Ointment type bile acid preparation with excellent palatability and preparation method thereof

Abstract

The invention relates to the technical field of animal medicine preparations, and discloses an ointment type bile acid preparation with excellent palatability and a preparation method thereof. Comprising the following materials: a phase change adjusting layer formed by compounding hydrogenated palm oil and medium chain triglyceride, intermolecular hydrogen bonds formed by beta-cyclodextrin embedded chicken flavor substances and bile acid, polyoxyethylene (40) hydrogenated castor oil, carbomer 940, a mucosa adhesive agent, a bitter screening agent, ursodesoxycholic acid and compound taurine. Through the synergistic effect of multiphase matrixes, the palatability is improved (the bitterness value is reduced to 9.8 + / -0.7 of 2.3 + / -0.5 vs original powder, and detection is performed by an electronic tongue), meanwhile, the bioavailability is improved (AUC0-24h is increased by 1.8 times), and the double effects of treatment and beauty treatment are achieved.

Description

Technical Field

[0001] This invention relates to the field of animal pharmaceutical formulation technology, specifically to an ointment-type bile acid formulation with excellent palatability and its preparation method. Background Technology

[0002] In the clinical treatment of hepatobiliary diseases in animals, bile acids, as endogenous active substances, play an irreplaceable role in promoting lipid metabolism, regulating hepatobiliary function, and inhibiting inflammatory responses. However, currently available commercially available bile acid preparations suffer from significant technical defects in their application, severely limiting their clinical efficacy. Tablets generally have a hardness >50N, making them difficult to soften in the animal's mouth and causing swallowing difficulties; capsules have a gelatin disintegration time >15min, failing to rapidly release the drug's flavor; powders have a particle size D90 >150μm, resulting in a strong granular texture and easily triggering choking. These factors collectively lead to an animal refusal rate >40%, especially for felines, whose taste receptor density is more than three times that of humans. Their taste buds are extremely sensitive to bitter substances (such as bile acids), making the palatability issues of conventional dosage forms even more severe.

[0003] After oral administration, the powder is significantly affected by the first-pass effect in the digestive tract, resulting in a loss of 35-40% of the active ingredients. This leads to an effective blood drug concentration that can be maintained for less than 4 hours, requiring frequent administration to maintain the therapeutic effect and increasing the risk of stress in animals.

[0004] The high hardness of tablets (>50N) causes a 12% rate of mechanical damage to the oral mucosa during swallowing, manifested as tongue ulcers or esophageal scratches; the allergic reaction rate caused by capsule shell residue reaches 5.7%, with common symptoms being facial edema and diarrhea. These additional injuries seriously affect animal medication compliance.

[0005] In existing technologies, improvements to the palatability of animal formulations are mostly limited to surface coating or simple flavoring agent additions, failing to address the fundamental problem from the perspective of the synergistic effect between the dosage form matrix and the active ingredient. Therefore, developing a novel formulation preparation method that can improve palatability from multiple dimensions, including matrix system design, active ingredient processing, and preparation process optimization, has become a pressing technical challenge in this field. Summary of the Invention

[0006] (a) Technical problems to be solved To address the shortcomings of existing technologies, this invention provides a palatable ointment-type bile acid preparation and its preparation method, thus solving the aforementioned problems.

[0007] (II) Technical Solution To achieve the above objectives, the present invention provides the following technical solution: an ointment-type bile acid preparation with excellent palatability, comprising the following materials: a phase change regulating layer composed of hydrogenated palm oil and medium-chain triglycerides, β-cyclodextrin encapsulating chicken flavorings to form intermolecular hydrogen bonds with bile acids, polyoxyethylene (40) hydrogenated castor oil, carbomer 940, a mucosal adhesive, a bitterness masking agent, ursodeoxycholic acid, and compound taurine.

[0008] Preferably, the hydrogenated palm oil and medium-chain triglycerides are compounded in a weight ratio of 3:7 to form a phase change regulating layer, and the encapsulation rate of β-cyclodextrin for chicken flavoring is greater than 98%.

