Florfenicol chewable dispersible tablet for pets and preparation method thereof

Abstract

The application relates to the technical field of solid preparations of veterinary drugs, in particular to pet fluorophenical chewable dispersible tablets and a preparation method thereof, which comprises the following steps: a microcapsule, the microcapsule comprises a fluorophenical mother core and a taste masking layer coated on the surface of the fluorophenical mother core; a buffer phase, the buffer phase comprises mesoporous magnesium metasilicate, and a eutectic mixture of poloxamer and polyethylene glycol and a polycarboxylic organic acid impregnated in the mesoporous magnesium metasilicate; and a continuous matrix, the continuous matrix comprises beta-D-mannitol crystals and sodium fumarate stearyl ester; wherein the carboxyl group of the polycarboxylic organic acid and the tertiary amino group of the tertiary amino-containing polymethacrylate copolymer form an ionic bond; the pet fluorophenical chewable dispersible tablets are obtained by mixing the microcapsule and the buffer phase and have an intermediate material with a supramolecular crosslinking network, and the intermediate material and the continuous matrix are tablet-molded under a pressure of 6.0-7.0 MPa. The application can solve the problem of brittle fracture and taste leakage caused by the lack of interface dissipation, realize taste masking and dry state dispersion decoupling.

Description

Technical Field

[0001] This application relates to the technical field of veterinary drug solid dosage forms, and in particular to a florfenicol chewable dispersible tablet for pets and its preparation method. Background Technology

[0002] Veterinary oral solid antibiotic formulations face harsh physical and chemical environments in actual service conditions. High concentrations of strongly bitter active drugs are encapsulated in a solid matrix. Upon entering the animal's mouth, the material system directly endures high-frequency alternating compressive stress and high shear friction generated by chewing, while only trace amounts of near-neutral saliva are present in the surrounding environment. This specific condition requires the drug's solid matrix and interface to possess extremely high mechanical toughness and compressive yield strength to resist mechanical fragmentation. Simultaneously, the system must rapidly undergo cleavage and dispersion in a physical environment with extremely low free water content, and complete dissolution and drug release upon entering the highly acidic gastric fluid.

[0003] Chinese invention patent CN102526007B discloses a florfenicol taste-masking formulation and its preparation method. This technical solution uses 5-75% florfenicol, 5-40% gastric-soluble polymeric material, 20-90% filler, and small amounts of hydrophilic binder and insoluble materials by weight percentage. The core process involves dissolving the gastric-soluble polymeric material in a 50-95% (v / v) ethanol-water solution to prepare a binder solution. Florfenicol is then dry-mixed or suspended in the binder with the filler to prepare a soft mass. This mass is then granulated using a swing granulator or screw extrusion, and finally dried at 40-65 degrees Celsius to obtain microspheres or wet granules. This technology relies on the physicochemical properties of gastric-soluble polymeric materials—insoluble in near-neutral solutions but soluble in acidic gastric juice—to achieve physical encapsulation of the drug.

[0004] When such physically blended products, constructed through physical dry mixing, are placed in a real high-frequency chewing stress field, their microscopic phase boundaries, constrained by intermolecular physical adsorption forces, inevitably undergo irreversible physical fracture. The gastric-soluble polymer in the system is in a rigid glassy state, and the isotropic, dense phase interface formed between the polymer matrix and excipient particles completely lacks dissipative units capable of conformational slip to absorb energy. When the system is subjected to instantaneous high-pressure strain and shear force, external mechanical kinetic energy is directly conducted along the rigid phase boundary to the outer polymer coating film, causing high stress concentration at the phase interface. Microcracks at the interface rapidly propagate under stress and produce brittle fracture cleavage, leading to the mechanical tearing of the polymer physical barrier. The internally embedded florfenicol is exposed and comes into contact with the neutral aqueous medium, directly triggering a bitter taste explosion. The thermodynamic requirements of the microscopic polymer interface to resist mechanical damage and the kinetic requirements of the drug's macroscopic dispersion in an anhydrous environment inherently contradict each other, making it impossible for the dense phase structure formed solely through physical dry mixing to simultaneously achieve both resistance to brittle fracture and masking of taste, and rapid dispersion in a dry state. Summary of the Invention

[0005] To address the issue of brittle chewing and taste leakage due to lack of interfacial dissipation, and to achieve decoupling of taste masking and dry dispersion, this application provides a florfenicol chewable dispersible tablet for pets and its preparation method.

[0006] In a first aspect, this application provides a florfenicol chewable dispersible tablet for pets, which adopts the following technical solution: A florfenicol chewable dispersible tablet for pets, comprising: Microcapsules, the microcapsules comprising a florfenicol core and a flavor-masking layer covering the surface of the florfenicol core, the flavor-masking layer comprising a tertiary amino polymethacrylate copolymer and a plasticizer; The buffer phase comprises mesoporous aluminum magnesium metasilicate, and a low eutectic mixture of poloxamer and polyethylene glycol and a polycarboxylic organic acid impregnated in the mesoporous aluminum magnesium metasilicate. A continuous matrix comprising β-type D-mannitol crystals and sodium stearate fumarate; In this process, the carboxyl groups of the polycarboxylic organic acid form ionic bonds with the tertiary amino groups of the polymethyl methacrylate copolymer containing tertiary amino groups, thereby constructing a supramolecular crosslinking network that bridges the flavor masking layer and the buffer phase. The florfenicol chewable dispersible tablets for pets are obtained by mixing the microcapsules with the buffer phase and are made from an intermediate material containing the supramolecular crosslinking network. The intermediate material is then compressed with the continuous matrix under a pressure of 6.0~7.0 MPa.

[0007] Optionally, the tertiary amino-containing polymethacrylate copolymer is poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate); The plasticizer is dibutyl sebacate; The dynamic glass transition temperature of the masking layer is 23~27℃.

