Coenzyme q10 nanoemulsion oral liquid with double stabilization structure and continuous preparation method thereof

Abstract

This invention relates to the field of pharmaceutical formulation technology, specifically disclosing a coenzyme Q10 nanoemulsion oral liquid with a dual-stabilized structure and its continuous preparation method. It solves technical problems such as the extremely poor water solubility of raw materials, easy oxidation and degradation of coenzyme Q10 during storage, unstable solutions prone to stratification, precipitation, and crystallization, low bioavailability, and imperfect production processes during the preparation of coenzyme Q10 oral liquid. This invention constructs a dual-stabilized system of "cyclodextrin inclusion complex core + nanoemulsion encapsulation shell," with the nanoemulsion particle size controlled at 50-200 nm. Verification shows excellent stability, high retention rate of active ingredients, and bioavailability 2-3 times higher than conventional oral liquids. The process is environmentally friendly and safe, employing aseptic positive pressure conveying or negative pressure extraction of materials during preparation, enabling large-scale continuous aseptic industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a coenzyme Q10 nanoemulsion oral liquid and its preparation method. Background Technology

[0002] Coenzyme Q10 is a highly lipid-soluble compound that is widely found in the mitochondria of living organisms. It is an important coenzyme for energy metabolism in cellular mitochondria and has various physiological functions such as anti-oxidation, enhancing immunity, protecting the cardiovascular system, and delaying aging. It is widely used in health foods, pharmaceutical preparations, and other fields.

[0003] However, Coenzyme Q10 itself has many physicochemical defects that limit its application and development in oral liquid formulations: First, Coenzyme Q10 has extremely poor water solubility, with a solubility of less than 0.01 mg / mL in water. When directly preparing oral liquids, it is prone to crystallization and stratification, resulting in poor formulation stability. Second, the Coenzyme Q10 molecule contains unsaturated double bonds, which are easily affected by light, heat, oxygen, and other factors, leading to oxidative degradation, reduced content of active ingredients, and loss of physiological activity. Third, the bioavailability of Coenzyme Q10 in conventional formulations is low. The fat-soluble Coenzyme Q10 is difficult to absorb in the gastrointestinal tract, and most of it is directly excreted from the body, failing to fully exert its pharmacological effects.

[0004] To address the aforementioned issues, researchers have developed various formulation technologies. Existing technologies commonly employ a one-step mixing inclusion method to directly mix cyclodextrin, drug, emulsifier, and oil phase to prepare inclusion nanoemulsions. This process is simple and a conventional method in the field, but it has inherent technical drawbacks: First, the hydrophobic cavities of cyclodextrin compete with the micelles of the emulsifier and the core of the oil phase for binding, resulting in a low drug inclusion rate, typically only 70%-80%. Second, the mixed system has poor thermodynamic stability, easily leading to phase separation, resulting in large and unevenly distributed emulsion particles with a polydispersity index (PDI) typically greater than 0.25. Third, the drug is not adequately protected by inclusion, making it susceptible to oxidative degradation under the influence of light, heat, and oxygen, resulting in low retention of active ingredients. Sui Xiaoyu et al. prepared a coenzyme Q10-γ-cyclodextrin inclusion complex using a solution method combined with high-pressure homogenization, achieving an encapsulation rate of 48.39% and improved bioavailability compared to the active pharmaceutical ingredient. However, their work stopped at the inclusion complex powder stage and did not further develop a delivery system. Fu Junhe et al. disclosed a method for preparing coenzyme Q10 oral liquid (see their master's thesis, "Research on Dosage Forms of Coenzyme Q10 Health Food"). The method uses emulsifiers such as Tween-80 for solubilization, adjusts the pH to 3.5, adds antioxidants such as sodium isoretinoin, and then sterilizes the liquid with steam at 100℃ for 30 minutes. While this method improves solubility to some extent, it is essentially a simple emulsification and solubilization system. Drug molecules are not effectively encapsulated, making them prone to degradation and precipitation during long-term storage. Furthermore, traditional moist heat sterilization severely damages heat-sensitive coenzyme Q10, resulting in significant loss of active ingredients. Dong Yingjie et al. reported a coenzyme Q10-prilol-cyclodextrin-phospholipid dispersion system, which was prepared by colloid milling combined with shear homogenization and finally spray drying to obtain a powder product. Although this technology introduces phospholipid components, the process is an integrated mixing and grinding process, which makes it difficult to ensure that the drug is effectively encapsulated by cyclodextrin first. Moreover, the final product is a dry powder, and the dispersion system formed after reconstitution is different from that of direct oral liquid formulations. It does not address the issues of taste adjustment, pH optimization and long-term liquid stability required for oral liquids.

