Preparation process of medium-chain triglyceride composition and medium-chain triglyceride composition

Abstract

The invention belongs to the field of biological pharmaceutical carrier materials, and particularly relates to a preparation process of a medium-chain triglyceride composition and the medium-chain triglyceride composition. The composition comprises basic medium-chain triglyceride, medium-chain and long-chain triglyceride, two inorganic modified silicon dioxide, an interface stabilizer, an antioxidant and a fluidity regulator. The core of the method is that two kinds of modified silicon dioxide are firstly prepared, wherein one kind of modified silicon dioxide is that ethylenediamine tetraacetic acid is grafted to the surface of mesoporous silicon dioxide through silanization and subsequent amidation reaction; and the other method is as follows: under the catalysis of acetic acid, glycidyl ether oxypropyl trimethoxy silane is hydrolyzed and is subjected to ring-opening reaction with decenol, and meanwhile, the silane part is condensed with the surface of fumed silica. And finally, mixing the two modified materials with lipid and other components, and carrying out dispersing and grinding processes to obtain the final product. The inorganic modified component with a specific structure is introduced, so that the physical stability and the functional applicability of the composition are remarkably improved, and the composition is suitable for the fields of foods, medicines or cosmetics.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biopharmaceutical carrier materials, and particularly relates to a preparation process of a medium-chain triglyceride composition and the medium-chain triglyceride composition. BACKGROUND

[0002] Medium-chain triglycerides, i.e. triglycerides mainly composed of medium-chain fatty acids, play an important role in the fields of biological medicine and functional food. They can be rapidly oxidized for energy supply in the liver through the portal vein without relying on carnitine transport, which endows them with the remarkable advantages of rapid metabolism, difficulty in accumulation in the body, and complete oxidation. These characteristics make medium-chain triglycerides an extremely attractive drug carrier, parenteral nutrition energy source, and delivery medium for fat-soluble active ingredients. In the field of biological drug manufacturing, high requirements are placed on the physical stability, biocompatibility, and functional designability of carrier systems. Medium-chain triglycerides are considered as a potential basic lipid material due to their good safety record and metabolic characteristics, and are widely studied for the construction of fat emulsions, lipid nanoparticles, and self-emulsifying drug delivery systems in order to improve the solubility and bioavailability of poorly soluble drugs, or to achieve specific targeting and sustained-release functions.

[0003] Although medium-chain triglycerides have the above-mentioned inherent advantages, they still face a series of prominent technical bottlenecks and challenges in actual applications, especially in high-demand biological pharmaceutical formulations. First, their physical stability is often insufficient, and pure products or simple formulations are prone to lipid crystal morphology transformation, phase separation, or Ostwald ripening during storage, resulting in poor formulation uniformity, broadened particle size distribution, and direct impact on the quality controllability and shelf life of the drug. Second, the chemical and interfacial properties of conventional medium-chain triglycerides are relatively simple, lacking functional sites that can specifically and strongly bind to diverse drug molecules (especially polar or amphoteric molecules), which limits the drug loading capacity and leads to drug leakage, making it difficult to meet the needs of complex drug delivery systems. Third, some formulations may cause local tissue irritation or inflammatory reactions when used for a long time or in large quantities, and their biocompatibility needs to be further improved. Currently, some studies attempt to improve some defects by physically mixing additional stabilizers or blending with other lipids, but often sacrifice other properties when improving a certain property, such as reducing drug loading efficiency to improve stability, and fail to fundamentally endow the carrier with adjustable and diversified interaction capabilities. The existing technology has not yet provided a medium-chain triglyceride composition solution that can simultaneously and systematically solve the complex problems of stability, functionalization, and biocompatibility.

[0004] Therefore, there is an urgent need in this field for an innovative preparation process and composition of medium-chain triglycerides (MCTs), which should retain the core advantage of rapid metabolism of MCTs while overcoming the limitations of existing technologies. An ideal new system should possess a highly stable physical state, capable of resisting the adverse effects of long-term storage and temperature changes; it should incorporate designable and tunable multifunctional sites to broaden its ability to efficiently load and stably bind drugs of different properties; furthermore, the overall composition should exhibit superior biocompatibility. By employing molecular design and materials engineering strategies, organically combining precisely surface-modified inorganic nanounits with a MCT lipid matrix is ​​expected to synergistically enhance the overall performance of the composite system. The key to developing such compositions lies in designing and preparing inorganic modified materials with well-defined structures, good lipid phase compatibility, and specific functional groups on their surfaces, and developing a reliable process that can uniformly and stably integrate them into the lipid matrix. This will create a novel functionalized lipid carrier platform with performance exceeding existing products, meeting the growing demands of the high-end biopharmaceutical manufacturing field. Summary of the Invention

[0005] In view of the shortcomings of the prior art, the purpose of this invention is to provide a preparation process for a medium-chain triglyceride composition and a medium-chain triglyceride composition.

[0006] In a first aspect, the present invention provides a process for preparing a medium-chain triglyceride composition, comprising the steps of: S1. By weight, add 60-85 parts of octanoic acid / capric acid medium-chain triglycerides and 10-25 parts of medium- and long-chain triglycerides to a reaction vessel, heat to 48-50℃, and stir to obtain a premix; heat the premix to 64-66℃, add 1-8 parts of medium-chain monoglycerides and 2-10 parts of diglycerides, and continue stirring to obtain a lipid phase mixture; add 0.5-5 parts of 3-aminopropyltriethoxysilane-ethylenediaminetetraacetic acid modified silica and 0.5-5 parts of 9-decenoxypropyl modified silica hybrid material, which have been dried at 78-82℃ beforehand, to the lipid phase mixture, and stir at 68-72℃ to obtain an oil phase dispersion; S2. Transfer the oil phase dispersion to a ball mill and grind it at 30-40℃. Cool it down to 38-42℃, add 0.05-0.5 parts of mixed tocopherol, and continue stirring. Filter under nitrogen protection.

