CN116350592A - A kind of stiripentol nanocrystal and its preparation method and application - Google Patents

Abstract

The invention provides a setitoyl alcohol nanocrystalline and a preparation method and application thereof. The prepared settop alcohol nanocrystalline can be rapidly dissolved in an aqueous medium, the in-vivo bioavailability is obviously improved, and the prepared settop alcohol nanocrystalline has small particle size, narrow distribution, good stability, small stabilizer dosage, safety and effectiveness, is 4.04 times higher than the blood concentration of a commercial dry suspension, can relatively reduce daily dose, and ensures patient compliance through pretreatment of low-speed shearing and homogenization of low pressure; in addition, the solidification is carried out through freeze drying, so that the settop alcohol nanocrystalline is more stable, the storage and the transportation are facilitated, and the obtained nanocrystalline freeze-dried powder is fast in redissolution and can keep the original particle size and dispersibility; the preparation method provided by the invention has the advantages of simple process and controllable process, and is easy for process amplification and industrial production.

Description

A kind of stiripentol nanocrystal and its preparation method and application

technical field

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a stiripentol nanocrystal and a preparation method and application thereof.

Background technique

Stiripentol (STP) is a poorly water-soluble drug (solubility is about 49.2 μg/ml), which is used to treat severe myoclonic epilepsy in infants with Dravet syndrome. At present, there are capsules and The dry suspension (250mg, 500mg two specifications) is on the market, administered 2 to 3 times a day, the recommended maximum total dose is 3000mg/day, and the blood drug concentration reaches the peak 2 to 3 hours after a single administration (4 ~22μg/mL), and generally need to be taken with meals to achieve the best effect. Stipopentol (STP) belongs to the BCSII class drug with low water solubility and high permeability. It dissolves slowly and incompletely in the gastrointestinal tract, and has poor stability in acidic environment. Due to the above-mentioned limitations of oral absorption, the drug's The daily oral dose is high, which seriously limits its further clinical application. Therefore, it is necessary to adopt preparation technology to increase its solubility, improve its dissolution rate, and promote its absorption in the body. The preparation has fast dissolution, high bioavailability, and good stability. Stippentol preparations.

At present, the commonly used nanocrystal preparation methods can be divided into "Bottom-up" method and "Top-down" method. The bottom-up method refers to the preparation method in which nano-crystals are constructed from molecular forms of drugs; the top-down method refers to the nano-crystals that are pulverized from larger particles to obtain nano-basic drug particles. The preparation of the bottom-up method includes solvent evaporation method, precipitation method, spray drying method, supercritical anti-solvent method, freeze-drying method and so on. The top-down method is based on mechanical pulverization, including ball milling, high-pressure homogenization and micro-jet high-pressure homogenization.

So far, there is no nanoscale stiripentol preparation listed both at home and abroad. Therefore, it is of great clinical value to design a new formulation of stiripentol that is safe, effective and convenient to use.

Contents of the invention

The purpose of the present invention is to provide a stiripentol nanocrystal and its preparation method and application for the above-mentioned deficiencies of the prior art.

To achieve the above object, the present invention adopts the following technical solutions:

The first object of the present invention is to provide a kind of stiripentol nanocrystal, described stiripentol nanocrystal comprises stiripentol, the first stabilizer, the second stabilizer and lyoprotectant, wherein, by mass In terms of parts, the stiripentol is 20-50 parts, the first stabilizer is 3-10 parts, the second stabilizer is 20-40 parts, the lyoprotectant is 1-10 parts, and the first The stabilizer includes one or more of surfactants and polymers; the second stabilizer is cellulose; the lyoprotectant is any one of sucrose, lactose, glucose and mannose.

Further, the surfactant is selected from sodium lauryl sulfate, cetyltrimethylammonium bromide, poloxamer, tyloxapol, carbomer 974P, lecithin, Tween Any one; the polymer is selected from any one of hypromellose, povidone, polyvinylpyrrolidone, polyvinyl alcohol, and gum arabic.

Further, the cellulose is selected from methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose and microcrystalline cellulose any of the.

Further, the particle size of the stiripentol nanocrystals is 100nm-500nm.