[0009] Preferably, the viscosity of the adhesive film is 3500-4500 cP, and the bitterness masking agent is 0.5% nano-sized silica.

[0010] Preferably, the ursodeoxycholic acid has a purity of ≥99% and a particle size D50 of 5-8 μm.

[0011] Another technical problem to be solved by the present invention is to provide a method for preparing an ointment-type bile acid preparation with excellent palatability, comprising the following steps: 1) Preparation of the phase change regulating layer: Hydrogenated palm oil (C16:0 content ≥90%) and medium-chain triglycerides (MCT, C8-C12 fatty acid content 85%) were compounded at a weight ratio of 3:7±0.5. The melt-cooling curve was precisely controlled by differential scanning calorimetry (DSC) to stabilize the phase change temperature of the formulation at 28-32℃. This temperature range ensures that the formulation remains solid at room temperature (25℃) for easy storage, while rapidly softening at the oral temperature of animals (38-39℃) to form a paste-like semi-fluid, eliminating the mechanical irritation of traditional tablets. 2) Construction of a sustained-release flavor system: Chicken flavor compounds were treated using β-cyclodextrin encapsulation technology, and ultrasonic-assisted encapsulation (300W power, 20min) was used to achieve an encapsulation rate >98%, forming inclusion microspheres with a diameter of 50-100nm. These microspheres interact with bile acid molecules through hydrogen bonds (FTIR detection showed a diameter of 3400cm). -1 (The hydroxyl absorption peak shifts) to form a supramolecular system, achieving continuous release of flavor substances (the release rate reaches 90% in artificial saliva after 8 hours), masking the bitterness of bile acids. 3) Mucosal adhesion agent compounding: Polyoxyethylene (40) hydrogenated castor oil and carbomer 940 were compounded at a weight ratio of 4:1. The viscosity of the system was controlled at 3500-4500 cP (37℃, shear rate 10s) by rotational viscometer. -1 This compound system undergoes hydrogen bond cross-linking in the oral saliva environment to form a viscous gel layer, which prolongs the oral retention time of the formulation to 8-10 minutes, providing sufficient time for drug absorption through the oral mucosa; 4) Ursodeoxycholic acid (UDCA) micronization: UDCA is pulverized to a particle size D50 of 5-8 μm and a specific surface area of ​​1.2 m² using airflow milling technology (nozzle pressure 0.8 MPa, classifier speed 12000 rpm). 2 / g increased to 5.6m 2 / g (BET detection) significantly improved the drug dissolution rate (the dissolution rate in pH 6.8 medium increased from 32% to 78% of the original powder in 15 min). 5) Compound Taurine Synergistic Process: Taurine and Vitamin B12 are added at a rate of 2-3% to form a complex (molar ratio 10:1). The complex was verified by ultraviolet spectrophotometry to enhance the absorption rate of fat-soluble vitamins (A, D3, E) by up to 40%, and to synergistically improve nutrient absorption disorders caused by liver and gallbladder diseases in animals. 6) Nanoscale bitterness shielding technology: 0.5% (w / w) of nano-silica (particle size 20-50 nm) was introduced. Scanning electron microscopy revealed that it formed a continuous physical barrier within the matrix, covering the surface of UDCA crystals, reducing the activation rate of the bitterness receptor TRPM5 by 78% (cell experiments detected Ca). 2+ (internal flow intensity); 7) Raw material pretreatment: Accurate weighing of active ingredients: Weigh 15.0000g of UDCA with a purity ≥99% and 3.0000g of compound taurine (taurine and vitamin B12 are premixed at a molar ratio of 10:1) using an analytical balance, and place them in the barrel of a sterilized high-shear emulsifier; Pretreatment of matrix raw materials: Measure 40.00g of MCT oil (GC detection shows C8-C12 fatty acid content of 85.2%) and 17.00g of hydrogenated palm oil (HPLC detection shows C16:0 content of 90.5%), transfer them to a stainless steel storage tank, and preheat to 40℃ to initially soften the palm oil; 8) Melt-dispersion process: Add the preheated base oil to the emulsifier barrel, turn on the temperature control system to raise the material temperature to 60℃±2℃, and disperse at a high speed of 8000rpm for 10min after the hydrogenated palm oil is completely melted. Monitor online with a laser particle size analyzer to ensure that UDCA is initially dispersed to D50 < 20μm; add 5.00g of β-cyclodextrin-encapsulated chicken flavoring (encapsulation rate 98.3%) and 0.500g of nano-silica (particle size 20nm, specific surface area 200m²) in steps. 2 (g), stir at low speed of 3000 rpm for 5 minutes to form a preliminary mixture. 9) Vacuum Homogenization Process: The mixture is transferred to a vacuum homogenizer, and the vacuum pump is turned on to reduce the pressure inside the chamber to -0.08MPa±0.01MPa, removing air from the system to prevent oxidation and deterioration. The homogenizer speed is set to 8000rpm, and the processing time is 15min. During this process, the cavitation effect is generated when the material passes through the slit by adjusting the homogenizing valve pressure (100-150bar), further refining the UDCA particles to D50=5-8μm and uniformly dispersing the nano-silica in the matrix (SEM observation shows that the silica particle spacing is <100nm). 10) Thickening and Molding Process: After homogenization, the circulating cooling water system was activated to reduce the material temperature to 45℃±1℃ at a rate of 5℃ / min. This temperature range ensures the fluidity of PEG-40 hydrogenated castor oil while preventing carbomer 940 degradation due to high temperatures. 8.00g of PEG-40 hydrogenated castor oil and 1.50g of carbomer 940 were added, and the mixture was stirred at 3000rpm until a semi-solid state was formed. Rheometer analysis showed that the storage modulus G' > 100Pa and the loss modulus G'' < 50Pa, exhibiting typical gel characteristics. 11) Post-processing: The ointment is sterilized by moist heat sterilization (115℃, 30min). The sterility of the preparation is ensured by microbial limit testing (total aerobic bacteria <100cfu / g, mold and yeast <10cfu / g). In a Class 100 clean area, the sterilized ointment is filled into aluminum-plastic composite tubes, 5g per tube. After sealing, the penetration test is performed (25℃, 10g weight, 5s). The qualified range is 120-150mm / 10g, and finally a light yellow homogeneous ointment is obtained.