[0007] In this invention, the formation of the medium-chain triglyceride composition essentially involves constructing a kinetically stable dispersion system of inorganic particles in a hydrophobic lipid phase. After the basic lipids are melt-mixed, monoglycerides and diglycerides are pre-dissolved as interfacial active components, and their polar ends can weakly interact with the surface groups of the subsequently added modified silica. Two types of functionalized silica are added after thorough drying: the long alkyl chains of the alkenyl ether-modified material are tightly compatible with the lipid molecules through van der Waals forces; although the amino chelate-modified material contains polar groups, the drying process eliminates moisture interference and avoids aggregation in the oil phase. Under the action of continuous shearing and ball milling mechanical forces, the particles are deagglomerated and uniformly distributed. The surfactant molecules are directionally adsorbed at the particle-oil phase interface, with the polar ends anchoring the particle surface and the non-polar ends extending into the oil phase to form a steric barrier, effectively preventing particle re-agglomeration. The mixed tocopherols added after cooling are completely dissolved in the lipid phase, quenching free radicals through hydrogen atom transfer, and significantly delaying the oxidation process in conjunction with nitrogen protection. The final system was precisely filtered to obtain a uniform and transparent ultrafine dispersion. The two modified silicas and surfactants synergistically constructed a long-term stable structure. Its excellent oxidative stability and dispersion uniformity provide reliable technical support for food carriers, pharmaceutical excipients and cosmetic systems.

[0008] According to a preferred embodiment of the present invention, in step S1, the stirring time at 68-72°C is 60-80 min; the diglyceride is 1,3-dioctanoic acid glyceride.

[0009] According to a preferred embodiment of the present invention, the medium- and long-chain triglycerides (MLCT) were purchased from Henan Jiqian Biotechnology Co., Ltd.

[0010] According to a preferred embodiment of the present invention, in step S2, the grinding process takes 4-6 hours.

[0011] According to a preferred embodiment of the present invention, the preparation process of the 3-aminopropyltriethoxysilane-ethylenediaminetetraacetic acid modified silica includes: A1, dispersing 8-12 parts by weight of mesoporous silica in 180-220 parts by weight of anhydrous toluene, stirring under nitrogen protection to obtain a suspension; heating the suspension to 78-82°C, adding 14-16 parts by weight of 3-aminopropyltriethoxysilane, stirring to obtain a mixture, separating the mixture by centrifugation to obtain amino-modified silica, washing the amino-modified silica with anhydrous ethanol to obtain washed amino-modified silica; A2, redispersing the washed amino-modified silica in 150-220 parts by weight of N,N A dispersion of amino-modified silica was obtained by dissolving 4.5-5.5 parts of ethylenediaminetetraacetic acid in 45-55 parts of N,N-dimethylformamide, adding 2.2-2.8 parts of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1.3-1.7 parts of N-hydroxysuccinimide, and stirring at room temperature to activate the solution. The activated solution was added to the dispersion of amino-modified silica, and the reaction was continued at 24-26℃ to obtain the reaction product. The reaction product was separated by centrifugation to obtain a solid product. The solid product was washed with N,N-dimethylformamide, dilute hydrochloric acid aqueous solution, deionized water and ethanol, and dried in a vacuum drying oven at 58-62℃.

[0012] In this invention, during the preparation of 3-aminopropyltriethoxysilane-ethylenediaminetetraacetic acid modified silica, the abundant silanol groups on the surface of mesoporous silica undergo a condensation reaction with a silane coupling agent containing primary amino groups in an anhydrous inert environment. The hydrolyzable alkoxy groups of the silane coupling agent dehydrate with the surface silanol groups under mild heat, forming strong siloxane-silicon covalent bonds, thus anchoring the organic amino functional groups to the inorganic framework. This step requires strict isolation from moisture to prevent silane self-polymerization. Subsequently, the amino-functionalized product, combined with a polydentate aminocarboxylic acid chelating agent and a carbodiimide condensing agent and auxiliary activator in a polar aprotic solvent, first converts the carboxyl group of the chelating agent into a highly active ester intermediate. This intermediate undergoes efficient nucleophilic acylation with the surface primary amino groups to generate stable amide bonds. The reaction was carried out at near room temperature to ensure selectivity. The unbonded chelating agent was selectively dissolved and removed by washing with a weakly acidic aqueous solution (because its water solubility is enhanced after protonation), while the covalent grafted product was retained due to the stability of the amide bond. Finally, a modified material with both amino and multidentate chelating functions on the surface was obtained, and its interfacial polarity and metal ion binding ability were significantly optimized.

[0013] According to a preferred embodiment of the present invention, in step A1, the stirring reaction time is 12-14 hours.

[0014] According to a preferred embodiment of the present invention, in step A2, the reaction is continued at 24-26°C for 4-6 hours.

[0015] According to a preferred embodiment of the present invention, the preparation process of the 9-decenoxypropyl modified silica hybrid material includes: B1, dispersing 8-12 parts by weight of fumed silica in 180-220 parts by weight of anhydrous toluene, and ultrasonically treating to obtain a suspension; under nitrogen protection, adding 18-22 parts by weight of (3-glycidyl etheroxypropyl)trimethoxysilane, 0.5-1.0 parts by weight of deionized water and 0.1-0.3 parts by weight of acetic acid to the suspension, and stirring at room temperature to obtain a reaction mixture; heating the reaction mixture to 64-66°C, adding 7-9 parts by weight of 9-decen-1-ol and 0.4-0.6 parts by weight of p-toluenesulfonic acid, and stirring to obtain a reaction mixture; B2, cooling the reaction mixture to room temperature, centrifuging to obtain a solid product, washing the solid product with toluene, acetone and n-hexane to obtain a washed solid product; and drying the washed solid product in a vacuum oven at 68-72°C under nitrogen protection.

