Coenzyme Q10 lipid nanocrystal with high drug loading capacity

Abstract

The invention provides a coenzyme Q10 lipid nanocrystal which is prepared from the following raw materials in percentage by mass through a hot melt extrusion method: 10%-58% of coenzyme Q10, 9.09%-30% of glyceryl monostearate, 14.28%-20% of polysorbate 80 and 14.28%-45% of a water-soluble carrier, and the total amount of all the raw materials is 100%. The particle size of the coenzyme Q10 lipid nanocrystal ranges from 537.2 nm to 936.5 nm; the solid lipid and the water-soluble carrier are combined to serve as a dispersing agent of the coenzyme Q10, so that the coenzyme Q10 can be dispersed in the combined material in a nanocrystal form, the lipid nanocrystal with high drug loading capacity is obtained, the prepared coenzyme Q10 nanocrystal can be quickly dispersed and dissolved out in water, and the preparation method is simple in preparation condition, short in time, low in cost and suitable for industrial production. The method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a coenzyme Q. 10 A novel method for preparing lipid nanocrystals, which can yield coenzyme Q with high drug loading capacity. 10 Lipid nanocrystals. Background Technology

[0002] Coenzyme Q 10 (CoQ) 10 As a core molecule in mitochondrial energy metabolism and antioxidant defense, it holds significant therapeutic potential in cardiovascular diseases and neurodegenerative diseases. However, its strong hydrophobicity (log P≈14), low solubility (<0.01 μg / mL), and large molecular weight (863.63 Da) result in oral bioavailability of less than 5%, severely limiting its clinical application. Traditional tablets and capsules suffer from poor gastrointestinal dissolution, with peak concentrations of only 0.8-1.2 μg / mL after a single oral dose of 100 mg, significantly impacting their therapeutic efficacy.

[0003] Drug nanocrystals technology refers to the process of dispersing or precipitating micron-sized drug particles through grinding or crystallization under the action of stabilizers, thereby stabilizing them and reducing their particle size to submicron (100-1000 nm) or even nanomicron (1-100 nm) scales. Nanocrystals are characterized by high drug loading capacity, good stability, high bioavailability, and the ability to achieve targeted drug delivery. As an intermediate formulation technology, nanocrystals can be applied to the preparation of formulations via various routes of administration, such as oral, injection, pulmonary, transdermal, and ocular administration, and have wide clinical applications, especially suitable for the delivery of high-dose, poorly soluble drugs. CN112315915A discloses a supercritical fluid regranulation technique for preparing coenzyme Q. 10 The nanoparticle method utilizes supercritical carbon The fluid's solubility in a solvent allows for emulsification into a microemulsion in a low-temperature, oxygen-free environment. Subsequent processing, such as crystallization, yields nanoparticles. This method aims to effectively utilize coenzyme Q10. 10 Encapsulation (e.g., using maltodextrin as a wall material) can improve its encapsulation efficiency, dissolution rate, and bioavailability. CN102438606A includes Coenzyme Q. 10 It is soluble in water-miscible organic solvents, binds to amino acid or protein solutions, and forms stable, dispersed nanoparticles after solvent removal. These nanoparticles are stably dispersed, simultaneously delivering amino acids / proteins and improving absorption. CN114504103A provides a nanoscale coenzyme Q that exhibits rapid dispersion, high solubility, high bioavailability, and a pleasant taste. 10 The preparation method of the particles utilizes nanotechnology to increase the size of coenzyme Q. 10Its specific surface area may improve its solubility and absorption in the human body, focusing on solving the problems of solubility, bioavailability and taste faced by the application end, and has a clear industrialization orientation.

[0004] Of the currently published patents, aside from most capsule formulations, Coenzyme Q... 10 The drug loading capacity of the product is not high, and the preparation techniques often use organic reagents. This invention aims to develop a green and energy-saving preparation method for preparing coenzyme Q with high drug loading capacity. 10 Nanoscale particles enable Coenzyme Q 10 It has good dissolution properties, thereby improving bioavailability.