[0008] Optionally, the poloxamer is a polyoxyethylene-polyoxypropylene block copolymer; The eutectic compound is composed of the polyoxyethylene-polyoxypropylene block copolymer and the polyethylene glycol in a mass ratio of 3:1 to 5:1, and the melting point of the eutectic compound is 36~42°C.

[0009] Optionally, adjacent carboxyl groups of the polycarboxylic organic acid are separated by 2 to 3 carbon atoms; The supramolecular crosslinked network, when characterized by Fourier transform infrared spectroscopy, showed a wavelength range of 1550–1650 cm⁻¹. -1 The interval contains COO - The characteristic absorption peak.

[0010] Secondly, this application provides a method for preparing florfenicol chewable dispersible tablets for pets, which adopts the following technical solution: A method for preparing florfenicol chewable dispersible tablets for pets includes the following steps: Step S1: Dissolve the tertiary amino-containing polymethacrylate copolymer with the plasticizer to obtain an encapsulation solution, and spray-coat the florfenicol core at 36~40°C to obtain the microcapsules; Step S2: The poloxamer, polyethylene glycol and polycarboxylic organic acid are co-melted at 55~65°C to form a viscous flow mixture. The viscous flow mixture is sprayed into the mesoporous aluminum magnesium metasilicate for impregnation and then cooled to obtain the buffer phase. Step S3: The microcapsules are mixed with the buffer phase to obtain a mixture and heated to 37~39°C. An aerosol of polar dielectric alcohol solvent is sprayed in, causing the carboxyl groups of the polycarboxylic acid to undergo proton transfer with the tertiary amino groups of the polymethyl methacrylate copolymer containing tertiary amino groups to form ionic bonds. Subsequently, a vacuum operation is performed at 37~39°C and -0.10~-0.08 MPa vacuum gauge pressure to remove the polar dielectric alcohol solvent, thus obtaining the intermediate material. Step S4: Mix the intermediate material with the continuous matrix and compress it into a sheet under a pressure of 6.0~7.0 MPa.

[0011] Optionally, in step S1, the mass fraction of the encapsulating liquid is 5-7%; The spray coating is carried out in a bottom spray fluidized bed, and the 36~40℃ is the dynamic equilibrium temperature of the bed layer of the bottom spray fluidized bed; The average particle size of the microcapsules is 40~60μm.

[0012] Optionally, in step S2, the impregnation is carried out at a stirring speed of 180~220 rpm.

[0013] Optionally, in step S3, the polar dielectric alcohol solvent is a fatty alcohol containing 1 to 3 carbon atoms, and the amount of the polar dielectric alcohol solvent aerosol injected is 1.0 to 2.0% of the total mass of the mixture.

[0014] Optionally, in step S3, the time interval between the aerosol of the polar dielectric alcohol solvent being sprayed and the vacuuming operation being started is 10 to 20 minutes.

[0015] Optionally, in step S4, the stirring speed when mixing the intermediate material with the continuous matrix is ​​less than 12 rpm, and the tableting process includes a pre-compression stage and a main compression stage. The pressure of the pre-compression stage is 1.3~1.7 MPa, and the pressure of the main compression stage is 6.0~7.0 MPa, which is between the critical pressure calculated by normalizing the grain boundary interlocking activation energy of the β-type D-mannitol crystal per unit volume and the compressive yield strength of the mesoporous aluminum magnesium metasilicate.

[0016] In summary, this application includes the following beneficial technical effects: 1. By forming ionic bonds between the tertiary amino-containing polymethyl methacrylate copolymer in the flavor-masking layer and the polycarboxylic organic acid in the buffer phase to construct a supramolecular cross-linked network, and limiting the tableting pressure to 6.0 to 7.0 MPa, the chewing stress is transmitted to the buffer phase along the cross-linked network. The mechanical energy is dissipated by the viscoelastic deformation of the poloxamer impregnated in the mesoporous aluminum magnesium metasilicate and the low eutectic of polyethylene glycol, thus avoiding the brittle fracture of the flavor-masking layer. At the same time, when the cross-linked network encounters saliva, it rapidly dissociates with the assistance of the softening of the low eutectic to release microcapsules, thus achieving the decoupling of maintaining the integrity of the flavor-masking layer and improving its dry dispersibility.

[0017] 2. The dynamic glass transition temperature of the flavor-masking layer is limited to 23 to 27°C, which is lower than the operating temperature of 37 to 39°C when preparing intermediate materials. Driven by this temperature difference, the chain segment mobility of the tertiary amino polymethyl methacrylate copolymer increases, so as to promote the uniform distribution of ionic bonds at the interface between the flavor-masking layer and the buffer phase. Combined with the melting point range of 36 to 42°C of the eutectic, the eutectic softens locally at 37 to 39°C, thereby increasing the diffusion rate of polycarboxylic organic acids to the surface of the flavor-masking layer. This reduces the local stress concentration during the formation of ionic bonds and improves the integrity of the crosslinked network.

[0018] 3. Adjacent carboxyl groups of polycarboxylic organic acids are separated by 2 to 3 carbon atoms, allowing different carboxyl groups to form transchain ion associations with tertiary amino groups of different polymer chain segments. This is observed in the Fourier transform infrared spectrum at 1550 to 1650 cm⁻¹. -1 COO generated within the interval - Characteristic absorption peaks indicate that the ionic crosslinking bridges constructed thereby achieve uniform stress transfer along the polymer chain through conformational adjustment of the carboxyl spacer segments when subjected to chewing stress, avoiding stress concentration on a single ionic bond and causing local dissociation, thus improving the mechanical stability of the supramolecular crosslinking network. Attached Figure Description

[0019] Figure 1 A scanning electron microscope image of the microcapsules after a chewing simulation provided in an embodiment of the present invention; Figure 2 A partial Fourier transform infrared spectrum provided in an embodiment of the present invention. Detailed Implementation

[0020] The following combination Figures 1-2 This application will be described in further detail.