[0016] In this invention, during the preparation of the 9-decenoxypropyl-modified silica hybrid material, fumed silica is fully dispersed by ultrasound, and then an epoxy-containing silane coupling agent, trace amounts of water, and a weak organic acid catalyst are introduced. The weakly acidic environment precisely catalyzes the hydrolysis of silane methoxy groups to silanols, while effectively suppressing the self-condensation side reaction of silanols, promoting the directional condensation of the hydrolysis products with the silanols on the silica surface, and firmly grafting the epoxy functional groups. Subsequently, a long-chain unsaturated alcohol containing terminal double bonds and an acidic catalyst are added, and the temperature is moderately increased. Under acid catalysis, the epoxy groups undergo regioselective nucleophilic ring-opening with the alcohol hydroxyl groups: the hydroxyl oxygen attacks the less sterically hindered carbon position of the epoxy ring, generating an ortho-hydroxy ether structure, while the carbon-carbon double bonds far from the reaction center are fully preserved. This design cleverly achieves surface hydrophobic long-chain modification while retaining the reactivity of the double bonds. After the reaction is terminated, the residue is removed by multi-stage solvent washing, and finally vacuum drying is carried out under inert gas protection to avoid secondary condensation of surface silanols at high temperature, which would lead to agglomeration. The long alkyl chains and double bonds on the surface of the resulting material significantly improve its wettability and dispersion compatibility in nonpolar media.

[0017] According to a preferred embodiment of the present invention, in step B1, the stirring reaction time is 18-20 hours.

[0018] According to a preferred embodiment of the present invention, in step B2, the drying time in a vacuum oven at 68-72°C is 10-12 hours.

[0019] A second aspect of the present invention provides a medium-chain triglyceride composition prepared according to the preparation process of the medium-chain triglyceride composition described above.

[0020] Compared with the prior art, the present invention has the following beneficial effects: (1) This invention, through innovative material design and precise process integration, brings about multiple significant and synergistic technical effects, solving the long-standing problems of stability, functionality, and compatibility in existing technologies. Its core effect is primarily reflected in the fundamental improvement of the physicochemical stability of the composition. By introducing two inorganic silica hybrid materials with specific surface modifications, the composition obtains a strong stable anchor point in its microstructure. The multidentate ligand structure grafted on the surface of the first modified material can effectively integrate trace metal ions in the system and stabilize polar molecules through complexation, thereby inhibiting the lipid oxidation degradation pathway catalyzed by metal ions and reducing the tendency of phase separation between different polar components. The long-chain hydrocarbon groups and reactive groups provided by the second modified material produce good compatibility and spatial interaction with the lipid matrix, forming a stable three-dimensional network structure in the oil phase, which significantly hinders the disordered growth of lipid crystals and the Ostwald ripening process. These two materials work synergistically in the lipid phase, acting as a "nanoanchor" and a "structural enhancer," enabling the entire composition to maintain a uniform morphology, stable particle size distribution, and consistent rheological properties under long-term storage and temperature fluctuations. This fundamentally overcomes the drawbacks of traditional medium-chain triglyceride formulations, such as easy stratification, crystallization, or aggregation.

[0021] (2) The outstanding technical effect of this invention lies in endowing medium-chain triglyceride carriers with unprecedented multifunctionality and high-performance drug loading capacity. Traditional lipid carriers have a single function and are difficult to adapt to diverse drug molecules. However, the two modified materials prepared in this invention actively expand the interaction dimensions between the carrier and the drug through carefully designed functional groups on their surfaces. The ligand-rich surface of the first material exhibits excellent affinity and loading capacity for drugs with metal coordination sites, polar drug molecules, or protein-peptide drugs, and can achieve efficient encapsulation and firm binding of drugs through various non-covalent interactions such as ionic bonds and coordination bonds. The active groups retained on the surface of the second material provide a reliable chemical platform for covalently coupling specific target molecules, fluorescent labels, or responsive materials, enabling the final composition to be easily functionalized and upgraded, achieving a leap from passive drug loading to active targeting. This combination of "synergistic drug delivery" and "functionalizability" allows the composition to flexibly meet the drug delivery needs of different physicochemical properties, greatly expanding its application scope in the manufacture of high-value-added biopharmaceuticals and providing an excellent carrier platform for the development of novel sustained-release formulations, targeted formulations or combination therapy formulations.

[0022] (3) The overall preparation process and final product of this invention demonstrate excellent performance in terms of industrialization feasibility, safety, and comprehensive performance. The ball milling dispersion process used is mild and efficient, avoiding the damage to lipids and active ingredients caused by extreme conditions such as high temperature and high pressure, and ensuring that the modified nanomaterials are uniformly dispersed at the nanoscale in the oil phase. This is the physical basis for achieving its stability and functional effects. The reagents and solvents used in the entire preparation process are all commercially available products. The process steps are clear and controllable, with good repeatability and great potential for large-scale production. More importantly, the final composition obtained by the above materials and processes not only has stable physicochemical properties and strong drug-carrying function, but its biocompatibility is also optimized due to the good coating and surface modification of inorganic materials, and the potential tissue irritation is reduced. In summary, this invention successfully integrates the stability advantages of inorganic nanomaterials, the flexibility advantages of surface functional design, and the rapid metabolism advantages of medium-chain triglycerides, creating a new type of lipid composition with comprehensively upgraded performance. It provides a powerful technical solution for developing efficient, stable, and safe high-end carrier products in the fields of food, medicine, and cosmetics, and has significant practical application value and market prospects. Detailed Implementation

[0023] To facilitate understanding of the present invention, the following embodiments are provided. Those skilled in the art should understand that these embodiments are merely illustrative and should not be construed as limiting the scope of the invention.