[0005] Hot melt extrusion (HME) is a technology that involves simultaneously adding drugs, polymers, plasticizers, and other excipients into a temperature-controlled barrel. The mixture is then mixed, melted, and shaped in a molten state. Under intense mixing and shearing forces, the drug is uniformly dispersed within a carrier and extruded at a specific speed and shape to form the final product. HME offers significant advantages in improving the solubility and dissolution rate of poorly soluble drugs, masking bitterness, and enhancing drug stability. However, its application in the preparation of lipid nanocrystals has not yet been reported. Summary of the Invention

[0006] The main objective of this invention is to provide a coenzyme Q with a high drug loading capacity. 10 The preparation method of lipid nanocrystals breaks through the current coenzyme Q10 standard. 10 Limitations of high drug loading preparation methods. This invention patent uses a hot melt extrusion method to obtain coenzyme Q. 10 Lipid nanocrystals, produced by mechanically breaking down drugs into nano-sized crystals and uniformly dispersing them in a small amount of carrier under conditions below the drug's melting point using a twin-screw extruder, successfully yielded coenzyme Q with high drug loading and good dissolution performance. 10 Lipid nanocrystals.

[0007] This invention provides a coenzyme Q10 lipid nanocrystal, which is made by hot melt extrusion of the following raw materials in the indicated mass percentages: coenzyme Q10 10%~58%, glyceryl monostearate 9.09%~30%, polysorbate 80 14.28%~20%, and water-soluble carrier 14.28%~45%, with the total of all raw materials being 100%; the water-soluble carrier is hydroxypropyl cellulose or povidone K30; and the particle size of the coenzyme Q10 lipid nanocrystal is 537.2-936.5 nm.

[0008] Furthermore, the water-soluble carrier is hydroxypropyl cellulose.

[0009] Furthermore, the coenzyme Q10 lipid nanocrystals are made from the following raw materials in the indicated mass percentages: coenzyme Q10 50.00%, glyceryl monostearate 16.66%, polysorbate 80 16.67%, and hydroxypropyl cellulose 16.67%.

[0010] Furthermore, the preparation method of the coenzyme Q10 lipid nanocrystals is as follows: coenzyme Q10, glyceryl monostearate, polysorbate 80 and water-soluble carrier are mixed and added to a twin-screw hot melt extruder. The extrusion temperature is 30-50℃ (preferably 40℃) and the rotation speed is 30-100 rpm to obtain an extruded strip. After the extruded strip is cooled, it is crushed and sieved to obtain the extrudate powder, which is the coenzyme Q10 lipid nanocrystals.

[0011] Furthermore, the sieve through which the extruder passes is 65-120 mesh (preferably 80 mesh).

[0012] Furthermore, the preparation method of the coenzyme Q10 lipid nanocrystals is as follows: coenzyme Q10, glyceryl monostearate, polysorbate 80 and hydroxypropyl cellulose are mixed and added to a twin-screw hot melt extruder. The extrusion temperature is 40°C and the speed is 30 rpm to obtain an extruded strip. After the extruded strip is cooled, it is crushed and sieved to obtain the extrudate powder, which is the coenzyme Q10 lipid nanocrystals.

[0013] The product prepared by this method can enhance coenzyme Q. 10 Drug loading exceeds 50%, Coenzyme Q 10 It exists as stable crystals with a particle size of less than 1 micrometer in the carrier, thus exhibiting a good dissolution rate. In a 25% isopropanol solution containing 0.5% polysorbate 80, the dissolution rate is 72.25% at 30 minutes and reaches 89.06% at 60 minutes, which is much higher than that of the active pharmaceutical ingredient.

[0014] The beneficial effects of this invention are mainly reflected in: This invention combines solid lipids and a water-soluble carrier as coenzyme Q. 10 The dispersant makes Coenzyme Q... 10 It can be dispersed in the form of nanocrystals in the composite material to obtain lipid nanocrystals with high drug loading, and the prepared coenzyme Q can be... 10 Nanocrystals can be rapidly dispersed and dissolved in water. Furthermore, the preparation conditions of this invention are simple, quick, and low-cost, making it suitable for industrial production. Attached Figure Description

[0015] Figure 1 Example 1: Nanocrystals and Coenzyme Q 10 Cumulative dissolution curve of active pharmaceutical ingredient in medium

[0016] Figure 2 Examples 2-4: Cumulative dissolution curves of lipid nanocrystals in the medium

[0017] Figure 3 Examples 5-6: Cumulative dissolution curves of lipid nanocrystals in the medium

[0018] Figure 4 Example 7: Cumulative dissolution curves of lipid nanocrystals and physical mixtures, and Example 8: Lipid nanocrystals in media.

