a specific surface area ranging from 130 to 170 m² / g. 2 / g, with unsubstituted free silanol groups remaining on the surface.

[0018] By employing the above-mentioned technical solution, isostearic acid, due to its methyl branched structure, possesses certain steric hindrance, allowing it to remain liquid at room temperature and be miscible with medium-chain triglycerides, thus preventing crystallization. Its specific acid value range provides free carboxyl groups to participate in in-situ reactions at the solid-liquid interface, while its low iodine value indicates the absence of unsaturated double bonds, reducing the risk of oxidative deterioration in the formulation. Furthermore, the hydrophobic fumed silica modified with dimethyldichlorosilane can be well dispersed in the continuous phase. Combined with its set specific surface area and retained density of free silanol groups, it is suitable for reversible hydrogen bonding with isostearic acid arginine salt, maintaining the thixotropic structure required for the suspension system and preventing irreversible gelation.

[0019] Secondly, the present invention provides a method for preparing a cat-specific anti-stress oral formulation containing pregabalin, using the following technical solution: A method for preparing a cat anti-stress oral formulation containing pregabalin, comprising the following steps: S1. Weigh each raw material according to its mass percentage; S2. Pump the medium-chain triglyceride into the vacuum reactor, add isostearic acid, and turn on the heating and stirring to completely dissolve the isostearic acid in the continuous phase. S3. Evacuate the reactor and, while maintaining the temperature and vacuum, turn on the high-speed dispersion disk to slowly draw the pregabalin-L-arginine co-ground powder into the reactor for constant temperature reaction through vacuum negative pressure. S4. Maintain stirring and vacuum to draw the anhydrous yeast extract powder into the vessel and maintain dispersion. S5. Cool the reactor jacket by introducing chilled water. S6. Turn off the high-speed dispersion disk, keep the low-speed stirring, release the vacuum in the reactor, add hydrophobic fumed silica in batches, re-evacuate the vacuum and run under low-speed stirring; S7. Stop the machine and release the vacuum. Transfer the material to a temporary storage tank for static aging. Then, package the finished product.

[0020] By adopting the above technical solution, the process route provided by this method combines the physicochemical properties of the raw materials and controls the fluid dynamics and temperature parameters accordingly during the preparation process. To ensure the smooth progress of the reaction, the addition and mixing of materials are carried out in stages.

[0021] During the preparation and feeding stages, using vacuum negative pressure to draw in the powder material reduces air bubbles adhering to the powder surface, which helps the medium-chain triglycerides wet the co-ground micropowder. After entering the isothermal reaction environment, the high-speed shearing action of the dispersion disk breaks up and disperses the co-ground micropowder in the system, allowing the L-arginine on the surface of the micropowder to be fully exposed in the continuous phase containing isostearic acid, thereby promoting the salt-forming reaction at the solid-liquid heterogeneous interface. After the interfacial reaction is completed, the system often requires a relatively stable environment to build a cross-linked network. At this time, cooling and switching to a low-speed stirring mode can provide suitable hydrogen bonding conditions for the free silanol groups of hydrophobic fumed silica and the polar groups at the micropowder interface, avoiding excessive mechanical shear force from destroying the non-covalent bonds that are forming. Finally, the internal stress is released through a static aging process, which promotes the stabilization of the three-dimensional physical cross-linked network.

[0022] Preferably, in step S2, the jacket heating is turned on and the temperature is increased to 60-70°C at a rate of 1.5-2.5°C / min.

[0023] By adopting the above technical solution, controlling the heating rate within a certain range during the heating process helps prevent excessively high local temperatures from causing oil phase oxidation. Raising the initial temperature of the reaction system to 60–70°C can reduce the viscosity of medium-chain triglycerides and accelerate the movement rate of isostearic acid molecules, which provides the necessary thermodynamic conditions for isostearic acid to diffuse to the solid-liquid interface and react.

[0024] Preferably, in step S3, the reactor is evacuated to -0.05 to -0.09 MPa, the high-speed dispersion disk is set to a speed of 1000 to 2000 rpm, and after the feeding is completed, the reactor is kept at a constant temperature of 60 to 70°C for 30 to 60 minutes.

[0025] By adopting the above technical solution, the vacuum level set in step S3 serves two purposes: firstly, to remove oxygen from the system, and secondly, to provide negative pressure for powder intake. Combined with a high-speed shearing action of 1000–2000 rpm, this breaks down agglomerates formed during powder storage. Maintaining a constant temperature reaction for 30–60 minutes ensures that the acid-base neutralization reaction at the solid-liquid interface proceeds relatively completely, allowing the generated isostearate to anchor on the surface of the microparticles, forming a sterically hindered oleophilic layer.

[0026] Preferably, in step S5, the temperature of the material inside the reactor is rapidly reduced to 30-40°C using a cooling gradient of 2.0-3.0°C / min.

[0027] By employing the above technical solution, and by setting a cooling gradient to rapidly remove heat from the system, the temperature is lowered to 30–40°C. This reduces the mobility of the isostearic acid long chains on the micropowder surface, gradually stabilizing the interfacial salt structure. Simultaneously, this temperature range also meets the requirements for establishing hydrogen bonds in the subsequent hydrophobic fumed silica, preventing thermal dissociation of the hydrogen bond network due to excessively high temperatures.

[0028] Preferably, step S6 is implemented as follows: the low-speed anchor-type wall scraping agitator is set to a speed of 20-50 rpm, hydrophobic fumed silica is added, and the vacuum is re-evacuated to -0.05--0.09 MPa for 20-40 minutes; in step S7, static aging is carried out at 20-25℃ for 1-3 hours.

[0029] By adopting the above technical solution, the subsequent stirring mode was switched from high-speed shearing to low-speed anchor-type wall-scraping stirring at 20-50 rpm, mainly to maintain macroscopic material mixing without generating destructive shear forces. Re-vacuuming removed any small amount of air introduced during the opening and feeding process. Running at low speed for 20-40 minutes helped silica distribute in the system and initially establish a chain-like framework. Subsequently, static aging was carried out at 20-25℃, allowing the particles in the suspension to gradually stabilize and arrange themselves under conditions without strong external interference, completing the hydrogen bonding association between silanol groups and arginine salt groups, and ultimately forming a thixotropic physical cross-linked network to ensure the formulation's anti-sedimentation performance during static standing.

