A method for preparing a poly-very long chain alcohol nanoparticle immediate release capsule

Abstract

The application discloses a preparation method of a polynonadecanol nanoparticle fast-release capsule. The polynonadecanol is dissolved in a binary solvent system, combined with a suitable additive, and nanoized through nano-spray drying to increase the specific surface area, so as to improve the dissolution rate, absorption rate and bioavailability of the drug, thereby enhancing the therapeutic effect of the drug. The preparation method has mild operation conditions, can well maintain the structure and activity of the drug, and has a significant application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a method for preparing a polyeicosanol nanoparticle fast-release capsule. Background Technology

[0002] Cardiovascular disease is a major threat to human health, with the elderly being a high-risk group. Cardiovascular disease poses a significant threat to the health of the elderly. With the aging of society, my country has entered an aging society, and the increasing elderly population makes aging-related issues particularly prominent, making cardiovascular disease a significant public health problem in my country.

[0003] Statins, a novel lipid-lowering drug, were developed in the 1980s and are now widely used in the prevention and treatment of cardiovascular diseases. Statins primarily work by competitively inhibiting reductase, the rate-limiting enzyme in endogenous cholesterol synthesis, thus blocking the intracellular hydroxymethylvalerate metabolic pathway. This reduces intracellular cholesterol synthesis, thereby feedback-stimulating an increase in the number and activity of low-density lipoprotein receptors on the cell membrane surface (mainly hepatocytes), significantly lowering LDL cholesterol levels and increasing serum total cholesterol clearance while decreasing its levels. In addition to regulating blood lipid levels, statins have also been found to have certain cardiovascular protective effects, mainly including improving vascular endothelial function, regulating the proliferation and apoptosis of vascular smooth muscle cells, inhibiting thrombus formation, anti-inflammatory effects, antioxidant effects, and stabilizing atherosclerotic plaques—effects beyond lipid regulation.

[0004] Many cardiovascular medications interact with statins through their metabolic pathways, leading to adverse drug reactions affecting liver and kidney function and muscle metabolism. In long-term clinical practice, some patients, especially elderly patients, have faced varying degrees of limitations in using statins, primarily due to intolerance of their adverse reactions. Other patients find that even with increased statin dosages, their lipid levels remain uncontrolled, and the risk of adverse reactions increases dramatically with higher doses. Eicosanol tablets, a herbal lipid-lowering drug from Cuba, can address this deficiency.

[0005] Eicosanol is a novel lipid-regulating drug extracted from sugarcane wax by Cuban scientists at the end of the last century. Its active ingredient is a mixture of eight major fatty alcohols. It inhibits cholesterol biosynthesis in the steps of acetate consumption and mevalonic acid synthesis, but does not directly inhibit the activity of methyldimethylcoenzyme (MDC). Furthermore, eicosanol can increase LDL uptake by hepatic cells by increasing LDL receptors, thereby reducing serum LDL-carrying LDL-C levels. Currently, the lipid-lowering effect and safety of eicosanol have been confirmed. In elderly subjects, the results of eicosanol use in older subjects are similar to or more pronounced than in younger subjects. Meanwhile, studies have reported that in addition to its lipid-regulating effects, eicosanol also has pleiotropic mechanisms of action, such as improving platelet aggregation rate, inhibiting endothelial thickening and smooth muscle proliferation, thus possessing anti-atherosclerotic effects.

[0006] Currently, only oral eicosanol tablets are available on the market. Originally developed by Dalma Laboratories Ltd. in Cuba, it received approval from the Cuban Drug Regulatory Authority for sale in Cuba in 1991. In China, it was first approved for import by the China Food and Drug Administration in 2006. Eicosanol is insoluble in water, has poor water solubility, and low oral bioavailability. Studies of commercially available eicosanol products have found that the bioavailability of existing formulations is generally low.

[0007] Therefore, it is necessary to provide a rapid-release formulation of polyeicosanol nanoparticles to improve the bioavailability of polyeicosanol in order to meet therapeutic needs. Summary of the Invention

[0008] The purpose of this invention is to provide a method for preparing polyeicosanol nanoparticle fast-release capsules, which can solve the defect of low bioavailability of polyeicosanol, resulting in limited efficacy.

[0009] In view of this, the solution of the present invention is as follows:

[0010] The first aspect of this invention is to provide a method for preparing a rapid-release capsule of polyeicosanol nanoparticles, comprising the steps of:

[0011] Add polyeicosanol, excipients, and surfactants to a binary solvent system and stir until dissolved to prepare a solution with a polyeicosanol concentration of 1–10 wt%.