[0005] Meanwhile, the existing preparation processes for Coenzyme Q10 oral liquids are mostly batch production, requiring solid-liquid separation and drying of intermediate materials. This results in dispersed process steps, making the materials susceptible to contamination during transportation. Furthermore, the sterilization process often employs moist heat sterilization, which, with prolonged high-temperature treatment, leads to oxidative degradation of Coenzyme Q10 and significant loss of active ingredients. In addition, existing formulations have a poor taste, with a noticeable bitterness and greasiness, resulting in low consumer acceptance.

[0006] Therefore, developing a method for preparing coenzyme Q10 oral liquid that achieves continuous aseptic production and possesses both high stability and high bioavailability has become a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0007] The purpose of this invention is to provide a coenzyme Q10 nanoemulsion oral liquid with a dual-stabilized structure and its continuous preparation method, so as to solve the problems of poor water solubility of coenzyme Q10, easy oxidation and degradation, low stability of oral liquid, low bioavailability, and discontinuous production process in the prior art.

[0008] To achieve the above-mentioned technical objectives, the technical solution adopted by the present invention is as follows: In a first aspect, the present invention provides a coenzyme Q10 nanoemulsion oral liquid with a dual stable structure, wherein the drug-loaded microparticles in the oral liquid comprise, from the inside out: (a) a core: an inclusion complex formed by hydroxypropyl-β-cyclodextrin encapsulating coenzyme Q10; and (b) a shell: a nanoemulsion layer formed by an emulsifier and an oil phase covering the surface of the core; the particle size of the drug-loaded microparticles is 50-200 nm, the polydispersity index (PDI) is <0.2, and the pH value of the oral liquid is 3.5-5.5.

[0009] Secondly, the present invention provides a continuous preparation method for the coenzyme Q10 oral liquid with the aforementioned dual-stabilized structure, specifically comprising the following steps: Step 1: Weigh out the following ingredients according to the specified amounts: Coenzyme Q10, hydroxypropyl-β-cyclodextrin, emulsifier, oil phase, xylitol, citric acid, and xanthan gum; Step 2: Coenzyme Q10 was included with hydroxypropyl-β-cyclodextrin to prepare a coenzyme Q10 cyclodextrin inclusion complex suspension; Step 3: Mix the emulsifier with the oil phase, and then mix it with the coenzyme Q10 cyclodextrin inclusion complex suspension that is sterilely pumped through a closed stainless steel pipeline under negative pressure. Prepare coenzyme Q10 nanoemulsion colostrum using a high-pressure homogenization method. Step 4: Dissolve xylitol, citric acid, and xanthan gum in purified water to prepare an aqueous phase. Mix this aqueous phase with coenzyme Q10 nanoemulsion colostrum and adjust the pH of the system to 3.5-5.5. Step 5: The mixed system is homogenized again under high pressure to obtain Coenzyme Q10 nano-emulsion. Step 6: Perform ultra-high temperature instantaneous sterilization on the coenzyme Q10 nano-emulsion, and then perform aseptic filling to obtain coenzyme Q10 oral liquid. In the preparation process of steps 2 to 6, all materials and intermediates are connected by closed stainless steel pipelines and conveyed to the next step by aseptic positive pressure or negative pressure, so as to achieve continuous aseptic production.

[0010] Furthermore, in step 1, the mass ratio of each main ingredient is as follows: Coenzyme Q10 1-5 parts, hydroxypropyl-β-cyclodextrin 8-15 parts, emulsifier 5-10 parts, oil phase 3-8 parts, xylitol 2-6 parts, citric acid 0.1-0.5 parts, and xanthan gum 0.05-0.2 parts. This ratio ensures the synergistic effect of the ingredients, guaranteeing both the full inclusion of Coenzyme Q10 and the stable formation of the nanoemulsion, while also achieving a balance between taste and formulation stability.

[0011] Furthermore, the emulsifier is one or more combinations of polyoxyethylene castor oil, polyglycerol fatty acid ester, and Tween 80, such that HLB=10-15.

[0012] Furthermore, the oil phase is one or more of medium-chain triglycerides, olive oil, linseed oil, coconut oil, etc.