The second object of the present invention is to provide a kind of preparation method of stiripentol nanocrystal, comprising the following specific steps:

Step S1, preparation of stiripentol nanocoarse suspension

Take the first stabilizer and the second stabilizer according to the measurement, and dissolve them in water by ultrasonic to obtain the water phase; take the stiripentol raw material drug according to the measurement, dissolve them in the organic solvent to obtain the organic phase; at a certain stirring speed and temperature , inject the organic phase into the water phase at a preset speed according to a preset ratio, and stir evenly to obtain a stiripentol nano-coarse suspension; the mass concentration of the first stabilizer in the water phase is 0.03mg/mL～ 0.1mg/mL, the mass concentration of the second stabilizer is 0.2mg/mL～0.4mg/mL; the mass concentration of stiripentol in the organic phase is 2.5mg/mL～12.5mg/mL;

Step S2, preparation of stiripentol nanocrystals

A freeze-drying protective agent is added to the stiripentol nano coarse suspension, and after being homogenized under high pressure, freeze-dried and solidified, powdery stiripentol nanocrystals are obtained.

Further, the organic solvent is one or more of methanol, ethanol, acetone, isopropanol, acetonitrile, DMSO, DMF and ethyl acetate.

Further, in step S1, the ultrasonic dissolution power of the stabilizer is 200w-450w, the volume ratio of the aqueous phase to the organic phase is 100:(4-8), the injection speed of the organic phase is 2mL/min-10mL/min, the stirring speed 200r/min～1000r/min, temperature 0～50℃.

Further, in step S2, the power of the high-pressure homogenization is 800 bar-1200 bar, and the number of homogenization cycles of the high-pressure homogenization ranges from 6 to 30 weeks.

Further, in step S2, the pre-freezing temperature for freeze-drying is -20° C. to 80° C., and the pre-freezing time is 6 to 24 hours.

The third object of the present invention is to provide an antiepileptic drug composition prepared by using the above-mentioned stiripentol nanocrystals.

Antiepileptic drug refers to a composition comprising nanocrystals of stiripentol and at least one selected from the following pharmaceutically acceptable and pharmacologically compatible components: filler, solvent, diluent, carrier, excipient, distribution Agents and receptors, delivery agents such as preservatives, stabilizers, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, thickeners, sweeteners, flavoring agents, fragrances, antibacterial agents, Fungicides, lubricants and prolonged delivery controlling agents, the choice and proportion will depend on the nature and route of administration and dosage. Examples of suitable suspending agents are ethoxylated isostearyl alcohols, polyoxyethylenes, sorbitol and sorbitol ethers, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Protection against microorganisms can be provided by various antibacterial and antifungal agents, such as parabens, chlorobutanol, sorbic acid, and the like. Antiepileptic drugs may also include isotonic agents, such as sugar, sodium chloride, and the like. Sustained action of the compositions can be brought about by the use of agents which slow the absorption of the active ingredient, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery agents include water, ethanol, polyols and mixtures thereof, natural oils such as olive oil, and organic esters for injection such as ethyl oleate. Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, and the like. Examples of disintegrating and distributing agents are starch, alginic acid and its salts and silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc and high molecular weight polyethylene glycols. Pharmaceutical compositions for the oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous and topical or rectal administration of the active ingredient alone or in combination with another active compound, as admixture with conventional pharmaceutical carriers in the form of Standard dosage forms are administered to animals and humans. Suitable standard administration forms include oral forms such as tablets, capsules, pills, powders, granules, chewing gum and oral solutions or suspensions; sublingual and buccal administration forms; aerosols; implants; Topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms; and rectal administration forms.