[0012] Compared with the prior art, the present invention provides a palatable ointment-type bile acid preparation and its preparation method, which has the following beneficial effects: 1. This palatable ointment-type bile acid preparation and its preparation method utilize nano-sized silica (addition amount 0.5%) to form a physical barrier, reducing the activation rate of the bitter taste receptor TRPM5 by 78%. At the same time, the chicken flavor compound encapsulated by β-cyclodextrin (encapsulation rate > 98%) masks the bitterness of bile acids through intermolecular hydrogen bonds. Electronic tongue detection shows that the bitterness value is reduced from 9.8±0.7 in the original powder to 2.3±0.5.

[0013] 2. This palatable ointment-type bile acid preparation and its preparation method, through the phase change regulating layer (hydrogenated palm oil and MCT compounded in a 3:7 ratio) rapidly softens at the animal oral temperature (38-39℃), eliminating the mechanical stimulation of traditional tablets, and increasing the autonomous feeding rate from <60% of commercially available products to >92% (the autonomous feeding rate of dogs in clinical verification reached 91.7%). Polyoxyethylene (40) hydrogenated castor oil and carbomer 940 are compounded to form a mucosal adhesion layer (viscosity 3500-4500cP), which prolongs the retention time of the preparation in the oral cavity to 8-10 minutes, avoiding the refusal to eat behavior caused by rapid swallowing.

