A tributyrin solid preparation and a preparation method thereof, and a feed additive comprising the solid preparation

Abstract

The application provides a tributyrin solid preparation and a preparation method thereof, and a feed additive containing the solid preparation, and belongs to the technical field of feed additives.The tributyrin and PLGA are dissolved in acetone, injected into a crystallization kettle through a nozzle under the condition of supercritical CO2, and the solvent is quickly extracted to form high-encapsulation-rate nanometer microspheres; the microspheres and an aqueous phase containing maltodextrin, hydroxypropyl-beta-cyclodextrin, gum arabic and the like are subjected to high-speed shearing and high-pressure homogenization treatment to form a submicron emulsion; finally, spherical microcapsule powder is prepared through spray drying, and the powder can be tabletted or filled into capsules.The solid preparation contains tributyrin, PLGA, a viscoelastic matrix and various functional excipients, has the characteristics of high encapsulation rate, uniform particle size, good stability and low water content, and when the solid preparation is used as a core component and is compounded with a protein carrier and a carbohydrate carrier, the prepared feed additive can effectively improve the processing stability, palatability and bioavailability of the tributyrin.

Description

Technical Field

[0001] This invention relates to the technical field, specifically to a solid preparation of tributyric acid glyceride and its preparation method, and a feed additive containing the solid preparation. Background Technology

[0002] Tributyrate is a triglyceride formed by the esterification of one glycerol molecule and three butyrate molecules. In vivo, it is hydrolyzed by lipases to release butyrate. Butyrate is a major energy source for intestinal epithelial cells and is crucial for maintaining intestinal barrier function, regulating gut microbiota, and exerting anti-inflammatory effects. Therefore, tributyrate, as a highly efficient butyrate delivery carrier, has broad application prospects in the prevention and adjuvant treatment of diseases such as colitis, irritable bowel syndrome (IBS), and even colorectal cancer.

[0003] However, tributylate is a colorless, oily liquid at room temperature with an extremely low melting point (approximately -75°C), making its development into conventional solid oral formulations (such as tablets and capsules) extremely difficult. Liquid formulations suffer from problems such as inaccurate dosage, poor stability, inconvenience in portability, and the inability to achieve colon-targeted delivery. Therefore, developing a solid formulation that can efficiently and stably encapsulate liquid tributylate in a solid matrix and achieve colon-targeted release is a key technological bottleneck in realizing its therapeutic value. Summary of the Invention

[0004] To address the above problems, the present invention provides a method for preparing a solid formulation of tributyric acid glyceride and a feed additive containing the solid formulation, characterized by comprising the following steps:

[0005] S1. Dissolve glyceryl tribaniate and PLGA in a 1:2-1:3 ratio at 100-150 mg / mL. -1 Acetone, in supercritical CO2 at 35-45℃ and 12-15 MPa, is dispensed via a nozzle at a rate of 2-3 mL / min. -1 The mixture is injected into a crystallization vessel, where acetone is rapidly extracted by CO2 to form microspheres with a particle size of 100-500 nm and an encapsulation rate of ≥90%. After purging with SC-CO2 for 30 min to remove residual solvent, the microspheres are collected.

[0006] S2. Add maltodextrin, hydroxypropyl-β-cyclodextrin compound, gum arabic, microcrystalline cellulose, sodium stearoyl lactylate, steviol glycosides, and sorbitol to purified water at a solid-liquid ratio of 1:3-1:4, stir at 50-60℃ for 15-20 min until completely swollen; then degas by sonication at 15 kHz for 5 min to obtain an aqueous phase system, and keep it at 40℃ for later use.

[0007] S3, at 1500 r·min -1 While stirring, the microspheres from step 1 were dispensed at a rate of 10 mL / min.-1 Slowly add the mixture to the aqueous phase system obtained in step 2, and start high-speed shearing to obtain a 5-10µm primary emulsion; then homogenize it twice under high pressure of 20MPa and temperature of 35-40℃ to refine the particles into a uniform emulsion of 0.5-2µm.

[0008] S4. Homogenize the emulsion at 15 mL / min -1 The air is fed into a spray drying tower with an inlet temperature of 150°C, an outlet temperature of 70-75°C, a negative pressure of -5kPa, and atomization at 400Hz through nozzles to form spherical microcapsule powder. After cyclone separation and recovery, the powder is dried at 25°C until the moisture content is ≤3%.