[0030] This invention provides an oral anti-stress formulation for cats containing pregabalin and its preparation method. It has the following beneficial effects: 1. This invention employs a technical solution of co-grinding pregabalin-L-arginine micropowder, isostearic acid, and hydrophobic fumed silica in the oil phase. An in-situ salt-forming reaction occurs within the system, forming a physical cross-linked network, achieving the technical effect of thixotropic formulation and preventing sedimentation after long-term standing. Compared to conventional physical mixing methods that directly add thickeners or suspending agents, this solution overcomes the shortcomings of existing technologies where microparticles are easily affected by gravity and settle and clump together, leading to uneven dosage. 2. This invention employs a co-grinding process of pregabalin and L-arginine, combined with a medium-chain triglyceride oil-phase dispersion technique. The binding layer on the powder surface forms a physical barrier, achieving the technical effect of reducing drug solubility in saliva and masking bitterness. Compared to existing technologies that rely on adding large amounts of flavoring agents or preparing coated microparticles for taste masking, this invention overcomes the shortcomings of insufficient taste masking or the release of bitterness after the coating breaks in the mouth, causing stress and refusal to take the medication in cats. 3. This invention employs a phased control method for the reaction temperature and mechanical shear force during the preparation process. High-temperature, high-speed dispersion and low-temperature, low-speed aging are implemented at different process stages, achieving thermodynamic stability of the cross-linked network and high batch-to-batch reproducibility. Compared to conventional liquid preparation methods that rely on continuous, high-intensity mechanical force, this invention overcomes the shortcomings of existing technologies that easily disrupt intermolecular hydrogen bonds, leading to the inability to form a suspended framework and unstable rheological characteristics of the system. Attached Figure Description

[0031] Figure 1 This is an infrared spectrum test result diagram of the test example of the present invention; Figure 2 The rheological test diagrams for the embodiments and comparative examples of the test examples of the present invention are shown, wherein (a) is a thixotropic hysteresis loop curve obtained by steady-state shear sweep, and (b) is a curve of the storage modulus and loss modulus obtained by dynamic oscillation sweep as a function of shear stress. Figure 3 The following is a graph showing the results of the accelerated dual chemical stability test of the test examples of the present invention, wherein (a) is a line graph showing the change in the percentage of pregabalin lactam generated as an impurity over time, and (b) is a line graph showing the change in the acid value of the chain triglyceride in the matrix over time. Figure 4 The following is a diagram showing the centrifugation stratification results of the ultimate physical stability test of the test examples of the present invention, wherein (a) is a distribution diagram of the oil phase precipitation rate of each sample, and (b) is a distribution diagram of the volume ratio of the bottom sediment of each sample. Figure 5 The figures show the in vitro taste-masking simulation and in vivo clinical palatability assessment of the test examples of the present invention, where (a) is a scatter plot of the change in the rapid dissolution rate in simulated saliva over time, and (b) is a normalized distribution plot of the multidimensional indicators of stress response and licking willingness of experimental animals. Detailed Implementation

[0032] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] The main raw materials and reagents used in the following examples and comparative examples have the following sources and specifications. Reagents not specifically mentioned are all commercially available analytical grade or higher grade products.

[0034] Pregabalin, CAS No. 148553-50-8, purity ≥99.0%.

[0035] L-arginine, CAS number 74-79-3, purity ≥99.0%.

[0036] Isostearic acid, CAS number 30399-84-9, is a mixture of saturated octadecano fatty acids with multiple methyl branched structures. It is liquid at room temperature, with an acid value ranging from 180 to 195 mg KOH / g and an iodine value ≤ 3.0 g I2 / 100g.

[0037] Medium-chain triglycerides, also known as caprylic and capric triglycerides, CAS number 65381-09-1, are mainly formed by the esterification of caprylic and capric acids with glycerol. At room temperature, they are colorless and transparent liquids with an acid value ≤0.1mg KOH / g and a moisture content ≤0.1%.

[0038] Hydrophobic fumed silica, CAS No. 68611-44-9, is fumed silica surface-modified with dimethyldichlorosilane, with a specific surface area ranging from 130 to 170 m². 2 / g, with unsubstituted free silanol groups remaining on the surface.

[0039] Anhydrous yeast extract powder, CAS No. 8013-01-2, moisture content ≤1.0%.

[0040] Preparation Example 1: This preparation example provides a method for preparing pregabalin-L-arginine co-ground micronized powder, including the following steps: Mix 80g pregabalin with 30g L-arginine until homogeneous; feed the mixture into a fluidized bed air jet mill, introduce dehumidified and cooled compressed air, control the working temperature in the grinding chamber to be constant at 12℃, set the grinding gas pressure to 0.7MPa, and continue high-energy grinding until the particle size distribution of the collected co-ground micro powder meets the requirement that D90 is less than 15μm, and discharge the material for later use.

[0041] Preparation Example 2: This preparation example provides a method for preparing pregabalin-L-arginine co-ground micronized powder, including the following steps: Mix 50g pregabalin with 20g L-arginine until homogeneous; feed the mixture into a fluidized bed air jet mill, introduce dehumidified and cooled compressed air, control the working temperature in the grinding chamber to be constant at 10℃, set the grinding gas pressure to 0.6MPa, and continue high-energy grinding until the particle size distribution of the collected co-ground micro powder meets the requirement that D90 is less than 15μm, and discharge the material for later use.

[0042] Preparation Example 3: This preparation example provides a method for preparing pregabalin-L-arginine co-ground micronized powder, including the following steps: Mix 100g pregabalin with 50g L-arginine until homogeneous; feed the mixture into a fluidized bed air jet mill, introduce dehumidified and cooled compressed air, control the working temperature in the grinding chamber to be constant at 15℃, set the grinding gas pressure to 0.8MPa, and continue high-energy grinding until the particle size distribution of the collected co-ground micro powder meets the requirement that D90 is less than 15μm, and discharge the material for later use.

[0043] Example 1: This example provides a cat anti-stress oral preparation containing pregabalin and its preparation method, including the following steps: 1. Weigh the raw materials according to the mass percentage: 11.0% of the co-ground micro powder obtained in Preparation Example 1, 1.0% of isostearic acid, 83.5% of medium-chain triglycerides, 1.5% of hydrophobic fumed silica, and 3.0% of anhydrous yeast extract powder. The sum of the mass percentages of each component is 100%.