[0012] Polyeicosanol solution was spray-dried to obtain polyeicosanol nanoparticles;

[0013] Polyeicosanol nanoparticles are mixed with a lubricant and filled into hollow capsules to obtain polyeicosanol nanoparticle fast-release capsules.

[0014] By weight and percentage, the components in the preparation method are: 60-90% polyeicosanol, 5-20% excipients, 1-20% surfactants, and 1-5% lubricants;

[0015] The binary solvent system consists of solvent A and solvent B; solvent A is selected from dichloromethane, chloroform or acetone, and solvent B is selected from ethanol or water.

[0016] Furthermore, the binary solvent system is selected from chloroform-ethanol solution, acetone-aqueous solution, or dichloroform-aqueous solution.

[0017] Furthermore, the mass ratio of solvent A to solvent B is 95:5.

[0018] Furthermore, the concentration of the polyeicosanol solution is 2–8 wt%;

[0019] Furthermore, the amounts of the polyeicosanol, excipients, surfactants, and lubricants, by mass percentage, are: 60-90% polyeicosanol, 5-15% excipients, 5-15% surfactants, and 1-4% lubricants.

[0020] Furthermore, the excipient is selected from at least one of trehalose, cyclodextrin, hydroxypropyl methylcellulose acetate succinate, and mannitol;

[0021] Furthermore, the surfactant is selected from at least one of lecithin, sodium stearate, and sodium dodecyl sulfate;

[0022] Furthermore, the lubricant is selected from at least one of sodium stearate, magnesium stearate, and glyceryl monostearate.

[0023] Furthermore, the spray drying process uses a nano spray dryer. After the polyeicosanol solution is introduced, it passes through a 4-7 μm spray cap metal film, and the sprayed particles are collected by forming an electrostatic field through UV electrodes.

[0024] Preferably, the spraying process is set with an inlet temperature of 50-100℃, a nozzle temperature of 80-120℃, a pump flow rate of 0.2-1L / min, and an air velocity of 80-160L / min.

[0025] Preferably, the particle size of the polyeicosanol nanoparticles collected after spray drying is 0.3-5 μm.

[0026] The second aspect of this invention is that the polyeicosanol nanoparticle fast-release capsules prepared by the method described in the first aspect have a polyeicosanol dissolution rate of 80% and a dissolution time of less than 5 minutes.

[0027] A third aspect of this invention is to propose the application of the polyeicosanol nanoparticle rapid-release capsules described in the second aspect in the preparation of lipid-lowering drugs.

[0028] Compared with the prior art, the beneficial effects of the present invention include, but are not limited to:

[0029] The preparation method described in this invention involves dissolving polyeicosanol in a binary solvent system, combining it with suitable adjuvants, and then nano-sized the particles through nano-spray drying to increase the specific surface area. This is beneficial for improving the drug's dissolution rate, absorption rate, and bioavailability, thereby enhancing its therapeutic effect as a drug.

[0030] The preparation method described in this invention uses readily available reagents and operates under mild conditions, which can better preserve the structure and activity of the drug. It is currently a suitable technical means for preparing thermosensitive biomolecular nanoparticles and has significant application prospects. Attached Figure Description

[0031] Figure 1 The results show the difference in the amount of polyeicosanol nanoparticles in the immediate-release capsules obtained in Example 1 of this invention.

[0032] Figure 2 This is a comparison curve of the dissolution rate of polyeicosanol nanoparticle rapid-release capsules in the embodiments of the present invention and the comparative examples. Detailed Implementation

[0033] The technical solution of the present invention will be clearly and completely described and verified below with reference to preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0034] In one embodiment, a method for preparing polyeicosanol nanoparticle fast-release capsules is provided. The method involves adding polyeicosanol, excipients, and surfactants to a binary solvent system and stirring until dissolved to prepare a polyeicosanol solution with a concentration of 1-10 wt%. The polyeicosanol solution is then introduced into a high-performance nanospray dryer for spray drying to obtain polyeicosanol nanoparticles. After being mixed with a lubricant, the nanoparticles are filled into hollow capsules to obtain polyeicosanol nanoparticle fast-release capsules.