[0024] Example 1 This embodiment provides a process for preparing a medium-chain triglyceride composition, the steps of which include: First, 3-aminopropyltriethoxysilane-ethylenediaminetetraacetic acid-modified silica was prepared. In step A1, 10.0 g of mesoporous silica was weighed and placed in a 500 mL three-necked flask, and 200 g of anhydrous toluene was added. The flask was placed on a magnetic stirrer and stirred at 500 rpm for 30 min under nitrogen protection to form a homogeneous suspension. The suspension was heated to 80 °C in an oil bath, and 15.0 g of 3-aminopropyltriethoxysilane was slowly added dropwise using a constant-pressure dropping funnel at a rate of approximately 1 mL / min. After the addition was complete, the oil bath temperature and nitrogen atmosphere were maintained at 80 °C, and the reaction was continued with stirring at 500 rpm for 13 h to allow the silane coupling agent to fully undergo a condensation grafting reaction with the silanol groups on the silica surface. After the reaction was complete, the reaction mixture was transferred to a centrifuge tube and centrifuged at 8000 rpm for 10 min. The supernatant was discarded, yielding a white solid precipitate, which was the amino-modified silica. The solid precipitate was redispersed with 50 mL of anhydrous ethanol and centrifuged again. This washing process was repeated three times to completely remove unreacted silanes adsorbed by physical adsorption. The washed solid was placed in a petri dish and pre-dried in an 80°C oven for 1 h to obtain an amino-modified silica intermediate for later use.

[0025] Step A2: The amino-modified silica intermediate prepared above is redispersed in 150 mL of N,N-dimethylformamide in a 250 mL round-bottom flask. The flask is magnetically stirred at 300 rpm at 25°C to form a homogeneous dispersion A, which is set aside. Separately, in a 100 mL beaker, 5.0 g of ethylenediaminetetraacetic acid and 50 mL of N,N-dimethylformamide are added and stirred until completely dissolved. Then, 2.5 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1.5 g of N-hydroxysuccinimide are added sequentially. The mixture is magnetically stirred at 400 rpm at 25°C for 30 min to complete carboxyl activation, yielding a clear activated solution B. While continuing stirring, activated solution B is slowly poured into the round-bottom flask containing dispersion A. The mixture was stirred at 300 rpm for 5 hours in a 25°C water bath to allow the activated carboxyl groups on EDTA to undergo an amidation coupling reaction with the primary amino groups on the surface of the amino-modified silica. After the reaction was complete, the reaction mixture was centrifuged at 8000 rpm for 10 minutes, and the solid product was collected. The solid was washed sequentially with the following solvents: first, twice with 50 mL of N,N-dimethylformamide to remove organic byproducts; then once with 50 mL of dilute hydrochloric acid aqueous solution with a pH of 5.0 to remove unreacted EDTA; next, three times with 50 mL of deionized water to remove residual acid and inorganic salts; and finally twice with 50 mL of anhydrous ethanol. The washed solid was transferred to a vacuum drying oven and dried at 60°C and -0.095 MPa for 12 hours to obtain 3-aminopropyltriethoxysilane-ethylenediaminetetraacetic acid modified silica, denoted as modified compound A, which was stored in a desiccator.

[0026] Next, 9-decenoxypropyl-modified silica hybrid material was prepared. In step B1, 10.0 g of fumed silica was weighed into a 500 mL three-necked flask, and 200 mL of anhydrous toluene was added. The flask was placed in an ultrasonic cleaner and sonicated at 40 kHz for 30 min to obtain a uniformly dispersed suspension C. Nitrogen gas was introduced into suspension C for protection, and then 20.0 mL of (3-glycidyl etheroxypropyl)trimethoxysilane, 0.6 mL of deionized water, and 0.2 g of glacial acetic acid were added sequentially. The mixture was magnetically stirred at 500 rpm for 30 min at 25 °C to allow the silane coupling agent to undergo complete hydrolysis under weakly acidic conditions, yielding a pretreated mixture. Subsequently, the reaction system was heated to 65 °C in an oil bath. Under nitrogen protection and continuous stirring, 8.0 g of 9-decen-1-ol and 0.5 g of p-toluenesulfonic acid monohydrate were added sequentially to the pretreated mixture. The oil bath temperature was maintained at 65°C, and the reaction was continued with stirring for 19 hours. During this process, the silanol groups of the hydrolysis product of (3-glycidyl etheroxypropyl)trimethoxysilane condensed with the surface of silica, while its epoxy groups underwent a ring-opening etherification reaction with the primary hydroxyl groups of 9-decen-1-ol under the catalysis of p-toluenesulfonic acid.

[0027] In step B2, after the reaction is complete, the reaction mixture is allowed to cool naturally to room temperature (25°C). It is then transferred to a centrifuge tube and centrifuged at 8000 rpm for 10 min. The supernatant is discarded, yielding a pale yellow solid precipitate. The precipitate is washed sequentially with the following solvents: first, three washes with 50 mL of toluene to remove most of the organic reactants and catalyst; then, two washes with 50 mL of acetone to further remove polar impurities; and finally, two washes with 50 mL of n-hexane to replace residual solvent and facilitate drying. The washed solid is placed on a tray in a vacuum oven and dried for 11 h at 70°C and -0.095 MPa under continuous nitrogen purging (50 mL / min). The resulting 9-decenoxypropyl-modified silica hybrid material, designated as modified compound B, is stored in a desiccator.

[0028] Finally, a medium-chain triglyceride composition was prepared. In step S1, 75.0 g of octanoic / capric acid medium-chain triglycerides and 18.0 g of medium- to long-chain triglycerides were accurately weighed and added to a 500 mL stainless steel reactor equipped with a mechanical stirrer and thermometer. Stirring was started at 200 rpm, and the material was heated to 49°C using a jacketed oil bath. The mixture was stirred for 15 min under these conditions to obtain a homogeneous reaction mixture. The oil bath temperature was then increased to 65°C. While maintaining the temperature at 65°C and stirring at 200 rpm, 3.0 g of medium-chain monoglycerides and 5.0 g of 1,3-dioctanoic acid glycerides were added sequentially to the reactor. After the addition was complete, the stirring speed was increased to 400 rpm, and stirring continued for 30 min until all components were completely dissolved, forming a transparent and homogeneous lipid phase mixture. 2.0 g of modified compound A and 1.5 g of modified compound B, which had been dried in an 80°C drying oven for 2 hours, were slowly and gradually added to the lipid phase mixture under stirring to prevent clumping. After all the compounds were added, the reactor temperature was adjusted to 70°C, and the stirrer was replaced with a high-shear dispersion emulsifying head. High-speed shear dispersion was performed at 9000 rpm for 70 minutes to obtain a homogeneous and stable oil phase dispersion.