[0013] Further, in step 2, the preparation process of the coenzyme Q10 cyclodextrin inclusion complex suspension is as follows: Hydroxypropyl-β-cyclodextrin is added to 8-12 times its mass of purified water and stirred in a water bath at 50-60℃ until completely dissolved, obtaining a cyclodextrin aqueous solution; coenzyme Q10 is dissolved in anhydrous ethanol and slowly added dropwise to the cyclodextrin aqueous solution. After the addition is complete, the mixture is stirred at a constant temperature for 2-4 hours, cooled to room temperature, and then refrigerated at 4℃ for 12-24 hours to obtain the coenzyme Q10 cyclodextrin inclusion complex suspension. This suspension is then transported to the next step via a closed stainless steel pipeline under sterile negative pressure and directly used for the preparation of nanoemulsion colostrum. This process can improve the inclusion rate of coenzyme Q10, which can reach over 90%, and significantly improves the water solubility and oxidative stability of the inclusion complex; at the same time, it eliminates the solid-liquid separation, drying, and pulverization steps, avoids the depolymerization and oxidation of the inclusion complex, reduces material transfer loss and contamination risk, and achieves continuous connection between the inclusion process and subsequent processes.

[0014] Further, in step 3, the preparation process of the coenzyme Q10 nanoemulsion colostrum is as follows: The emulsifier is mixed with the oil phase and magnetically stirred for 10-15 minutes until homogeneous, obtaining an oil phase mixture. A coenzyme Q10 cyclodextrin inclusion complex suspension, transported under sterile positive or negative pressure via a closed stainless steel pipeline, is added to the oil phase mixture and ultrasonically dispersed for 15-20 minutes at an ultrasonic power of 250-500W. Then, 5-8 times its mass of purified water is slowly added, followed by high-speed shear emulsification for 10-15 minutes at a shear rate of 8000-12000 r / min, yielding the coenzyme Q10 nanoemulsion colostrum. The combination of ultrasonic dispersion and high-speed shearing ensures uniform dispersion of the inclusion complex in the oil phase, laying the foundation for the subsequent formation of the nanoemulsion.

[0015] Furthermore, in step 4, a 1 mol / L citric acid solution or a 1 mol / L sodium hydroxide solution is added to adjust the pH of the system, preferably to 4.0. A weakly acidic environment can further improve the oxidative stability of coenzyme Q10, while also improving the taste of the oral liquid and masking the bitterness of coenzyme Q10.

[0016] Further specifying, in step 5, the high-pressure homogenization process parameters are: homogenization pressure 40-120 MPa, homogenization cycles 3-5 times, and homogenization temperature controlled at 30-40℃. These parameters can reduce the particle size of the nanoemulsion primary to 50-200 nm with uniform particle size distribution and a PDI < 0.2, significantly improving the stability of the nanoemulsion.

[0017] Further specifying the process parameters for ultra-high temperature instantaneous sterilization in step 6, the parameters are: sterilization temperature 115-140℃, sterilization time 3-5s, and rapid cooling to 25-30℃ after sterilization. Ultra-high temperature instantaneous sterilization can minimize the oxidative degradation of coenzyme Q10 by high temperature while ensuring sterilization effect, and the retention rate of effective components can reach more than 95%.

[0018] In the Coenzyme Q10 oral liquid prepared by this invention, nanoemulsions are used as drug-carrying particles with a particle size of 50-200 nm and a polydispersity index (PDI) of <0.2. After accelerated, long-term and influencing factor tests, all quality indicators of the formulation meet the requirements and have excellent stability. The bioavailability of Coenzyme Q10 is 2-3 times higher than that of conventional Coenzyme Q10 oral liquid.

[0019] Compared with the prior art, the present invention has the following beneficial effects: 1. A dual-stabilizing "core-shell" structure solves the problems of water solubility and oxidative degradation: This invention first uses hydroxypropyl-β-cyclodextrin to encapsulate coenzyme Q10, utilizing the hydrophobic cavities of cyclodextrin to encapsulate coenzyme Q10, forming a cyclodextrin inclusion complex core. This significantly improves the water solubility of coenzyme Q10 while preventing direct contact with external oxygen and light, thus initially enhancing its oxidative stability. The shell is formed by a nanoemulsion layer composed of emulsifiers and an oil phase, providing secondary encapsulation and protection for the core. This invention forms a dual-stabilizing system of "cyclodextrin inclusion complex core + nanoemulsion encapsulated shell," and its clear double-layer protective structure is visible under a lens. In contrast, in the traditional one-step mixing encapsulation method, the hydrophobic cavities of cyclodextrin compete with the micelles of the emulsifier and the core of the oil phase for binding, resulting in a low drug encapsulation rate and failing to form a stable and consistent double-layer protective structure. This invention completely solves the technical problems of poor water solubility and easy oxidative degradation of coenzyme Q10. After stability testing, the effective ingredient retention rate of the formulation remains above 90%.

