Preparation method of policosanol nanoparticle quick-release capsule

Abstract

The invention discloses a preparation method of policosanol nanoparticle quick-release capsules, which comprises the following steps: dissolving policosanol in a binary solvent system, combining with a proper auxiliary agent, and nanocrystallizing particles and increasing the specific surface area in a nano spray drying manner, thereby being beneficial to improving the dissolution rate, the absorption rate and the bioavailability of a medicine; therefore, the treatment effect of the medicine is enhanced; the preparation method is mild in operation condition, can well maintain the structure and activity of the medicine, and has a remarkable application prospect.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, and in particular to a method for preparing a policosanol nanoparticle rapid-release capsule. Background Art

[0002] Cardiovascular disease is an important disease that currently affects human health. The elderly are at high risk of cardiovascular disease, which poses a considerable threat to their health. With the aging process of society, my country has entered an aging society, the elderly population is gradually increasing, and the aging problem is particularly prominent, making cardiovascular disease an important public health issue in my country.

[0003] Statins, as a new type of lipid-lowering drug, were developed in the 1980s and are currently widely used in the prevention and treatment of cardiovascular diseases. Statins mainly reduce intracellular cholesterol synthesis by competitively inhibiting endogenous cholesterol synthesis rate-limiting enzyme reductase, blocking the intracellular hydroxymevalonic acid metabolic pathway, thereby feedback stimulating the increase in the number and activity of low-density lipoprotein receptors on the cell membrane surface (mainly hepatocytes), significantly reducing the level of low-density lipoprotein cholesterol, increasing the clearance of serum total cholesterol and reducing the level. While regulating blood lipid levels, statins have also been found to have certain cardiovascular protective effects, mainly improving endothelial function, regulating the proliferation and apoptosis of vascular smooth muscle cells, inhibiting thrombosis, anti-inflammatory, anti-oxidation and stabilizing atherosclerotic plaques, and other effects other than regulating blood lipids.

[0004] A variety of cardiovascular drugs interact with the metabolic pathways of statins, and have certain adverse drug reactions on liver and kidney function and muscle metabolism. In long-term clinical practice, some patients, especially elderly patients, are restricted to varying degrees in the use of statins, mainly because they cannot tolerate the adverse reactions of statins. Some patients increase the dosage of statins but their blood lipid levels still cannot meet the standard, and the risk of adverse reactions of statins increases sharply with increasing dosage. Policosanol tablets are a plant lipid-lowering drug from Cuba that can make up for this defect.

[0005] Policosanol is a new lipid-regulating drug extracted from sugarcane wax by Cuban scientists at the end of the last century. Its active ingredient is a mixture of 8 major fatty alcohols. It can inhibit the biosynthesis of cholesterol in the consumption of acetate and the synthesis of mevalonic acid, but does not directly inhibit the activity of mevalonate coenzyme. In addition, policosanol can also increase the uptake of LDL by liver cells by increasing LDL receptors, thereby reducing the level of LDLC carried by serum low-density lipoprotein. At present, the lipid-lowering effect and safety of policosanol have been confirmed. In the elderly population, the results of policosanol use in subjects aged 5 years are similar to or more obvious than those in young subjects. At the same time, studies have reported that in addition to regulating blood lipids, policosanol also has pleiotropic mechanisms of action, such as improving platelet aggregation rate, inhibiting endothelial thickening and smooth muscle proliferation, and thus has an anti-atherosclerotic effect.

[0006] At present, the only oral policosanol tablets on the market were developed by Cuba's Dalma Laboratories Ltd. and approved by the Cuban Food and Drug Administration in 1991 for sale in Cuba. In China, it was first approved by the China Food and Drug Administration in 2006 and imported into China. Policosanol is insoluble in water, has poor water solubility, and has low oral bioavailability. Based on the study of commercially available policosanol drugs, it was found that the bioavailability of existing preparations was low.