[0044] 2. Pump the medium-chain triglyceride into a vacuum reactor equipped with a jacketed temperature control and a two-way stirrer, add isostearic acid, turn on the jacket heating and raise the temperature to 65°C at a rate of 2.0°C / min, and turn on the stirring to completely dissolve the isostearic acid in the continuous phase.

[0045] 3. Evacuate the reactor to -0.08MPa. While maintaining the temperature and vacuum, turn on the high-speed dispersion disc and set the speed to 1500rpm. Slowly draw the co-ground powder into the reactor through the vacuum negative pressure. After the feeding is complete, react at a constant temperature of 65℃ for 45 minutes.

[0046] 4. Maintain stirring and vacuum, and draw the anhydrous yeast extract powder into the vessel and maintain dispersion for 10 minutes.

[0047] 5. Pour chilled water into the jacket of the reactor to rapidly reduce the temperature of the material inside the reactor to 35°C at a cooling gradient of 2.5°C / min.

[0048] 6. When the system reaches 35°C, immediately turn off the high-speed dispersion disk and keep only the low-speed anchor scraper stirring set at 30 rpm; release the vacuum in the reactor, slowly add hydrophobic fumed silica in two batches, re-evacuate the vacuum to -0.08 MPa, and run under low-speed stirring for 30 minutes.

[0049] 7. Stop the machine and release the vacuum. Transfer the material to a temporary storage tank and statically age it at 25°C for 2 hours. Then, package it to obtain the finished product.

[0050] Example 2: This example provides a cat anti-stress oral preparation containing pregabalin and its preparation method, including the following steps: 1. Weigh the raw materials according to the following mass percentages: 8.75% of the co-ground micro powder obtained in Preparation Example 2, 0.5% of isostearic acid, 85.0% of medium-chain triglycerides, 1.75% of hydrophobic fumed silica, and 4.0% of anhydrous yeast extract powder. The sum of the mass percentages of each component is 100%.

[0051] 2. Pump the medium-chain triglyceride into a vacuum reactor equipped with a jacketed temperature control and a two-way stirrer, add isostearic acid, turn on the jacket heating and raise the temperature to 60°C at a rate of 1.5°C / min, and turn on the stirring to completely dissolve the isostearic acid in the continuous phase.

[0052] 3. Evacuate the reactor to -0.05MPa. While maintaining the temperature and vacuum, turn on the high-speed dispersion disc and set the speed to 1000rpm. Slowly draw the co-ground powder into the reactor through the vacuum negative pressure. After the feeding is complete, react at a constant temperature of 60℃ for 30 minutes.

[0053] 4. Maintain stirring and vacuum, and draw the anhydrous yeast extract powder into the vessel and maintain dispersion for 10 minutes.

[0054] 5. Pour chilled water into the jacket of the reactor to rapidly reduce the temperature of the material inside the reactor to 30°C at a cooling gradient of 2.0°C / min.

[0055] 6. When the system reaches 30°C, immediately turn off the high-speed dispersion disk and keep only the low-speed anchor scraper stirring set at 20 rpm; release the vacuum in the reactor, slowly add hydrophobic fumed silica in two batches, re-evacuate the vacuum to -0.05 MPa, and run under low-speed stirring for 20 minutes.

[0056] 7. Stop the machine and release the vacuum. Transfer the material to a temporary storage tank and statically age it at 20°C for 1 hour. Then, package it to obtain the finished product.

[0057] Example 3: This example provides a cat anti-stress oral preparation containing pregabalin and its preparation method, including the following steps: 1. Weigh the raw materials according to the following mass percentages: 15.0% of the co-ground micro powder obtained in Preparation Example 3, 1.5% of isostearic acid, 77.5% of medium-chain triglycerides, 2.0% of hydrophobic fumed silica, and 4.0% of anhydrous yeast extract powder. The sum of the mass percentages of each component is 100%.

[0058] 2. Pump the medium-chain triglyceride into a vacuum reactor equipped with a jacketed temperature control and a two-way stirrer, add isostearic acid, turn on the jacket heating and raise the temperature to 70°C at a rate of 2.5°C / min, and turn on the stirring to completely dissolve the isostearic acid in the continuous phase.

[0059] 3. Evacuate the reactor to -0.09MPa. While maintaining the temperature and vacuum, turn on the high-speed dispersion disc and set the speed to 2000rpm. Slowly draw the co-ground powder into the reactor through vacuum negative pressure. After the feeding is complete, react at a constant temperature of 70℃ for 60 minutes.

[0060] 4. Maintain stirring and vacuum, and draw the anhydrous yeast extract powder into the vessel and maintain dispersion for 15 minutes.

[0061] 5. Pour chilled water into the jacket of the reactor to rapidly reduce the temperature of the material inside the reactor to 40℃ at a cooling gradient of 3.0℃ / min.

[0062] 6. When the system reaches 40°C, immediately turn off the high-speed dispersion disk and keep only the low-speed anchor wall scraper stirring set at 50 rpm; release the vacuum in the reactor, slowly add hydrophobic fumed silica in three portions, re-evacuate the vacuum to -0.09 MPa, and run under low-speed stirring for 40 minutes.

[0063] 7. Stop the machine and release the vacuum. Transfer the material to a temporary storage tank and statically age it at 25°C for 3 hours. Then, package it to obtain the finished product.

[0064] Example 4: This example provides a pregabalin-containing oral anti-stress preparation for cats and its preparation method, including the following steps: 1. Weigh the raw materials according to the mass percentage: 11.0% of the co-ground micro powder obtained in Preparation Example 1, 1.0% of isostearic acid, 83.5% of medium-chain triglycerides, 1.5% of hydrophobic fumed silica, and 3.0% of anhydrous yeast extract powder. The sum of the mass percentages of each component is 100%.

[0065] 2. Pump the medium-chain triglyceride into a vacuum reactor equipped with a jacketed temperature control and a two-way stirrer, add isostearic acid, turn on the jacket heating and raise the temperature to 65°C at a rate of 2.0°C / min, and turn on the stirring to completely dissolve the isostearic acid in the continuous phase.

[0066] 3. Evacuate the reactor to -0.08MPa. While maintaining the temperature and vacuum, turn on the high-speed dispersion disc and set the speed to 1500rpm. Slowly draw the co-ground powder into the reactor through the vacuum negative pressure. After the feeding is complete, react at a constant temperature of 65℃ for 45 minutes.