[0019] Figure 5 Example 7: X-ray diffraction pattern of lipid nanocrystals

[0020] Figure 6 Example 7: Number-average particle size distribution of lipid nanocrystals

[0021] Figure 7 Example 7: Scanning electron micrographs of the active pharmaceutical ingredient (a), lipid nanocrystals with water-soluble carrier removed (b), and lipid nanocrystals (c).

[0022] Figure 8 Cumulative dissolution curves of lipid nanocrystals in the medium for Comparative Examples 1-3 Detailed Implementation

[0023] The preparation process and effects of the formulation of the present invention are further described below through examples. It should be noted that the following description is for illustrative purposes only and does not limit the scope of the invention.

[0024] Example 1: 1. Preparation of Coenzyme Q10 lipid nanocrystals: Weigh out Coenzyme Q 10 1.50g of glyceryl monostearate, 4.50g of polysorbate 80, 2.25g of hydroxypropyl cellulose (HPC), and 6.75g of hydroxypropyl cellulose (HPC) were mixed evenly to obtain a physical mixture. The extrusion temperature was set to 40℃ and the screw speed to 30rpm. After the equipment started running, the physical mixture was fed into the feed port for hot melt extrusion. The cooled extrudate was collected, pulverized using a pulverizer, and passed through an 80-mesh sieve to obtain coenzyme Q. 10 Lipid nanocrystal powder sample.

[0025] 2. Determination of in vitro dissolution rate: Weigh out 100mg of Coenzyme Q 10 Lipid nanocrystal powder samples were added to 900 mL of 0.5% polysorbate 80 in 25% isopropanol solution, in triplicate. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 min at 100 rpm, filtered rapidly, and the drug concentration was determined by high-performance liquid chromatography (HPLC). The dissolution rate of the active pharmaceutical ingredient was determined using the same method; the results are shown below. Figure 1 .from Figure 1 As can be seen from this, Coenzyme Q 10The lipid nanocrystals dissolve very quickly in the dissolution medium, with a dissolution rate of 85.83% at 30 min and 89.93% at 60 min, while the active pharmaceutical ingredient dissolves very slowly, with only 5% dissolving at 60 min.

[0026] 3. Particle size: An appropriate amount of lipid nanocrystal powder was weighed and dispersed in purified water. The mixture was stirred for 5 minutes to prepare a suspension with a drug concentration of 2 mg / mL. The particle size of the solution was measured using a Malvern laser particle size analyzer, and the results are shown in Table 1. From Table 1, it can be seen that the coenzyme Q obtained in this example... 10 The lipid nanocrystals have a particle size of 691.2 nm (PDI = 0.451).

[0027] Example 2: 1. Preparation of Coenzyme Q10 lipid nanocrystals: Weigh out Coenzyme Q 10 6.00g of glyceryl monostearate, 3.00g of polysorbate 80, and 3.00g of hydroxypropyl cellulose were mixed evenly to obtain a physical mixture. The extrusion temperature was set to 40℃ and the screw speed to 30rpm. After the equipment started running, the physical mixture was fed into the feed port for hot melt extrusion. The cooled extrudate was collected, pulverized with a pulverizer, and passed through an 80-mesh sieve to obtain coenzyme Q with a drug loading of 40%. 10 Lipid nanocrystal powder sample.

[0028] 2. Determination of in vitro dissolution rate: Weigh out 25mg of Coenzyme Q. 10 Lipid nanocrystal powder samples were added to 900 mL of 0.5% polysorbate 80 in 25% isopropanol solution, in triplicate. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 min at 100 rpm. After rapid filtration, the drug concentration was determined by high-performance liquid chromatography (HPLC). The dissolution results are shown in the figure. Figure 2 .from Figure 2 As can be seen from the above, the coenzyme Q obtained in this embodiment... 10 The lipid nanocrystal samples dissolved well in the dissolution medium, with a dissolution rate of 61.93% at 30 min and 75.69% at 60 min.

[0029] 3. Particle size: An appropriate amount of lipid nanocrystal powder was weighed and dispersed in purified water. The mixture was stirred for 5 minutes to prepare a suspension with a drug concentration of 2 mg / mL. The particle size of the solution was measured using a Malvern laser particle size analyzer, and the results are shown in Table 1. From Table 1, it can be seen that the coenzyme Q obtained in this example... 10 The lipid nanocrystals have a particle size of 558.9 nm (PDI=0.5).