[0009] S5. Compress the powder into tablets, add 0.5-1.0wt% magnesium stearate, and complete the solid formulation.

[0010] Furthermore, in step S5, a capsule filling step is used instead of a powder compression step. An automatic filling machine is used to fill the empty capsules with powder at a dose of 200-300 mg / capsule, ensuring that the tributyric acid glyceride content in each capsule deviates by ≤±5%, and then the capsules are sealed.

[0011] Furthermore, the pressure of the supercritical carbon dioxide is limited to 13-15 MPa, and the purging step after microsphere collection uses a CO2 flow rate of 8-10 L·min. -1 The content of residual acetone in the microspheres was reduced to ≤0.1%.

[0012] Furthermore, the degassing step of the aqueous system employs an ultrasonic power of 150W, a frequency of 20kHz, and a processing time of 8min, and high-speed shear emulsification is performed immediately after degassing.

[0013] Furthermore, the inlet air temperature of the spray drying is controlled at 148-152℃ and the outlet air temperature is controlled at 68-72℃, and the average particle size of the final microcapsule powder is controlled at 1.2-1.8µm, and the moisture content is ≤2.5%.

[0014] This invention also provides a glyceryl tributylate solid formulation, prepared by the above-described method for preparing glyceryl tributylate solid formulations, comprising the following components:

[0015] Tributyric acid glyceride, with a mass fraction of 30% to 45%;

[0016] A polylactic acid-glycolic acid copolymer with a mass fraction of 20% to 35%;

[0017] Maltodextrin, hydroxypropyl-β-cyclodextrin complex, low-viscosity gum arabic, and microcrystalline cellulose constitute a viscoelastic matrix.

[0018] Sodium stearoyl lactylate is used as a dispersing agent;

[0019] Steviosides and sorbitol are used as sweeteners;

[0020] Magnesium stearate is used as a lubricating agent;

[0021] The residual acetone and water were removed by supercritical carbon dioxide precipitation and spray drying, and the final moisture content was ≤3%.

[0022] Furthermore, the mass fraction of the hydroxypropyl-β-cyclodextrin compound is 10% to 15%; the mass fraction of low-viscosity gum arabic is 2% to 4%; the mass fraction of microcrystalline cellulose is 3% to 6%; the mass fraction of sodium stearoyl lactylate is 0.8% to 1.5%; and the mass fraction of magnesium stearate is 0.5% to 1.0%.

[0023] This invention also proposes a feed additive containing a solid formulation of tributyric acid ester, comprising: a solid formulation of tributyric acid ester, with a mass fraction of 30%-45%; a protein carrier, with a mass fraction of 5%-12%; a carbohydrate carrier, with a mass fraction of 10%-20%; a processing aid, with a mass fraction of 0.1%-0.5%; a fluidizing agent, with a mass fraction of 0.5%-2%; a sweetness regulator, with a mass fraction of 0.5%-2%; functional trace elements, with a mass fraction of 0.01%-0.5%; and other excipients.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] This application utilizes a supercritical antisolvent method to prepare glyceryl tribanilate into nanoscale drug-loaded microspheres, improving dispersibility and inclusion rate; employs composite emulsification and high-pressure homogenization technologies to refine particle size and reduce surface oil content; and achieves solid-state formulation production through spray drying and molding processes, balancing stability and practicality. Attached Figure Description

[0026] Figure 1 Electron micrograph of the surface morphology of the glyceryl tribaniate-polymer drug-loaded microspheres prepared in Example 1;

[0027] Figure 2 The images show the effects of different scale ratios. Detailed Implementation

[0028] The present invention will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make several changes and improvements without departing from the concept of the present invention. These all fall within the protection scope of the present invention.

[0029] Tributyric acid glyceride, a natural short-chain fatty acid ester, is widely used in areas such as intestinal health regulation and nutrient absorption promotion. However, its high lipid solubility, poor stability, and low oral bioavailability limit its application in solid dosage forms. This invention combines the stable molding advantages of emulsification-spray drying with the precise particle size control of supercritical antisolvent precipitation. Through a four-step core process—supercritical drug-loaded microsphere preparation, composite emulsification homogenization, spray drying curing, and molding—a solid dosage form of tributyric acid glyceride with high drug loading, low surface oil content, good stability, and high bioavailability is constructed.