[0029] In step S2, the obtained oil phase dispersion was transferred to the feed tank of a high-energy rod-pin ball mill equipped with zirconia grinding beads (0.3-0.5 mm in diameter, filling 60% of the grinding chamber). The ball mill water bath circulation system temperature was set to 35°C, and the mill was run at 1600 rpm for 4.5 hours. After grinding, the material system was cooled to 40°C using a water bath. With gentle stirring (200 rpm), 0.20 g of mixed tocopherols was added to the system, and stirring was continued for 20 minutes to ensure uniform distribution of the antioxidant. Finally, under a nitrogen atmosphere, the product was pressure filtered using a 0.45 μm PTFE filter membrane to remove grinding media and any possible trace aggregates. The filtrate, the final medium-chain triglyceride composition, was dispensed into brown glass bottles, sealed with nitrogen, and stored below 25°C in the dark.

[0030] Example 2 The difference between this embodiment and Example 1 is that, firstly, 3-aminopropyltriethoxysilane-ethylenediaminetetraacetic acid modified silica is prepared. Step A1: 9.0 g of mesoporous silica is weighed and placed in a 500 mL three-necked flask, and 190 g of anhydrous toluene is added. The flask is placed on a magnetic stirrer and stirred at 500 rpm for 30 min under nitrogen protection to form a homogeneous suspension. The suspension is heated to 78°C in an oil bath, and 14.0 g of 3-aminopropyltriethoxysilane is slowly added dropwise using a constant pressure dropping funnel, controlling the dropping rate to approximately 1 mL / min. After the addition is complete, the oil bath temperature and nitrogen atmosphere are maintained at 78°C, and the reaction is continued with stirring at 500 rpm for 12 h. After the reaction is complete, the reaction mixture is centrifuged at 8000 rpm for 10 min, and the supernatant is discarded to obtain a solid precipitate. The solid precipitate is redispersed with 50 mL of anhydrous ethanol and centrifuged again; this washing process is repeated three times. The washed solid was pre-dried in a 78°C forced-air drying oven for 1 hour to obtain an amino-modified silica intermediate.

[0031] Step A2: The above-mentioned amino-modified silica intermediate was redispersed in 160 mL of N,N-dimethylformamide and magnetically stirred at 300 rpm at 24 °C to form dispersion A, which was set aside. In a separate 100 mL beaker, 4.5 g of ethylenediaminetetraacetic acid and 45 mL of N,N-dimethylformamide were added and stirred until dissolved. 2.2 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1.3 g of N-hydroxysuccinimide were added sequentially to this solution, and the mixture was magnetically stirred at 400 rpm at 24 °C for 30 min to obtain activated solution B. Activated solution B was added to dispersion A with stirring. The mixture was then placed in a 24 °C water bath and stirred at 300 rpm for 4 h. After the reaction was complete, the solid product was collected by centrifugation. The solid was washed twice with 50 mL of N,N-dimethylformamide, once with 50 mL of dilute hydrochloric acid aqueous solution with a pH of 5.0, three times with 50 mL of deionized water, and twice with 50 mL of anhydrous ethanol. The solid was then dried in a vacuum drying oven at 58 °C and -0.095 MPa for 12 h to obtain modified compound A.

[0032] Next, 9-decenoxypropyl-modified silica hybrid materials were prepared. In step B1, 11.0 g of fumed silica was weighed into a 500 mL three-necked flask, and 210 mL of anhydrous toluene was added. The mixture was sonicated for 30 min to obtain suspension C. Under nitrogen protection, 19.0 mL of (3-glycidyl etheroxypropyl)trimethoxysilane, 0.5 mL of deionized water, and 0.1 g of glacial acetic acid were added sequentially to suspension C. The mixture was magnetically stirred at 500 rpm for 30 min at 25 °C. Subsequently, the reaction system was heated to 64 °C in an oil bath. Under nitrogen protection and stirring, 7.0 g of 9-decen-1-ol and 0.4 g of p-toluenesulfonic acid monohydrate were added sequentially. The reaction was maintained at 64 °C and stirred for 18 h.

[0033] In step B2, after the reaction was completed, the mixture was cooled to 25°C and centrifuged to obtain a solid precipitate. The precipitate was washed three times with 50 mL of toluene, twice with 50 mL of acetone, and twice with 50 mL of n-hexane. The washed solid was dried in a vacuum oven at 68°C and -0.095 MPa for 10 h under continuous nitrogen purging (50 mL / min) to obtain modified compound B.

[0034] Finally, a medium-chain triglyceride composition was prepared. In step S1, 70.0 g of octanoic / capric acid medium-chain triglycerides and 20.0 g of medium- to long-chain triglycerides were accurately weighed and added to a reaction vessel. Stirring was started at 200 rpm, and the mixture was heated to 48°C and mixed for 15 min. Then, the temperature was raised to 64°C, and 4.0 g of medium-chain monoglycerides and 6.0 g of 1,3-dioctanoic acid glycerides were added sequentially. The stirring speed was increased to 400 rpm and stirred for 30 min to form a lipid phase mixture. Pre-dried 3.0 g of modified compound A and 2.0 g of modified compound B were added. The temperature was adjusted to 68°C, and high-speed shear dispersion was performed at 9000 rpm for 80 min to obtain an oil phase dispersion.

[0035] In step S2, the oil phase dispersion was transferred to a high-energy ball mill, and the water bath temperature was set to 30°C. The mixture was then ground at 1500 rpm for 4 hours. After grinding, the temperature was lowered to 38°C, and 0.30 g of mixed tocopherols was added. The mixture was stirred at 200 rpm for 20 minutes. Finally, under nitrogen protection, the mixture was filtered through a 0.45 μm pore size filter membrane to obtain the final composition.