[0014] 3. This palatable ointment-type bile acid preparation and its preparation method: After micronization, the particle size D50 of UDCA is controlled at 5-8 μm, and the specific surface area is significantly increased. The cumulative release rate reaches 95% in 120 min in pH 6.8 medium, which is 13% higher than that of commercial tablets (82%). Vacuum homogenization process (-0.07 to -0.09 MPa, 8000-10000 rpm) ensures that UDCA crystals are uniformly coated with lipid matrix, reducing the first-pass effect loss in the digestive tract. Pharmacokinetic data show that AUC0-24h is 1.8 times higher than that of the original powder. Compound taurine (added amount 2-3%) can enhance the absorption rate of fat-soluble vitamins by 40%, and synergistically improve the nutritional metabolism of animals with hepatobiliary diseases with UDCA. After 4 weeks of clinical treatment, the ALT of affected dogs decreased by 68.3±5.2 U / L, which is significantly higher than that of commercial tablets (41.7±6.8 U / L).

[0015] 4. This palatable ointment-form bile acid preparation and its preparation method eliminate the hardness problem caused by traditional tablets, thus avoiding mechanical damage to the oral mucosa. Furthermore, the absence of a capsule shell prevents allergic reactions. The sterilization and filling process ensures the sterility of the preparation. Acute toxicity tests show an LD50 > 5g / kg, classifying it as practically non-toxic. Long-term toxicity tests showed no abnormalities in any animal organs. The ointment can be directly applied to the animal's mouth or food, eliminating the need for forced administration and reducing animal stress. It is suitable for companion animals such as dogs and cats, especially addressing the problem of felines refusing to eat due to their high taste sensitivity. By improving liver and gallbladder function and nutrient absorption, the preparation significantly improves tear stain problems in animals. Clinical trials showed an 88% improvement rate in tear stain index in affected dogs, a 56% increase compared to commercially available products (32%), meeting pet owners' needs for healthy animal appearance.

[0016] 5. The ointment-type bile acid preparation with excellent palatability and its preparation method have key process parameters (such as vacuum homogenization pressure, phase transition temperature, and viscosity) optimized by orthogonal experiments, with good repeatability. The prepared preparation has a stable penetration value of 120-150 mm / 10g and a phase transition temperature of 28-32℃, which is suitable for industrial production. Detailed Implementation

[0017] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. 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.

[0018] Example 1: A palatable ointment-type bile acid preparation, characterized by comprising the following materials: a phase change regulating layer composed of hydrogenated palm oil and medium-chain triglycerides, β-cyclodextrin encapsulating chicken flavor and forming intermolecular hydrogen bonds with bile acids, polyoxyethylene (40) hydrogenated castor oil, carbomer 940, a mucosal adhesive, a bitterness masking agent, ursodeoxycholic acid, and compound taurine. The phase change regulating layer is composed of hydrogenated palm oil and medium-chain triglycerides in a weight ratio of 3:7; the β-cyclodextrin encapsulation rate of the chicken flavor is greater than 98%; the viscosity of the mucosal adhesive is 3500-4500 cP; the bitterness masking agent is 0.5% nano-sized silica; and the purity of the ursodeoxycholic acid is ≥99%, with a particle size D50 of 5-8 μm.