[0030] Example 1

[0031] Preparation method of glyceryl tartrate solid dosage form

[0032] 1. Supercritical antisolvent precipitation - preparation of glyceryl tartrate / PLGA drug-loaded nanospheres

[0033] First, glyceryl tributylate and PLGA are dissolved in acetone at a specific mass ratio to form a high-concentration oil phase mother liquor. Then, under supercritical carbon dioxide (SC-CO2) conditions, the oil phase is rapidly injected into a crystallization vessel through a high-pressure nozzle. This allows for strong extraction of acetone by the SC-CO2, resulting in a sharp decrease in the solubility of glyceryl tributylate and PLGA, leading to rapid precipitation and the formation of nanoscale drug-loaded microspheres with a controllable particle size range of 100-500 nm and an encapsulation efficiency exceeding 90%. The core function of this step is to transform the active oil phase into uniformly sized, surface-active microspheres, providing operable solid particles for subsequent aqueous dispersion and emulsification.

[0034] 2. Construction and pretreatment of the aqueous system

[0035] After the microspheres are prepared, they need to be dispersed in an aqueous system. Maltodextrin, compound cyclodextrin, gum arabic, microcrystalline cellulose, sodium stearoyl lactylate, steviol glycosides, and sorbitol are added to the aqueous formulation, and the mixture is fully swollen in a 50-60℃ water bath, allowing the cyclodextrin and other carriers to expand and acquire good inclusion capacity. Subsequently, ultrasonic degassing is used to eliminate air bubbles in the system and prevent voids from forming during subsequent emulsification. The viscosity, solid-liquid ratio (1:3-1:4), and presence of surfactants in this aqueous system provide the necessary viscoelastic environment for the uniform dispersion of the microspheres, enabling them to remain stable during subsequent high-speed shearing and high-pressure homogenization processes.

[0036] 3. Compound emulsification - two-stage homogenization

[0037] After the aqueous phase system is ready, the composite emulsification stage begins. First, the prepared nanospheres are slowly added to the preheated aqueous suspension (40°C) at a rate of 10 mL / min. -1 The feeding rate was adjusted to avoid localized aggregation. Subsequently, the feed rate was increased to 1500 rpm.-1 Start the high-speed shear emulsifier (2800 rpm) while stirring. -1 After shearing for 15 minutes, a milky white primary emulsion is formed with a particle size of approximately 5-10 µm. At this stage, the emulsion is still coarse, with a relatively loose particle distribution. To further refine the particle size and improve uniformity, a secondary homogenization is required: the primary emulsion is fed into a high-pressure homogenizer, set to a pressure of 20 MPa, circulated twice for 5 minutes each time, and the temperature is controlled at 35-40°C using jacket cooling water to prevent emulsifier deactivation. The impact, shearing, and cavitation effects of high-pressure homogenization further compress the particle size to 0.5-2 µm, significantly reducing the oil content and improving the surface smoothness of the microcapsules. This step achieves a complete transformation from oil-phase microspheres to aqueous emulsification to particle size refinement, enabling the microspheres to form uniform and fine composite particles in the aqueous phase, providing an ideal atomization matrix for subsequent drying.

[0038] 4. Spray drying - curing and molding

[0039] The refined emulsion is then cured in a spray drying tower. The core principle of spray drying is to atomize the emulsion into fine droplets, rapidly evaporate the solvent in hot air (inlet 150℃, outlet 70-75℃), and solidify PLGA and glyceryl tartrate into spherical microcapsule powder inside the droplets. Negative pressure (approximately -5kPa) and high-speed atomization (400Hz) ensure that the droplets dry quickly, preventing thermal degradation of the active ingredients. A cyclone separator recovers the fine powder, with an overall yield exceeding 99%, and the powder is placed in a dryer to cool to room temperature to prevent moisture absorption. This step transforms the composite particles in the emulsion into a dry, stable solid powder, providing a directly usable raw material form for subsequent tableting or filling.

[0040] 5. Molding

[0041] The dried microcapsule powder can be further processed into a final dosage form according to product requirements. If tableting is used, 0.5-1.0 wt% magnesium stearate is added to the powder as a lubricant, and the powder is compressed using a tablet press at 5-8 MPa to obtain tablets with a hardness of 3-5 kgf and a disintegration time ≤30 min, ensuring rapid release of the active ingredient after oral administration. If capsule filling is used, an automatic filling machine is used to fill empty capsules with the powder at a dosage of 200-300 mg / capsule, ensuring that the tributyrate content in each capsule deviates by ≤±5%, followed by sealing to prevent powder leakage. Whether tableting or filling, the goal is to transform the microcapsule powder obtained in the preceding steps into a final, consumer-ready solid dosage form.