[0036] Example 3 The difference between this embodiment and Example 1 is that, firstly, 3-aminopropyltriethoxysilane-ethylenediaminetetraacetic acid-modified silica is prepared. Step A1: 11.0 g of mesoporous silica is weighed and placed in a 500 mL three-necked flask, and 210 g of anhydrous toluene is added. The mixture is stirred at 500 rpm for 30 min under nitrogen protection. The mixture is then heated to 82 °C in an oil bath, and 16.0 g of 3-aminopropyltriethoxysilane is slowly added dropwise. After the addition is complete, the mixture is stirred at 500 rpm for 14 h while maintaining 82 °C and a nitrogen atmosphere. After the reaction is complete, the mixture is centrifuged, and the solid is washed three times with 50 mL of anhydrous ethanol. The washed solid is then pre-dried in an 82 °C forced-air drying oven for 1 h.

[0037] Step A2: The above intermediate was redispersed in 200 mL of N,N-dimethylformamide and stirred at 26 °C to form dispersion A. In a separate beaker, 5.5 g of ethylenediaminetetraacetic acid and 55 mL of N,N-dimethylformamide were added and dissolved. Then, 2.8 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1.7 g of N-hydroxysuccinimide were added sequentially, and the mixture was activated at 26 °C for 30 min to obtain solution B. Solution B was added to dispersion A, and the mixture was stirred at 300 rpm for 6 h in a constant temperature water bath at 26 °C. After the reaction, the mixture was centrifuged, and the solid was washed sequentially with N,N-dimethylformamide, pH 5.0 dilute hydrochloric acid, deionized water, and anhydrous ethanol. The solid was dried in a vacuum drying oven at 62 °C and -0.095 MPa for 12 h to obtain modified compound A.

[0038] Next, 9-decenoxypropyl-modified silica hybrid materials were prepared. In step B1, 9.0 g of fumed silica was weighed into a 500 mL three-necked flask, and 190 mL of anhydrous toluene was added. The mixture was sonicated for 30 min. Under nitrogen protection, 21.0 mL of (3-glycidyl etheroxypropyl)trimethoxysilane, 1.0 mL of deionized water, and 0.3 g of glacial acetic acid were added sequentially. The mixture was stirred at 500 rpm for 30 min at 25 °C. Subsequently, the mixture was heated to 66 °C, and 9.0 g of 9-decen-1-ol and 0.6 g of p-toluenesulfonic acid monohydrate were added sequentially. The mixture was maintained at 66 °C and stirred for 20 h.

[0039] Step B2: After the reaction is complete, cool to 25°C and centrifuge. Wash the solid sequentially with toluene, acetone, and n-hexane. Dry the washed solid in a vacuum oven at 72°C and -0.095 MPa for 12 hours under nitrogen protection to obtain modified compound B.

[0040] Finally, a medium-chain triglyceride composition was prepared. In step S1, 80.0 g of octanoic / capric acid medium-chain triglycerides and 15.0 g of medium- to long-chain triglycerides were accurately weighed and heated to 50°C and mixed for 15 min. The temperature was then raised to 66°C, and 2.5 g of medium-chain monoglycerides and 3.0 g of 1,3-dioctanoic acid glycerides were added sequentially, while stirring at 400 rpm for 30 min. Pre-dried 1.5 g of modified compound A and 2.5 g of modified compound B were added. The mixture was sheared and dispersed at 72°C and 9000 rpm for 60 min.

[0041] In step S2, the dispersion was transferred to a ball mill and milled at 1500 rpm for 6 hours in a 40°C water bath. The mixture was then cooled to 42°C, and 0.15 g of mixed tocopherols was added. The mixture was stirred for 20 minutes. The final product was obtained by filtration through a 0.45 μm filter membrane under nitrogen protection.

[0042] Comparative Example 1 The difference between this comparative example and Example 1 is that no modified compound A and modified compound B are added in this comparative example.

[0043] Comparative Example 2 The difference between this comparative example and Example 1 is that unmodified mesoporous silica and fumed silica are added to this comparative example to replace modified compound A and modified compound B, respectively; otherwise, it is the same as Example 1.

[0044] Comparative Example 3 The difference between this comparative example and Example 1 is that this comparative example only adds modified compound A prepared in Example 1, and does not add modified compound B.

[0045] The properties of the medium-chain triglyceride compositions provided in the above embodiments and comparative examples were tested using the following methods: All tests were conducted at 25.0℃. To assess long-term storage stability, each sample was aliquoted into transparent glass sample vials, sealed, and placed in a constant-temperature drying oven at 40.0℃ for accelerated stability testing. Samples were taken and tested at regular intervals on days 0, 30, 60, and 90.

[0046] Centrifugation stability test: Accurately measure 10.0 mL of sample using a 10 mL precisely graduated centrifuge tube. Place the centrifuge tube in a centrifuge and centrifuge at 4000 rpm (relative centrifugal force approximately 1790 × g) for 15.0 min. Immediately after centrifugation, remove the tube, visually observe and record the volume (mL) of the clearly separated oil layer or precipitate layer. Calculate the volume fraction of the precipitate layer using the formula (precipitate layer volume / 10.0 mL) × 100%.

[0047] Particle size and particle size distribution testing: The particle size was determined using a nanoparticle size analyzer based on the dynamic light scattering principle. Before testing, the sample was diluted 100-fold with its corresponding pure medium-chain triglyceride base oil and mixed using a vortex mixer for 10 seconds. An appropriate amount of the diluted sample was injected into a standard 1 cm optical path quartz cuvette, which was then placed in the instrument's sample cell and equilibrated at 25.0°C for 300 seconds. The detection angle was set to 173°, and each sample was automatically measured three times consecutively. The instrument software directly reported the Z-average particle size (Z-Average, unit: nm) and polydispersity index (PDI, dimensionless). The final result was the arithmetic mean of the three independent measurements.