Compared with the prior art, the beneficial effects brought by the technical solution provided by the present invention are:

(1) The stiripentol nanocrystals prepared by the present invention can dissolve rapidly in the aqueous medium, and significantly improve the bioavailability in the body, through the pretreatment of low-speed shear and the homogenization of low pressure, the simultaneously prepared The nanocrystalline stiripentol has small particle size, narrow distribution, good stability, less stabilizer dosage, is safe and effective, and the area under the drug-time curve is 4.04 times higher than that of commercially available dry suspensions, which can relatively reduce the daily dose and ensure Moreover, solidification by freeze-drying makes stiripentol nanocrystals more stable, which is convenient for storage and transportation. The obtained nanocrystal freeze-dried powder is reconstituted quickly and can maintain the original particle size and dispersibility ;

(2) The preparation method provided by the present invention has simple process, controllable process, and is easy for process enlargement and industrial production.

Description of drawings

Fig. 1 is the PXRD figure of the stiripentol nanocrystal prepared by embodiment 1;

Fig. 2 is the in vitro dissolution curve in water of stiripentol nanocrystals, stiripentol physical mixture and stiripentol bulk drug prepared in Example 1.

Detailed ways

If no specific technique or condition is indicated in the present invention, it shall be carried out according to the technique or condition described in the literature in this field or according to the product manual. The reagents or instruments used were not indicated by the manufacturer, and they were all commercially available conventional products.

The reagent information used in this implementation is as follows:

Sodium dodecyl sulfate, abbreviated as SDS, CAS No.: 151-21-3; Cetyltrimethylammonium bromide, abbreviated as CTAB, CAS No.: 57-09-0; Poloxamer 188, Abbreviated as F68, CAS No.: 9003-11-6; Poloxamer 407, abbreviated as F127, CAS No.: 9003-11-6; Carbomer 974P, CAS No.: 9003-01-4; Hypromellose Polyvinylpyrrolidone, abbreviated as HMPC, CAS No.: 9004-65-3; Povidone, abbreviated as PVP, CAS No.: 9003-39-8; Polyvinylpyrrolidone, abbreviated as PVP K30, CAS No.: 9003-39-8; Tyloxapol, CAS No.: 25301-02-4; Methylcellulose, abbreviated as MC, CAS No.: 9004-67-5; Carboxymethylcellulose, abbreviated as CMC, CAS No.: 9004-32-4 ; Ethylcellulose, abbreviated as EC, CAS No.: 9004-57-3; Hydroxyethylcellulose, abbreviated as HEC, CAS No.: 9004-62-0; Hydroxypropylcellulose, abbreviated as HPC, CAS No. : 9004-64-2; cellulose acetate, abbreviated as CA, CAS No.: 9004-35-7; microcrystalline cellulose, abbreviated as MCC, CAS No.: 9004-34-6.

Both the first stabilizer and the second stabilizer used in the present invention are of pharmaceutical excipient grade.

Commercially available stiripentol dry suspension was purchased from Biocodex.

The performance characterization method of stiripentol nanosuspension and nanomicelle is as follows:

1) Determination of Size, PDI and Zeta

Using a Malvern laser particle size analyzer, the STP nanocrystalline powder is suspended in water, and the particle size (Size), dispersion index (PDI) and Zeta potential value are measured. Experimental conditions: the solute is STP, the refractive index is 1.578, the solvent is water, the refractive index is 1.330, the temperature is 25°C, the equilibration time is 60s, the parallel measurement is performed 3 times, and the average value is obtained.

2) X-ray diffraction (PXRD)

Spread the powder of STP nanocrystalline powder, auxiliary materials and physical mixture evenly in the sample tank, press the glass slide to make the surface smooth, fix the sample holder on the PXRD and test it. Measuring conditions: the anode target is Cu-Kα target, the tube voltage is 40kV, the tube current is 40mA, the scanning speed is 0.1s/step, the scanning step is 0.02° per step, and the scanning range is from 4° to 50° (2θ).

In order to make the purpose, technical solution and advantages of the present invention clearer, the specific implementation manners of the present invention will be further described in detail below in conjunction with specific examples and accompanying drawings.

STP: stiripentol.

PM: physical mixture of stiripentol is mixing stiripentol with the first stabilizer, the second stabilizer and the lyoprotectant in a certain proportion.

The instruments and equipment involved in the examples are described as follows: Freeze Dryer (FreeZone) Labconco, USA; High Pressure Homogenizer (AH-NANO) ATS Industrial Systems Co., Ltd.