[0019] A method for preparing an ointment-type bile acid preparation with excellent palatability, characterized by comprising the following steps: 1) Preparation of the phase change regulating layer: Hydrogenated palm oil (C16:0 content ≥90%) and medium-chain triglycerides (MCT, C8-C12 fatty acid content 85%) were compounded at a weight ratio of 3:7±0.5. The melt-cooling curve was precisely controlled by differential scanning calorimetry (DSC) to stabilize the phase change temperature of the formulation at 28-32℃. This temperature range ensures that the formulation remains solid at room temperature (25℃) for easy storage, while rapidly softening at the oral temperature of animals (38-39℃) to form a paste-like semi-fluid, eliminating the mechanical irritation of traditional tablets. 2) Construction of a sustained-release flavor system: Chicken flavor compounds were treated using β-cyclodextrin encapsulation technology, and ultrasonic-assisted encapsulation (300W power, 20min) was used to achieve an encapsulation rate >98%, forming inclusion microspheres with a diameter of 50-100nm. These microspheres interact with bile acid molecules through hydrogen bonds (FTIR detection showed a diameter of 3400cm). -1 (The hydroxyl absorption peak shifts) to form a supramolecular system, achieving continuous release of flavor substances (the release rate reaches 90% in artificial saliva after 8 hours), masking the bitterness of bile acids. 3) Mucosal adhesion agent compounding: Polyoxyethylene (40) hydrogenated castor oil and carbomer 940 were compounded at a weight ratio of 4:1. The viscosity of the system was controlled at 3500-4500 cP (37℃, shear rate 10s) by rotational viscometer. -1This compound system undergoes hydrogen bond cross-linking in the oral saliva environment to form a viscous gel layer, which prolongs the oral retention time of the formulation to 8-10 minutes, providing sufficient time for drug absorption through the oral mucosa; 4) Ursodeoxycholic acid (UDCA) micronization: UDCA is pulverized to a particle size D50 of 5-8 μm and a specific surface area of ​​1.2 m² using airflow milling technology (nozzle pressure 0.8 MPa, classifier speed 12000 rpm). 2 / g increased to 5.6m 2 / g (BET detection) significantly improved the drug dissolution rate (the dissolution rate in pH 6.8 medium increased from 32% to 78% of the original powder in 15 min). 5) Compound Taurine Synergistic Process: Taurine and Vitamin B12 are added at a rate of 2-3% to form a complex (molar ratio 10:1). The complex was verified by ultraviolet spectrophotometry to enhance the absorption rate of fat-soluble vitamins (A, D3, E) by up to 40%, and to synergistically improve nutrient absorption disorders caused by liver and gallbladder diseases in animals. 6) Nanoscale bitterness shielding technology: 0.5% (w / w) of nano-silica (particle size 20-50 nm) was introduced. Scanning electron microscopy revealed that it formed a continuous physical barrier within the matrix, covering the surface of UDCA crystals, reducing the activation rate of the bitterness receptor TRPM5 by 78% (cell experiments detected Ca). 2+ (internal flow intensity); 7) Raw material pretreatment: Accurate weighing of active ingredients: Weigh 15.0000g of UDCA with a purity ≥99% and 3.0000g of compound taurine (taurine and vitamin B12 are premixed at a molar ratio of 10:1) using an analytical balance, and place them in the barrel of a sterilized high-shear emulsifier; Pretreatment of matrix raw materials: Measure 40.00g of MCT oil (GC detection shows C8-C12 fatty acid content of 85.2%) and 17.00g of hydrogenated palm oil (HPLC detection shows C16:0 content of 90.5%), transfer them to a stainless steel storage tank, and preheat to 40℃ to initially soften the palm oil; 8) Melt-dispersion process: Add the preheated base oil to the emulsifier barrel, turn on the temperature control system to raise the material temperature to 60℃±2℃, and disperse at a high speed of 8000rpm for 10min after the hydrogenated palm oil is completely melted. Monitor online with a laser particle size analyzer to ensure that UDCA is initially dispersed to D50 < 20μm; add 5.00g of β-cyclodextrin-encapsulated chicken flavoring (encapsulation rate 98.3%) and 0.500g of nano-silica (particle size 20nm, specific surface area 200m²) in steps. 2 (g), stir at low speed of 3000 rpm for 5 minutes to form a preliminary mixture. 9) Vacuum Homogenization Process: The mixture is transferred to a vacuum homogenizer, and the vacuum pump is turned on to reduce the pressure inside the chamber to -0.08MPa±0.01MPa, removing air from the system to prevent oxidation and deterioration. The homogenizer speed is set to 8000rpm, and the processing time is 15min. During this process, the cavitation effect is generated when the material passes through the slit by adjusting the homogenizing valve pressure (100-150bar), further refining the UDCA particles to D50=5-8μm and uniformly dispersing the nano-silica in the matrix (SEM observation shows that the silica particle spacing is <100nm). 10) Thickening and Molding Process: After homogenization, the circulating cooling water system was activated to reduce the material temperature to 45℃±1℃ at a rate of 5℃ / min. This temperature range ensures the fluidity of PEG-40 hydrogenated castor oil while preventing carbomer 940 degradation due to high temperatures. 8.00g of PEG-40 hydrogenated castor oil and 1.50g of carbomer 940 were added, and the mixture was stirred at 3000rpm until a semi-solid state was formed. Rheometer analysis showed that the storage modulus G' > 100Pa and the loss modulus G'' < 50Pa, exhibiting typical gel characteristics. 11) Post-processing: The ointment is sterilized by moist heat sterilization (115℃, 30min). The sterility of the preparation is ensured by microbial limit testing (total aerobic bacteria <100cfu / g, mold and yeast <10cfu / g). In a Class 100 clean area, the sterilized ointment is filled into aluminum-plastic composite tubes, 5g per tube. After sealing, the penetration test is performed (25℃, 10g weight, 5s). The qualified range is 120-150mm / 10g, and finally a light yellow homogeneous ointment is obtained.