[0042] Example 2

[0043] Supercritical process parameter verification

[0044] Fixed baseline conditions: glyceryl tartrate to PLGA ratio 1:2.5, acetone concentration 125 mg / mL -1 Nozzle velocity 2.5 mL·min -1 SC-CO2 purging for 30 min at a flow rate of 9 L / min -1 .

[0045] Example 2-1: Supercritical parameters set to 12 MPa / 35℃

[0046] Under the fixed basic conditions described above, glyceryl tartrate and PLGA were dissolved in acetone and injected into a crystallization vessel through a nozzle at 35°C and 12MPa supercritical CO2 environment. After extraction, the mixture was purged with SC-CO2 and the microspheres were collected.

[0047] Measurement results:

[0048] detection indicators numerical values Particle size distribution (D10 / D50 / D90) 85nm / 220nm / 480nm Encapsulation rate 88.2% Residual acetone content 0.12%

[0049] Under these parameters, the microsphere size distribution is relatively wide, the encapsulation efficiency is close to but not ≥90%, and the residual acetone slightly exceeds the requirement of ≤0.1%, which needs to be optimized.

[0050] Example 2-2: Supercritical parameters set to 13.5 MPa / 40℃

[0051] The operation steps are the same as in Example 2-1, except that the supercritical conditions are adjusted to 40℃ and 13.5MPa.

[0052] Measurement results:

[0053] detection indicators numerical values Particle size distribution (D10 / D50 / D90) 110nm / 280nm / 420nm Encapsulation rate 94.5% Residual acetone content 0.08%

[0054] Under these parameters, the microspheres have a uniform particle size distribution, a D50 in the middle range of 100-500nm, an encapsulation rate of ≥90%, and residual acetone of ≤0.1%, meeting the core indicator requirements.

[0055] Examples 2-3: Supercritical parameters set to 15 MPa / 45℃

[0056] The operation steps are the same as in Example 2-1, except that the supercritical conditions are adjusted to 45℃ and 15MPa.

[0057] Measurement results:

[0058] detection indicators numerical values Particle size distribution (D10 / D50 / D90) 130nm / 310nm / 390nm Encapsulation rate 93.8% Residual acetone content 0.06%

[0059] Under these parameters, the microspheres have a more concentrated particle size, and the encapsulation efficiency and residual acetone meet the standards. However, compared with 13.5 MPa / 40℃, the energy consumption is higher and there is no significant performance improvement.

[0060] Determination of the optimal parameter range: Based on the three sets of data, 13.5-15MPa / 40-45℃ is the optimal range for the supercritical process, among which 13.5MPa / 40℃ is the parameter combination with the highest cost performance.

[0061] Example 3

[0062] Trisuccinate solid dosage form

[0063] This formulation uses glyceryl tributylate as the active ingredient and polylactic-co-glycolic acid copolymer (PLGA) as the drug-carrying polymer, supplemented with various food-grade excipients to form a stable microcapsule powder, which can ultimately be compressed into tablets or filled into capsules. Its specific composition is as follows:

[0064] Active ingredient: Tributyrate, 30%-45% by mass. This fatty acid ester provides the main functional oil and requires high encapsulation (≥90%) in microspheres.

[0065] Drug-loaded polymer: Polylactic acid-glycolic acid copolymer (PLGA), molecular weight 5000-10000 Da, mass fraction 20%-35%. PLGA co-precipitates with glyceryl tartrate in a supercritical carbon dioxide environment to form uniformly sized nanospheres, which play a role in controlled release and protection of the active ingredient.

[0066] Sweeteners / flavoring agents: Steviosides (≥90%), 0.5%-1.5% by mass; Sorbitol, 1%-3% by mass. Together, they impart natural sweetness and fruity aroma to the formulation, enhancing its palatability.

[0067] Viscoelastic matrix: 10%-15% by mass of maltodextrin (DE15-20) and compound cyclodextrin (β-cyclodextrin:hydroxypropyl-β-cyclodextrin = 1:1); 2%-4% by mass of low-viscosity gum arabic; and 3%-6% by mass of microcrystalline cellulose. These polysaccharides and cellulose form a high-viscosity, well-swellable matrix in the aqueous phase, which can fully encapsulate the nanospheres, prevent aggregation, and improve emulsion stability.