[0035] Polyeicosanol is insoluble in water, has poor water solubility, and low oral bioavailability. In the above examples, polyeicosanol nanoparticles were prepared by dissolving polyeicosanol in a binary solvent system and using nano-spray drying technology, resulting in higher bioavailability. The advantages of this technology in preparing polyeicosanol nanoparticles are mainly reflected in: nano-sized particles, increasing specific surface area, which is beneficial to improving the drug's dissolution rate, absorption rate, and bioavailability, thereby enhancing the therapeutic effect; and the mild operating conditions, which can better maintain the structure and activity of the drug, making it a suitable technology for preparing thermosensitive biomolecular nanoparticles.

[0036] In the above embodiments, by weight and percentage, the components in the preparation method are: 60-90% polyeicosanol, 5-20% excipient, 1-20% surfactant, and 1-5% lubricant; preferably 60-90% polyeicosanol, 5-15% excipient, 1-15% surfactant, and 1-4% lubricant.

[0037] In a preferred embodiment, the binary solvent system consists of solvent A and solvent B; solvent A is selected from dichloromethane, chloroform, or acetone, and solvent B is selected from ethanol or water; more preferably, the binary solvent system is selected from chloroform-ethanol solution, acetone-water solution, or dichloromethane-water solution.

[0038] In a preferred embodiment, the mass concentration of polyeicosanol in the binary solvent system is 2-8%.

[0039] In a preferred embodiment, the excipient is selected from at least one of trehalose, cyclodextrin, hydroxypropyl methylcellulose acetate succinate, and mannitol; the surfactant is selected from at least one of lecithin, sodium stearate, and sodium lauryl sulfate; and the lubricant is selected from at least one of sodium stearate, magnesium stearate, and glyceryl monostearate.

[0040] In a preferred embodiment, the spray drying process uses a nano-spray dryer, such as the B-90HP high-performance nano-spray dryer. The operation involves introducing a polyeicosanol solution into the machine, which then passes through a 4-7 μm metal film on the spray cap. An electrostatic field is formed by setting UV electrodes to collect the sprayed particles. The spray process is set with an inlet temperature of 50–100°C, a nozzle temperature of 80–120°C, a pump flow rate of 0.2–1 L / min, and an air velocity of 80–160 L / min.

[0041] In the above embodiments, taking the B-90HP high-performance nano-spray dryer as an example, the nano-spray drying device includes a high-frequency vibrating atomizing nozzle, a laminar flow heating system, and a high-voltage electrostatic collector. Traditional spray dryers atomize the liquid material through a rotary atomizer, pressure nozzle, or two-fluid nozzle, resulting in large particles with poor particle size uniformity. The nano-spray dryer, however, uses piezoelectric ceramics to drive a porous metal diaphragm to vibrate up and down at high frequency, spraying the liquid material from micropores to form precisely sized microdroplets that enter the hot drying gas. The laminar flow heating system is achieved through porous metal foam. During operation, the gas is heated by passing through the hot porous metal foam layer. This heating method helps optimize energy input, enabling rapid, uniform, and fine heating of the gas, making it an ideal method for drying heat-sensitive drugs. In the particle collection section, traditional cyclone separation technology cannot collect particles smaller than 2 micrometers in diameter, while the nano-spray dryer innovatively uses a high-voltage electrostatic field composed of star-shaped and cylindrical electrodes. In this electrostatic field, particle collection no longer depends on its mass, achieving highly efficient recovery of fine particles. Compared with traditional polyeicosanol formulation preparation processes, the preparation of polyeicosanol drug nanoparticles by nanospray drying results in smaller and more uniformly distributed particle sizes, ranging from 300 nanometers to 5 micrometers. Hot air drying ensures rapid and thorough drying, resulting in dry powder with low moisture content and almost zero organic solvent residue. The electrostatic collection method leads to high dry powder recovery yield.

[0042] The following are preferred implementation examples. For those examples where the reagent or instrument manufacturer is not specified, conventional products can be purchased from the market. For those examples where specific conditions are not specified, standard conditions or manufacturer-recommended conditions can be followed.

[0043] Example 1

[0044] The formulation of the immediate-release formulation of polyeicosanol nanoparticles is as follows:

[0045]

[0046] Preparation method of this type of rapid-release formulation of polyeicosanol nanoparticles:

[0047] 1) Preparation of drug solution: Mix chloroform and ethanol at a ratio of 95:5 (% w / w) to prepare a binary solvent system; then add the active pharmaceutical ingredient, polyeicosanol, hydroxypropyl methylcellulose acetate succinate, and lecithin to the binary solvent system under high-speed stirring, and continue stirring to fully dissolve the drug solution, preparing a drug solution with a concentration of 5% (material concentration), and continue stirring for later use.