[0020] Following the optimized preparation method described above, 1000g of an ointment-type bile acid preparation was prepared. The specific process parameters are as follows: Vacuum homogenization: -0.08MPa, 9000rpm, 15min Phase change matrix ratio: 170g hydrogenated palm oil, 400g MCT oil Active ingredients: UDCA 150g, compound taurine 30g, nano SiO2 5g Mucosal adhesion agent: PEG-40 hydrogenated castor oil 80g, carbomer 940 15g The prepared formulation was tested and found to be: Physical properties: Penetration 132 mm / 10 g, phase transition temperature 29.5℃ Particle size distribution: UDCAD50 = 6.3 μm, nano-SiO2 is uniformly dispersed. Encapsulation efficiency: The β-cyclodextrin encapsulation material achieved an encapsulation efficiency of 98.6%. Microbiological indicators: Meets the requirements of the 2020 edition of the Chinese Veterinary Pharmacopoeia. Example 2: Clinical efficacy verification: Sixty dogs diagnosed with chronic hepatitis (ALT > 100 U / L, weight 5-10 kg) were randomly divided into an experimental group (n=30) and a control group (n=30), as follows: Experimental group: The formulation of this invention, 0.5g / dose, twice daily, orally. Control group: Commercially available UDCA tablets (hardness 60N), 50mg / time, twice daily, orally. Four weeks after treatment, the test results were as follows: Liver function indicators: The decrease in ALT in the experimental group was 68.3±5.2 U / L, while that in the control group was 41.7±6.8 U / L (P<0.01); the decrease in AST in the experimental group was 56.7±4.8 U / L, while that in the control group was 32.5±5.3 U / L (P<0.01).

[0021] Palatability evaluation: A double-blind method was used to observe the feeding behavior of animals. The spontaneous feeding rate in the experimental group was 91.7%, while that in the control group was only 53.3% (χ²). 2 =18.7, P<0.01).

[0022] Improvement of tear stains: The tear stain index was measured by an image analysis system. The improvement rate was 88% in the experimental group and 32% in the control group (P<0.01), and the difference was statistically significant.

[0023] In vitro dissolution and bioavailability study Dissolution comparison: In pH 6.8 phosphate buffer, the dissolution curve was determined by paddle method (100 rpm, 37℃). The cumulative release rate of the formulation of this invention reached 95% in 120 min, while that of commercial tablets was only 82%, with a significant difference (t=12.5, P<0.01).

[0024] Bioavailability: Six Beagle dogs were selected for a crossover experiment. The experimental group was given the formulation of this invention (0.5 g / dog), while the control group was given a commercially available powder (50 mg / dog). Blood samples were collected to determine the drug concentration. The results showed that the AUC0-24h of the experimental group was 22.3 μg·h / mL, while that of the control group was 12.1 μg·h / mL, representing a 1.8-fold increase in bioavailability (P < 0.01).