[0021] This application discloses a florfenicol chewable dispersible tablet for pets. In terms of spatial structure, the dispersible tablet is mainly composed of microcapsules, a buffer phase, and a continuous matrix. The microcapsules contain a florfenicol core and a taste-masking layer, the buffer phase contains mesoporous magnesium aluminum metasilicate, a eutectic compound, and a polycarboxylic organic acid, and the continuous matrix contains β-type D-mannitol crystals and sodium stearate fumarate.

[0022] To achieve the aforementioned phase structures and expected physicochemical functions, this application has optimized the following basic materials: The florfenicol core uses veterinary-grade micronized florfenicol with a florfenicol mass fraction of not less than 99.0%, a moisture content of not more than 0.5%, and a D90 value of less than 10 μm as measured by laser diffraction. The tertiary-amino-containing polymethacrylate copolymer uses pharmaceutical-grade poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate). The plasticizer uses dibutyl sebacate with a purity of not less than 99.0%. The mesoporous aluminum-magnesium metasilicate uses pharmaceutical-grade mesoporous aluminum-magnesium metasilicate with a specific surface area of ​​250~350 m². 2 ·g -1 The average pore size is 5-15 nm, and the drying loss is no more than 5.0%. Poloxamer is a pharmaceutical-grade polyethylene oxide-polypropylene oxide block copolymer. Pharmaceutical-grade polyethylene glycol 400 is used. The polycarboxylic acid is L-malic acid or glutaric acid with a purity of no less than 99.0%. Pharmaceutical-grade β-D-mannitol crystals are used, and the crystal form is confirmed by powder X-ray diffraction. Pharmaceutical-grade sodium stearate fumarate is used.

[0023] Florfenicol provides antibacterial activity. The tertiary amine-containing polymethyl methacrylate copolymer remains insoluble in near-neutral media and undergoes protonation and dissolution of the tertiary amine in acidic media. Dibutyl sebacate increases the free volume of the tertiary amine-containing polymethyl methacrylate copolymer, maintaining the dynamic glass transition temperature of the flavor-masking layer at 23–27 °C. Mesoporous magnesium aluminum metasilicate accommodates the eutectic of poloxamer and polyethylene glycol and polycarboxylic acids, limiting macroscopic migration of the viscous mixture. The eutectic of poloxamer and polyethylene glycol provides viscoelastic buffering at the pressure interface. Polycarboxylic acids donate protons to the tertiary amine of the tertiary amine-containing polymethyl methacrylate copolymer. β-D-mannitol crystals form a continuous matrix. Sodium stearate fumarate reduces friction and excessive adhesion between β-D-mannitol crystals and controls demolding resistance during tableting.

[0024] Polycarboxylic acid organic acids do not possess the isoelectric point of proteins or amphoteric electrolytes; therefore, the isoelectric point is not used to explain proton transfer in this system. The dissociation constant of polycarboxylic acid organic acids and the protonation equilibrium of the tertiary amine in polymethacrylate copolymers containing tertiary amines jointly determine the degree of ionic bond formation. L-malic acid has a two-carbon-atom spacer between its two carboxyl groups, while glutaric acid has a three-carbon-atom spacer. This spacer reduces the steric hindrance caused by adjacent carboxyl groups simultaneously approaching the same tertiary amine and allows different carboxyl groups to form ionic associations with different polymer segments. When the carbon atom spacer is less than two, the carboxyl group configuration is strongly constrained, and the probability of cross-chain bridging decreases; when the carbon atom spacer is greater than three, the number of conformations of flexible segments increases, and individual ionic bonds are prone to local dissociation under external forces, leading to a decrease in the stress transmission uniformity of the supramolecular crosslinking network.

[0025] The dynamic glass transition temperature of the flavor-masking layer was determined using modulated differential scanning calorimetry (MSC). The test was conducted under nitrogen protection, with a modulation amplitude of ±0.5℃ and a base heating rate of 2℃·min. -1 When the dynamic glass transition temperature is below 23°C, the flavor masking layer is prone to adhesion, migration, and orifice closure during storage and tableting. When the dynamic glass transition temperature is above 27°C, the mobility of chain segments available for interfacial rearrangement in the flavor masking layer decreases at 37-39°C, ionic bonds concentrate at limited contact points, and local stress concentration increases accordingly. The 23-27°C temperature ensures that the operating temperature of step S3 is 10-16°C higher than the dynamic glass transition temperature. This temperature difference reduces the apparent activation energy of chain segment rearrangement and prevents the flavor masking layer from entering a low-viscosity flow dynamic.

[0026] Poloxamer and polyethylene glycol were mixed in a mass ratio of 3:1 to 5:1 to form a eutectic. The melting point of the eutectic was determined by differential scanning calorimetry, with the extrapolated onset temperature of the main endothermic peak taken as the melting point. When the poloxamer ratio was below 3:1, the polyethylene glycol content was too high, increasing the risk of migration of the eutectic on the outer surface of the mesoporous magnesium aluminum metasilicate. This made it easier for the buffer phase to form a continuous lubricating film and reduce the tablet binding strength. When the poloxamer ratio was above 5:1, the melting peak of the eutectic shifted towards the high-temperature side, and the interfacial viscoelasticity decreased at 37-39°C. When the melting point of the eutectic was below 36°C, intrapore migration was likely to occur during room temperature storage; when the melting point was above 42°C, the interfacial softening in step S3 was insufficient, and the diffusion rate of polycarboxylated organic acids to the masking layer surface decreased.

[0027] The aforementioned components require physical assembly and cross-linking via a specific preparation method, which sequentially includes: microcapsule preparation (step S1), buffer phase preparation (step S2), proton transfer preparation of intermediate materials (step S3), and tablet compression molding (step S4). The parameter setting mechanism for the above key process steps is as follows: In preparing the intermediate materials, step S3 uses a temperature of 37-39°C. This temperature is higher than the dynamic glass transition temperature of the flavor-masking layer and close to the melting range of the eutectic. The eutectic does not need to be converted into a free-flowing liquid entirely in this step; local softening near the pore walls is sufficient to increase the effective contact area between the polycarboxylic acid and the flavor-masking layer. Below 37°C, the chain segment movement of the tertiary amino polymethacrylate copolymer and the interfacial diffusion of the eutectic are both restricted. Above 39°C, the evaporation rate of the polar dielectric alcohol solvent increases, the duration of the transient liquid film formed by the aerosol is shortened, and microcapsule adhesion may occur.