[0067] 4. Maintain stirring and vacuum, and draw the anhydrous yeast extract powder into the vessel and maintain dispersion for 10 minutes.

[0068] 5. Pour chilled water into the jacket of the reactor to rapidly reduce the temperature of the material inside the reactor to 35°C at a cooling gradient of 2.5°C / min.

[0069] 6. When the system reaches 35°C, immediately turn off the high-speed dispersion disk and keep only the low-speed anchor scraper stirring set at 50 rpm; release the vacuum in the reactor, slowly add hydrophobic fumed silica in two batches, re-evacuate the vacuum to -0.08 MPa, and run under low-speed stirring for 40 minutes.

[0070] 7. Stop the machine and release the vacuum. Transfer the material to a temporary storage tank and statically age it at 25°C for 3 hours. Then, package it to obtain the finished product.

[0071] Comparative Example 1: Compared with Example 1, the difference is that isostearic acid is not added, and the mass percentage of medium-chain triglycerides is increased to 84.5% accordingly, while the rest are the same.

[0072] Comparative Example 2: Compared with Example 1, the difference is that isostearic acid is replaced by linear stearic acid in equal mass, while the rest are the same.

[0073] Comparative Example 3: Compared with Example 1, the difference is that L-arginine is not added, and the dry mechanical-chemical co-grinding is not performed in the preparation process. Instead, the same mass of pregabalin raw powder is directly pulverized to the same particle size and then fed into the feed. At the same time, the mass percentage of medium-chain triglycerides is increased to 86.5%, and the rest are the same.

[0074] Comparative Example 4: Compared with Example 1, the difference lies in the change of preparation process: instead of dry mechanical-chemical co-grinding as in Example 1, pregabalin and L-arginine are directly pulverized to the same particle size and then physically mixed; and the 65°C heating in-situ reaction step is omitted, and all components are directly homogenized and mixed at 25°C by high-speed dispersion, while the rest are the same.

[0075] Comparative Example 5: Compared with Example 1, the difference is that L-arginine and isostearic acid are not added, the mass percentage of hydrophobic fumed silica is increased to 7.0%, the mass percentage of medium-chain triglycerides is adjusted to 82.0%, and the co-grinding and heating isothermal reaction steps are omitted. All powders are directly added to the oil phase and physically mixed and homogenized at room temperature. All other aspects are the same.

[0076] Test Example 1: Test objective: To verify the specific occurrence of the lattice interface ion pair association effect between pregabalin and L-arginine and the in-situ reaction of isostearic acid in this invention.

[0077] Test steps: 1. Take 2g each of pregabalin powder and L-arginine powder and place them in a vacuum drying oven. Dry at 40°C for 24 hours to remove surface moisture. Take 2g of the co-ground micropowder obtained in Preparation Example 1 and dry it under the same conditions for later use. For the finished product of the formulation in Example 1, take an appropriate amount of sample and place it in a centrifuge tube. Add excess anhydrous n-hexane as the elution solvent, and sonicate for 15 minutes to fully dissolve the medium-chain triglycerides. Then, centrifuge at 8000 rpm for 10 minutes to separate the bottom solid precipitate. After discarding the supernatant, repeat the washing and centrifugation operation three times. Place the final solid phase in a fume hood to evaporate the residual solvent naturally, and then place it in a vacuum drying oven at 40°C in the dark for 24 hours.

[0078] 2. Pre-treatment of the spectrum was carried out using the potassium bromide tableting method. The four groups of solid samples that had been dried were mixed with spectrally pure potassium bromide in an agate mortar at a mass ratio of approximately 1:100 and ground thoroughly until the powder was uniform and free of particles.

[0079] 3. Transfer the ground mixed powder to a standard tableting mold and press it into a uniform and transparent test sheet under a pressure of 10 MPa for 2 minutes.

[0080] 4. Place the prepared sample in the sample testing chamber of the Fourier transform infrared spectrometer, and set the scanning wavelength range to 4000 to 400 cm⁻¹. -1 Spectral resolution of 4 cm -1 The cumulative number of scans was 32. During the test, a blank potassium bromide pellet was used as the background baseline for real-time subtraction. The infrared absorption spectrum data of each sample were recorded, and the wavenumbers of absorption peaks of specific characteristic functional groups were extracted and recorded.

[0081] The test data is shown in Table 1.

[0082] Table 1: Wavenumber Extraction Records of Infrared Spectral Characteristic Absorption Peaks in Examples and Control Groups (Unit: cm⁻¹) -1 )

[0083] Conclusion: Based on Table 1 and Figure 1 According to the data, pregabalin raw powder is 1642.3cm. -1 The characteristic free carboxyl carbonyl stretching vibration peak was observed at 1567.8 cm⁻¹, while in the co-ground micropowder of Preparation Example 1 after mechanochemical treatment, this absorption band was significantly broadened and weakened to a very weak shoulder peak. The significant shift in the core functional group peak position indicates strong intermolecular interactions at the solid-phase interface. This was followed by newly formed characteristic peaks representing the asymmetric and symmetric stretching vibrations of the carboxylate anion, at 1567.8 cm⁻¹. -1 and 1399.5cm -1 The peak is clearly visible, and the strong polar guanidin C=N stretching vibration peak of L-arginine increases from 1678.9 cm⁻¹ in the original powder. -1 A significant redshift to 1664.2 cm -1 The spectral shift data provides physicochemical evidence, indicating that the high-frequency collisional mechanical energy provided by fluidized bed gas pulverization overcomes steric hindrance, prompting the carboxyl group of pregabalin and the guanidinium group of L-arginine to spontaneously construct a robust ion-pair association structure on the newly fractured surface. Spatial charge transfer facilitates the deprotonation of the pregabalin terminus, increasing the activation barrier for intramolecular nucleophilic acyl substitution from the source of reaction kinetics.

[0084] The infrared absorption characteristics of the solid precipitate extracted from the finished formulation in Example 1 showed that, while retaining the spectral framework of the co-ground micropowder, a new coordination structure was formed. The previously red-shifted guanidinyl C=N characteristic peak continued to shift to the lower frequency region, reaching 1659.7 cm⁻¹. -1 This progressive displacement phenomenon suggests that the unencapsulated surface arginine in the extract underwent further heterogeneous salt formation with isostearic acid during the isothermal phase of the liquid phase. The extracted solid phase was at 2924.5 cm⁻¹. -1 The significantly enhanced absorption intensity of the CH stretching vibration of nearby asymmetric aliphatic hydrocarbons provides even stronger evidence, clearly pointing to the successful attachment of multi-branched 18C aliphatic hydrocarbon chains to the surface of inorganic particles. Precipitated phases that have undergone repeated and vigorous elution with nonpolar solvents typically fail to retain free fatty acid components. The detection of such a high-intensity aliphatic hydrocarbon chain signal in the system indicates that isostearate arginine salt is attached in situ to the powder interface via extremely strong secondary bond bridging.