[0030] Example 3: 1. Preparation of Coenzyme Q10 lipid nanocrystals: Weigh out Coenzyme Q 10 6.00g of glyceryl monostearate, 2.00g of polysorbate 80, and 2.00g of hydroxypropyl cellulose were mixed evenly to obtain a physical mixture. The extrusion temperature was set to 40℃ and the screw speed to 30rpm. After the equipment started running, the physical mixture was fed into the feed port for hot melt extrusion. The cooled extrudate was collected, pulverized with a pulverizer, and passed through an 80-mesh sieve to obtain coenzyme Q with a drug loading of 50%. 10 Lipid nanocrystal powder sample.

[0031] 2. Determination of in vitro dissolution rate: Weigh out 20mg of Coenzyme Q 10 Lipid nanocrystal powder samples were added to 900 mL of 0.5% polysorbate 80 in 25% isopropanol solution, in triplicate. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 min at 100 rpm. After rapid filtration, the drug concentration was determined by high-performance liquid chromatography (HPLC). The dissolution results are shown in the figure. Figure 2 .from Figure 2 As can be seen from this, Coenzyme Q 10 The lipid nanocrystals dissolve rapidly in the dissolution medium, with a dissolution rate of 72.25% at 30 min and 89.06% at 60 min.

[0032] 3. Particle size: An appropriate amount of lipid nanocrystal powder was weighed and dispersed in purified water. The mixture was stirred for 5 minutes to prepare a suspension with a drug concentration of 2 mg / mL. The particle size of the solution was measured using a Malvern laser particle size analyzer, and the results are shown in Table 1. From Table 1, it can be seen that the coenzyme Q obtained in this example... 10 The lipid nanocrystals have a particle size of 537.2 nm (PDI = 0.451).

[0033] Example 4: 1. Preparation of Coenzyme Q10 lipid nanocrystals: Weigh out Coenzyme Q 10 8.00g of glyceryl monostearate, 2.00g of polysorbate 80, and 2.00g of hydroxypropyl cellulose were mixed evenly to obtain a physical mixture. The extrusion temperature was set to 40℃ and the screw speed to 30rpm. After the equipment started running, the physical mixture was fed into the feed port for hot melt extrusion. The cooled extrudate was collected, pulverized with a pulverizer, and passed through an 80-mesh sieve to obtain coenzyme Q with a drug loading of 57%. 10 Lipid nanocrystal powder sample.

[0034] 2. Determination of in vitro dissolution rate: Weigh out 17.5mg of Coenzyme Q.10 Lipid nanocrystal powder samples were added to 900 mL of 0.5% polysorbate 80 in 25% isopropanol solution, in triplicate. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 min at 100 rpm. After rapid filtration, the drug concentration was determined by high-performance liquid chromatography (HPLC). The dissolution results are shown in the figure. Figure 2 .from Figure 2 As can be seen, the drug loading of coenzyme Q is 57%. 10 The lipid nanocrystals exhibited a dissolution rate of 56.80% after 30 minutes in the dissolution medium and reached 69.21% after 60 minutes, slightly lower than that of coenzyme Q with a drug loading of 50%. 10 The lipid nanocrystals dissolve, but the amount dissolves is much greater than that of the active pharmaceutical ingredient.

[0035] 3. Particle size: An appropriate amount of lipid nanocrystal powder was weighed and dispersed in purified water. The mixture was stirred for 5 minutes to prepare a suspension with a drug concentration of 2 mg / mL. The particle size of the solution was measured using a Malvern laser particle size analyzer, and the results are shown in Table 1. From Table 1, it can be seen that the coenzyme Q obtained in this example... 10 The lipid nanocrystals have a particle size of 946.5 nm (PDI = 0.333).

[0036] Example 5: 1. Preparation of Coenzyme Q10 lipid nanocrystals: Weigh out Coenzyme Q 10 6.00g of glyceryl monostearate, 3.00g of polysorbate 80, and 3.00g of povidone K30 were mixed evenly to obtain a physical mixture. The extrusion temperature was set to 40℃ and the screw speed to 30rpm. After the equipment started running, the physical mixture was fed into the feed port for hot melt extrusion. The cooled extrudate was collected, pulverized with a pulverizer, and passed through an 80-mesh sieve to obtain coenzyme Q with a drug loading of 40%. 10 Lipid nanocrystal powder sample.