[0048] 2) Preparation of polyeicosanol nanoparticles: The inlet temperature of the B-90HP high-performance nanospray dryer was set to 70℃, the nozzle temperature to approximately 90℃, the pump flow rate to 0.8L / min, and the air velocity to 140L / min. The drug solution was introduced via a peristaltic pump, passing through a 5.5-micron spray cap metal film to form a spray. The atomized droplets were rapidly evaporated by the dry, hot air flow, forming dry powder particles. These particles were then electrostatically collected at the particle collection electrode below by the electrostatic field formed by the UV electrode.

[0049] 3) After the spray drying is complete, turn off the power, remove the electrostatic collector, collect the dry powder, and obtain polyeicosanol nanoparticles;

[0050] 4) Total mixing: Weigh out sodium stearate fumarate and polyeicosanol nanoparticles according to the formula ratio, place them in a hopper mixer and mix for 5 minutes at a speed of 10 rpm to obtain a polyeicosanol nanoparticle mixture.

[0051] 5) Filling: The mixture of polyeicosanol nanoparticles is filled according to the theoretical fill weight to form polyeicosanol nanoparticle instant-release capsules.

[0052] Example 2

[0053] The formulation of the immediate-release formulation of polyeicosanol nanoparticles is as follows:

[0054]

[0055] Preparation method of this type of rapid-release formulation of polyeicosanol nanoparticles:

[0056] 1) Preparation of drug solution: Acetone-water is stirred evenly at a ratio of 95:5 (% w / w) to prepare a binary solvent system; then, the active pharmaceutical ingredients, hydroxypropyl methylcellulose acetate succinate, and lecithin are added to the binary solvent system under high-speed stirring. The mixture is stirred continuously to ensure that the drug solution is fully dissolved, and a drug solution with a concentration of 8% is prepared. The mixture is stirred continuously and set aside for later use.

[0057] 2) Preparation of polyeicosanol nanoparticles: The inlet temperature of the B-90HP high-performance nanospray dryer was set to 65℃, the nozzle temperature to approximately 95℃, the pump flow rate to 0.5L / min, and the air velocity to 120L / min. The drug solution was introduced via a peristaltic pump, passing through a 4.5-micron spray cap metal film to form a spray. The atomized droplets were rapidly evaporated by the dry, hot air flow, forming dry powder particles. These particles were then electrostatically collected at the particle collection electrode below by the electrostatic field formed by the UV electrode.

[0058] Steps 3)-5) are the same as in Example 1, producing polyeicosanol nanoparticle fast-release capsules.

[0059] Example 3

[0060] The formulation of the immediate-release formulation of polyeicosanol nanoparticles is as follows:

[0061]

[0062] Preparation method of this type of rapid-release formulation of polyeicosanol nanoparticles:

[0063] 1) Preparation of drug solution: Mix dichloromethane and water at a ratio of 95:5 (% w / w) to prepare a binary solvent system; then add the active pharmaceutical ingredient, polyeicosanol, hydroxypropyl methylcellulose acetate succinate, and lecithin to the binary solvent system under high-speed stirring. Continue stirring to ensure that the drug solution is fully dissolved and prepared into a drug solution with a concentration of 3% (material concentration). Continue stirring and set aside for later use.

[0064] 2) Preparation of polyeicosanol nanoparticles: The inlet temperature of the B-90HP high-performance nanospray dryer was set to 80℃, the nozzle temperature to approximately 100℃, the pump flow rate to 1L / min, and the air velocity to 150L / min. The drug solution was introduced via a peristaltic pump, passing through a 7.0-micron spray cap metal film to form a spray. The atomized droplets were rapidly evaporated by the dry, hot air flow, forming dry powder particles. These particles were then electrostatically collected at the particle collection electrode below by the electrostatic field formed by the UV electrode.

[0065] Steps 3)-5) are the same as in Example 1, producing polyeicosanol nanoparticle fast-release capsules.

[0066] Example 4

[0067] The formulation of the immediate-release formulation of polyeicosanol nanoparticles is as follows:

[0068]

[0069] The preparation method is the same as in Example 1 of the invention.