[0085] The microscopic evolution mechanism of this solid-phase spectrum reveals the actual transformation path of this formulation system in engineering practice. The drug microenvironment departs from the traditional physical microcapsule encapsulation path relying on polymer film formation, instead utilizing the interfacial self-assembly behavior of multiple components under different thermodynamic time windows. The pregabalin molecule is stably confined within the ion coordination center during the initial co-grinding stage, while the remaining catalytic basic groups are selectively consumed and passivated by isostearic acid during the thermodynamic incubation stage. This in-situ reaction gradient extending from the inside out eliminates the risk of transesterification damage to the continuous phase triglyceride by the strongly basic excipients. The generated amphiphilic byproducts effectively fill the polar gaps between silica particles, constructing a stable microstructural foundation for the entire suspension network to resist long-term gravitational sedimentation.

[0086] Test Example 2: Test objective: To verify the ability of isostearate arginine salt of the present invention to synergistically construct spatial physical entanglement and mesoscopic cross-linked networks with hydrophobic silica.

[0087] Test steps: 1. Set the temperature of the rotational rheometer test platform to 25°C and select a metal conical rotor with a diameter of 40 mm and a cone angle of 2°. Carefully transfer appropriate amounts of the finished formulations prepared in Example 1, Comparative Example 1, and Comparative Example 2 onto the test platform using a wide-mouth pipette. Slowly press down the rotor to adjust the measurement gap to the set 50 μm, and scrape off any excess sample squeezed out from the edges with a silicone scraper. After covering with a solvent evaporation trap, place the sample on the constant temperature stage to allow it to stand and equilibrate, thus eliminating the shear history caused by the sampling and coating processes.

[0088] 2. Perform steady-state shear scan tests to obtain thixotropic hysteresis loop data. Control the rotor speed via software to maintain a shear rate of 0.1 s. -1 up to 100s -1 The shear rate increases logarithmically within the range, completing the upward scan phase; then, a downward scan immediately follows, decreasing logarithmically within the same rate range. The instrument records and outputs the apparent viscosity and shear stress corresponding to each set shear rate point, and runs a built-in script to calculate the hysteresis loop integral area of ​​the envelope between the upward and downward stress curves.

[0089] 3. Perform dynamic oscillation scanning tests. The oscillation frequency is fixed at 1 Hz, and the applied shear stress is gradually increased logarithmically from 0.1 Pa to 500 Pa during amplitude scanning. During this process, the dynamic curves of storage modulus (G') and loss modulus (G'') as a function of stress are acquired in real time. The average plateau modulus value within the low-stress linear viscoelastic region is extracted, and the critical stress value corresponding to the intersection of the G' and G'' curves is recorded as the dynamic yield stress of the system.

[0090] The test data is shown in Table 2.

[0091] Table 2: Results of rheological key parameters measured in the examples and control groups

[0092] Conclusion: Based on Table 2 and Figure 2 According to the data, Example 1 exhibits significant solid elastic behavior characteristics in the linear viscoelastic region of the low-stress area, with a storage modulus G' reaching 324.63 Pa, far exceeding the loss modulus G'', which represents viscous dissipation, at 86.27 Pa. In previous conventional oil-containing suspension formulation development practices, relying solely on such a low addition of 1.5% hydrophobic fumed silica typically only forms an extremely fragile siloxane weak hydrogen bond network in the continuous phase. This engineering experience is fully confirmed in the data of Comparative Example 1. Due to the lack of isostearic acid as a polar core, the G' and G'' values ​​of Comparative Example 1 are both extremely low and inverted, indicating that the system is essentially in a viscous fluid state, making it physically difficult to resist the long-term gravitational sedimentation of internal particles. When linear stearic acid was used to replace the isostearic acid of this invention, the modulus data of Comparative Example 2 showed a certain degree of recovery, but the network strength remained at a low level. Experimental data suggest that the in-situ generated polar amino acid salts can indeed form interfacial hydrogen bond bridges with the free silanol groups on the silica surface. However, in Comparative Example 2, due to the thermodynamic compatibility differences between straight-chain alkanes and nonpolar medium-chain triglycerides, the molecular chains tend to fold tightly and self-aggregate, losing their ability to extend in space. In stark contrast, the isostearic acid used in Example 1 has numerous and irregular methyl branches. This significant steric hindrance causes the octadecane alkane chain to maintain a highly extended conformation in the oil phase, thereby forming a high-intensity spatial physical entanglement with the surrounding free silica inorganic particles. This transforms the entire rheological system from a simple weakly flocculated particle state into a stable three-dimensional synergistic cross-linked network.

[0093] This significant change in the mesoscopic network topology is directly reflected in the macroscopic yield strength and thixotropic recovery capabilities. Rheological tests show that Example 1 exhibits a dynamic yield stress as high as 68.52 Pa, indicating that the network structure can withstand considerable internal gravitational shear without irreversible deformation when placed in the packaging bottle, sufficient to keep micron-sized, high-density pregabalin co-ground powder suspended and stable in the oil phase for a long time. As the external shear rate increases and enters the high-strain failure range, physical entanglements and polar hydrogen bonds are rapidly broken, and the system exhibits typical non-Newtonian fluid shear-thinning behavior. The thixotropic hysteresis loop area in the rheological parameters is 1456.18 Pa / s. Combined with macroscopic smearing experiments, it can be confirmed that the large area of ​​hysteresis loops corresponds to a relatively long time required for the mesoscopic network to complete structural reconstruction after the removal of external forces. This time-dependent viscosity hysteresis recovery property not only endows the formulation with excellent spreadability upon oral administration, but also effectively avoids rapid exposure of the drug on the tongue, thereby achieving a masking effect against the strong bitterness of pregabalin.

[0094] Test Example 3: Test objective: To evaluate the degradation degree of the active pharmaceutical ingredient and the matrix's resistance to rancidity under accelerated aging conditions, and to verify the actual effect of multidimensional physicochemical regulation mechanism on improving the dual chemical stability of the system.