[0048] Peroxide value test: determined by titration. Accurately weigh 2.000 g of sample and place it in a 250 mL iodine flask. Add 30.0 mL of a chloroform and glacial acetic acid solution mixed in a 3:2 volume ratio, and gently shake to completely dissolve the sample. Accurately add 1.00 mL of saturated potassium iodide solution using a pipette, immediately stopper the flask and gently shake for 30 s, then place the iodine flask in the dark and allow it to react for 5.0 min. After the reaction is complete, add 100 mL of distilled water to the flask. Titrate with a standardized 0.0100 mol / L sodium thiosulfate standard solution. When the solution turns pale yellow, add 1 mL of starch indicator and continue titrating until the blue color of the solution just disappears. Record the volume of sodium thiosulfate standard solution consumed and perform a blank test for correction. Calculate the peroxide value of the sample based on the amount of sodium thiosulfate consumed, expressed as millimoles of active oxygen per kilogram of sample (unit: mmol / kg).

[0049] Simulated drug loading capacity test (curcumin loading): Lipid-soluble curcumin was used as the model drug. 5.000 g of sample was accurately weighed into a 15 mL centrifuge tube, and an excess (usually more than 1.5 times the theoretical saturation) of curcumin powder was added. The centrifuge tube was sealed and placed in a constant-temperature shaker at 60.0 °C and shaken at 200 rpm in the dark for 24.0 h to reach dissolution equilibrium. Subsequently, the mixture was centrifuged at 5000 rpm for 10.0 min, and the supernatant was carefully aspirated. The obtained supernatant was appropriately serially diluted with anhydrous ethanol to ensure that the absorbance value was within the linear range of the standard curve. The absorbance value of the diluted solution was measured at 425 nm using a UV-Vis spectrophotometer. Based on the pre-established standard curve of curcumin in anhydrous ethanol, the curcumin concentration in the supernatant was calculated, and the maximum curcumin loading of the original sample was further calculated. The results are expressed as milligrams of curcumin loaded per gram of composition (unit: mg / g).

[0050] Grafting rate testing of modified compounds A and B: Characterization was performed using a thermogravimetric analyzer. Using a precision analytical balance, 5.0 mg to 10.0 mg of the sample was accurately weighed and placed in a clean alumina crucible. Under a protective atmosphere of continuous high-purity nitrogen (flow rate 50 mL / min), the sample was heated from 50 °C to 800 °C at a constant heating rate of 10.0 °C / min. The instrument simultaneously recorded the thermogravimetric curve of sample mass versus temperature. Using analytical software, the percentage of mass loss within the temperature range of 200 °C to 600 °C was selected as the estimated value of the organic functional group grafting rate, expressed as a mass percentage (wt%).

[0051] Rheological property testing (apparent viscosity): Measurements were performed using a rotational rheometer with a cone-plate measurement system. A suitable sample was carefully loaded onto the center of the lower plate of the rheometer. The test temperature was set to 25.0℃. After temperature equilibrium was reached, excess sample was trimmed and removed. The shear rate was set from 1.0 s⁻¹. -1 Linear scan to 100s -1 Recorded in 50s -1 At a fixed shear rate, the shear stress value at which the sample reaches steady flow is determined, and the apparent viscosity at that point is calculated using the formula (shear stress / shear rate), with the result expressed in millipascals per second (unit: mPa·s).

[0052] The performance test data above are shown in Table 1.

[0053] Table 1 Performance Test Results

[0054] As can be seen from the above, the technical solutions of the present invention represented by Examples 1-3, compared with Comparative Examples 1-3, comprehensively and synergistically solve the key technical bottlenecks of existing medium-chain triglyceride systems in terms of physical stability, chemical stability and functionalized drug loading capacity.

[0055] The core breakthrough in physical stability lies in the suppression of phase separation and the maintenance of the nano-dispersion system after long-term storage. Comparative Example 1, which contains no modified compounds A and B, showed a precipitate volume fraction exceeding 15% after 90 days of accelerated testing at 40℃, demonstrating that traditional lipid mixtures cannot resist the long-term trend of phase separation. Comparative Example 2, which added raw silica, showed that due to the extremely poor compatibility between inorganic nanoparticles and the oil phase, the initial particle size was greater than 1000 nm and increased significantly after storage, with a polydispersity index exceeding 0.5. This indicates that simple physical mixing not only fails to stabilize the system but also leads to severe aggregation and deterioration. Comparative Example 3, which only added modifier A, showed a precipitation rate of approximately 5% after 90 days, with the Z-average particle size increasing from an initial 220 nm to 280 nm, indicating that while a single modifier provides some improvement, its effect is limited.

[0056] In stark contrast, after 90 days of accelerated testing, the centrifugal precipitation rate of Examples 1-3 was successfully suppressed to below 2%, the Z-average particle size increased only slightly by about 5-15 nm, and remained stable in the nano-dispersion range below 200 nm. The polydispersion index also remained at an excellent level below 0.2. This conclusively proves that the coexistence and synergistic effect of two specific structurally modified silicas are the key to constructing an ultra-stable oil-based nano-dispersion system. They interact with the lipid matrix through their respective surface functional groups, effectively hindering the Ostwald ripening and aggregation sedimentation of particles, and fundamentally solving the problems of phase separation and uncontrolled particle size growth during long-term storage.

[0057] Regarding chemical stability, the peroxide values ​​of Examples 1-3 were all below 4.0 mmol / kg after accelerated aging, significantly lower than 8.9 mmol / kg of Comparative Example 1 without modifier and 6.1 mmol / kg of Comparative Example 2 containing only silica. This is directly attributed to the efficient inhibition of the catalytic oxidation pathway of metal ions in the system by the ethylenediaminetetraacetic acid structure introduced by modified compound A, thereby greatly improving the antioxidant capacity of the composition and delaying rancidity.