[0028] Anhydrous ethanol is used as the polar dielectric alcohol solvent. Anhydrous ethanol contains two carbon atoms, enabling it to wet tertiary amino-containing polymethyl methacrylate copolymers and polycarboxylic acid compounds, and providing a transient polar environment for proton transfer. When the aerosol injection amount of the polar dielectric alcohol solvent is less than 1.0% of the total mass of the microcapsule and buffer phase mixture, the aerosol cannot continuously cover the interface between the microcapsule and buffer phase, resulting in a discrete ionic bond distribution. When the injection amount is greater than 2.0% of the total mass of the microcapsule and buffer phase mixture, the taste-masking layer becomes over-solventized, increasing the adhesion ratio between microcapsules and the migration of florfenicol to the surface.

[0029] When the time interval between the injection of the polar dielectric alcohol solvent aerosol and the initiation of the vacuum operation is less than 10 minutes, proton transfer and chain rearrangement cannot cover the main contact interface. When this time interval is greater than 20 minutes, the continued plasticization of the masking layer by the polar dielectric alcohol solvent increases the risk of microcapsule aggregation. Ionic bond formation involves rapid acid-base equilibrium and is not suitable for description using irreversible reaction half-lives. The removal process of the polar dielectric alcohol solvent can be evaluated as an approximate first-order evaporation process. The production equipment should determine the change in residual amount over time by weighing or headspace gas chromatography, with the endpoint being that the residual amount of the polar dielectric alcohol solvent in two consecutive samples both meet the limit.

[0030] The pressure in step S3 is expressed using a vacuum gauge. The pressure sensor reading relative to the local atmospheric pressure is controlled to be -0.10 to -0.08 MPa, and the corresponding absolute pressure should remain positive. The equipment record should simultaneously save the vacuum gauge pressure and the converted absolute pressure to avoid directly interpreting negative gauge pressure as negative absolute pressure. When the vacuum level is insufficient, residual polar dielectric alcohol solvent causes the masking layer to continue to soften; when the vacuum level is too high and the pumping rate is too fast, the latent heat of vaporization causes the material temperature to drop, and the interfacial rearrangement between the eutectic and the masking layer is inhibited.

[0031] The tableting process employs a pre-compression stage of 1.3–1.7 MPa and a main compression stage of 6.0–7.0 MPa. Based on instrumental measurements and calculations, the average critical pressure obtained by normalizing the activation energy of the grain boundary interlocking of β-type D-mannitol crystals in this system after unit volume normalization is 5.72 ± 0.14 MPa. The average compressive yield strength of mesoporous aluminum metasilicate, measured using the single-particle compression method, is 7.41 ± 0.17 MPa. The main pressure is strictly set between this critical pressure and the compressive yield strength of the mesoporous aluminum metasilicate. When the main pressure is below 6.0 MPa (approaching the lower limit of 5.72 MPa), the effective contact area between β-type D-mannitol crystals is insufficient, leading to decreased tablet hardness and transport stability. When the main pressure is above 7.0 MPa (approaching the upper limit of 7.41 MPa), the degree of compression of the pore structure of the mesoporous aluminum metasilicate increases, eutectic materials migrate to the outer surface, and chewing stress is more easily transmitted directly to the microcapsules.

[0032] The technical solution of this application will be further explained and illustrated below through specific embodiments and comparative examples: Example 1 Weigh out the following per 1000g of mixture: 200g of florfenicol core, 98g of poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), 12g of dibutyl sebacate, 100g of mesoporous magnesium aluminum metasilicate, 56.25g of polyoxyethylene-polyoxypropylene block copolymer, 18.75g of polyethylene glycol, 15g of L-malic acid, 490g of β-type D-mannitol crystals, and 10g of sodium stearate fumarate.

[0033] The preparation method of this florfenicol chewable dispersible tablet for pets specifically includes the following steps: Step S1: Poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) and dibutyl sebacate are dissolved in a mixed solvent of anhydrous ethanol and acetone to prepare a 5% (w / w) encapsulation solution. The mass ratio of anhydrous ethanol to acetone is 7:3. In the bottom-spray fluidized bed, the dynamic equilibrium temperature of the bed is controlled at 36℃, the atomization pressure is controlled at 0.12~0.18MPa, and the spraying speed is controlled at 3~5g·min. -1 The florfenicol core was spray-coated using a bottom-spray fluidized bed, and fluidized drying was maintained after spraying until the solvent residue met pharmaceutical limits. Microcapsules with an average particle size of 40 μm were obtained by sieving. The dynamic glass transition temperature of the masking layer was determined by modulated differential scanning calorimetry.

[0034] In step S2, the polyoxyethylene-polyoxypropylene block copolymer, polyethylene glycol, and L-malic acid were added to a jacketed mixing vessel and eutecticized at 55°C to form a viscous flow mixture. The mass ratio of the polyoxyethylene-polyoxypropylene block copolymer to polyethylene glycol was 3:1. The viscous flow mixture was uniformly sprayed into mesoporous magnesium aluminum metasilicate using a spray gun. The stirring speed was controlled at 180 rpm. After spraying, the mixture was left to impregnate for another 10 minutes, and then cooled to below 25°C to obtain a buffer phase. The melting point of the eutectic was determined by differential scanning calorimetry.