The present invention uses the anti-solvent method combined with the high-pressure homogenization method to prepare stiripentol nanocrystal suspension, adopts freeze-drying and solidifying stiripentol nano-suspension to prepare stiripentol nanocrystal, and the micelles average particle size and PDI for the evaluation index.

Example 1

Preparation of stiripentol nanocrystals

Weigh 3 parts of the first stabilizer HPMC, 20 parts of the second stabilizer HPC and 3 parts of lyoprotectant sucrose into 100ml of pure water, place it on a magnetic stirrer at 200rpm and stir until completely dissolved. Under the condition of 250w, dissolve them in water respectively to obtain the water phase, weigh 20 parts of STP raw materials, dissolve them in 8ml of isopropanol, and set the volume ratio of the organic phase to the water phase at 4:100 at a stirring speed of 1000r/min and a temperature of Under the condition of 0°C, the organic phase was injected into the water phase at a speed of 6mL/min to obtain a coarse suspension, which was added to a high-pressure homogenizer (HPH), and the homogenization in the high-pressure homogenizer was Under the condition of mass power of 1000bar, after 6 weeks of high-pressure homogeneous circulation, the stiripentol nanocrystal suspension was obtained, placed at room temperature for 24 hours, pre-frozen at -80°C for 6 hours, and freeze-dried to obtain powdered stiripentol alcohol nanocrystals. The obtained stiripentol nanocrystal particle size is 466.5nm, and the PDI is 0.275.

The stiripentol nanocrystals that embodiment 1 prepares are characterized as follows:

As shown in Figure 1, both the STP raw material drug and the drug-assisted physical mixture have the same position and corresponding number of diffraction peaks. The diffraction peak intensity of STP nanocrystals is weak, but the peak positions are consistent, indicating that although the drug in the nanocrystals is in a crystalline state However, due to the loading of HPMC, the intensity of some diffraction peaks of the drug is weakened, which also proves that the particle size of the drug is reduced.

In order to better explore the bioavailability characteristics of stiripentol nanocrystals, an in vitro dissolution study and bioavailability evaluation were carried out. The details are as follows:

(1) In vitro dissolution study

The dissolution profile of STP nanocrystals was determined by small cup method. Measuring conditions: the dissolution medium is water, the volume of the dissolution medium is 250mL, the rotation speed is 100rpm/min, and the temperature is 37.0°C. Weigh 3 samples of STP, physical mixture, and STP nanocrystalline powder (equivalent to 10 mg of STP), weigh them accurately, and put them into the dissolution vessel at the same time. Start timing when the raw material drug contacts the dissolution medium, take samples at 2, 5, 10, 20, 30, 45, 60, 90, 120, 240, 480, and 720 minutes respectively, draw 5 mL each time and replenish 5 mL of the dissolution medium in time, use Filter through a 0.45 μm pore filter membrane, take the filtrate as the test sample, and measure the absorbance at a wavelength of 270 nm by ultraviolet spectrophotometry.

The preparation process of the STP physical mixture is as follows: 20 parts of stiripentol raw material drug, 3 parts of HPMC, 20 parts of HPC and 3 parts of sucrose are uniformly mixed.

The results are shown in Figure 2. As an insoluble drug, STP dissolves slowly, and the dissolution curve is significantly accelerated after being made into nanocrystals. Taking the cumulative dissolution rate of 90% as the investigation index, the time for nanocrystals is 32 minutes, and the time for drug-assisted physical mixtures is about 90 minutes. , the bulk drug is about 190min, it can be seen that the dissolution behavior of the stiripentol nanocrystals of the present invention in water is fast dissolution, and the dissolution rate of the stiripentol nanocrystals is obviously higher than that of the stiripentol raw material and the physical mixture of stiripentol .

(2) Bioavailability

(2.1) Dosing regimen and blood sample processing

Weigh about an appropriate amount of STP nanocrystalline powder, weigh it accurately, and use 0.5% sodium carboxymethylcellulose as a dispersion solvent to prepare a suspension with a concentration of 100 mg/mL. Adult Wistar rats (body weight 200±10g) were fed adaptively for one week, fasted for 12 hours before administration, and injected 0.2 mL of STP nanocrystal suspension into the tail vein on the second day (STP dose was 100 mg/kg). At 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours after administration, 0.5 mL of whole blood was collected from the orbital venous plexus under anesthesia, and anticoagulated with heparin (50 units/mL). Immediately centrifuge at 3000r/min for 5min to separate the plasma and store it at -20°C until extraction.