[0020] 2. Significantly Improved Bioavailability: This invention controls the particle size of the drug-loaded microparticles within the nanometer range of 50-200 nm, with a uniform particle size distribution (PDI < 0.2). These nanometer-sized bilayer microparticles can be rapidly absorbed by the body through the gastrointestinal mucosal epithelial cells. Testing shows that the bioavailability of this invention is more than twice that of conventional coenzyme Q10 oral solution.

[0021] 3. Continuous Aseptic Production Process: This invention is the first to integrate inclusion complex preparation, nanoemulsion encapsulation, and aseptic filling into a complete continuous production line. Key technical points include: ① The inclusion complex suspension is used directly for subsequent emulsification without drying, avoiding inclusion complex depolymerization and drug oxidation caused by the drying process; ② All materials and intermediates are transported under aseptic positive pressure or negative pressure through closed pipelines, completely eliminating material transfer contamination and process interruptions in batch production; ③ Seamless integration from raw materials to finished products is achieved, increasing production efficiency by more than 50% compared to traditional batch processes, and significantly reducing batch-to-batch product variability. This process innovation provides a completely new solution for industrial intelligent manufacturing.

[0022] 4. Ultra-high temperature instantaneous sterilization protects active ingredients: This invention abandons the traditional long-term moist heat sterilization process and adopts ultra-high temperature instantaneous sterilization at 115-140℃ for 3-5 seconds, followed by rapid cooling. Compared with the traditional sterilization method of 100℃ for 30 minutes, this invention increases the retention rate of active ingredients to over 95%, minimizing the oxidative degradation of coenzyme Q10 caused by high temperatures.

[0023] 5. Improved taste, suitable for long-term use: This invention uses xylitol as a sweetener to replace traditional sucrose, which not only improves the bitterness and greasiness of the oral liquid, but also makes it suitable for diabetic patients; the addition of xanthan gum adjusts the viscosity of the preparation, making the taste smooth; at the same time, the pH is adjusted to weakly acidic (preferably 4.0), which further masks the bitterness and greatly improves consumer acceptance.

[0024] 6. Strong compatibility with excipients and environmentally friendly and safe process: This invention screens various emulsifiers (polyoxyethylene castor oil, polyglycerol fatty acid esters, etc.) and oil phases (medium-chain triglycerides, olive oil, etc.), all of which can achieve stable nanoemulsion preparation, facilitating flexible formulation based on raw material supply in industrial production. All raw materials are food-grade or pharmaceutical-grade, with no toxic or harmful solvent residues, meeting green and environmentally friendly requirements. Attached Figure Description

[0025] Figure 1 This is a flowchart illustrating the continuous preparation process of the Coenzyme Q10 nanoemulsion oral liquid with a dual stable structure according to the present invention. Detailed Implementation

[0026] In the following description, only certain exemplary embodiments are briefly described. As those skilled in the art will recognize, the described embodiments can be modified in various ways without departing from the spirit or scope of the embodiments of the invention. Therefore, the drawings and description are considered to be exemplary in nature and not restrictive.

[0027] The embodiments of the present invention will be described in detail below.

[0028] Example 1 This embodiment discloses a method for preparing a coenzyme Q10 nanoemulsion oral liquid with a dual-stabilized structure, such as... Figure 1 As shown, it includes the following steps: Step 1: Weigh the raw materials according to the following parts by weight: 2 parts coenzyme Q10, 10 parts hydroxypropyl-β-cyclodextrin, 6 parts polyoxyethylene castor oil, 4 parts medium-chain triglycerides, 3 parts xylitol, 0.2 parts citric acid, 0.1 parts xanthan gum, and 70 parts purified water; Step 2: Hydroxypropyl-β-cyclodextrin was added to 10 times its weight of purified water and stirred in a water bath at 55°C until completely dissolved to obtain a cyclodextrin aqueous solution. Coenzyme Q10 was dissolved in anhydrous ethanol and slowly added dropwise to the cyclodextrin aqueous solution at a rate of 1.5 mL / min. After the addition was completed, the mixture was stirred at a constant temperature of 55°C for 3 h. After cooling to room temperature, it was refrigerated at 4°C for 18 h to obtain a coenzyme Q10 cyclodextrin inclusion complex suspension with an inclusion rate of 92.5%. This suspension was then aseptically pumped through a closed stainless steel pipeline under negative pressure and directly used for the preparation of the nanoemulsion colostrum in the subsequent step 3.