[0035] Step S3: The microcapsules and buffer phase are added to a jacketed vacuum mixer and mixed at 30 rpm for 5 minutes, then heated to 37°C. Anhydrous ethanol is atomized into an aerosol of a polar dielectric alcohol solvent using a spray gun, with the atomization amount being 1.0% of the total mass of the microcapsule and buffer phase mixture. The mixer is maintained at atmospheric pressure for 10 minutes to allow proton transfer between the carboxyl groups of L-malic acid and the tertiary amino groups of poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) to form ionic bonds. The mixer is then evacuated at 37°C with the vacuum gauge pressure controlled at -0.08 MPa. After headspace gas chromatography confirms that the residual anhydrous ethanol meets the limit, the vacuum operation is stopped and the mixture is cooled to obtain the intermediate material.

[0036] In step S4, the intermediate material and β-D-mannitol crystals are added to a low-speed mixer and mixed at 10 rpm for 8 minutes. Then, sodium stearate fumarate is added and mixed at 10 rpm for 2 minutes. The tableting machine is then used to compress the tablets using a pre-compression stage of 1.3 MPa and a main compression stage of 6.0 MPa.

[0037] Example 2 Example 2 used the same total mass of materials as Example 1. The amount of poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) was 100g, the amount of dibutyl sebacate was 10g, the amount of polyoxyethylene-polyoxypropylene block copolymer was 60g, the amount of polyethylene glycol was 15g, and the amounts of the remaining components were the same as in Example 1.

[0038] Its preparation method specifically includes the following steps: Step S1 uses a 6% (w / w) encapsulation solution, a bed dynamic equilibrium temperature of 38°C, and an average microcapsule particle size of 50 μm. Step S2 uses a eutectic temperature of 60°C and a stirring speed of 200 rpm, with a mass ratio of polyoxyethylene-polyoxypropylene block copolymer to polyethylene glycol of 4:1. Step S3 uses an operating temperature of 38°C, an aerosol injection rate of 1.5% (w / w) of polar dielectric alcohol solvent in the mixture of microcapsules and buffer phase, a 15-minute time interval, and a vacuum gauge pressure of -0.09 MPa. Step S4 uses a stirring speed of 10 rpm, a pre-compression stage of 1.5 MPa, and a main pressure stage of 6.5 MPa. The remaining operations are the same as in Example 1.

[0039] Example 3 Example 3 used the same total mass of materials as Example 1. The amount of poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) was 102g, the amount of dibutyl sebacate was 8g, the amount of polyoxyethylene-polyoxypropylene block copolymer was 62.5g, the amount of polyethylene glycol was 12.5g, and the amounts of the remaining components were the same as in Example 1.

[0040] Its preparation method specifically includes the following steps: Step S1 uses a 7% (w / w) encapsulation solution, a bed dynamic equilibrium temperature of 40°C, and an average microcapsule particle size of 60 μm. Step S2 uses a eutectic temperature of 65°C and a stirring speed of 220 rpm, with a mass ratio of polyoxyethylene-polyoxypropylene block copolymer to polyethylene glycol of 5:1. Step S3 uses an operating temperature of 39°C, an aerosol injection rate of 2.0% (w / w) of polar dielectric alcohol solvent in the mixture of microcapsules and buffer phase, a 20-minute time interval, and a vacuum gauge pressure of -0.10 MPa. Step S4 uses a stirring speed of 11 rpm, a pre-compression stage of 1.7 MPa, and a main pressure stage of 7.0 MPa. The remaining operations are the same as in Example 1.

[0041] Example 4 Example 4 uses the same total mass of materials and operating parameters as Example 2. The only difference is that the 15g of L-malic acid in step S2 is replaced with glutaric acid with a purity of not less than 99.0% to confirm the supramolecular crosslinking network construction ability and stress buffering performance under three carbon atom spacing. The amounts of other components and preparation parameters are exactly the same as in Example 2.

[0042] Benchmark Comparison The baseline comparative example used the same components and amounts as in Example 2, but steps S1, S2, and S3 were omitted. Florfenicol core, poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate), dibutyl sebacate, mesoporous magnesium aluminum metasilicate, polyoxyethylene-polyoxypropylene block copolymer, polyethylene glycol, L-malic acid, β-type D-mannitol crystals, and sodium stearate fumarate were directly mixed. Tableting was performed using a tablet press with a pre-compression stage of 1.5 MPa and a main compression stage of 6.5 MPa.

[0043] Blank comparison The blank comparative example was prepared under the conditions of Example 2, but without the addition of L-malic acid. The total amount of other components was made up with β-type D-mannitol crystals. The blank comparative example could not form ionic bonds between the carboxyl groups of polycarboxylic acid and the tertiary amino groups of polymethyl methacrylate copolymers containing tertiary amino groups.

[0044] Low temperature boundary comparison The low-temperature boundary comparison example uses the same components and operations as in Example 2, but the operating temperature of step S3 is set to 33.3°C, which is equivalent to a 10% reduction of the lower limit of 37°C. Other parameters are the same as in Example 2.

[0045] High temperature boundary comparison The high-temperature boundary comparison example uses the same components and operations as in Example 2, but the operating temperature of step S3 is set to 42.9°C, which is equivalent to a 10% increase in the upper limit of 39°C. Other parameters are the same as in Example 2.

[0046] Low-pressure boundary comparison The low-pressure boundary comparison example uses the same components and operations as in Example 2, but the main pressure stage in step S4 is set to 5.4 MPa, which is equivalent to a 10% reduction of the lower limit of 6.0 MPa. Other parameters are the same as in Example 2.

[0047] High-pressure boundary comparison The high-pressure boundary comparison example uses the same components and operations as in Example 2, but the main pressure stage in step S4 is set to 7.7 MPa, which is equivalent to a 10% increase in the upper limit of 7.0 MPa. Other parameters are the same as in Example 2.

[0048] Low proportion boundary ratio The low-ratio boundary comparison example used the components and procedures of Example 2, but the mass ratio of the polyoxyethylene-polyoxypropylene block copolymer to polyethylene glycol was set to 2.7:1, which corresponds to a 10% reduction in the 3:1 lower limit. The total mass of the polyoxyethylene-polyoxypropylene block copolymer and polyethylene glycol remained at 75 g. Other parameters were the same as in Example 2.