[0007] Therefore, it is necessary to provide a rapid-release preparation of polyunsaturated fatty alcohol nanoparticles to improve the bioavailability of polyunsaturated fatty alcohol to meet the needs of treatment. Summary of the invention

[0008] The object of the present invention is to provide a method for preparing a policosanol nanoparticle rapid-release capsule, which is used to solve the defect that the bioavailability of policosanol is low, resulting in limited efficacy.

[0009] In view of this, the scheme of the present invention is:

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

[0011] Adding polyunsaturated glycol, excipients, and surfactants into a binary solvent system and stirring until dissolved to prepare a solution having a polyunsaturated glycol concentration of 1 to 10 wt %;

[0012] The policosanol solution is spray-dried to obtain policosanol nanoparticles;

[0013] The policosanol nanoparticles are mixed with a lubricant and filled into hollow capsules to obtain policosanol nanoparticle rapid-release capsules;

[0014] By weight and 100%, the components in the preparation method are: 60-90% of polyunsaturated alcohol, 5-20% of excipient, 1-20% of surfactant, and 1-5% of lubricant;

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

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

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

[0018] Further, the concentration of the polyunsaturated alcohol solution is 2 to 8 wt %;

[0019] Furthermore, the amounts of the polyunsaturated glycol, excipient, surfactant and lubricant are as follows by mass: 60-90% polyunsaturated glycol, 5-15% excipient, 5-15% surfactant and 1-4% lubricant.

[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 lauryl sulfate;

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

[0023] Furthermore, the spray drying process uses a nano spray dryer. After the polyunsaturated alcohol solution is introduced, it passes through a 4-7 μm spray-covered metal film, and an electrostatic field is formed by setting a UV-electrode to collect the sprayed particles.

[0024] Preferably, the spray process sets the inlet temperature to 50-100°C, the nozzle temperature to 80-120°C, the pump flow rate to 0.2-1 L / min, and the air flow rate to 80-160 L / min.

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

[0026] The second aspect of the present invention is to provide a rapid-release capsule of polycosanol nanoparticles obtained by the preparation method of the first aspect, wherein the dissolution time of the polycosanol solubility of 80% is less than 5 minutes.

[0027] The third aspect of the present invention is to propose the use of the policosanol 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 of the present invention comprises dissolving polyunsaturated glycol in a binary solvent system, combining with a suitable auxiliary agent, and nano-sizing the particles by nano-spray drying to increase the specific surface area, thereby facilitating improving the dissolution rate, absorption rate and bioavailability of the drug, thereby enhancing the therapeutic effect as a drug.

[0030] The preparation method of the present invention has readily available reagents, mild operating conditions, can better maintain the structure and activity of the drug, is currently the most suitable technical means for preparing thermosensitive biomacromolecule nanoparticles, and has significant application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The results of the difference in filling amount of the policosanol nanoparticle rapid-release capsules obtained in Example 1 of the present invention are shown.

[0032] Figure 2 The dissolution rate comparison curve of the policosanol nanoparticle rapid-release capsules of the embodiment of the present invention and the comparative example is shown. DETAILED DESCRIPTION

[0033] The technical solution of the present invention will be clearly and completely described and verified in conjunction with the preferred embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] In one embodiment, a method for preparing a policosanol nanoparticle rapid-release capsule is provided, wherein policosanol, an excipient, and a surfactant are added to a binary solvent system and stirred until dissolved to prepare a solution having a policosanol concentration of 1 to 10 wt %; the policosanol solution is then introduced into a high-performance nano spray dryer for spray drying to obtain policosanol nanoparticles, which are then mixed with a lubricant and filled into hollow capsules to obtain policosanol nanoparticle rapid-release capsules.

[0035] Policosanol is insoluble in water, has poor water solubility, and has low oral bioavailability. In the above embodiment, Policosanol nanoparticles are prepared by dissolving Policosanol in a binary solvent system using nano spray drying technology, which has higher bioavailability. The advantages of this technology in preparing Policosanol nanoparticles are mainly reflected in: nano-scale particles, increasing specific surface area, which is conducive to improving the dissolution rate, absorption rate and bioavailability of drugs, thereby enhancing the therapeutic effect; the operating conditions are mild, and the structure and activity of the drug can be better maintained. It is currently a technical means more suitable for preparing thermosensitive biomacromolecule nanoparticles.