[0029] Step 3: Mix polyoxyethylene castor oil with medium-chain triglycerides and stir magnetically for 12 min until homogeneous to obtain an oil phase mixture; add a coenzyme Q10 cyclodextrin inclusion complex suspension, which is sterilely pumped through a closed stainless steel pipeline under negative pressure, to the oil phase mixture, and sonicate at 350W for 18 min. Then slowly add 6 times its mass of purified water and emulsify at 10000 r / min for 12 min to obtain a coenzyme Q10 nanoemulsion colostrum. Step 4: Add xylitol, citric acid, and xanthan gum to purified water and stir to dissolve, prepare an aqueous phase, mix it with coenzyme Q10 nanoemulsion colostrum, and add 1 mol / L citric acid solution to adjust the pH of the system to 4.0; Step 5: The mixed system was homogenized under high pressure at 100 MPa for 4 times, and the homogenization temperature was controlled at 35℃ to obtain coenzyme Q10 nanoemulsion. The nanoemulsion particle size was measured to be 120 nm and the PDI was 0.15. Step 6: Perform ultra-high temperature instantaneous sterilization on the coenzyme Q10 nano-emulsion at a temperature of 138°C for 4 seconds. After sterilization, rapidly cool to 28°C and then perform aseptic filling to obtain coenzyme Q10 oral liquid.

[0030] Example 2 This embodiment discloses a method for preparing a coenzyme Q10 nanoemulsion oral liquid, comprising the following steps: Step 1: Weigh the raw materials according to the following parts by weight: 1 part coenzyme Q10, 8 parts hydroxypropyl-β-cyclodextrin, 5 parts compound emulsifier (polyglycerol fatty acid ester: Tween 80), 3 parts olive oil, 2 parts xylitol, 0.1 parts citric acid, and 0.05 parts xanthan gum; Step 2: Hydroxypropyl-β-cyclodextrin was added to 8 times its weight of purified water and stirred in a 50°C water bath until completely dissolved to obtain a cyclodextrin aqueous solution. Coenzyme Q10 was dissolved in anhydrous ethanol and slowly added dropwise to the cyclodextrin aqueous solution at a rate of 1 mL / min. After the addition was completed, the mixture was stirred at a constant temperature of 50°C for 2 h. After cooling to room temperature, it was refrigerated at 4°C for 12 h to obtain a coenzyme Q10 cyclodextrin inclusion complex suspension with an inclusion rate of 90.3%. This suspension was then aseptically pumped through a closed stainless steel pipeline under negative pressure and directly used for the preparation of the nanoemulsion colostrum in the subsequent step 3. Step 3: Mix the compound emulsifier (polyglycerol fatty acid ester: Tween 80) with olive oil and stir magnetically for 10 minutes until homogeneous to obtain an oil phase mixture; add the coenzyme Q10 cyclodextrin inclusion complex suspension, which is sterilely pumped through a closed stainless steel pipeline under negative pressure, to the oil phase mixture, and sonicate at 300W for 15 minutes. Then slowly add 5 times its mass of purified water and emulsify at 8000r / min for 10 minutes to obtain coenzyme Q10 nanoemulsion colostrum. Step 4: Add xylitol, citric acid, and xanthan gum to purified water and stir to dissolve, prepare an aqueous phase, mix it with coenzyme Q10 nanoemulsion colostrum, and adjust the pH of the system to 3.5 using 1 mol / L citric acid solution; Step 5: The mixed system was homogenized three times under high pressure at 80 MPa, and the homogenization temperature was controlled at 30℃ to obtain Coenzyme Q10 nanoemulsion. The nanoemulsion particle size was measured to be 80 nm and the PDI was 0.12. Step 6: Perform ultra-high temperature instantaneous sterilization on the coenzyme Q10 nano-emulsion at a temperature of 135°C for 3 seconds. After sterilization, rapidly cool to 25°C and then perform aseptic filling to obtain coenzyme Q10 oral liquid.