[0070] Example 5

[0071] The formulation of the immediate-release formulation of polyeicosanol nanoparticles is as follows:

[0072]

[0073] The preparation method is the same as in Example 1 of the invention.

[0074] Comparative Example 1 (Changing Excipients)

[0075] The formulation of the immediate-release formulation of polyeicosanol nanoparticles is as follows:

[0076]

[0077] The preparation method is the same as in Example 1 of the invention.

[0078] Comparative Example 2 (Changing the surfactant)

[0079] The formulation of the immediate-release formulation of polyeicosanol nanoparticles is as follows:

[0080]

[0081] The preparation method is the same as in Example 1 of the invention.

[0082] Comparative Example 3 (Changing the binary solvent system)

[0083] The formulation of the immediate-release formulation of polyeicosanol nanoparticles is as follows:

[0084] Element Dosage (mg) Proportion(%) Polyeicosanol 160 74.42 hydroxypropyl methylcellulose acetate succinate 40 18.60 Lecithin 10 4.65 Sodium fumarate stearate 5 2.33 Ethanol-water solution 95:5 (% w / w) 3990 / total 215 /

[0085] Comparative Example 4 (Lubricant Replacement)

[0086] The formulation of the immediate-release formulation of polyeicosanol nanoparticles is as follows:

[0087]

[0088] The preparation method is the same as in Example 1 of the invention.

[0089] Comparative Example 5 (with a change in preparation process)

[0090] The formulation of the immediate-release preparation of polyeicosanol nanoparticles is the same as in Example 1.

[0091] The preparation method is as follows:

[0092] 1) Preparation of drug solution: Mix chloroform and ethanol at a ratio of 95:5 (% w / w) to prepare a binary solvent system; then add the active pharmaceutical ingredient, polyeicosanol, hydroxypropyl methylcellulose acetate succinate, and lecithin to the binary solvent system under high-speed stirring, and continue stirring to fully dissolve the drug solution to prepare a 5% drug solution. Continue stirring for later use.

[0093] 2) Preparation of polyeicosanol granules: The inlet temperature of the spray dryer was set to 70℃, the pump flow rate to 0.8L / min, and the air velocity to 140L / min. The drug solution was introduced through a peristaltic pump and passed through a 0.7mm spray nozzle. After spray drying was completed, the dry powder was collected to obtain polyeicosanol granules.

[0094] Comparative Example 6

[0095] The prescription and dosage ratio are the same as in Example 1.

[0096] Preparation method of this type of polyeicosanol immediate-release formulation:

[0097] 1) Preparation of drug solution: Same as in Example 1.

[0098] 2) Preparation of polyeicosanol nanoparticles: The drug solution is continuously stirred and introduced through a peristaltic pump, passing through metal films of spray caps smaller than 4.0 micrometers and larger than 7.0 micrometers respectively, forming a spray. The atomized droplets are rapidly evaporated by the dry, hot air stream, forming dry powder particles. These particles are electrostatically collected at the particle collection electrode below by the electrostatic field formed by the UV-electrode. A B-90HP high-performance nanospray dryer is used, with an inlet temperature set at 40–120℃, a nozzle temperature at approximately 80–160℃, a pump flow rate of 0.2–1.2 L / min, and an air velocity of 60–180 L / min.

[0099] Data and Conclusions

[0100] 1. Detection of fill volume variation and residual solvent

[0101] According to the formulation and preparation process of Example 1, three batches of polyeicosanol nanoparticles were filled into gelatin empty capsules according to the theoretical fill amount. The fill amount difference of the polyeicosanol nanoparticle instant-release capsules was detected, and the residual solvent was detected according to the residual solvent determination method of the 2020 edition of the Chinese Pharmacopoeia.

[0102] Results of dosage variation are as follows Figure 1 As shown. Figure 1 The results showed that the differences in the fill weight of the three batches of polyeicosanol nanoparticle immediate-release capsules could be controlled within ±5% of the theoretical tablet weight, with RSD values ​​of 1.23%, 1.23%, and 1.23% for the three batches, respectively.

[0103] The fill weight fluctuations of the three batches were 1.46% and 1.37%, respectively, and were stable and controllable. Similarly, the fill weight difference tests for Examples 2-5 were conducted in the same manner as above, and the average RSD of the fill weight was less than 2%, which met the requirements.