Take 0.5ml of plasma sample, add 1.5ml of organic solvent, vortex for 5min, centrifuge at 3000r/min for 10min, suck out the organic solvent, blow dry under nitrogen, repeat solvent extraction 3 times. Add 0.1 ml of solvent to the dry matter to dissolve, after centrifugation, absorb the supernatant, and wait for HPLC injection analysis.

(2.2) HPLC chromatographic analysis

The STP concentration of plasma samples was determined by HPLC. Chromatographic column: Kromasil C18 column (10nm-5μm, 4.6mm×250mm) (Hanbon Science Technology Co., Ltd), mobile phase: methanol-acetonitrile-1% acetic acid solution (50:10:40), detection wavelength: 270nm, Flow rate: 0.8mL/min, column temperature: room temperature, injection volume: 20μL. The internal standard is xanthone. Under this condition, the chromatographic peak separation diagram is shown in the figure below. It can be seen from the figure that the retention times of STP and the internal standard xanthone are 12.115 min and 9.138 min respectively, and the blank plasma sample does not interfere with the determination.

The results showed that after gastrointestinal administration of STP nanocrystalline freeze-dried powder to rats, the blood concentration was higher than that of the commercially available dry suspension, the AUC _0-t increased by 4.04 times, and the relative bioavailability was significantly improved.

Example 2

Preparation of stiripentol nanocrystals

Weigh 5 parts of the first stabilizer HPMC, 30 parts of the second stabilizer HPC and 5 parts of lyoprotectant sucrose and add them into 100ml of pure water, and dissolve them in water under the condition of ultrasonic power of 200w to obtain the water phase, and weigh 30 parts of STP raw material, dissolved in 8ml of isopropanol, according to the volume ratio of organic phase to water phase 6:100, under the conditions of stirring speed of 600r/min and temperature of 25°C, the organic phase was mixed at a speed of 2mL/min Inject into the aqueous phase to obtain a coarse suspension, add the above-mentioned coarse suspension into a high-pressure homogenizer (HPH), and under the condition of 800bar homogenization power of the high-pressure homogenizer, after 14 weeks of high-pressure homogeneous circulation, The stiripentol nanocrystal suspension was obtained, placed at room temperature for 24 hours, pre-frozen at -80° C. for 24 hours, and freeze-dried to obtain powdered stiripentol nanocrystals. The obtained stiripentol nanocrystal particle diameter is 435.7nm, and PDI is 0.456.

Example 3

Preparation of stiripentol nanocrystals

Weigh 10 parts of the first stabilizer HPMC, 40 parts of the second stabilizer HPC and 10 parts of lyoprotectant sucrose and add them into 100ml of pure water, and dissolve them in water respectively under the condition of ultrasonic power of 450w to obtain the water phase, and weigh 50 parts of STP raw materials, dissolved in 4ml of isopropanol, according to the volume ratio of organic phase to water phase 8:100, under the conditions of stirring speed of 200r/min and temperature of 50°C, the organic phase was mixed at a speed of 10mL/min Inject into the aqueous phase to obtain a coarse suspension, add the above-mentioned coarse suspension into a high-pressure homogenizer (HPH), under the condition of 1200bar homogenization power of the high-pressure homogenizer, after 26 weeks of high-pressure homogeneous circulation, The stiripentol nanocrystal suspension was obtained, placed at room temperature for 24 hours, pre-frozen at -80° C. for 12 hours, and freeze-dried to obtain powdered stiripentol nanocrystals. The obtained stiripentol nanocrystal particle diameter is 422.6nm, and PDI is 0.378.

Example 4

It is basically the same as Example 1, except that the first stabilizer is SDS, the second stabilizer is MC, and the lyoprotectant is lactose. The obtained stiripentol nanocrystal particle size is 379.2nm, and the PDI is 0.315.