[0031] Comparative Example 1 (One-step mixed package is valid) To further illustrate the advantages of the stepwise double-layer encapsulation process of this invention, a coenzyme Q10 oral solution was prepared using a conventional one-step mixing encapsulation method as a comparative example, including the following steps: The raw materials and excipients were weighed exactly the same as in Example 1: 2 parts coenzyme Q10, 10 parts hydroxypropyl-β-cyclodextrin, 6 parts polyoxyethylene castor oil, 4 parts medium-chain triglycerides, 3 parts xylitol, 0.2 parts citric acid, and 0.1 parts xanthan gum.

[0032] The initial mixture was prepared using a one-step mixing and packaging method: Hydroxypropyl-β-cyclodextrin, polyoxyethylene castor oil, and medium-chain triglycerides were simultaneously added to 10 times their volume of purified water and stirred in a 55°C water bath until dissolved, thus obtaining a mixture. Coenzyme Q10 was dissolved in anhydrous ethanol and slowly added dropwise to the above mixture at a rate of 1.5 mL / min. After the addition was complete, the mixture was stirred at a constant temperature of 55°C for 3 h. After cooling to room temperature, it was refrigerated at 4°C for 18 h to obtain the initial mixture. Subsequent steps, including sonication, shearing, aqueous phase mixing, pH adjustment, high-pressure homogenization, sterilization, and filling, were completely consistent with those in Example 1.

[0033] Comparative Example 2 (without nanoemulsion encapsulation layer) To illustrate the necessity of nanoemulsion encapsulation, a coenzyme Q10 oral solution was prepared as a comparative example using a method that only involves the direct dispersion of inclusion complexes, including the following steps: Prepare a coenzyme Q10 cyclodextrin inclusion complex suspension according to step 2 of Example 1; dissolve xylitol, citric acid, and xanthan gum in purified water, mix with the inclusion complex suspension, adjust the pH to 4.0, do not add emulsifiers or oil phase, do not prepare nanoemulsions, directly homogenize under high pressure and then sterilize and fill.

[0034] Comparative Example 3 (Dong Yingjie et al. - Cyclodextrin phospholipid Dispersion System) References (Dong Yingjie et al., Central South Pharmaceutical Journal, 2020, Vol. 18, No. 10) Methods for preparing Coenzyme Q10-Peptolyl-Cyclodextrin-Phospholipid Dispersion System Powder (Dong Yingjie et al., Central South Pharmaceutical Journal, 2020, Vol. 18, No. 10) Methods for preparing Coenzyme Q10-Peptolyl-Cyclodextrin-Phospholipid Dispersion System Powder: Weigh out 10 g of coenzyme Q10, 2 g of prilol, and 50 g of β-cyclodextrin. Add 7 times the amount of purified water and stir at 80°C to form a paste. Grind the paste using a colloid mill for 20 cycles. Separately weigh out 3 g of soybean lecithin, add a small amount of purified water to disperse it into a uniform aqueous solution, mix it with the grinding solution, dilute with purified water to a solid content of 12%, and homogenize by shearing at 10,000 r / min for 2 min. Spray dry to obtain a dispersed powder. Reconstitute with water before use as an oral solution.

[0035] Comparative Example 4 (Fu Junhe et al. - Conventional Solubilized Oral Solution) References (Fu Junhe's Master's Thesis, "Dosage Form Research of Coenzyme Q10 Health Food"): Optimal process for preparing conventional solubilized coenzyme Q10 oral solution: Weigh out an appropriate amount of coenzyme Q10, use 250 mg of Tween-80 and 150 mg of polyoxyethylene fatty acid 40 ester as emulsifiers, add 7.5 mg of sodium isosorbide C as an antioxidant, adjust the pH to 3.5, add water to 50 mL, and sterilize by steaming at 100℃ for 30 min to obtain the final product.

[0036] Performance testing experiment To further verify the technical effect of the present invention, the Coenzyme Q10 oral solution prepared in Example 1 of the present invention was used as the test sample. Influencing factor test, accelerated stability test and long-term stability test were carried out in accordance with the "Guidelines for Drug Stability Testing". The appearance, particle size, PDI, Coenzyme Q10 content, pH value and other indicators of the sample were examined. The results are as follows.

[0037] Experiment 1: Influencing Factors Experiment 1.1 High Temperature Test: After filling, the samples were placed at 60℃ for 10 days. Samples were taken and tested on the 5th and 10th days, and the results are shown in the table below: 1.2 Strong Light Test: Samples were placed in a sealed transparent container and exposed to 4500 lx ± 500 lx light for 10 days. Samples were taken and tested on the 5th and 10th days, and the results are shown in the table below: Results analysis: After being placed at 60℃ and 4500lx strong light for 10 days, the sample showed no obvious changes in appearance, no stratification or crystallization, and no significant changes in particle size, PDI, and pH value. The coenzyme Q10 retention rate was above 97%, indicating that the sample has good stability to high temperature and strong light.