[0036] In the above embodiment, the components in the preparation method are, by weight and in 100%, 60-90% polyunsaturated glycol, 5-20% excipient, 1-20% surfactant, and 1-5% lubricant; preferably 60-90% polyunsaturated glycol, 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 one of dichloromethane, chloroform or acetone, and solvent B is selected from one of ethanol and water; more preferably, the binary solvent system is selected from one of chloroform-ethanol solution, acetone-water solution, or dichloromethane-water solution.

[0038] In a preferred embodiment, the mass concentration of policosanol 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 hard sodium fumarate, magnesium stearate, and glyceryl monostearate.

[0040] In a preferred embodiment, the spray drying process uses a nano spray dryer, such as a B-90HP high-performance nano spray dryer; the operation process is that after the polyunsaturated alcohol solution is introduced into the machine, it passes through a 4-7 μm spray cover metal film, and the sprayed particles are collected by setting a UV-electrode to form an electrostatic field. The spray process is set to have an inlet temperature of 50-100°C, a nozzle temperature of 80-120°C, a pump flow rate of 0.2-1L / min, and an air flow rate of 80-160L / min.

[0041] In the above embodiment, taking the B-90HP high-performance nano spray dryer as an example, the nano spray drying device includes a high-frequency vibration atomizing nozzle, a laminar heating system and a high-voltage electrostatic collector. The conventional spray dryer realizes the atomization of the feed liquid through a rotary atomizer, a pressure nozzle or a two-fluid nozzle, and the generated particles are large and the particle size uniformity is poor. The nano spray dryer drives the porous metal diaphragm to vibrate up and down at high frequency through piezoelectric ceramics, and the feed liquid is ejected from the micropores to form a droplet aerosol with a precise size into the hot drying gas. The laminar heating system is realized by porous metal foam. During operation, the gas is heated by passing through the hot porous metal foam layer. This heating method helps to optimize the energy input, and can realize fast, uniform and subtle heating of the gas, which is an ideal way to dry heat-sensitive drugs. In the particle collection part, the traditional cyclone separation technology cannot collect particles with a particle size less than 2 microns, and the nano spray dryer innovatively adopts a high-voltage electrostatic field composed of a star electrode and a cylindrical electrode. In the electrostatic field, the collection of particles no longer depends on their mass, and high-efficiency fine particle recovery is achieved. Compared with the traditional preparation process of polyunsaturated alcohol preparations, the polyunsaturated alcohol drug nanoparticles prepared by the nano spray dryer have a smaller particle size and are evenly distributed, and particles of 300 nanometers to 5 microns can be prepared; hot air drying is used, the preparation speed is fast, the drying is thorough, the moisture content of the obtained dry powder is small, and the organic solvent residue is almost zero; the electrostatic collection method is used, and the dry powder recovery yield is high.

[0042] The following are preferred implementation examples. If the manufacturer of the reagent or instrument is not specified in the examples, conventional products can be purchased from the market. If the specific conditions are not specified, conventional conditions or conditions recommended by the manufacturer can be followed.

[0043] Example 1

[0044] The prescription of the policosanol nanoparticle rapid-release preparation is as follows:

[0045]

[0046] Preparation method of the polyunsaturated alcohol nanoparticle rapid-release preparation:

[0047] 1) Preparation of drug solution: Chloroform-ethanol is stirred evenly at a ratio of 95:5 (% w / w) to prepare a binary solvent system; then the raw materials policosanol, hydroxypropyl methylcellulose acetate succinate, and lecithin are added to the binary solvent system under high-speed stirring, and the stirring is continued to allow the drug solution to be fully dissolved to prepare a drug solution with a concentration of 5% of the feed liquid concentration, and the stirring is continued for standby use.