[0104] The residual solvents were tested according to the method for determining residual solvents in the 2020 edition of the Chinese Pharmacopoeia. The residual amounts of binary solvents in Examples 1-5 were not detected (the test results were all 0), which is less than the limit of 0.5% stipulated in the Chinese Pharmacopoeia. This indicates that the immediate-release capsules prepared by this process are safe for use.

[0105] 2. Particle size and yield

[0106] According to the formulation and preparation process of Example 1, three batches of polyeicosanol nanoparticles were prepared in parallel. The particle size and distribution of the three batches of polyeicosanol nanoparticles were analyzed by dry method determination mode of Malvern laser diffraction particle size analyzer, and the yield was calculated.

[0107]

[0108] The data in the table above show that the yields of the three batches of polyeicosanol nanoparticles are all greater than 98%, which is a high yield, exceeding the industry average of 90%, and the yields are close. According to the particle size distribution data, the particle size of the three batches is very small and uniformly distributed, indicating that the preparation process is stable.

[0109] The average particle size and yield of the polyeicosanol nanoparticles prepared in Examples 1-5 and some comparative examples are shown in the table below.

[0110]

[0111] Compared to Example 1, Comparative Example 1 used lactose as the excipient. Lactose has good water solubility and biocompatibility, and is less irritating to the human body. However, due to its strong hygroscopicity, lactose is easily affected by moisture during powder collection. A large number of polyeicosanol nanoparticles adhered to the electrostatic collector and could not be collected. The collected polyeicosanol nanoparticles easily agglomerated and clumped together, resulting in a very low yield of only 50%, significantly lower than the yield of this invention. This demonstrates that the selected excipient is beneficial to the preparation of this novel technology and can ensure a high yield.

[0112] Compared to Example 1, Comparative Example 2 used a nonionic surfactant, polyethylene glycol, instead of surfactant. The resulting polyeicosanoyl alcohol nanoparticles had a lower yield and recovery rate, with a yield of only 55%. This was mainly because the nanospray dryer used an electrostatic particle collector, and the electric field generated inside the collector was more conducive to collecting particles containing ionic surfactants. This indicates that the selected ionic surfactant is more beneficial to the preparation of this novel technology, ensuring a higher yield.

[0113] Compared to Example 1, Comparative Example 3 used a new binary solvent system. The prepared drug solution was a suspension, and during the spray preparation process, the drug solution clogged the metal film of the spray cap, causing the preparation process to be interrupted. The main reason is that eicosanol is only slightly soluble in chloroform and insoluble in water, methanol, or ethanol. Furthermore, the APIs are not soluble in this binary solvent system. This indicates that the selected binary solvent system is beneficial to the preparation of this novel technology because eicosanol is only slightly soluble in chloroform, and the addition of ethanol contributes to the stability of the binary solvent system.

[0114] Comparative Example 5, compared to Example 1, used conventional spray drying technology to prepare polyeicosanol particles. The yield was only 75.1%, lower than that of Example 1, and the particle size was larger than that of the particles in Example 1 of this invention. This indicates that the nano-spray drying technology used to prepare polyeicosanol nanoparticles results in finer particles with a larger specific surface area, which is more conducive to in vitro dissolution.

[0115] Compared to Example 1, Comparative Example 6, when the inlet temperature was set to 40°C, resulted in incomplete drying of the material, causing the polyeicosanol nanoparticles to easily agglomerate, with a yield of only 40%, far lower than the yield of Example 1. When the inlet temperature was set to above 100°C, the relative humidity of the drying gas was reduced, and particles with low moisture content were formed, but there was a risk of damaging the activity of heat-sensitive substances. The effects of different screen sizes (less than 4 micrometers and greater than 7 micrometers) were also compared. The results showed that the particles produced by using a spray cap with an aperture smaller than 4 micrometers were spherical with a smooth surface, but the spray efficiency would decrease, and the shear force on the material would increase, resulting in a final yield of 67.5%, lower than the yield of Example 1. Using a spray cap with an aperture larger than 7 micrometers, the resulting spherical particles had both smooth and wrinkled surfaces, but the larger the aperture, the larger the droplets, leading to uneven particle distribution. The preparation of good polyeicosanol nanoparticles is related to factors such as inlet temperature, spray cap size, pump flow rate, and air flow rate. After countless irregular trials, the required process parameters were obtained, and the resulting polyeicosanol nanoparticles have high yield and concentrated particle size distribution.