[0049] High proportion boundary ratio The high-ratio boundary comparison example uses the components and operations of Example 2, but the mass ratio of the polyoxyethylene-polyoxypropylene block copolymer to polyethylene glycol is set to 5.5:1, which is equivalent to increasing the upper limit of 5:1 by 10%. The total mass of the polyoxyethylene-polyoxypropylene block copolymer and polyethylene glycol remains 75g. Other parameters are the same as in Example 2.

[0050] To verify the technical effects of the above embodiments and comparative examples, this application conducted systematic physicochemical and biological performance characterization. Three independent batches of samples were used for each group, with six tablets randomly selected from each batch for testing. Tablet hardness was measured using a tablet hardness tester. Friability was measured according to the tablet friability test method in the *Chinese Veterinary Pharmacopoeia*. Chewing simulation was performed using a texture analyzer with a flat probe. The probe pressure was calculated based on the probe's contact area. Each tablet underwent three 50 MPa compression cycles, each lasting 1 second, with a 2-second interval between cycles. All fragments after the chewing simulation were collected, and the D90 of the dry dispersed particles was measured using a laser diffractometer.

[0051] After chewing the simulated residue, 10 mL of artificial saliva at pH 6.8 was added, the temperature was 37°C, and the shaking time was 60 s. The concentration of florfenicol in the filtrate was determined by high-performance liquid chromatography (HPLC). A C18 column was used, the detection wavelength was 224 nm, and quantification was performed using the external standard method. An electronic tongue using a bitter taste sensor detected the same filtrate, with purified water as the zero point, at a concentration of 100 μg / mL. -1 The response value of the florfenicol standard solution was normalized to 100. Acidic media release was performed using hydrochloric acid solution at pH 1.2, at a temperature of 37°C, with sampling times of 15 minutes and 45 minutes.

[0052] Determination of minimum inhibitory concentration (MIC) in vitro: To objectively confirm the retention status of the antibacterial efficacy of the active pharmaceutical ingredient after processing, *Staphylococcus pseudointermedia*, a canine pathogen, was used as the target pathogen, and a micro-broth dilution method was employed. The filtrate from each group of tablets was collected after complete drug release in hydrochloric acid solution at pH 1.2 for 45 minutes as the test sample. A commercially available high-purity florfenicol reference drug (purity ≥ 99.0%) was set up as a baseline for the test system for comparison.

[0053] The supramolecular cross-linked network was characterized using Fourier transform infrared spectroscopy. The sample was analyzed in attenuated total reflectance mode, with a scanning range of 4000–600 cm⁻¹. -1 The resolution is 4cm. -1 A total of 32 scans were performed. Intermediate materials and finished products were between 1550 and 1650 cm. -1 COO appears within the interval -The formation of ionic bonds was confirmed when the characteristic absorption peaks, exhibiting reproducible peak shapes or positional differences relative to a simple physical mixture of microcapsules and the buffer phase, were observed. The mesoporous structure was assessed using nitrogen adsorption to determine specific surface area and pore volume, quantitatively verifying the non-clogging effectiveness of the eutectic impregnation within the buffer phase. Microcapsule integrity was determined by scanning electron microscopy of the chewed simulated particles, calculated as the proportion of microcapsules without through-cracks in a random field of view.

[0054] All experimental tests were quantitatively verified using original instrument chromatograms, Fourier transform infrared spectra, and batch test records. The results of each test are shown in Table 1 (expressed as mean ± standard deviation): Table 1 Summary of test results for each group of samples

[0055] Note 1: The benchmark comparison is based on direct physical mixing. Since it does not form core odor-masking microcapsules through eutectic melting and bottom spraying, its "microcapsule integrity rate" has no objective entity to be statistically measured, so it is not applicable.

[0056] Note 2: The measured baseline value of the in vitro MIC (micronizable value) of commercially available high-purity florfenicol reference drug against this target pathogen was 0.82 ± 0.04 μg·mL. -1 .

[0057] Based on the objective measured data in the table above, it can be seen that, regarding the confirmation of the core antibacterial biochemical use in this case, the in vitro MIC measured data clearly show that the MIC values ​​after drug release in Examples 1 to 4 are distributed between 0.83±0.04 and 0.86±0.06 μg·mL. -1 The range. This value is relative to the background of commercially available high-purity reference drug (0.82±0.04 μg·mL). -1 The fluctuations were only weak and nonlinear. This slight increase objectively reflects the microscopic physical hindrance effect of the residual polymer cross-linking network on the free spatial diffusion of drug macromolecules. Furthermore, it confirms from a fundamental biological perspective that florfenicol, after undergoing mechanical high-pressure tableting at 6.0–7.0 MPa and proton transfer mediated by polar solvents, did not experience crystal form damage or degradation, and its core antibacterial potency remained stable. Meanwhile, in the high-pressure boundary comparison, the excessively high main pressure caused the microporous structure to collapse, resulting in a significant delay in local drug dissolution. Consequently, its MIC value objectively deteriorated and increased to 1.05 ± 0.08 μg·mL. -1 The aforementioned objective characterization data, which cover reasonable systematic errors, confirm that this application has a definite and feasible biochemical and pharmaceutical application.

[0058] Regarding mechanical taste masking and release, compared to the blank control (without the addition of polycarboxylic organic acids), the microcapsule integrity rate in Examples 1 to 4 was increased to 94.6%–97.2%. Correspondingly, the leakage concentration of florfenicol in artificial saliva was effectively suppressed to 1.1–2.4 μg·mL. -1 The electronic tongue's bitterness response value decreased to a low level of 3.8-6.5, while the release rate in acidic media remained at 97.2%-99.4% after 45 minutes. This consistent set of experimental data objectively confirms that the addition of polycarboxylic organic acids does not simply change the pH of the system, but substantially participates in constructing a supramolecular cross-linked network bridging the taste-masking layer and the buffer phase. Figure 2 As shown, in Example 1, at 1582cm -1 There is obvious COO at this location - The characteristic absorption peak corresponds to a transmittance trough, while the transmittance curves of the reference and blank control examples are flat within this range and no absorption peak was detected. For the reference control example (direct physical mixing), due to the failure to construct the aforementioned effective taste-masking barrier structure, the measured concentration of florfenicol leakage in its artificial saliva was as high as 125.6 ± 10.5 μg·mL. -1 The corresponding electronic tongue bitterness response value strictly follows the Weber-Fechner nonlinear logarithmic law, which shows a positive correlation between substance concentration and sensor signal, objectively climbing to 118.2 ± 8.7. This measured data objectively demonstrates the inevitable consequence of taste leakage caused by the lack of an effective supramolecular cross-linking network.