[0068] Emulsifying / dispersing agent: Sodium stearoyl lactylate, mass fraction 0.8%-1.5%. This surfactant reduces interfacial tension during high-speed shearing and high-pressure homogenization, enabling the microspheres to be uniformly dispersed in the aqueous phase, ultimately yielding fine composite particles with a particle size of 0.5-2µm.

[0069] Tableting aid: Magnesium stearate, mass fraction 0.5%-1.0%. Its function is to reduce powder friction, ensure smooth tableting, achieve a tablet hardness of 3-5 kgf, and a disintegration time ≤30 min. This tableting aid is only used during the tableting process.

[0070] Dehumidifiers: Acetone with a water content ≤0.5% is used for supercritical precipitation; purified water is used for aqueous phase preparation and has been completely removed in the final product, serving only to dissolve, extract and degas in the process.

[0071] After mixing the above components according to the stated mass fraction range, the mixture undergoes supercritical antisolvent precipitation, composite emulsification-secondary homogenization, and spray drying processes to obtain microcapsule powder with a particle size of 1-2 µm and a moisture content of ≤3%. This powder can be directly used for tableting or capsule filling to form oral solid dosage forms, exhibiting good flowability, uniform distribution of active ingredients, and controllable release characteristics, meeting the quality requirements of food / health products or functional drugs.

[0072] Example 4

[0073] Feed additives containing glyceryl tartrate solid formulations

[0074] In feed additives containing tributylate solid formulations, in addition to the core active ingredient tributylate solid formulation, excipients are added to achieve functions such as carrier, anti-caking, thickening, palatability improvement, and nutritional fortification. The excipient components mainly include:

[0075] 1. Protein carriers

[0076] Casein, whey protein isolate, sodium caseinate, or any combination thereof can provide good emulsification / encapsulation capabilities and improve amino acid supply.

[0077] 2. Carbohydrate carriers

[0078] Carbohydrate carriers can be selected from any one or a combination of the following: maltodextrin, solid corn syrup, resistant dextrin, maltose, polydextrose, glucose syrup, etc., to adjust viscosity, improve powder flowability and serve as an energy source.

[0079] Other traditional carriers, such as starch, corn starch, and dextrin, are often used as carriers or fillers in enterprise standards.

[0080] 3. Processing aids

[0081] Alkaline additives such as sodium hydroxide and potassium hydroxide can adjust the pH of the system and promote the dissolution or cross-linking of proteins or carbohydrates.

[0082] 4. Fluidizing agent

[0083] Silica, vermiculite, maifanite, tricalcium phosphate, diatomaceous earth, light calcium carbonate powder, talc, bentonite, etc., are used to prevent powder from clumping and improve flowability.

[0084] 5. Sweeteners

[0085] Steviosides, sorbitol, and food flavorings can improve animal feed intake.

[0086] 6. Functional Trace Elements

[0087] Vitamin E, selenium, zinc, etc., can be added in small amounts to the formula as needed to achieve nutritional fortification.

[0088] 7. Other auxiliary materials

[0089] Silica gel, zeolite, activated carbon, glycerin, etc., are used to adjust hygroscopicity or provide additional moisture-proof functions.

[0090] In a preferred embodiment, the specific composition of the feed additive is as follows: 30% glyceryl tartrate, 25% PLGA as a microsphere carrier, 10% maltodextrin as a carbohydrate carrier, 5% sodium caseinate as a protein carrier, 2% silicon dioxide as an anti-caking agent, 0.8% steviol glycosides as a sweetener, 0.1% vitamin E as a functional additive, and the remainder is purified water and acetone, controlled to be ≤0.5%.

[0091] Example 5

[0092] Validation Examples of Hydroxypropyl-β-Cyclodextrin Complex

[0093] The aqueous phase was kept at a solid-liquid ratio of 1:3.5, stirred at 55℃ for 18 min, and then ultrasonically degassed at 150W, 20kHz for 8 min.