[0048] 2) Preparation of polyunsaturated alcohol nanoparticles: The inlet temperature of the B-90HP high-performance nano spray dryer was set to 70°C, the nozzle temperature was about 90°C, the pump flow rate was 0.8L / min, and the air flow rate was 140L / min. The drug solution was introduced through a peristaltic pump and passed through a 5.5-micron spray cap metal film to form a spray. The atomized droplets were quickly evaporated by the dry hot air flow to form dry powder particles, which were electrostatically collected at the particle collection electrode below through the electrostatic field formed by the UV-electrode.

[0049] 3) After the spray drying is completed, the power is turned off, the electrostatic collector is removed, and the dry powder is collected to obtain polyunsaturated alcohol nanoparticles;

[0050] 4) Total mixing: Weigh sodium stearate fumarate and polyunsaturated alcohol nanoparticles according to the prescription ratio, place in a hopper mixer for mixing, the mixing time is 5 minutes, the speed is 10 rpm, to obtain a polyunsaturated alcohol polyunsaturated alcohol nanoparticle mixture;

[0051] 5) Filling: The policosanol nanoparticle mixture is filled according to the theoretical filling amount to obtain policosanol nanoparticle rapid-release capsules.

[0052] Example 2

[0053] The prescription of the policosanol nanoparticle rapid-release preparation is as follows:

[0054]

[0055] Preparation method of the polyunsaturated alcohol nanoparticle rapid-release preparation:

[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 raw materials policosanol, hydroxypropyl methylcellulose acetate succinate, and lecithin are added to the binary solvent system under high-speed stirring, and the stirring is continued to allow the drug solution to be fully dissolved to prepare a drug solution with a concentration of 8% of the feed liquid concentration, and the stirring is continued for standby use.

[0057] 2) Preparation of polyunsaturated alcohol nanoparticles: The inlet temperature of the B-90HP high-performance nano spray dryer was set to 65°C, the nozzle temperature was about 95°C, the pump flow rate was 0.5L / min, and the air flow rate was 120L / min. The drug solution was introduced through a peristaltic pump and passed through a 4.5-micron spray cap metal film to form a spray. The atomized droplets were quickly evaporated by the dry hot air flow to form dry powder particles, which were electrostatically collected at the particle collection electrode below through the electrostatic field formed by the UV-electrode.

[0058] Steps 3)-5) are the same as in Example 1, to obtain polycosanol nanoparticle rapid-release capsules.

[0059] Example 3

[0060] The formula of the policosanol nanoparticle rapid-release preparation is as follows:

[0061]

[0062] Preparation method of the polyunsaturated alcohol nanoparticle rapid-release preparation:

[0063] 1) Preparation of drug solution: dichloromethane-water is stirred evenly at a ratio of 95:5 (% w / w) to prepare a binary solvent system; then the raw materials policosanol, hydroxypropyl methylcellulose acetate succinate, and lecithin are added to the binary solvent system under high-speed stirring, and the stirring is continued to allow the drug solution to be fully dissolved to prepare a drug solution with a concentration of 3% of the feed liquid concentration, and the stirring is continued for standby use.

[0064] 2) Preparation of polyunsaturated alcohol nanoparticles: The inlet temperature of the B-90HP high-performance nano-spray dryer was set to 80°C, the nozzle temperature was about 100°C, the pump flow rate was 1L / min, and the air flow rate was 150L / min. The drug solution was introduced through a peristaltic pump and passed through a 7.0-micron spray cap metal film to form a spray. The atomized droplets were quickly evaporated by the dry hot air flow to form dry powder particles, which were electrostatically collected at the particle collection electrode below through the electrostatic field formed by the UV-electrode.

[0065] Steps 3)-5) are the same as in Example 1, to obtain polycosanol nanoparticle rapid-release capsules.

[0066] Example 4

[0067] The formula of the policosanol nanoparticle rapid-release preparation is as follows:

[0068]

[0069] The preparation method is the same as that of Invention Example 1.