[0025] Safety assessment: Acute toxicity tests (mice, gavage dose 5 g / kg) and long-term toxicity tests (dogs, 0.5 g / kg·d, for 90 consecutive days) were conducted on the formulation of this invention. The results showed that: Acute toxicity: No animal deaths were reported; LD50 > 5 g / kg, classifying it as practically non-toxic.

[0026] Long-term toxicity: Histological examination of various organs showed no abnormalities, and blood biochemical indicators (ALT, AST, BUN, CREA, etc.) were all within the normal range, indicating that the preparation is safe.

[0027] The beneficial effects of this invention are: through the synergistic effect of multiphase matrix, palatability is improved (bitterness value is reduced to 2.3±0.5 vs. original powder 9.8±0.7, detected by electronic tongue), while bioavailability is improved (AUC0-24h increases by 1.8 times), thus having both therapeutic and cosmetic effects.

[0028] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A palatable ointment-type bile acid preparation, characterized in that: The product includes the following materials: a phase change regulating layer composed of hydrogenated palm oil and medium-chain triglycerides, β-cyclodextrin encapsulating chicken flavorings and forming intermolecular hydrogen bonds with bile acids, polyoxyethylene (40) hydrogenated castor oil, carbomer 940, mucosal adhesive, bitterness masking agent, ursodeoxycholic acid and compound taurine.

2. The ointment-type bile acid preparation with excellent palatability according to claim 1, characterized in that: The hydrogenated palm oil and medium-chain triglycerides are compounded in a weight ratio of 3:7 to form a phase change regulating layer, and the β-cyclodextrin encapsulates chicken flavor ingredients with an encapsulation rate of more than 98%.

3. The ointment-type bile acid preparation with excellent palatability according to claim 1, characterized in that: The viscosity of the adhesive film is 3500-4500 cP, and the bitterness masking agent is 0.5% nano-sized silica.

4. The ointment-type bile acid preparation with excellent palatability according to claim 1, characterized in that: The ursodeoxycholic acid has a purity of ≥99% and a particle size D50 of 5-8 μm.

5. The method for preparing a palatable ointment-type bile acid preparation according to any one of claims 1-5, characterized in that: Includes the following steps: 1) Preparation of the phase change regulating layer: Hydrogenated palm oil (C16:0 content ≥90%) and medium-chain triglycerides (MCT, C8-C12 fatty acid content 85%) were compounded at a weight ratio of 3:7±0.

5. The melt-cooling curve was precisely controlled by differential scanning calorimetry (DSC) to stabilize the phase change temperature of the formulation at 28-32℃. This temperature range ensures that the formulation remains solid at room temperature (25℃) for easy storage, while rapidly softening at animal oral temperature (38-39℃) to form a paste-like semi-fluid, eliminating the mechanical irritation of traditional tablets. 2) Construction of a sustained-release flavor system: Chicken flavor compounds were treated using β-cyclodextrin encapsulation technology, and ultrasonic-assisted encapsulation (300W, 20min) was used to achieve an encapsulation rate >98%, forming inclusion microspheres with a diameter of 50-100nm. These microspheres interact with bile acid molecules through hydrogen bonding (FTIR detection showed a diameter of 3400cm). -1 (The hydroxyl absorption peak shifts) to form a supramolecular system, achieving continuous release of flavor substances (the release rate reaches 90% in artificial saliva after 8 hours), masking the bitterness of bile acids; 3) Mucosal adhesion agent compounding: Polyoxyethylene (40) hydrogenated castor oil and carbomer 940 were compounded at a weight ratio of 4:

1. The viscosity of the system was controlled at 3500-4500 cP (37℃, shear rate 10s) by rotational viscometer. -1 This compound system undergoes hydrogen bond cross-linking in the oral saliva environment to form a viscous gel layer, which prolongs the oral retention time of the formulation to 8-10 minutes, providing sufficient time for drug absorption through the oral mucosa; 4) Ursodeoxycholic acid (UDCA) micronization: UDCA is pulverized to a particle size D50 of 5-8 μm and a specific surface area of ​​1.2 m² using airflow milling technology (nozzle pressure 0.8 MPa, classifier speed 12000 rpm). 2 / g increased to 5.6m 2 / g (BET detection), significantly improved drug dissolution rate (dissolution rate increased from 32% to 78% of the original powder in 15 min in pH 6.8 medium); 5) Compound Taurine Synergistic Process: Taurine and Vitamin B12 are added at a rate of 2-3% to form a complex (molar ratio 10:1). The complex was verified by ultraviolet spectrophotometry to enhance the absorption rate of fat-soluble vitamins (A, D3, E) by up to 40%, and to synergistically improve nutrient absorption disorders caused by liver and gallbladder diseases in animals. 6) Nanoscale bitterness shielding technology: 0.5% (w / w) of nano-silica (particle size 20-50 nm) was introduced. Scanning electron microscopy revealed that it formed a continuous physical barrier within the matrix, covering the surface of UDCA crystals, reducing the activation rate of the bitterness receptor TRPM5 by 78% (cell experiments detected Ca). 2+ (internal flow intensity); 7) Raw material pretreatment: Accurate weighing of active ingredients: Weigh 15.0000g of UDCA with a purity ≥99% and 3.0000g of compound taurine (taurine and vitamin B12 premixed at a molar ratio of 10:1) using an analytical balance, and place them in the barrel of a sterilized high-shear emulsifier; Pretreatment of matrix raw materials: Measure 40.00g of MCT oil (GC detection showed C8-C12 fatty acid content of 85.2%) and 17.00g of hydrogenated palm oil (HPLC detection showed C16:0 content of 90.5%), transfer them to a stainless steel storage tank, and preheat to 40℃ to initially soften the palm oil; 8) Melt-dispersion process: Add the preheated base oil to the emulsifier barrel, turn on the temperature control system to raise the material temperature to 60℃±2℃, and after the hydrogenated palm oil is completely melted, disperse at a high speed of 8000rpm for 10min. Monitor online with a laser particle size analyzer to ensure that UDCA is initially dispersed to D50<20μm; add 5.00g of β-cyclodextrin-encapsulated chicken flavoring (encapsulation rate 98.3%) and 0.500g of nano-silica (particle size 20nm, specific surface area 200m²) in steps. 2 (g), stir at a low speed of 3000 rpm for 5 minutes to form a preliminary mixture. 9) Vacuum Homogenization Process: The mixture is transferred to a vacuum homogenizer. The vacuum pump is turned on to reduce the pressure inside the chamber to -0.08MPa±0.01MPa, removing air from the system to prevent oxidation and deterioration. The homogenizer speed is set to 8000rpm, and the processing time is 15min. During this process, the cavitation effect is generated when the material passes through the slit by adjusting the homogenizing valve pressure (100-150bar), further refining the UDCA particles to D50=5-8μm and uniformly dispersing the nano-silica in the matrix (SEM observation shows that the silica particle spacing is <100nm). 10) Thickening and Molding Process: After homogenization, the circulating cooling water system is activated to reduce the material temperature to 45℃±1℃ at a rate of 5℃ / min. This temperature range ensures the fluidity of PEG-40 hydrogenated castor oil while preventing carbomer 940 degradation due to high temperatures. 8.00g of PEG-40 hydrogenated castor oil and 1.50g of carbomer 940 are added, and the mixture is stirred at 3000rpm until a semi-solid state is formed. Rheometer analysis shows that the storage modulus G' > 100Pa and the loss modulus G'' < 50Pa, exhibiting typical gel characteristics. 11) Post-processing: The ointment is sterilized by moist heat sterilization (115℃, 30min). The sterility of the preparation is ensured by microbial limit testing (total aerobic bacteria <100cfu / g, mold and yeast <10cfu / g). In a Class 100 clean area, the sterilized ointment is filled into aluminum-plastic composite tubes, 5g per tube. After sealing, the penetration test is performed (25℃, 10g weight, 5s). The acceptable range is 120-150mm / 10g, and a light yellow homogeneous ointment is finally obtained.