[0095] Test steps: 1. The finished formulations of Examples 1 to 4 and Comparative Examples 1, 3, and 4 were filled into vials and sealed. The samples were then placed in a constant temperature and humidity chamber at a set temperature of 40℃±2℃ and a relative humidity of 75%±5% for accelerated aging tests. Samples from the corresponding batches were taken out at 0 months (initial), 3 months, and 6 months for subsequent analysis and determination.

[0096] 2. Accurately weigh appropriate amounts of samples from each time point and place them in volumetric flasks. Add a mobile phase consisting of methanol-water-phosphate buffer and perform ultrasonic extraction. Centrifuge at 8000 rpm and filter the supernatant through a 0.45 μm microporous membrane. Analyze the samples using a high-performance liquid chromatograph (HPLC) equipped with a UV detector at a wavelength of 210 nm. Record and calculate the peak area of ​​the impurity pregabalinolactam, and calculate its mass percentage in the total drug using the external standard method. This percentage will be used as performance indicator A.

[0097] 3. Following the general rules for determining the acid value of fats and oils as specified in the pharmacopoeia, accurately weigh approximately 5g of the samples retained at each of the above time points into an Erlenmeyer flask, and dissolve them completely in a neutral ethanol-ether mixture. Using phenolphthalein as an indicator, perform manual titration with a standardized 0.1mol / L potassium hydroxide titrant until the solution turns a faint red color that does not fade within 30 seconds. Record the volume of titrant consumed and calculate the change in acid value of the continuous phase triglycerides (unit: mg KOH / g), which will be used as assessment indicator B.

[0098] The test data is shown in Table 3.

[0099] Table 3: Results of pregabalin lactam formation rate and oil phase acid value determination under accelerated conditions in the examples and control groups.

[0100] Conclusion: Based on Table 3 and Figure 3 The data showed that the formulation exhibited significant degradation differences under high temperature and humidity conditions of 40°C. When examining the chemical stability of the active pharmaceutical ingredient pregabalin, the results indicated that, throughout the accelerated reaction period of up to 6 months in Examples 1 to 4, the formation rate of lactam impurities was consistently suppressed to a very low baseline of 0.2%, far below the impurity limits stipulated in the pharmacopoeia. In the past, in the development of conventional powder suspensions, due to the extremely close physical distance between the amino and carboxyl groups within the pregabalin molecule, nucleophilic acyl substitution easily occurs upon heating to overcome steric hindrance. Once this spontaneous ring-closing reaction is initiated, its degradation rate accelerates significantly. In Comparative Example 3, due to the lack of L-arginine, the lactam formation rate significantly increased to 4.87% in the 6th month, failing to meet the pharmaceutical stability limits. Even with the addition of the same proportion of arginine in the formulation, if only simple physical mixing at room temperature is used as in Comparative Example 4, the impurity formation rate is still as high as 3.52%. The above data differences indicate that simple dispersion at room temperature is insufficient to promote effective interaction between the two powder surfaces. It is necessary to use high-frequency collisions and mechanical-chemical work to forcibly peel off the lattice surface and promote ion pair association in order to effectively inhibit the ring-closure degradation activity of pregabalin at the molecular level.

[0101] Improving the degradation of the active pharmaceutical ingredient alone is insufficient to guarantee the overall stability of the system. The resistance of the continuous phase carrier to rancidity during long-term storage constitutes another key factor determining the long-term stability of the formulation. The results of the matrix acid value assessment showed that Comparative Example 1, without added isostearic acid, exhibited an acid value exceeding 1.0 mg KOH / g in the third month, and by the sixth month, it had reached a severe rancidity level of 3.42 mg KOH / g. Early formulation screening experiments indicated that directly introducing arginine microparticles with a strongly basic guanidine group into medium-chain triglycerides resulted in a high concentration of OH at the interface. -This inevitably catalyzes the hydrolysis of ester bonds and may even trigger complex transesterification reactions. Data from Examples 1 to 4 demonstrate that by introducing isostearic acid beforehand within a specific thermodynamic window, the free, strongly basic catalytic sites at the powder interface can be precisely consumed. Notably, Comparative Example 4, which employed physical mixing to eliminate the need for in-situ heating, not only failed to guarantee the chemical stability of the active pharmaceutical ingredient, but its oil phase acid value also significantly increased to 2.58 mg KOH / g. The reason for this difference in data is that the system viscosity is too high and the molecular thermal motion is slow at room temperature, preventing free isostearic acid from penetrating to the surface of inorganic particles to complete acid-base neutralization within a limited time. The remaining catalytic sites then slowly catalyze the degradation of the surrounding oil matrix during subsequent months of storage.

[0102] Combining the comparative data from the two dimensions mentioned above confirms that the technical solution of this invention is not a simple stacking of excipient components, but rather a physicochemical regulation process based on a strict spatiotemporal sequence. From the hydrogen bond donor embedding in the co-grinding stage to the in-situ passivation of the interface in the liquid-phase heat treatment stage, each process step precisely addresses specific degradation technology defects. Examples 1 to 4 exhibited high batch consistency and excellent anti-aging properties in both stringent indicators. This dual stability not only means that the product can maintain its efficacy during the actual shelf life, but also avoids the potential digestive tract irritation to sick pets caused by rancidity. This result further confirms that deeply integrating the chemical reactions at the microscopic interface with the macroscopic rheological preparation process can substantially solve the storage and transportation problems of complex multiphase suspension formulations under harsh environments without increasing the cost of complex physical microcapsule coating.

[0103] Test Example 4: Test objective: To verify the physical anti-settling ability and structural robustness of the organic-inorganic synergistic cross-linked network of the formulation under extreme centrifugal gravity field.

[0104] Test steps: 1. Select glass graduated centrifuge tubes with uniform inner diameter, and load them with the formulation samples of Examples 1 to 4 and Comparative Examples 1, 2 and 3 respectively. The loading volume should be controlled to about two-thirds of the total volume of the tube. Record the total height data of the initial sample column.

[0105] 2. Place the centrifuge tubes filled with samples symmetrically in the rotor of a high-speed benchtop centrifuge, set the working temperature of the centrifuge chamber to a constant 25°C, adjust the centrifuge speed to 5000 rpm, and run continuously for 30 minutes to apply physical stress far exceeding that of normal gravity.