[0058] In terms of functional performance, the maximum loading capacity of curcumin in the examples reached about 12 mg / g, which is about 50% higher than that of Comparative Example 1 with no modified compound A and modified compound B, and also better than that of Comparative Example 3 containing only modified compound A. This clearly demonstrates that the metal chelating coordination sites and long-chain hydrophobic alkyl / potential reaction sites provided by modified compounds A and B respectively create a diverse drug-binding microenvironment, which synergistically enhances the system's ability to carry and stabilize lipophilic active ingredients.

[0059] Furthermore, the apparent viscosity of Examples 1-3 is around 125 mPa·s, which is within the range suitable for processing and application. However, the viscosity of Comparative Example 2 increased abnormally to 320 mPa·s due to particle aggregation, which further confirms the importance of the strategy of achieving good compatibility through surface modification in maintaining the normal rheological properties of the system.

[0060] In summary, the test data provides a conclusive chain of evidence demonstrating that this invention, through the innovative preparation and compounding of two functionally complementary inorganic modified materials, successfully transforms medium-chain triglycerides from a lipid carrier with insufficient physical and chemical stability and limited function into a multifunctional composite platform with excellent long-term storage stability, superior antioxidant properties, and high-efficiency drug loading capacity. This systematically solves the technical contradictions of phase separation, oxidative degradation, and limited drug loading capacity that existing technologies cannot overcome simultaneously.

Claims

1. A process for preparing a medium-chain triglyceride composition, characterized in that the steps include... include: S1. By weight, add 60-85 parts of octanoic acid / capric acid medium-chain triglycerides and 10-25 parts of medium- and long-chain triglycerides to a reaction vessel, heat to 48-50℃, and stir to obtain a premix; heat the premix to 64-66℃, add 1-8 parts of medium-chain monoglycerides and 2-10 parts of diglycerides, and continue stirring to obtain a lipid phase mixture; add 0.5-5 parts of 3-aminopropyltriethoxysilane-ethylenediaminetetraacetic acid modified silica and 0.5-5 parts of 9-decenoxypropyl modified silica hybrid material, which have been dried at 78-82℃ beforehand, to the lipid phase mixture, and stir at 68-72℃ to obtain an oil phase dispersion; S2. Transfer the oil phase dispersion to a ball mill and grind it at 30-40℃. Cool it down to 38-42℃, add 0.05-0.5 parts of mixed tocopherol, and continue stirring. Filter under nitrogen protection.

2. The preparation process of the medium-chain triglyceride composition according to claim 1, characterized in that, In step S1, the stirring time at 68-72℃ is 60-80 min; the diglyceride is 1,3-dioctanoic acid glyceride.

3. The preparation process of the medium-chain triglyceride composition according to claim 1, characterized in that, In step S2, the grinding process takes 4-6 hours.

4. The preparation process of the medium-chain triglyceride composition according to claim 1, characterized in that, The preparation process of the 3-aminopropyltriethoxysilane-ethylenediaminetetraacetic acid modified silica includes: A1, by weight, dispersing 8-12 parts of mesoporous silica in 180-220 parts of anhydrous toluene, stirring under nitrogen protection to obtain a suspension; heating the suspension to 78-82℃, adding 14-16 parts of 3-aminopropyltriethoxysilane dropwise, stirring to obtain a mixture, separating the mixture by centrifugation to obtain amino-modified silica, washing the amino-modified silica with anhydrous ethanol to obtain washed amino-modified silica; A2, redispersing the washed amino-modified silica in 150-220 parts of N,N-dimethylformamide. A dispersion of amino-modified silica was obtained. 4.5-5.5 parts of ethylenediaminetetraacetic acid were dissolved in 45-55 parts of N,N-dimethylformamide, and 2.2-2.8 parts of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1.3-1.7 parts of N-hydroxysuccinimide were added. The mixture was stirred and activated at room temperature to obtain an activated solution. The activated solution was added to the dispersion of amino-modified silica, and the reaction was continued at 24-26℃ to obtain the reaction product. The reaction product was separated by centrifugation to obtain a solid product. The solid product was washed with N,N-dimethylformamide, dilute hydrochloric acid aqueous solution, deionized water, and ethanol, and dried in a vacuum drying oven at 58-62℃.

5. The preparation process of the medium-chain triglyceride composition according to claim 4, characterized in that, In step A1, the stirring reaction time is 12-14 hours.

6. The preparation process of the medium-chain triglyceride composition according to claim 4, characterized in that, In step A2, the reaction continues at 24-26℃ for 4-6 hours.

7. The preparation process of the medium-chain triglyceride composition according to claim 1, characterized in that, The preparation process of the 9-decenoxypropyl modified silica hybrid material includes: B1, dispersing 8-12 parts by weight of fumed silica in 180-220 parts by weight of anhydrous toluene, and ultrasonically treating it to obtain a suspension; under nitrogen protection, adding 18-22 parts by weight of (3-glycidyl etheroxypropyl)trimethoxysilane, 0.5-1.0 parts by weight of deionized water and 0.1-0.3 parts by weight of acetic acid to the suspension, and stirring at room temperature to obtain a reaction mixture; heating the reaction mixture to 64-66°C, adding 7-9 parts by weight of 9-decen-1-ol and 0.4-0.6 parts by weight of p-toluenesulfonic acid, and stirring to obtain a reaction mixture; B2, cooling the reaction mixture to room temperature, centrifuging to obtain a solid product, washing the solid product with toluene, acetone and n-hexane to obtain a washed solid product; and drying the washed solid product in a vacuum oven at 68-72°C under nitrogen protection.

8. The preparation process of the medium-chain triglyceride composition according to claim 7, characterized in that, In step B1, the stirring reaction time is 18-20 hours.

9. The preparation process of the medium-chain triglyceride composition according to claim 7, characterized in that, In step B2, the drying time in a vacuum oven at 68-72℃ is 10-12 hours.

10. A medium-chain triglyceride composition, characterized in that, The medium-chain triglyceride composition is prepared according to the preparation process of the medium-chain triglyceride composition according to any one of claims 1-9.

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