Example 5

It is basically the same as Example 1, except that the organic solvent is DMSO. The obtained stiripentol nanocrystals had a particle size of 202.7nm and a PDI of 0.781.

Example 6

Basically the same as Example 1, the difference is: the organic solvent is ethyl acetate. The obtained stiripentol nanocrystal particle diameter is 432.8nm, PDI is 0.553.

Example 7

It is basically the same as Example 1, except that the organic solvent is methanol. The obtained stiripentol nanocrystal particle diameter is 986.2nm, and PDI is 0.456.

Example 8

It is basically the same as Example 1, except that the organic solvent is ethanol. The obtained stiripentol nanocrystal particle diameter is 953.9nm, and PDI is 0.437.

Example 9

Basically the same as Example 1, the difference is: the organic solvent is acetonitrile. The obtained stiripentol nanocrystal particle diameter is 731.6nm, PDI is 0.572.

Example 10

It is basically the same as Example 1, except that the second stabilizer is different and can be selected from any one of EC, HPC, CA, CMC, HEC and MCC. The prepared stiripentol nano crystal particle diameter ranges from 100nm to 500nm.

During the experiment, it was found that compared with before freeze-drying, the turbidity value of the stiripentol nanocrystal suspension after freeze-drying and redissolving increased, indicating that the drug particles were obviously agglomerated, and the freeze-drying process had a negative effect on the nanocrystals. The stability of the crystal has a certain influence; the STP nanocrystalline powder after freeze-drying is resuspended after being placed in accelerated conditions (40°C, RH 75%) for 10 days. The turbidity values of the MC, EC, HPC, CA, and HPMC samples showed signs of decreasing, indicating that the drug particles settled slightly faster, while the turbidity values of MC, EC, HPC, CA, and HPMC samples showed signs of increasing, indicating that the drug particles might have agglomerated; but in comparison, MC and HPC samples with the least change in turbidity, indicating more stability.

Comparative example 1

Basically the same as Example 1, the difference is that the first stabilizer is different, design 9 groups of tests, test 1 is cetyltrimethylammonium bromide; test 2 is poloxamer 188; test 3 is polyvinylpyrrolidone; Trial 4 was Tyloxapol; Trial 5 was Gum Arabic; Trial 6 was Carbomer 974P; Trial 7 was Lecithin; Trial 8 was Tween; Trial 9 was polyvinyl alcohol.

During the experiment, it was found that the addition of HPMC or SDS can better reduce the aggregation of drug crystals. The particle size of stiripentol is small and uniformly dispersed, while the addition of cetyltrimethylammonium bromide and poloxamer 188 , polyvinylpyrrolidone, tyloxapol, carbomer 974P, lecithin, polyvinyl alcohol, and Tween all had a small amount of crystal aggregation, and the aggregation of hexadecyltrimethylammonium bromide and gum arabic was relatively Severe and relatively large crystal size.

Comparative example 2

Basically the same as Example 1, the difference is that the mass parts of stiripentol bulk drug are different, two groups of experiments are designed, test 1 takes by weighing 15 parts of stiripentol bulk drug, test 2 takes by weighing 55 parts of stiripentol API. Test 1: the particle size of the stiripentol nanocrystals was 982.5 nm, and the PDI was 0.348; Test 2: the particle size of the stiripentol nanocrystals was 957.8 nm, and the PDI was 0.372.

Comparative example 3

It is basically the same as Example 1, except that the stirring speed and temperature in the anti-solvent preparation are different. Two sets of experiments are designed, the stirring speed of Experiment 1 is 1200r/min; the temperature of Experiment 2 is 60°C. Test 1: the particle size of the stiripentol nanocrystals was 1182.3 nm, and the PDI was 0.448; Test 2: the particle size of the stiripentol nanocrystals was 682.1 nm, and the PDI was 0.578.