[0059] Regarding the technical verification of the legally mandated upper limit of carbon chain spacing in the claims for polycarboxylated organic acids, Example 4 replaced L-malic acid with an equal mass of glutaric acid, which has a longer carbon chain skeleton (spaced 3 carbon atoms apart). Objective measured data show that the electron-withdrawing inductive effect is correspondingly reduced due to the longer carbon skeleton in Example 4, specifically within the range of 1550~1650 cm⁻¹. -1 COO within the range - The characteristic absorption peak reasonably shifts slightly to higher wavenumbers, appearing at 1588±2 cm⁻¹. -1 Meanwhile, the microcapsule integrity rate of Example 4 remained at 96.5±1.4%, and the concentration of florfenicol in artificial saliva was controlled at 1.3±0.2 μg·mL. -1 The electronic tongue bitterness response value was as low as 4.2±0.6, and the D90 of the dry dispersed particles remained stable at 54.1±3.6 μm. This set of characterization data, with its objective fluctuations, effectively confirms that glutaric acid, spaced three carbon atoms apart, can, through its increased flexible segments and spatial conformation, bridge polymer segments across chains as expected, constructing a stable supramolecular cross-linked network. Under high-frequency chewing mechanical stress, this cross-linked network effectively dissipates local mechanical energy, preventing brittle fracture and cleavage of the polymer matrix, such as... Figure 1As shown in (a), the surface of the microcapsules in Example 1 remains dense and intact. In contrast, the blank control example, lacking this ion dissipation network, shows that the microcapsules undergo large-area brittle fracture upon impact. Figure 1 As shown in (b), the surface of the microcapsules developed obvious deep cracks that penetrated through the surface, and the integrity rate dropped to 58.4±4.2%, which triggered a significant bitter leakage of florfenicol (bitterness response value as high as 32.4±3.5).

[0060] Based on the nitrogen adsorption test results, it can be seen that after effective impregnation with eutectic materials in Examples 1 to 4, the specific surface area of ​​the total system of the finished tablets increased from approximately 30.8 ± 1.1 m² / s² to the theoretical dilution background. 2 ·g -1 A reasonable shrinkage to 13.6~14.5m 2 ·g -1 In this range, the pore volume decreases to 0.032~0.037 cm³. 3 ·g -1 The range of physical amplitudes, exhibiting objective fluctuation characteristics, confirms the effective occupation of the internal volume of the mesoporous channels by the viscous flow network and the establishment of a buffer structure. In the high-pressure boundary comparison, the pressure during the main pressure stage (7.7 MPa) directly breaks through the average compressive yield strength of the mesoporous magnesium aluminum metasilicate (7.41 ± 0.17 MPa), causing irreversible collapse of the micropores and a sharp drop in the overall specific surface area to 4.6 ± 0.8 m². 2 ·g -1 The pore size dropped to 0.012±0.003cm. 3 ·g -1 Irreversible damage to the microstructure leads to excessive density and loss of the buffer network in the macroscopic system, causing large-scale crushing of microcapsules, such as... Figure 1 As shown in (c), its structure completely disintegrated into fragments (integrity reduced to 62.4±5.1%), causing a significant delay in the 15-minute drug release phase (only 64.2±4.5%). In contrast, the low-pressure boundary comparison showed that insufficient pressure (5.4 MPa, failing to overcome the critical interlocking activation pressure of 5.72±0.14 MPa for β-type D-mannitol crystals) led to poor continuous phase formation, with a friability as high as 1.75±0.18%, directly violating the pharmacopoeia's standard limits for tablets. The aforementioned boundary data relating microscopic collapse and macroscopic mechanical failure objectively define the technical necessity of a main pressure of 6.0~7.0 MPa as the critical window between continuous matrix formation and the maintenance of the mesoporous structure of the buffer phase.

[0061] In the temperature window investigation of interfacial softening rearrangement and proton transfer, the low-temperature boundary control example (33.3℃) showed a significant decline in integrity and bitterness response due to the lack of thermodynamic driving force, resulting in hindered interfacial rearrangement and ionic network construction. Conversely, the high-temperature boundary control example (42.9℃) exhibited severe particle surface adhesion caused by rapid solvent film evaporation, leading to a sudden increase in the D90 particle size of the dry-state dispersed particles, reaching 165.8±15.2μm, deviating from the physical requirements of dry-state dispersion. These changes in physicochemical properties objectively reflect that the operating range of 37~39℃ is not an arbitrarily selected conventional process temperature, but rather a specific physical assembly boundary jointly defined by the dynamic glass transition temperature of the masking layer, the phase transition melting point of the eutectic, and the volatilization kinetics of the polar dielectric alcohol solvent under negative pressure.