[0094] Example 5-1: Combination of compound ratio and degree of substitution

[0095] Four compounding schemes were set up, with β-cyclodextrin:hydroxypropyl-β-cyclodextrin = 1:1 / 1:2 and degree of substitution DS = 0.6 / 1.0. The compound was prepared into an aqueous phase with maltodextrin, gum arabic, etc. in step S2. Microspheres prepared by supercritical fluid extraction were added, and the inclusion rate was measured after high-speed shearing. The emulsion stability was measured after standing for 24 hours.

[0096] Measurement results:

[0097] β-Cyclodextrin: Hydroxypropyl-β-Cyclodextrin Substitution DS Inclusion rate Centrifugation separation time for emulsification stability 1:1 0.6 87.3% 12h 1:1 1.0 92.5% 28h 1:2 0.6 89.1% 18h 1:2 1.0 94.2% 35h

[0098] Conclusion: The optimal solution is a degree of substitution (DS) of 1.0 and a compounding ratio of 1:1.5, which can balance inclusion rate and emulsification stability. The hydroxypropyl-β-cyclodextrin compound can be clearly identified as this specification.

[0099] Verification of specific maltodextrin models, fixed aqueous phase formulation: maltodextrin accounts for 30% of the viscoelastic matrix, and other excipients are in the proportions specified in step S2.

[0100] Example 3-2: Maltodextrins with different DE values

[0101] Operating steps: Select three types of maltodextrin (DE15, DE20, DE18), prepare an aqueous phase according to step S2, and measure the viscosity of the viscoelastic matrix at 40°C using a rotational viscometer; after emulsifying the aqueous phase with microspheres (same as in Example 5-1), spray dry with an inlet air temperature of 150°C and an outlet air temperature of 72°C, and calculate the microcapsule formation rate: collected powder mass / theoretical powder mass × 100%.

[0102] Measurement results:

[0103] Maltodextrin Models Viscosity at 40℃ (mPa·s) Microcapsule formation rate DE15 850 96.8% DE20 620 93.5% DE18 730 95.2%

[0104] Conclusion: DE15 maltodextrin is the optimal choice, as its viscosity ensures uniform dispersion of microspheres and the highest microcapsule formation rate (≥96%), making it the recommended specification for maltodextrin. If viscosity adjustment is required, DE18 maltodextrin can be used as a substitute.

[0105] Comparative Example 1: Conventional emulsification spray drying method, without supercritical microsphere preparation steps.

[0106] The purpose of Comparative Example 1 is to verify the necessity of the core step in this invention—the supercritical antisolvent precipitation method for preparing drug-loaded nanospheres. Comparative Example 1 employs a conventional technique involving the direct emulsification of liquid tricresyl ester.

[0107] Preparation method:

[0108] (1) Step S1 in this invention is omitted.

[0109] (2) The liquid glyceryl tartrate is directly mixed with the aqueous phase prepared in step S2.

[0110] (3) The high-speed shearing and high-pressure homogenization of step S3 are carried out directly to form an emulsion.

[0111] (4) The subsequent steps are spray drying in step S4 and tableting in step S5.

[0112] In Comparative Example 1, due to the lack of protection from PLGA-formed nanospheres, glyceryl tribaniate was more easily exposed on the surface of the emulsion droplets during emulsification. During spray drying, it was prone to volatilization, oxidation, or migration to the particle surface, resulting in a significantly lower encapsulation efficiency (≥90%) compared to the present invention. Direct emulsification of the liquid oil phase easily leads to oil-to-powder separation during drying, resulting in powder agglomeration, poor flowability, and poor storage stability. Controlling the droplet size in direct emulsification is difficult, resulting in a wider droplet distribution and making it hard to achieve the 0.5-2µm uniformity of the present invention, thus affecting the product's solubility and bioavailability.

[0113] Comparative Example 2: Homogenization without high pressure

[0114] Comparative Example 2 aims to verify the importance of high-pressure homogenization as a key step in obtaining uniform, fine emulsions, which in turn form ideal microcapsules.

[0115] Preparation method

[0116] (1) Microspheres are prepared according to step S1 of the present invention.

[0117] (2) Prepare the aqueous phase according to step S2.

[0118] (3) In step S3, only high-speed shearing is performed to prepare the primary emulsion (5-10µm), but the subsequent two high-pressure homogenization processes at 20MPa are omitted.

[0119] (4) The primary emulsion is directly spray-dried in S4 and tableted in S5.