Comparative example 4

Basically the same as Example 1, the difference is that the high-pressure homogenization conditions are different, two groups of experiments are designed, the homogenization power of test 1 is 1200 bar, and the high-pressure homogenization cycle is 4 weeks; the homogenization power of test 2 is 600 bar, and the high-pressure homogenization cycle is 28 weeks. Test 1: the particle size of the stiripentol nanocrystals was 1022.3nm, and the PDI was 0.538; Test 2: the particle size of the stiripentol nanocrystals was 1258.3nm, and the PDI was 0.491.

In the case of no conflict, the above-mentioned embodiments and features in the embodiments herein may be combined with each other.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection of the present invention. within range.

Claims (10)

1. a stiripentol nanocrystal, is characterized in that, described stiripentol nanocrystal comprises stiripentol, the first stabilizing agent, the second stabilizing agent and lyoprotectant, wherein, by mass parts In total, the stiripentol is 20-50 parts, the first stabilizer is 3-10 parts, the second stabilizer is 20-40 parts, the lyoprotectant is 1-10 parts, and the first stabilizer It includes one or more of surfactants and polymers; the second stabilizer is cellulose; and the lyoprotectant is any one of sucrose, lactose, glucose and mannose. 2. stiripentol nanocrystal as claimed in claim 1, is characterized in that, described tensio-active agent is selected from sodium lauryl sulfate, cetyl trimethyl ammonium bromide, poloxamer, Any one of tyloxapol, carbomer 974P, lecithin, Tween, and the polymer is selected from any of hypromellose, povidone, polyvinylpyrrolidone, polyvinyl alcohol, gum arabic A sort of. 3. stiripentol nanocrystals as claimed in claim 3, is characterized in that, described cellulose is selected from methyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose Any of cellulose acetate, cellulose acetate, hydroxypropylmethylcellulose and microcrystalline cellulose. 4. The stiripentol nanocrystal according to claim 1, characterized in that, the particle diameter of the stiripentol nanocrystal is 100nm˜500nm. 5. a preparation method of stiripentol nanocrystals as described in any one of claim 1-4, it is characterized in that, adopt anti-solvent method to combine high-pressure homogenization method to prepare stiripentol nanocrystal suspension , and then solidified by freeze-drying technology, which specifically includes the following steps: Step S1, preparation of stiripentol nanosuspension Take the first stabilizer and the second stabilizer according to the measurement, and dissolve them in water by ultrasonic to obtain the water phase; take the stiripentol raw material drug according to the measurement, dissolve them in the organic solvent to obtain the organic phase; at a certain stirring speed and temperature , inject the organic phase into the water phase at a preset speed according to a preset ratio, and stir evenly to obtain a stiripentol nanosuspension; the mass concentration of the first stabilizer in the water phase is 0.03mg/mL～0.1 mg/mL, the mass concentration of the second stabilizer is 0.2mg/mL～0.4mg/mL; the mass concentration of stiripentol in the organic phase is 2.5mg/mL～12.5mg/mL; Step S2, preparation of stiripentol nanocrystals A freeze-drying protective agent is added to the stiripentol nano-suspension, and after being homogenized under high pressure, freeze-dried and solidified, powdery stiripentol nano-crystals are obtained. 6. preparation method as claimed in claim 5, is characterized in that, described organic solvent is any one in methyl alcohol, ethanol, acetone, propylene glycol, Virahol, acetonitrile, DMSO, DMF and ethyl acetate. 7. The preparation method according to claim 6, characterized in that, in step S1, the ultrasonic dissolution power of the stabilizer is 200w～450w, the volume ratio of the aqueous phase to the organic phase is 100:(4～8), the organic phase The injection speed is 2mL/min-10mL/min, the stirring speed is 200r/min-1000r/min, and the temperature is 0-50°C. 8. The preparation method according to claim 7, characterized in that, in step S2, the power of the high-pressure homogenization is 800 bar-1200 bar, and the number of homogenization cycles of the high-pressure homogenization ranges from 6 to 30 weeks. 9. The preparation method according to claim 8, characterized in that, in step S2, the pre-freezing temperature for freeze-drying is -20°C--80°C, and the pre-freezing time is 6-24 hours. 10. An antiepileptic drug composition, characterized in that it is prepared by using the stiripentol nanocrystal according to any one of claims 1-4.

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