[0038] Experiment 2: Accelerated Stability Test The samples from Example 1 and Comparative Examples 1, 2, 3, and 4 were filled into glass bottles and sealed. They were then stored at 40℃±2℃ and 75%±5% relative humidity for 6 months. Samples were taken and tested at months 1, 2, 3, and 6. The results are shown in the table below: The results showed that the oral liquid prepared in the embodiments of the present invention had the best stability under accelerated conditions, with a retention rate of over 96% after 6 months and no change in appearance; while all comparative examples showed varying degrees of instability.

[0039] Experiment 3: Comparison of Sterilization Methods The same batch of coenzyme Q10 nano-emulsion was treated with ultra-high temperature instantaneous sterilization (138℃, 4s) and conventional moist heat sterilization (100℃, 30min) according to this invention, respectively. The changes in coenzyme Q10 content before and after sterilization were measured, and the results are as follows: The results show that the ultra-high temperature instantaneous sterilization method used in this invention can significantly reduce the degradation of heat-sensitive coenzyme Q10, and the retention rate is 12.5 percentage points higher than that of the traditional method.

[0040] Experiment 4: Taste Evaluation Test Twenty healthy volunteers were selected to participate in a blind taste test of Example 1, Comparative Example 3 (after reconstitution), and Comparative Example 4. The evaluation indicators included bitterness, oiliness, and overall acceptability (out of 10). The results are as follows: The results showed that the oral liquid of the present invention, with the addition of xylitol and xanthan gum and pH adjusted to 4.0, had a significantly better taste than the comparative example.

[0041] Experiment 5: Bioavailability Test Forty SD rats were randomly divided into four groups of ten each. Each group was administered the samples from Example 1 and the comparative example via gavage. The dosage of coenzyme Q10 was 30 mg / kg. Blood samples were collected at 0.5, 1, 2, 4, 6, 8, 12, and 24 h after administration to measure the drug concentration. The area under the curve (AUC) was calculated, and the results are as follows: Note: The AUC of the active pharmaceutical ingredient (coenzyme Q10 suspension) is approximately 3.90 μg·h / mL.

[0042] The results showed that the bioavailability of Example 1 of the present invention was 2.19 times that of conventional solubilized oral liquid (Comparative Example 4) and 2.50 times that of one-step mixing method (Comparative Example 1). In the one-step mixing encapsulation method, cyclodextrin, emulsifier, and oil were mixed at the same time, and each excipient competed for binding with coenzyme Q10, which could not achieve sufficient encapsulation and sealing. Moreover, the particle size was much larger than 200 nm, and the PDI was > 0.3, which deviated from the particle size range of nanoemulsions. It was prone to stratification and crystallization, resulting in low bioavailability. It was 3.50 times that of no nanoemulsion encapsulation layer (Comparative Example 2) and 2.4 times that of phospholipid encapsulation layer (Comparative Example 3), which fully demonstrated the advantages of the dual delivery structure of "cyclodextrin encapsulation core + nanoemulsion shell".

[0043] Experiment 6: Comparison of Continuous Production Efficiency Taking the production of 100 L of Coenzyme Q10 oral liquid as an example, the time consumption and batch-to-batch differences between the continuous production process of this invention and the traditional batch production process are compared: The results show that the continuous process efficiency of the present invention is improved by about 78%, the product quality uniformity is significantly improved, and the pollution risk and inclusion compound dissociation problem caused by intermediate transfer are completely avoided.

[0044] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. It should be noted that any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A coenzyme Q10 nanoemulsion oral solution with a dual-stabilized structure, characterized in that: The drug-loaded microparticles in the oral liquid have a dual stable structure, including an inclusion complex core formed by cyclodextrin and coenzyme Q10, and a nanoemulsion shell formed by emulsifier and oil phase. The particle size of the drug-loaded microparticles is 50-200 nm, and the polydispersity index (PDI) is <0.

2.