[0106] 3. After centrifugation, remove the centrifuge tubes smoothly and use a vernier caliper with an accuracy of 0.02 mm to measure the height of the transparent clear oil layer precipitated at the top of the centrifuge tube and the height of the compacted solid powder precipitate layer at the bottom of the tube. Divide the measured height data by the initial total height of the sample column to calculate the oil phase precipitation rate and the volume ratio of the bottom sediment for each group of samples.

[0107] The test data is shown in Table 4.

[0108] Table 4: Results of determination of key physical stability indicators after high-speed centrifugation in the examples and control groups

[0109] Conclusion: Based on Table 4 and Figure 4 The data from Examples 1 to 4 show that under extreme centrifugal force of 5000 rpm, high macroscopic homogeneity was maintained, with oil phase precipitation controlled below 1.5% and the highest volume percentage of bottom sediment only 1.81%. In the development of existing oil-based suspensions, the problem of irreversible sedimentation and agglomeration of microparticles due to density differences during long-term storage is often encountered. Simply increasing the thickener concentration is often insufficient to resist the shear stress caused by a continuous gravitational field. The extremely low phase separation levels exhibited by these four examples indirectly confirm the existence of a stable three-dimensional support framework within the system. This framework network possesses sufficient yield stress to stably suspend the high-density co-ground powder, preventing the separation of the solid and liquid phases.

[0110] The decreased physical stability of each comparative example further validated this crosslinking mechanism. Comparative Example 1 removed isostearic acid, which is required for the in-situ reaction, and Comparative Example 3 directly removed arginine, which provides polar salt-forming centers. The absence of these two groups led to severe oil-water separation of more than 14% after centrifugation, with the bottom compacted into dense precipitates that were difficult to redisperse. The lack of polar or non-polar bridging ends in the formulation prevents the in-situ generation of surfactants. In this case, the trace amounts of hydrophobic silica in the system can only spontaneously form a weak siloxane network relying on residual silanol groups on the surface. This fragile intermolecular force is unable to withstand the high-intensity shear damage brought about by the centrifugal field.

[0111] The deeper network failure mechanism manifests in the microscopic changes in the spatial conformation of fatty acid carbon chains. Comparative Example 2, which replaced isostearic acid with linear stearic acid in equal amounts, showed an oil phase precipitation rate of 8.36%, indicating a significant stability degradation compared to the examples. In a nonpolar medium-chain triglyceride matrix, linear fatty acids tend to undergo intramolecular coiling or parallel aggregation due to differences in interfacial tension, making it difficult to maintain a spatially extended conformation. The irregular methyl branches in the isostearic acid molecule effectively increase the steric hindrance of the 18-carbon backbone. This large branched structure undergoes high-density physical interpenetration with adjacent inorganic silicon particles in the dispersion medium. The rigid constraints at the topological level promote deep synergy between organic and inorganic components, significantly broadening the rheological limit of the entire suspension system.

[0112] Test Example 5: Test objective: To verify the ability of this invention to inhibit the instantaneous burst of bitter drugs with extremely low inorganic silicon powder addition, and the actual acceptability of the formulation in clinical administration to pets.

[0113] Test steps: 1. Prepare artificial saliva with a pH of 6.8 and place it in a petri dish. Maintain the ambient temperature at 37°C using a constant-temperature water bath to recreate the microphysiological environment of the floor of the oral cavity. Take approximately 0.5g of each of the finished formulations from Example 1 and Comparative Example 5, and gently squeeze them into the surface of the artificial saliva using a needleless syringe. Do not turn on any stirring or shaking devices throughout the test period to simulate the static adhesion and retention state in the real oral cavity. Using a micropipette, accurately extract 100μL of local liquid at 2, 4, 6, 8, and 10 seconds after contact with the liquid surface. Immediately add pre-cooled methanol to stop the dissolution process. Subsequently, determine the release amount of pregabalin by high-performance liquid chromatography and calculate the rapid dissolution rate at different time points.

[0114] 2. Twenty-four healthy adult cats requiring neuropathic pain intervention were randomly selected from a designated veterinary hospital as subjects for in vivo clinical testing and divided into two equal groups. A crossover observational design was used, with equal doses of Example 1 and Comparative Example 5 applied to the back of the cats' forepaws or directly squeezed into the oral cavity behind the molars.

[0115] 3. Two licensed veterinarians conducted blinded, independent observations within 5 minutes of drug administration. A 5-point scale was used to subjectively score the experimental cats' willingness to lick the medication, with 1 point representing extreme resistance or even escape, and 5 points representing voluntarily licking the medication completely. The number of cats in each group exhibiting excessive salivation was recorded and converted into an incidence rate. The average total number of instances of violent head shaking, dry heaving, or actual vomiting during drug administration was precisely calculated.

[0116] The test data is shown in Table 5.

[0117] Table 5: In vitro rapid dissolution rate and in vivo clinical palatability assessment results of the examples and comparative examples

[0118] Conclusion: Based on Table 5 and Figure 5 Data shows that compounds like pregabalin, with their amino acid backbones, release a strong bitter taste upon dissolution. This physicochemical property constitutes a significant compliance barrier in veterinary clinical practice, especially in sensitive felines. In vitro simulated oral static dissolution data revealed drastically different interfacial anti-hydration states. Comparative Example 5 achieved a rapid dissolution rate of 19.46% within an extremely short window of the first 10 seconds, indicating that the drug, exceeding the physiological threshold for masking taste, underwent explosive release upon contact with water. Comparative Example 5 followed the traditional development practices for suspension formulations, typically increasing the macroscopic viscosity of the oil phase medium by adding up to 7.0% hydrophobic silica to physically encapsulate the drug. However, the pure inorganic silica network is highly susceptible to instantaneous microstructural collapse under capillary wetting at the aqueous interface. In Example 1, the rapid dissolution rate was controlled at 2.31%. The in-situ generated isostearate arginine salt formed a highly extended physical entanglement network between silica particles. This gel skeleton with obvious thixotropic recovery characteristics maintained a tough hydrophobic shell when it encountered surface moisture, effectively blocking the rapid penetration of water molecules into the internal polar drug core from the mesoscopic dynamics level.