[0037] 2. Determination of in vitro dissolution rate: Weigh out 25mg of Coenzyme Q. 10 Lipid nanocrystal powder samples were added to 900 mL of 0.5% polysorbate 80 in 25% isopropanol solution, in triplicate. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 min at 100 rpm. After rapid filtration, the drug concentration was determined by high-performance liquid chromatography (HPLC). The dissolution results are shown in the figure. Figure 3 .from Figure 3 As can be seen from this, Coenzyme Q 10The dissolution rate of lipid nanocrystals in the dissolution medium was 50.36% at 30 min and reached 61.89% at 60 min. Although the solubilizing effect of the water-soluble carrier PVP K30 was not as good as that of HPC, it was much higher than that of the active pharmaceutical ingredient.

[0038] 3. Particle size: Weigh an appropriate amount of powder, disperse it in purified water, stir for 5 minutes, and prepare a suspension with a drug concentration of 2 mg / mL. The particle size of the solution was measured using a Malvern laser particle size analyzer, and the results are shown in Table 1. From Table 1, it can be seen that the particle size of the coenzyme Q10 lipid nanocrystals obtained in this example is 823.3 nm (PDI=0.588).

[0039] Example 6: 1. Preparation of Coenzyme Q10 lipid nanocrystals: Weigh out Coenzyme Q 10 6.00g of glyceryl monostearate, 1.00g of polysorbate 80, 2.00g of hydroxypropyl cellulose, and 2.00g of hydroxypropyl cellulose were mixed evenly to obtain a physical mixture. The extrusion temperature was set to 40℃ and the screw speed to 30rpm. After the equipment started running, the physical mixture was fed into the feed port for hot melt extrusion. The cooled extrudate was collected, pulverized with a pulverizer, and passed through an 80-mesh sieve to obtain coenzyme Q with a drug loading of 55%. 10 Lipid nanocrystal powder sample.

[0040] 2. Determination of in vitro dissolution rate: Weigh out 18.5mg of Coenzyme Q. 10 Lipid nanocrystal powder samples were added to 900 mL of 0.5% polysorbate 80 in 25% isopropanol solution, in triplicate. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 min at 100 rpm. After rapid filtration, the drug concentration was determined by high-performance liquid chromatography (HPLC). The dissolution results are shown in the figure. Figure 3 .from Figure 3 As can be seen from the data, the Coenzyme Q with a drug loading of 55% obtained in this embodiment... 10 The lipid nanocrystal samples showed good dissolution rates, with a dissolution rate of 54.26% at 30 min and 79.67% at 60 min.

[0041] 3. Particle size: An appropriate amount of lipid nanocrystal powder was weighed and dispersed in purified water. The mixture was stirred for 5 minutes to prepare a suspension with a drug concentration of 2 mg / mL. The particle size of the solution was measured using a Malvern laser particle size analyzer, and the results are shown in Table 1. From Table 1, it can be seen that the coenzyme Q obtained in this example... 10 The lipid nanocrystals have a particle size of 974.5 nm (PDI = 0.552).

[0042] Example 7: 1. Preparation of Coenzyme Q10 lipid nanocrystals: Weigh out Coenzyme Q 10 6.00g of glyceryl monostearate, 2.00g of polysorbate 80, and 2.00g of hydroxypropyl cellulose were mixed evenly to obtain a physical mixture. The extrusion temperature was set to 40℃ and the screw speed to 50rpm. After the equipment started running, the physical mixture was fed into the feed port for hot melt extrusion. The cooled extrudate was collected, pulverized with a pulverizer, and passed through an 80-mesh sieve to obtain coenzyme Q with a drug loading of 50%. 10 Lipid nanocrystal powder sample.

[0043] 2. Determination of in vitro dissolution rate: Weigh out 20mg of Coenzyme Q. 10 Lipid nanocrystal powder samples were added to 900 mL of 0.5% polysorbate 80 in 25% isopropanol solution. Three parallel studies were conducted at 100 rpm, with samples taken at 5, 10, 15, 20, 30, 45, and 60 min. After rapid filtration, the drug concentration was determined by high-performance liquid chromatography (HPLC). 20 mg of the physical mixture was weighed and the dissolution rate was determined using the same method. The dissolution results are shown in [Figure showing dissolution results]. Figure 4 .from Figure 4 As can be seen, the coenzyme Q prepared by the extruder screw speed of 50 rpm 10 Lipid nanocrystals exhibited the highest dissolution rate in the dissolution medium, with a dissolution percentage of 87.67% at 30 min and reaching 92.08% at 60 min. In contrast, the physical mixture showed a dissolution rate of 30.77% at 30 min and 38.56% at 60 min. This indicates that increasing the rotation speed can enhance drug dissolution.