[0116] 3. Dissolution rate test

[0117] Dissolution was determined according to the method described in Appendix XC, Method II of the Chinese Pharmacopoeia 2020 Edition, Part II. Samples from Examples 1-5 of this invention, Comparative Example 4, and a commercially available polyeicosanol preparation were taken and tested at 5, 10, 15, 20, 30, 45, and 60 minutes using 900 ml of phosphate buffer solution at pH 6.8 as the solvent and a rotation speed of 50 rpm. The dissolution curves are shown below. Figure 2 As shown.

[0118] Figure 2 Based on the in vitro dissolution curve data of Examples 1-5, the rapid-release formulation of the polyeicosanol nanoparticles of the present invention exhibits a relatively fast dissolution rate in vitro, exceeding 40% after 3 minutes and exceeding 85% after 5 minutes, which is 15-20% faster than the commercially available formulations. This indicates that the preparation technology used in the present invention is beneficial for in vitro dissolution. In Comparative Example 4, after replacing the lubricant, the in vitro dissolution was 10-15% slower than in the examples, indicating that the lubricant selected in the present invention is beneficial for the rapid dissolution of the polyeicosanol nanoparticles.

[0119] 4. Bioavailability test

[0120] Using beagles as test animals, a two-formulation, two-period crossover experimental design was employed to conduct in vivo pharmacokinetic studies on the tablet formulations from Example 1 and commercially available formulations. An in vivo analytical method for polyeicosanol was established, and pharmacokinetic parameters were calculated using a non-compartmental model. The bioavailability of polyeicosanol in both formulations was also calculated. Taking the formulation from Example 1 as an example, the AUC of polyeicosanol was determined in animal studies. 0-tThe value was 1162.6 ± 42.8 ng·h·mL -1 Compared to commercially available formulations, 957.5 ± 61.1 ng·h·mL -1 Significant improvement.

[0121] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a rapid-release capsule of polyeicosanol nanoparticles, characterized in that the steps include... include: Add polyeicosanol, excipients, and surfactants to a binary solvent system and stir until dissolved to prepare a solution with a polyeicosanol concentration of 1–10 wt%. Polyeicosanol solution was spray-dried to obtain polyeicosanol nanoparticles; Polyeicosanol nanoparticles are mixed with a lubricant and filled into hollow capsules to obtain polyeicosanol nanoparticle fast-release capsules. By weight and percentage, the components in the preparation method are: 60-90% polyeicosanol, 5-20% excipient, 1-20% surfactant, and 1-5% lubricant; The binary solvent system consists of solvent A and solvent B; solvent A is selected from dichloromethane, chloroform, or acetone, and solvent B is selected from ethanol or water; the mass ratio of solvent A to solvent B is 95:

5. The excipient is selected from at least one of trehalose, cyclodextrin, hydroxypropyl methylcellulose acetate succinate, and mannitol; the surfactant is selected from at least one of lecithin, sodium stearate, and sodium lauryl sulfate; and the lubricant is selected from at least one of sodium stearate, magnesium stearate, and glyceryl monostearate.

2. The preparation method according to claim 1, characterized in that, The binary solvent system is selected from chloroform-ethanol solution, acetone-aqueous solution, or dichloroform-aqueous solution.

3. The preparation method according to claim 1, characterized in that, The concentration of the polyeicosanol solution is 2-8 wt%; And / or, the amounts of the polyeicosanol, excipients, surfactants and lubricants, by mass percentage, are: 60-90% polyeicosanol, 5-15% excipients, 5-15% surfactants, and 1-4% lubricants.

4. The preparation method according to claim 1, characterized in that, The spray drying process uses a nano spray dryer. After the polyeicosanol solution is introduced, it passes through a 4-7 μm spray cap metal film. An electrostatic field is formed by setting UV electrodes to collect the sprayed particles.

5. The preparation method according to claim 4, characterized in that, The spraying process is set with an inlet temperature of 50–100°C, a nozzle temperature of 80–120°C, a pump flow rate of 0.2–1 L / min, and an air velocity of 80–160 L / min.

6. The preparation method according to claim 4, characterized in that, The polyeicosanol nanoparticles collected after spray drying have a particle size of 0.3-5 μm.

7. The polyeicosanol nanoparticle fast-release capsules obtained by the preparation method according to any one of claims 1-6, characterized in that, Its polyeicosanol dissolution rate is 80% and the dissolution time is less than 5 minutes.

8. The use of the polyeicosanol nanoparticle rapid-release capsules according to claim 7 in the preparation of lipid-lowering drugs.

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