[0119] The differences between in vitro rheology and interfacial permeation kinetics naturally translate into real-world animal clinical drug administration scenarios. When the formulation was actually applied to experimental cats that were extremely sensitive to oral foreign body sensation and extreme bitterness, the trends of various stress biochemical indicators in vivo accurately confirmed the preliminary predictions of the in vitro dissolution data. In Comparative Example 5, the inorganic silica powder concentration of up to 7.0% could only maintain a basic physical suspension, inevitably leading to rough physical friction stimulation of the formulation on the oral mucosa. This tactile discomfort, combined with the explosive chemical bitterness, created a negative synergistic effect, directly causing 83.3% of the tested cats to exhibit uncontrollable excessive salivation. The average number of head-shaking and gagging episodes was as high as 5.1 per cat, and their low licking willingness score of 1.62 indicates that traditional high-concentration inorganic silica powder formulations have significant compliance defects in in vivo clinical applications.

[0120] Achieving efficient physical encapsulation and isolation without increasing the foreign body sensation in the oral mucosa constitutes the core challenge of formulation optimization. Example 1, relying on an extremely low 1.5% fumed silica powder content combined with in-situ crosslinking, provides a feasible process approach. The focus of constructing the spatial network structure shifts to the mesoscopic entanglement of long-chain fatty acids and microparticles. The formulation exhibits a fine and uniform semi-solid dosage form in macroscopic rheology, eliminating the astringent and frictional sensation caused by high silica powder content at its source. After ingesting the formulation, the test animals maintained a generally stable physiological state. Occasional slight salivation was controlled to an extremely low proportion. A high licking willingness score of 4.45 indicates that most test animals showed high compliance similar to that of ingesting conventional nutritional pastes, significantly reducing drug rejection reactions. The engineering design of multiphase suspension systems should not stop at solving the physical stratification problem within the packaging bottle. Utilizing solid-liquid interface chemical regulation to reduce the absolute amount of inorganic excipients is an effective technical approach to improve the acceptability of such formulations in animal clinical administration.

[0121] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A cat-specific anti-stress oral formulation containing pregabalin, characterized in that, Made from raw materials comprising the following percentages by weight: Pregabalin-L-arginine co-ground micronized powder: 8.75%~15.0%; Isostearic acid: 0.5%–1.5%; Medium-chain triglycerides: 77.5%–85.0%; Hydrophobic fumed silica: 1.5%–2.0%; Anhydrous yeast extract powder: 3.0%–4.0%.

2. The pregabalin-containing oral anti-stress preparation for cats according to claim 1, characterized in that, The oral formulation is made from the following raw materials in the indicated weight percentages: Pregabalin-L-arginine co-ground micronized powder: 11.0%; Isostearic acid: 1.0%; Medium-chain triglycerides: 83.5%; Hydrophobic fumed silica: 1.5%; Anhydrous yeast extract powder: 3.0%.

3. The pregabalin-containing oral anti-stress preparation for cats according to claim 1, characterized in that, In the pregabalin-L-arginine co-ground micro powder, the mass ratio of pregabalin to L-arginine is 2:1 to 8:

3.

4. The pregabalin-containing oral anti-stress preparation for cats according to claim 1, characterized in that, The pregabalin-L-arginine co-ground micro powder is prepared by a method including the following steps: pregabalin and L-arginine are mixed evenly and then fed into a fluidized bed air jet mill. Dehumidified and cooled compressed air is introduced, the working temperature in the grinding chamber is controlled to be constant at 10-15℃, and the grinding gas pressure is set to 0.6-0.8MPa for high-energy grinding until the particle size distribution of the collected co-ground micro powder meets the requirement that D90 is less than 15μm.

5. The pregabalin-containing oral anti-stress preparation for cats according to claim 1, characterized in that, The characteristic parameters of the raw material satisfy the following conditions: The isostearic acid is a mixture of saturated octadecano fatty acids with multiple methyl branched structures. It is liquid at room temperature, with an acid value ranging from 180 to 195 mg KOH / g and an iodine value ≤ 3.0 g I2 / 100g. The hydrophobic fumed silica is fumed silica surface-modified with dimethyldichlorosilane, with a specific surface area ranging from 130 to 170 m². 2 / g, with unsubstituted free silanol groups remaining on the surface.

6. A method for preparing a cat-containing anti-stress oral formulation according to any one of claims 1-5, characterized in that, Includes the following steps: S1. Weigh each raw material according to its mass percentage; S2. Pump medium-chain triglycerides into a vacuum reactor, add isostearic acid, and turn on heating and stirring to completely dissolve isostearic acid in the continuous phase. S3. Evacuate the reactor and, while maintaining the temperature and vacuum, turn on the high-speed dispersion disk to slowly draw the pregabalin-L-arginine co-ground powder into the reactor for constant temperature reaction through vacuum negative pressure. S4. Maintain stirring and vacuum to draw the anhydrous yeast extract powder into the vessel and maintain dispersion. S5. Cool the reactor jacket by introducing chilled water. S6. Turn off the high-speed dispersion disk, keep the low-speed stirring, release the vacuum in the reactor, add hydrophobic fumed silica in batches, re-evacuate the vacuum and run under low-speed stirring; S7. Stop the machine and release the vacuum. Transfer the material to a temporary storage tank for static aging. Then, package the finished product.

7. The method for preparing the pregabalin-containing oral anti-stress preparation for cats according to claim 6, characterized in that, In step S2, the jacket heating is turned on and the temperature is increased to 60-70°C at a rate of 1.5-2.5°C / min.

8. The method for preparing the pregabalin-containing oral anti-stress preparation for cats according to claim 6, characterized in that, In step S3, the reactor is evacuated to -0.05 to -0.09 MPa, the high-speed dispersion disk is set to a speed of 1000 to 2000 rpm, and after the feeding is completed, the reaction is carried out at a constant temperature of 60 to 70°C for 30 to 60 minutes.

9. The method for preparing the pregabalin-containing oral anti-stress preparation for cats according to claim 6, characterized in that, In step S5, the temperature of the material inside the reactor is rapidly reduced to 30-40℃ using a cooling gradient of 2.0-3.0℃ / min.

10. The method for preparing the pregabalin-containing oral anti-stress preparation for cats according to claim 6, characterized in that, The specific implementation method of step S6 is as follows: the speed of the low-speed anchor-type scraper is set to 20-50 rpm, hydrophobic fumed silica is added, and then the vacuum is re-evacuated to -0.05 to -0.09 MPa, and run for 20-40 minutes. In step S7, static aging is carried out at 20–25°C for 1–3 hours.

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