2. The method for preparing the coenzyme Q10 nanoemulsion oral liquid with a dual stable structure according to claim 1, characterized in that: Specifically, the steps include the following: Step 1: Weigh the main ingredients according to the specified amounts: Coenzyme Q10, hydroxypropyl-β-cyclodextrin, emulsifier, oil phase, xylitol, citric acid, and xanthan gum; Step 2: Coenzyme Q10 was included with hydroxypropyl-β-cyclodextrin to prepare a coenzyme Q10 cyclodextrin inclusion complex suspension; Step 3: Mix the emulsifier with the oil phase, then mix with the coenzyme Q10 cyclodextrin inclusion complex suspension, and prepare coenzyme Q10 nanoemulsion colostrum using a high-pressure homogenization method; Step 4: Add xylitol, citric acid, and xanthan gum to purified water and stir to dissolve, prepare an aqueous phase, mix with coenzyme Q10 nanoemulsion colostrum, and adjust the pH of the system to 3.5-5.5; Step 5: The mixed system is homogenized again under high pressure to obtain Coenzyme Q10 nano-emulsion. Step 6: Perform ultra-high temperature instantaneous sterilization on the coenzyme Q10 nano-emulsion, and then perform aseptic filling to obtain coenzyme Q10 oral liquid.

3. The method for preparing coenzyme Q10 nanoemulsion oral liquid according to claim 2, characterized in that: In step 1, the mass ratio of each main raw material is as follows: 1-5 parts coenzyme Q10, 8-15 parts hydroxypropyl-β-cyclodextrin, 5-10 parts emulsifier, 3-8 parts oil phase, 2-6 parts xylitol, 0.1-0.5 parts citric acid, and 0.05-0.2 parts xanthan gum.

4. The method for preparing coenzyme Q10 nanoemulsion oral liquid according to claim 2, characterized in that: The emulsifier is one or more of polyoxyethylene castor oil, polyglycerol fatty acid ester, and Tween 80, with an HLB value of 10-15; the oil phase is one or more of medium-chain triglycerides, olive oil, linseed oil, and coconut oil.

5. The method for preparing coenzyme Q10 nanoemulsion oral liquid according to claim 2, characterized in that: In step 2, the preparation process of the coenzyme Q10 cyclodextrin inclusion complex suspension is as follows: hydroxypropyl-β-cyclodextrin is added to 8-12 times its mass of purified water and stirred in a water bath at 50-60℃ until completely dissolved to obtain a cyclodextrin aqueous solution; coenzyme Q10 is dissolved in anhydrous ethanol and slowly added dropwise to the cyclodextrin aqueous solution. After the addition is complete, the mixture is stirred at a constant temperature for 2-4 hours, cooled to room temperature, and then placed in a refrigerator at 4℃ for 12-24 hours to obtain the coenzyme Q10 cyclodextrin inclusion complex suspension.

6. The method for preparing coenzyme Q10 nanoemulsion oral liquid according to claim 2, characterized in that: In step 3, the preparation process of the coenzyme Q10 nanoemulsion colostrum is as follows: the emulsifier is mixed with the oil phase and magnetically stirred for 10-15 min until homogeneous to obtain an oil phase mixture; the coenzyme Q10 cyclodextrin inclusion complex suspension is added to the oil phase mixture and ultrasonically dispersed for 15-20 min at an ultrasonic power of 250-500 W; then 5-8 times its mass of purified water is slowly added, and high-speed shear emulsification is performed for 10-15 min at a shear rate of 8000-12000 r / min to obtain the coenzyme Q10 nanoemulsion colostrum.

7. The method for preparing coenzyme Q10 nanoemulsion oral liquid according to claim 2, characterized in that: In step 4, add 1 mol / L citric acid solution or 1 mol / L sodium hydroxide solution to adjust the pH of the system, preferably to 4.

0.

8. The method for preparing coenzyme Q10 nanoemulsion oral liquid according to claim 2, characterized in that: In step 5, the process parameters for high-pressure homogenization are: homogenization pressure 40-120MPa, homogenization times 3-5 times, and homogenization temperature controlled at 30-40℃.

9. The method for preparing a coenzyme Q10 nanoemulsion oral liquid according to claim 2, characterized in that: In step 6, the process parameters for ultra-high temperature instantaneous sterilization are: sterilization temperature 115-140℃, sterilization time 3-5s, and rapid cooling to 25-30℃ after sterilization.

10. The method for preparing coenzyme Q10 nanoemulsion oral liquid according to any one of claims 2-9, characterized in that: In the preparation process from step 2 to step 6, all materials and intermediates are connected by closed stainless steel pipelines and conveyed to the next step by aseptic positive pressure or negative pressure, so as to achieve continuous aseptic production.

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