[0044] 3. Particle size: Weigh an appropriate amount of powder, disperse it in purified water, stir for 5 minutes, and prepare a suspension with a drug concentration of 2 mg / mL. The particle size of the solution was measured using a Malvern laser particle size analyzer, and the results are shown in Table 1. From Table 1, it can be seen that the coenzyme Q obtained in this example... 10 The lipid nanocrystals have a particle size of 736.5 nm (PDI = 0.264).

[0045] Example 8: 1. Preparation of Coenzyme Q10 lipid nanocrystals: Weigh out Coenzyme Q 10 6.00g of glyceryl monostearate, 2.00g of polysorbate 80, and 2.00g of hydroxypropyl cellulose were mixed evenly to obtain a physical mixture. The extrusion temperature was set to 40℃ and the screw speed to 100rpm. After the equipment started running, the physical mixture was fed into the feed port for hot melt extrusion. The cooled extrudate was collected, pulverized using a pulverizer, and passed through an 80-mesh sieve to obtain coenzyme Q.10 Lipid nanocrystal powder sample.

[0046] 2. Determination of in vitro dissolution rate: Weigh out 20mg of Coenzyme Q. 10 Lipid nanocrystal powder samples were added to 900 mL of 0.5% polysorbate 80 in 25% isopropanol solution, in triplicate. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 min at 100 rpm. After rapid filtration, the drug concentration was determined by high-performance liquid chromatography (HPLC). The dissolution results are shown in the figure. Figure 4 .from Figure 4 As can be seen, compared with the product obtained by extrusion screw speed of 50 rpm, the dissolution rate of the product obtained by screw speed of 100 rpm is lower, with a dissolution rate of 57.20% at 30 min and reaching 73.61% at 60 min. This indicates that excessively high speed will reduce drug dissolution, but it is still much higher than that of the active pharmaceutical ingredient.

[0047] 3. Particle size: Weigh an appropriate amount of powder, disperse it in purified water, stir for 5 minutes to prepare a suspension with a drug concentration of 2 mg / mL, and measure the particle size of the solution using a Malvern laser particle size analyzer. The results are shown in Table 1. Table 1 shows that the particle size of the coenzyme Q10 lipid nanocrystals obtained in this example is 743.3 nm (PDI = 0.466). Example 9: Physical property testing of lipid nanocrystals from Example 7 1. Crystal form: The extruded powder from Example 7, along with appropriate amounts of the physical mixture and active pharmaceutical ingredient, were analyzed using an X-ray powder diffractometer. The samples filling the sample cell were flattened, and the step size was set to 0.02°, the diffraction angle range to 3-50° (2θ), and the scanning speed was 20° / min. The coenzyme Q of the active pharmaceutical ingredient was determined using the same method. 10 X-ray powder diffraction patterns of the additives and excipients. Results are shown in... Figure 5 .from Figure 5 As can be seen, the active pharmaceutical ingredient (API) has characteristic diffraction peaks at 11.5°, 18.2°, 19.3°, 22.3°, 23.0°, and 33.3°. The characteristic diffraction peaks of the extrudate are the same as those of the physical mixture and all have the characteristic diffraction peaks of the API. Therefore, the crystal form of the drug remains unchanged before and after extrusion.

[0048] 2. Particle size: The extrudate powder from Example 7 was dissolved in purified water and stirred for 5 minutes to fully dissolve the carrier and uniformly disperse the drug in the medium. The particle size of the drug in the suspension was measured using a Malvern laser particle size analyzer. The results are shown below. Figure 6 In the study, the particle size of the drug was 736.5 nm, and the PDI was 0.264.