[0120] Comparative Example 2 showed coarse and uneven particle size: the primary emulsion subjected only to high-speed shearing had a large particle size (5-10µm) and uneven distribution. After direct spray drying, the resulting microcapsule powder also had a correspondingly large and uneven particle size; poor physical stability: the coarse droplets were more prone to aggregation, sedimentation, or stratification before spray drying, leading to poor production reproducibility and large batch-to-batch variations. Uncontrollable release behavior: the larger particle size slowed down its disintegration and release rate in gastrointestinal fluids, potentially preventing the achievement of the desired rapid release effect.

[0121] Comparative Example 3: Using a single wall material, without PLGA and composite matrix

[0122] Comparative Example 3 was used to verify the synergistic effect of the composite system composed of PLGA and various excipients such as maltodextrin and hydroxypropyl-β-cyclodextrin used in this invention, especially the function of PLGA in colon-targeted release.

[0123] Preparation method

[0124] (1) Replace the wall material PLGA in step S1 with an equal amount of maltodextrin and dissolve it together with glyceryl tartrate in acetone.

[0125] (2) Attempts were made to carry out supercritical processes, but because maltodextrin behaves differently in acetone and supercritical CO2 than PLGA, it may not be able to form dense microspheres.

[0126] (3) The subsequent steps are the same as those in the original patent.

[0127] Comparative Example 3: Microsphere formation is difficult or the structure is loose. Maltodextrin is not a typical synthetic biodegradable polymer. Its sphericity and encapsulation effect in the supercritical antisolvent process are far inferior to PLGA, which may lead to a sharp decrease in encapsulation efficiency. Lack of colon-targeting: Common excipients such as maltodextrin can be rapidly enzymatically hydrolyzed in the stomach and small intestine. Lacking PLGA, a polymer that is stable in the upper digestive tract and degrades only under the action of colonic microbial enzymes, the formulation will prematurely release tributyrate in the upper digestive tract, failing to achieve the core function of colon-targeted delivery. Insufficient mechanical strength: Microspheres or microcapsules formed from single maltodextrin may have poor mechanical strength and are easily broken during tableting, leading to stability problems.

[0128] like Figure 2 As shown, the effects of different comparative ratios were compared. The vertical axis represents the initial release rate of tributylate. The red line represents the initial release rate of the solid tributylate formulation prepared in Example 1 of this invention in the intestine, and the blue lines represent the initial burst release data of the three comparative ratios. It can be seen that this invention uses PLGA as the core wall material, combined with other excipients to form a viscoelastic matrix. This not only ensures efficient encapsulation and spheroidization, but more importantly, it utilizes the pH-sensitive and enzymatic hydrolysis characteristics of PLGA to achieve colon-targeted release of tributylate, greatly improving its effectiveness and specificity as an intestinal regulator.

[0129] As can be seen from the three comparative examples above, in the technical solution of this invention, supercritical antisolvent technology solves the problems of primary encapsulation and nano-sizing of liquid active ingredients; high-pressure homogenization technology ensures the homogeneity and stability of the formulation intermediates; and the composite excipient system endows the product with the advanced function of colon-targeted release. The absence of any key step or the replacement of core materials will lead to a regression in the product's encapsulation efficiency, stability, or functional properties.

[0130] Specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various changes or modifications within the scope of the claims, which do not affect the essence of the present invention. Unless otherwise specified, the embodiments and features described in this application can be arbitrarily combined with each other.