[0070] Example 5

[0071] The formula of the policosanol nanoparticle rapid-release preparation is as follows:

[0072]

[0073] The preparation method is the same as that of Invention Example 1.

[0074] Comparative Example 1 (changing excipient)

[0075] The prescription of the policosanol nanoparticle rapid-release preparation is as follows:

[0076]

[0077] The preparation method is the same as that of Invention Example 1.

[0078] Comparative Example 2 (Changing the surfactant)

[0079] The prescription of the policosanol nanoparticle rapid-release preparation is as follows:

[0080]

[0081] The preparation method is the same as that of Invention Example 1.

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

[0083] The prescription of the policosanol nanoparticle rapid-release preparation is as follows:

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

[0085] Comparative Example 4 (Replacing Lubricant)

[0086] The prescription of the policosanol nanoparticle rapid-release preparation is as follows:

[0087]

[0088] The preparation method is the same as that of Invention Example 1.

[0089] Comparative Example 5 (Changing the Preparation Process)

[0090] The formulation of the policosanol nanoparticle rapid-release preparation is the same as that in Example 1.

[0091] The preparation method is as follows:

[0092] 1) Preparation of drug solution: Chloroform-ethanol is stirred evenly at a ratio of 95:5 (% w / w) to prepare a binary solvent system; then the raw materials policosanol, hydroxypropyl methylcellulose acetate succinate, and lecithin are added to the binary solvent system under high-speed stirring, and the stirring is continued to allow the drug solution to be fully dissolved to prepare a drug solution with a concentration of 5%, and the stirring is continued for standby use.

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

[0094] Comparative Example 6

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

[0096] The preparation method of the policosanol rapid-release preparation:

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

[0098] 2) Preparation of polyunsaturated alcohol nanoparticles: The drug solution is continuously stirred, and the solution is introduced through a peristaltic pump, passing through a spray cap metal film of less than 4.0 microns and greater than 7.0 microns, respectively, to form a spray, and the atomized droplets are quickly evaporated by the dry hot air flow to form dry powder particles, which are electrostatically collected at the particle collection electrode below through the electrostatic field formed by the UV-electrode. The B-90HP high-performance nano spray dryer is set with an inlet temperature of 40-120°C, a nozzle temperature of about 80-160°C, a pump flow of 0.2-1.2L / min, and an air flow rate of 60-180L / min.

[0099] Data and conclusions

[0100] 1. Filling volume difference and residual solvent detection

[0101] According to the prescription and preparation process of Example 1, three batches of polyunsaturated alcohol nanoparticles were filled into hollow gelatin capsules according to the theoretical filling amount, and the filling amount differences of the polyunsaturated alcohol nanoparticle rapid-release capsules were detected, and the residual solvents were detected according to the residual solvent determination method of the "Chinese Pharmacopoeia" 2020 edition.

[0102] The results of the difference in loading volume are as follows Figure 1 shown. Figure 1 The results showed that the differences in the filling amounts of the three batches of polyunsaturated alcohol nanoparticles rapid-release capsules could be controlled within the range of ±5% of the theoretical tablet weight, and the RSD values ​​of the three batches were 1.23%,

[0103] 1.46%, 1.37%, the fluctuation of the three batches of loading volume is stable and controllable. Similarly, according to the above method, the loading volume difference detection is carried out on Examples 2-5 respectively, and the average RSD of the loading volume is less than 2%, which meets the requirements.

[0104] The residual solvents were detected in accordance with the residual solvent determination method of 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 were all less than the limit of 0.5% stipulated in the Chinese Pharmacopoeia, indicating that the rapid-release capsules produced by this preparation process are safe for use.

[0105] 2. Particle size and yield

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

[0107]

[0108] The data in the above table show that the yields of the three batches of polyunsaturated alcohol nanoparticles are all greater than 98%, which are relatively high, all greater than the 90% yield in the same industry, and the yields are close; according to the particle size distribution data, the particle sizes of the three batches are all very small and evenly distributed, indicating that the preparation process is stable.