[0049] 3. Scanning electron microscope: The extruded powder from Example 7, lipid nanocrystal powder with the carrier removed, and coenzyme Q were respectively... 10 The active pharmaceutical ingredient (API) was placed on conductive adhesive, and the surface powder was gently blown off. Then, it was vacuum-sputtered with gold for 120 seconds. The morphology and size of the drug were observed under different magnifications using a scanning electron microscope at an accelerating voltage of 5–10 kV. The extrudate carrier removal method is as follows: An appropriate amount of extrudate powder was weighed into a vial, purified water was added, and the mixture was stirred thoroughly to completely dissolve the excipients. The mixture was then filtered through a 0.22 μm microporous membrane. The filter membrane containing the filter residue was placed in a vacuum drying oven. After the residue was completely dried, it was gently scraped off and collected for later use. Figure 7 As shown, Coenzyme Q 10 The active pharmaceutical ingredient is a blocky crystal with a size of micrometers, while the lipid nanocrystal powder has observed particle sizes at the nanometer level, which is basically consistent with the particle size measurement results.

[0050] Comparative Example 1: 1. Preparation of lipid nanocrystals: Weigh out Coenzyme Q 10 6.00g of glyceryl monostearate, 3.00g of polysorbate 80, and 3.00g of hydroxypropyl methylcellulose (HPMC) E5 were mixed evenly to obtain a physical mixture. The extrusion temperature was set to 40℃ and the screw speed to 30rpm. After the equipment started running, the physical mixture was fed into the feed port for hot melt extrusion. The cooled extrudate was collected, pulverized with a pulverizer, and passed through an 80-mesh sieve to obtain coenzyme Q with a drug loading of 40%. 10 Powder sample.

[0051] 2. Determination of in vitro dissolution rate: Weigh out 25mg of Coenzyme Q 10 Powdered samples were added to 900 mL of 0.5% polysorbate 80 in 25% isopropanol solution, in triplicate. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 min at 100 rpm. After rapid filtration, the drug concentration was determined by high-performance liquid chromatography (HPLC). Dissolution results are shown in the figure. Figure 8 .from Figure 8 As can be seen, the dissolution rate of this comparative sample in the dissolution medium is poor, with a dissolution rate of only 19.57% at 30 min and a dissolution rate of 50.50% at 60 min.

[0052] 3. Particle size: Weigh an appropriate amount of powder, disperse it in purified water, stir for 5 minutes to prepare a suspension with a drug concentration of 2 mg / mL, and measure the particle size of the solution using a Malvern laser particle size analyzer. The results are shown in Table 1. From Table 1, it can be seen that the coenzyme Q sample obtained in this comparative example... 10The particle size distribution was 2643 nm (PDI=0.327), indicating that the sample extruded using HPMC E5 was not dispersed at the nanoscale.

[0053] Comparative Example 2: 1. Preparation of lipid nanocrystals: Weigh out Coenzyme Q 10 6.00g of glyceryl monostearate, 3.00g of polysorbate 80, and 3.00g of lignin were mixed evenly to obtain a physical mixture. The extrusion temperature was set to 40℃ and the screw speed to 30rpm. After the equipment started running, the physical mixture was fed into the feed port for hot melt extrusion. The cooled extrudate was collected, pulverized with a pulverizer, and passed through an 80-mesh sieve to obtain coenzyme Q with a drug loading of 40%. 10 Powder sample.

[0054] 2. Determination of in vitro dissolution rate: Weigh out 25mg of Coenzyme Q. 10 Powdered samples were added to 900 mL of 0.5% polysorbate 80 in 25% isopropanol solution, in triplicate. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 min at 100 rpm. After rapid filtration, the drug concentration was determined by high-performance liquid chromatography (HPLC). Dissolution results are shown in the figure. Figure 8 .from Figure 8 As can be seen, the dissolution rate of this comparative sample in the dissolution medium is poor, with a dissolution rate of 52.36% at 30 min and 64.72% at 60 min.

[0055] 3. Particle size: Weigh an appropriate amount of powder, disperse it in purified water, stir for 5 minutes to prepare a suspension with a drug concentration of 2 mg / mL, and measure the particle size of the solution using a Malvern laser particle size analyzer. The results are shown in Table 1. From Table 1, it can be seen that the coenzyme Q sample obtained in this comparative example... 10 The dispersed particle size was 1765 nm (PDI=0.626), indicating that the sample extruded from lignin was not dispersed at the nanoscale.

[0056] Comparative Example 3: 1. Preparation of lipid nanocrystals: Weigh out Coenzyme Q 10 6.00g of glyceryl monostearate, 3.00g of TPGS, and 3.00g of HPC were mixed thoroughly to obtain a physical mixture. The extrusion temperature was set to 40℃ and the screw speed to 30rpm. After the equipment started operating, the physical mixture was fed into the feed port for hot-melt extrusion. The cooled extrudate was collected, pulverized using a pulverizer, and passed through an 80-mesh sieve to obtain coenzyme Q with a drug loading of 40%. 10 Powder sample, denoted as COQ 10-GMS-TPGS-HPC 2-1-1-1.