Claims

1. A process for the preparation of a solid formulation of tributyrin, characterized in that, Comprising the following steps: S1, dissolve tributyrin and PLGA in 100-150 mg·mL -1 acetone, in supercritical CO2 at 45℃, 15 MPa, with nozzle at a speed of 2-3 mL·min -1 inject into crystallization kettle, acetone is quickly extracted by CO2 to form microspheres with a particle size of 100-500 nm and an encapsulation rate of ≥90%; collect after blowing off residual solvent for 30 min; S2, maltodextrin, hydroxypropyl-β-cyclodextrin complex, gum arabic, microcrystalline cellulose, sodium stearoyl lactylate, stevioside, sorbitol are added to purified water according to the solid-liquid ratio of 1:3-1:4, stirred at 50-60℃ for 15-20min until completely swollen; then 15kHz, 5min ultrasonic degassing, get water phase system, keep 40℃ for standby; The complexing ratio of hydroxypropyl-β-cyclodextrin complex is β-cyclodextrin: hydroxypropyl-β-cyclodextrin = 1:1.5, degree of substitution DS = 1.0; S3, at 1500 r·min -1 The microspheres of step 1 were added to the aqueous phase system obtained in step 2 at 10 mL·min -1 The microspheres of step 1 were added to the aqueous phase system obtained in step 2 at 10 mL·min The microspheres of step 1 were added to the aqueous phase system obtained in step 2 at 10 mL·min S4, the homogeneous emulsion was fed into the spray drying tower at 15 mL·min -1 with an inlet air temperature of 150℃, an outlet air temperature of 70-75℃, a negative pressure of -5 kPa, and a nozzle frequency of 400 Hz for atomization to form spherical microcapsule powder; after cyclone separation and recovery, the product was dried at 25℃ until the water content was ≤3%. S5, powder tabletting, add 0.5-1.0wt% magnesium stearate, complete solid preparation; The mass fraction of tributyrin in the solid preparation is 30% to 45%; The mass fraction of PLGA is 20% to 35%; The mass fraction of hydroxypropyl-β-cyclodextrin complex is 10% to 15%; The mass fraction of gum arabic is 2% to 4%; The mass fraction of microcrystalline cellulose is 3% to 6%; The mass fraction of sodium stearoyl lactate is 0.8% to 1.5%; The mass fraction of stevioside is 0.5%-1.5%; The mass fraction of sorbitol is 1%-3%.

2. The process for the preparation of tributyrin solid formulation as claimed in claim 1 wherein, In the step S5, the capsule filling step is used instead of the powder tabletting step. The powder is filled into the hollow capsule at a dose of 200-300mg / grain using an automatic filling machine to ensure that the content of tributyrin in each grain deviates by ≤±5%, and then the sealing process is carried out.

3. The process for the preparation of tributyrin solid formulation as claimed in claim 1 wherein, The pressure of the supercritical carbon dioxide is limited to 13-15 MPa, and the purging step after the microsphere collection uses a CO2 flow rate of 8-10 L·min -1 , reducing the content of residual acetone in the microspheres to ≤0.1%.

4. The process for the preparation of tributyrin solid formulation as claimed in claim 1, wherein, The degassing step of the water phase system uses ultrasonic power of 150W, frequency of 20kHz, and processing time of 8min, and high-speed shearing emulsification is carried out immediately after degassing.

5. The method of preparing a tributyrin solid formulation according to claim 1, characterized in that, The inlet air temperature of the spray drying is controlled at 148-152℃, and the outlet air temperature is controlled at 68-72℃. The average particle size of the microcapsule powder obtained finally is controlled at 1.2-1.8µm, and the water content is ≤2.5%.

6. A solid state formulation of tributyrin characterized in that, Prepared by the preparation method of claim 1, comprising the following components: Tributyrin, mass fraction 30% to 45%; Polylactic acid-glycolic acid copolymer, mass fraction 20% to 35%; Maltodextrin, hydroxypropyl-β-cyclodextrin complex, low viscosity gum arabic and microcrystalline cellulose, which constitute a viscoelastic matrix; Sodium stearoyl lactate is used as a dispersing aid; Stevioside and sorbitol are used as sweeteners; Magnesium stearate is used as a lubricating aid; Residual acetone and water removed after supercritical carbon dioxide precipitation and spray drying, final water content ≤3%.

7. The tributyrin solid-state formulation according to claim 6, characterized in that, The mass fraction of hydroxypropyl-β-cyclodextrin complex is 10% to 15%; The mass fraction of low viscosity gum arabic is 2% to 4%; The mass fraction of microcrystalline cellulose is 3% to 6%; The mass fraction of sodium stearoyl lactate is 0.8% to 1.5%; The mass fraction of magnesium stearate is 0.5% to 1.0%.

8. A feed additive comprising a tributyrin solid formulation, characterized in that, Comprising: The solid preparation of tributyrin prepared by the preparation method of any one of claims 1-5, the mass fraction of which is 30%-45%; the mass fraction of the protein carrier is 5%-12%; the mass fraction of the carbohydrate carrier is 10%-20%; the mass fraction of the processing aid is 0.1%-0.5%; the mass fraction of the fluidizing agent is 0.5%-2%; the mass fraction of the sweet taste regulator is 0.5%-2%; the mass fraction of the functional trace element is 0.01%-0.5%; and the mass fraction of other auxiliary materials is 0.01%-0.5%.

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