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

[0110]

[0111] Comparative Example 1 Compared with Example 1, the excipient is replaced with lactose. Lactose has good water solubility and good biocompatibility, and is less irritating to the human body. However, due to the strong hygroscopicity of lactose, it is very easy to get damp when collecting powder. A large amount of polyunsaturated alcohol nanoparticles adhere to the electrostatic collector and cannot be collected. The collected polyunsaturated alcohol nanoparticles are easy to agglomerate and adhere, resulting in a very low yield of only 50%, which is much lower than the yield of the present invention. It shows that the selected excipient is conducive to the preparation of the new preparation technology and can ensure a higher yield;

[0112] Comparative Example 2 Compared with Example 1, the surfactant was replaced with non-ionic surfactant polyethylene glycol, and the yield and recovery rate of the prepared polyunsaturated alcohol nanoparticles were lower, and the yield was only 55%. The main reason is that the nano spray dryer uses an electrostatic particle collector, and the electric field generated inside the collector is more conducive to collecting particles containing ionic surfactants. This shows that the selected ionic surfactant is more conducive to the preparation of the new preparation technology and can ensure a higher yield;

[0113] Comparative Example 3 is relative to Example 1. After replacing the new binary solvent system, the prepared drug solution presents a suspension. During the spray preparation process, the drug solution blocks the spray cover metal film and the preparation process is interrupted. The main reason is that polyunsaturated alcohol is slightly soluble in chloroform, but insoluble in water, methanol or ethanol. Moreover, when using this binary solvent system, the API is not soluble in the binary solvent system. This shows that the selected binary solvent system is conducive to the preparation of the new preparation technology, because polyunsaturated alcohol is slightly soluble in chloroform, and the addition of ethanol is conducive to the stability of the binary solvent system.

[0114] Comparative Example 5 Compared with Example 1, the conventional spray drying technology was used to prepare polyunsaturated alcohol particles, and the yield of the preparation was only 75.1%, which was lower than that of the example, and the particle size was larger than that of Example 1 of the present invention. This shows that the polyunsaturated alcohol nanoparticles prepared by the nano spray drying technology are finer, have a larger specific surface area, and are more conducive to in vitro dissolution.

[0115] Comparative Example 6 Compared with Example 1, when the inlet temperature is set to 40°C, the material is not completely dried, the polyunsaturated alcohol nanoparticles are easy to agglomerate, and the yield is only 40%, which is much lower than the yield of Example 1; when the inlet temperature is set to be higher than 100°C, the relative humidity of the drying gas is reduced, and particles with a low moisture content are formed, but there is a risk of destroying the activity of heat-sensitive substances; at the same time, the effects of sieves of different sizes (less than 4 microns and greater than 7 microns) are compared. The results show that the particles produced by using a spray cap with an aperture of less than 4 microns are spherical and have a smooth surface, but because the spray efficiency will become lower, the shear force on the material will also increase, resulting in a final yield of 67.5% lower than the yield of the embodiment; using a spray cap with an aperture greater than 7 microns, the spherical particles obtained have both smooth surfaces and wrinkled surfaces, but because the larger the aperture, the larger the droplets, resulting in uneven particle distribution. The preparation of good polyunsaturated alcohol nanoparticles is related to factors such as inlet temperature, spray cap size, pump flow, air flow, etc. After countless irregular attempts, the required process parameters were obtained. The obtained polyunsaturated alcohol nanoparticles have high yield and concentrated particle size distribution.

[0116] 3. Dissolution rate test

[0117] According to the dissolution test method (Appendix XC Method 2 of Part II of the 2020 edition of the Chinese Pharmacopoeia), Examples 1 to 5 of the present invention, Comparative Example 4, and commercially available polyunsaturated alcohol preparations were measured, using 900 ml of pH 6.8 phosphate buffer as solvent, rotating speed 50 rpm, and operating according to the law. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 minutes. The dissolution curve was tested as shown in FIG. Figure 2 shown.