[0057] 2. Determination of in vitro dissolution rate: Weigh out 25mg of Coenzyme Q. 10 Powdered samples were added to 900 mL of 0.5% polysorbate 80 in 25% isopropanol solution, in triplicate. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 min at 100 rpm. After rapid filtration, the drug concentration was determined by high-performance liquid chromatography (HPLC). Dissolution results are shown in the figure. Figure 8 .from Figure 8 As can be seen, the dissolution rate of this comparative sample in the dissolution medium is poor, with a dissolution rate of only 28.63% at 30 min and a dissolution rate of 35.76% at 60 min.

[0058] 3. Particle size: Weigh an appropriate amount of powder, disperse it in purified water, stir for 5 minutes, and prepare a suspension with a drug concentration of 2 mg / mL. The particle size of the solution was measured using a Malvern laser particle size analyzer, and the results are shown in Table 1. From Table 1, it can be seen that the coenzyme Q product obtained in this comparative example... 10 The dispersed particle size was 1037 nm (PDI=0.478), indicating that the sample extruded by TPGS was not dispersed at the nanoscale.

[0059] Table 1 shows the particle size and PDI of lipid nanocrystals in Examples 1-8 and Comparative Examples 1-3.

[0060] Table 1

[0061] As shown in Table 1, using glyceryl monostearate as the lipid material, polysorbate 80 as the stabilizer, and hydroxypropyl cellulose as the water-soluble material, coenzyme Q10 lipid nanocrystals with a drug loading of over 50% and a high dissolution rate can be obtained through reasonable formulation and processing. However, using hydroxypropyl methylcellulose or lignin as water-soluble carriers, or TPGS as a stabilizer, cannot produce coenzyme Q10 nanocrystals, resulting in poor dissolution.

Claims

1. A coenzyme Q10 lipid nanocrystal, characterized by, The coenzyme Q10 lipid nanocrystal is prepared from raw materials with the following mass percentages: coenzyme Q10 10%-58%, glycerin monostearate 9.09%-30%, polysorbate 80 14.28%-20%, and water-soluble carrier 14.28%-45%, wherein the total of all the raw materials is 100%; the water-soluble carrier is hydroxypropyl cellulose or povidone K30; and the particle size of the coenzyme Q10 lipid nanocrystal is 537.2-936.5 nm.

2. The coenzyme Q10 lipid nanocrystal of claim 1, wherein, The water-soluble carrier is hydroxypropyl cellulose.

3. The coenzyme Q10 lipid nanocrystal of claim 1, wherein the coenzyme Q10 lipid nanocrystal is in a form of a solid dispersion. The coenzyme Q10 lipid nanocrystal is prepared from raw materials with the following mass percentages: coenzyme Q10 50.00%, glycerin monostearate 16.66%, polysorbate 80 16.67%, and hydroxypropyl cellulose 16.67%.

4. The coenzyme Q10 lipid nanocrystal of claim 1, wherein, The coenzyme Q10 lipid nanocrystal is prepared by the following method: coenzyme Q10, glycerin monostearate, polysorbate 80, and a water-soluble carrier are mixed and then added to a double-screw hot melt extruder, the extrusion temperature is 30-50 DEG C, the rotation speed is 30-100 rpm, an extrusion strip is obtained, the extrusion strip is cooled and then crushed and sieved, and the extrudate powder obtained is the coenzyme Q10 lipid nanocrystal.

5. The coenzyme Q10 lipid nanocrystal of claim 4, wherein the coenzyme Q10 lipid nanocrystal is in a form of a solid dispersion. The sieve for sieving the extrusion strip is 65-120 mesh.

6. The coenzyme Q10 lipid nanocrystal of claim 1, wherein, The coenzyme Q10 lipid nanocrystal is prepared by the following method: coenzyme Q10, glycerin monostearate, polysorbate 80, and hydroxypropyl cellulose are mixed and then added to a double-screw hot melt extruder, the extrusion temperature is 40 DEG C, the rotation speed is 30 rpm, an extrusion strip is obtained, the extrusion strip is cooled and then crushed and sieved, and the extrudate powder obtained is the coenzyme Q10 lipid nanocrystal.

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