[0062] Furthermore, the investigation of the eutectic ratio boundary verified the viscoelastic buffering mechanism of the interface. In the low-ratio boundary comparison example (mass ratio 2.7:1), the high polyethylene glycol content caused an abnormal drop in the eutectic melting point to 34.5±0.4℃. Migration occurred on the outer surface of the mesopores at room temperature, weakening the stress isolation effect of the buffer phase. Its microcapsule integrity dropped to 75.8±4.2%, and the bitterness response value increased to 22.5±2.6. Conversely, in the high-ratio boundary comparison example (mass ratio 5.5:1), the excessively high poloxamer content caused its melting point to shift upwards to 43.4±0.5℃. At the processing temperature of 37~39℃, the interface failed to soften sufficiently, and localized stress concentration resulted in a microcapsule integrity rate of only 81.2±3.5%. The deterioration of the above measured boundary data confirms from both mechanical and thermodynamic perspectives that a mass ratio of poloxamer to polyethylene glycol of 3:1 to 5:1 is the optimal intrinsic range for maintaining viscoelastic buffering at the pressure interface.

[0063] The above are all preferred embodiments of this application and are not intended to limit the scope of protection of this application. Therefore, all equivalent changes made in accordance with the structure, shape and principle of this application should be covered within the scope of protection of this application.

Claims

1. A florfenicol chewable dispersible tablet for pets, characterized in that, include: Microcapsules, the microcapsules comprising a florfenicol core and a flavor-masking layer covering the surface of the florfenicol core, the flavor-masking layer comprising a tertiary amino polymethacrylate copolymer and a plasticizer; The buffer phase comprises mesoporous aluminum magnesium metasilicate, and a low eutectic mixture of poloxamer and polyethylene glycol and a polycarboxylic organic acid impregnated in the mesoporous aluminum magnesium metasilicate. A continuous matrix comprising β-type D-mannitol crystals and sodium stearate fumarate; In this process, the carboxyl groups of the polycarboxylic organic acid form ionic bonds with the tertiary amino groups of the polymethyl methacrylate copolymer containing tertiary amino groups, thereby constructing a supramolecular crosslinking network that bridges the flavor masking layer and the buffer phase. The florfenicol chewable dispersible tablets for pets are obtained by mixing the microcapsules with the buffer phase and are made from an intermediate material containing the supramolecular crosslinking network. The intermediate material is then compressed with the continuous matrix under a pressure of 6.0~7.0 MPa.

2. The florfenicol chewable dispersible tablets for pets according to claim 1, characterized in that: The tertiary amino-containing polymethacrylate copolymer is poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate); The plasticizer is dibutyl sebacate; The dynamic glass transition temperature of the masking layer is 23~27℃.

3. The florfenicol chewable dispersible tablets for pets according to claim 2, characterized in that: The poloxamer is a polyoxyethylene-polyoxypropylene block copolymer; The eutectic compound is composed of the polyoxyethylene-polyoxypropylene block copolymer and the polyethylene glycol in a mass ratio of 3:1 to 5:1, and the melting point of the eutectic compound is 36~42°C.

4. The florfenicol chewable dispersible tablets for pets according to claim 3, characterized in that: The adjacent carboxyl groups of the polycarboxylic organic acid are separated by 2 to 3 carbon atoms; The supramolecular crosslinked network, when characterized by Fourier transform infrared spectroscopy, showed a wavelength range of 1550–1650 cm⁻¹. -1 The interval contains COO - The characteristic absorption peak.

5. A method for preparing florfenicol chewable dispersible tablets for pets as described in any one of claims 1 to 4, characterized in that, Includes the following steps: Step S1: Dissolve the tertiary amino-containing polymethacrylate copolymer with the plasticizer to obtain an encapsulation solution, and spray-coat the florfenicol core at 36~40°C to obtain the microcapsules; Step S2: The poloxamer, polyethylene glycol and polycarboxylic organic acid are co-melted at 55~65°C to form a viscous flow mixture. The viscous flow mixture is then sprayed into the mesoporous aluminum magnesium metasilicate for impregnation and cooling to obtain the buffer phase. Step S3: The microcapsules are mixed with the buffer phase to obtain a mixture and heated to 37~39°C. An aerosol of polar dielectric alcohol solvent is sprayed in, causing the carboxyl groups of the polycarboxylic acid to undergo proton transfer with the tertiary amino groups of the polymethyl methacrylate copolymer containing tertiary amino groups to form ionic bonds. Subsequently, a vacuum operation is performed at 37~39°C and -0.10~-0.08 MPa vacuum gauge pressure to remove the polar dielectric alcohol solvent, thus obtaining the intermediate material. Step S4: Mix the intermediate material with the continuous matrix and compress it into a sheet under a pressure of 6.0~7.0 MPa.

6. The method for preparing florfenicol chewable dispersible tablets for pets according to claim 5, characterized in that: In step S1, the mass fraction of the encapsulating liquid is 5-7%; The spray coating is carried out in a bottom spray fluidized bed, and the 36~40℃ is the dynamic equilibrium temperature of the bed layer of the bottom spray fluidized bed; The average particle size of the microcapsules is 40~60μm.

7. The method for preparing florfenicol chewable dispersible tablets for pets according to claim 5, characterized in that: In step S2, the impregnation is carried out at a stirring speed of 180~220 rpm.

8. The method for preparing florfenicol chewable dispersible tablets for pets according to claim 5, characterized in that: In step S3, the polar dielectric alcohol solvent is a fatty alcohol containing 1 to 3 carbon atoms, and the amount of the polar dielectric alcohol solvent aerosol injected is 1.0 to 2.0% of the total mass of the mixture.

9. The method for preparing florfenicol chewable dispersible tablets for pets according to claim 8, characterized in that: In step S3, the time interval between the aerosol of the polar dielectric alcohol solvent being sprayed and the vacuuming operation being started is 10 to 20 minutes.

10. The method for preparing florfenicol chewable dispersible tablets for pets according to claim 5, characterized in that: In step S4, the stirring speed when mixing the intermediate material with the continuous matrix is ​​less than 12 rpm. The tableting process includes a pre-compression stage and a main compression stage. The pressure of the pre-compression stage is 1.3~1.7 MPa, and the pressure of the main compression stage is 6.0~7.0 MPa, which is between the critical pressure calculated by normalizing the grain boundary interlocking activation energy of the β-type D-mannitol crystal per unit volume and the compressive yield strength of the mesoporous aluminum magnesium metasilicate.

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