[0118] Figure 2 According to the in vitro dissolution curve data of Examples 1 to 5, the policosanol nanoparticle rapid-release preparation of the present invention has a relatively fast dissolution rate in vitro, with a dissolution rate exceeding 40% after 3 minutes and exceeding 85% after 5 minutes, which is 15 to 20% faster than the dissolution of commercially available preparations, indicating that the preparation technology used in the present invention is conducive to in vitro dissolution. After replacing the new lubricant in Comparative Example 4, the in vitro dissolution was 10 to 15% slower than that in the examples, indicating that the lubricant selected in the present invention is conducive to the rapid dissolution of policosanol nanoparticles.

[0119] 4. Bioavailability Testing

[0120] Beagle dogs were used as experimental animals, and a double-preparation double-period crossover experimental design was adopted to conduct in vivo pharmacokinetic experiments on Example 1 and commercially available preparation tablets. An in vivo analysis method for policosanol was established, and the pharmacokinetic parameters were calculated using a non-compartmental model method. The bioavailability of policosanol in the two preparations was calculated respectively. Taking the preparation obtained in Example 1 as an example, the animal experiment measured the AUC of policosanol. 0-tThe value is 1162.6±42.8ng·h·mL -1 , compared with 957.5±61.1ng·h·mL of the commercial preparation -1 Significantly improved.

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

Claims

1. A method for preparing polyunsaturated fatty alcohol nanoparticle rapid-release capsules, characterized in that the steps include: Adding polyunsaturated glycol, excipients, and surfactants into a binary solvent system and stirring until dissolved to prepare a solution having a polyunsaturated glycol concentration of 1 to 10 wt %; The policosanol solution is spray-dried to obtain policosanol nanoparticles; The policosanol nanoparticles are mixed with a lubricant and filled into hollow capsules to obtain policosanol nanoparticle rapid-release capsules; By weight and 100%, the components in the preparation method are: 60-90% of polyunsaturated alcohol, 5-20% of excipient, 1-20% of surfactant, and 1-5% of lubricant; The binary solvent system consists of solvent A and solvent B; solvent A is selected from one of dichloromethane, chloroform or acetone, and solvent B is selected from one of ethanol and water.

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

3. The preparation method according to claim 1, characterized in that: The mass ratio of the solvent A to the solvent B is 95:

5.

4. The preparation method according to claim 1, characterized in that: The concentration of the polyunsaturated alcohol solution is 2 to 8 wt %; And / or, the amounts of the polyunsaturated glycol, excipient, surfactant and lubricant are as follows by mass: 60-90% polyunsaturated glycol, 5-15% excipient, 5-15% surfactant and 1-4% lubricant.

5. The preparation method according to claim 1, characterized in that: The excipient is selected from at least one of trehalose, cyclodextrin, hydroxypropyl methylcellulose acetate succinate, and mannitol; And / or, the surfactant is selected from at least one of lecithin, sodium stearate, and sodium lauryl sulfate; And / or, the lubricant is selected from at least any one of hard sodium fumarate, magnesium stearate, and glyceryl monostearate.

6. The preparation method according to claim 1, characterized in that: The spray drying process uses a nano spray dryer. After the polyunsaturated alcohol solution is introduced, it passes through a 4-7 μm spray-covered metal film, and an electrostatic field is formed by setting a UV-electrode to collect the sprayed particles.

7. The preparation method according to claim 6, characterized in that: The spray process sets the inlet temperature to 50-100° C., the nozzle temperature to 80-120° C., the pump flow rate to 0.2-1 L / min, and the air flow rate to 80-160 L / min.

8. The preparation method according to claim 6, characterized in that: The particle size of the polyunsaturated alcohol nanoparticles collected after spray drying is 0.3-5 μm.

9. The policosanol nanoparticle rapid-release capsule obtained by the preparation method according to any one of claims 1 to 8, characterized in that: The dissolution time of the polyunsaturated glycol is less than 5 minutes when the solubility of the polyunsaturated glycol is 80%.

10. Use of the policosanol nanoparticle rapid-release capsule according to claim 9 in the preparation of lipid-lowering drugs.

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