A stiripentol nanocrystal, its preparation method and application

Abstract

The present invention provides stiripentol nanocrystals, a preparation method thereof and an application thereof. The stiripentol nanocrystals prepared by this method can be rapidly dissolved in an aqueous medium, and significantly improve the in vivo bioavailability. Through the pretreatment of low-speed shearing and the homogenization under low pressure, the prepared stiripentol nanocrystals have small particle size, narrow distribution, good stability, low dosage of stabilizer, are safe and effective, and the blood drug concentration is 4.04 times higher than that of the commercially available dry suspension. The daily dose can be relatively reduced, ensuring patient compliance. Moreover, through lyophilization for solidification, the stiripentol nanocrystals are more stable, which is beneficial to storage and transportation. The obtained freeze-dried powder of the nanocrystals can be rapidly redissolved and can maintain the original particle size and dispersibility. The preparation method provided by the present invention has a simple process, is controllable in process, and is easy to scale up and industrially produce.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to stiripentol nanocrystals, a preparation method thereof and applications thereof. Background Art

[0002] Stiripentol (STP) is a drug poorly soluble in water (solubility is about 49.2 μg / ml), and is used for treating severe myoclonic epilepsy in infants and young children with Dravet syndrome. At present, capsule and dry suspension (two specifications of 250 mg and 500 mg) have been marketed abroad, and are administered 2 - 3 times a day. The recommended maximum total dose is 3000 mg / day. The blood drug concentration reaches the peak (4 - 22 μg / mL) 2 - 3 hours after single administration, and generally needs to be taken with meals to achieve the best effect. Stiripentol (STP) belongs to BCS II drugs with low water solubility and high permeability, has slow and incomplete dissolution in the gastrointestinal tract, and poor stability in an acidic environment. Due to the above limitations of oral absorption, the daily oral dose of this drug is relatively high, which severely limits its further clinical application. Therefore, pharmaceutical technology needs to be adopted to increase its solubility, improve the dissolution rate, and promote its absorption in the body, so as to prepare a stiripentol preparation with fast dissolution, high bioavailability and good stability.

[0003] Currently, the commonly used means for preparing nanocrystals can be divided into the "Bottom-up" method and the "Top-down" method. The Bottom-up method refers to a preparation method in which nanocrystals are constructed from the molecular form of the drug; the Top-down method refers to a method in which nanocrystals are obtained by crushing larger particles into basic drug particles at the nanoscale. The preparation of the Bottom-up method includes the solvent evaporation method, precipitation method, spray drying method, supercritical antisolvent method, freeze drying method, etc. The Top-down method is based on mechanical crushing, including ball milling method, high-pressure homogenization method and microfluidic high-pressure homogenization method, etc.

[0004] So far, no nanoscale stiripentol preparation has been marketed at home and abroad. Therefore, designing a new safe, effective and convenient-to-use stiripentol preparation has important clinical value. Summary of the Invention

[0005] The purpose of the present invention is to provide stiripentol nanocrystals, a preparation method thereof and applications thereof in view of the above deficiencies of the prior art.

[0006] To achieve the above purpose, the present invention adopts the following technical solutions:

[0007] The first object of the present invention is to provide a stiripentol nanocrystal, which comprises stiripentol, a first stabilizer, a second stabilizer and a lyoprotectant. Among them, by mass, the stiripentol is 20-50 parts, the first stabilizer is 3-10 parts, the second stabilizer is 20-40 parts, and the lyoprotectant is 1-10 parts. The first 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.

[0008] Further, the surfactant is selected from any one of sodium dodecyl sulfate, cetyltrimethylammonium bromide, poloxamer, tyloxapol, carbomer 974P, lecithin, and tween; the polymer is selected from any one of hypromellose, polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinyl alcohol, and gum arabic.

[0009] Further, the cellulose is selected from any one of methylcellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, cellulose acetate, hypromellose and microcrystalline cellulose.

[0010] Further, the particle size of the stiripentol nanocrystal is 100nm to 500nm.

[0011] The second object of the present invention is to provide a method for preparing a stiripentol nanocrystal, which comprises the following specific steps:

[0012] Step S1, preparation of a crude stiripentol nanosuspension

[0013] Weigh the first stabilizer and the second stabilizer, dissolve them in water by ultrasonic treatment to obtain an aqueous phase; weigh the stiripentol raw material drug and dissolve it in an organic solvent to obtain an organic phase; at a certain stirring speed and temperature, inject the organic phase into the aqueous phase at a preset speed according to a preset ratio, and stir evenly to obtain a crude stiripentol nanosuspension; the mass concentration of the first stabilizer in the aqueous phase is 0.03mg / mL to 0.1mg / mL, and the mass concentration of the second stabilizer is 0.2mg / mL to 0.4mg / mL; the mass concentration of stiripentol in the organic phase is 2.5mg / mL to 12.5mg / mL;

[0014] Step S2, preparation of stiripentol nanocrystals

[0015] Add a lyoprotectant to the crude stiripentol nanosuspension, after high-pressure homogenization, freeze-dry and solidify to obtain powdery stiripentol nanocrystals.

[0016] Further, the organic solvent is one or more of methanol, ethanol, acetone, isopropanol, acetonitrile, DMSO, DMF and ethyl acetate.

[0017] Further, in step S1, the ultrasonic dissolution power of the stabilizer is 200 w to 450 w, the volume ratio of the aqueous phase to the organic phase is 100:(4 - 8), the injection rate of the organic phase is 2 mL / min to 10 mL / min, the stirring speed is 200 r / min to 1000 r / min, and the temperature is 0 to 50 °C.

[0018] Further, in step S2, the power of high-pressure homogenization is 800 bar to 1200 bar, and the range of the number of homogenization cycles of high-pressure homogenization is 6 to 30 cycles.

[0019] Further, in step S2, the pre-freezing temperature of freeze-drying is -20 °C to 80 °C, and the pre-freezing time is 6 to 24 hours.

[0020] The third object of the present invention is to provide an antiepileptic drug composition prepared from the above-mentioned stiripentol nanocrystals.

[0021] Antiepileptic drugs refer to compositions comprising stiripentol nanocrystals and at least one pharmaceutically acceptable and pharmacologically compatible component selected from the following: fillers, solvents, diluents, carriers, excipients, dispersants and acceptors, delivery agents such as preservatives, stabilizers, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, thickening agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and extended delivery control agents, the selection and proportion of which depend on the nature and route of administration and the dose. Examples of suitable suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ethers, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth gum and mixtures thereof. Various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid, etc. can be used to provide protection against microorganisms. Antiepileptic drugs may also include isotonic agents such as sugars, sodium chloride, etc. The sustained action of the composition can be achieved by using reagents that slow down the absorption of the active ingredient, such as 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, etc. Examples of disintegrants and dispersants are starch, alginic acid and its salts and silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc and high molecular weight polyethylene glycol. Pharmaceutical compositions for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous and topical or rectal administration of the active ingredient, alone or in combination with another active compound, can be administered to animals and humans in standard dosage forms as mixtures with conventional pharmaceutical carriers. Suitable standard dosage forms include oral forms such as tablets, capsules, pills, powders, granules, chewing gums 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.

[0022] Compared with the prior art, the beneficial effects brought by the technical solution provided by the present invention are as follows:

[0023] (1) The stiripentol nanocrystals prepared by the present invention can be rapidly dissolved in an aqueous medium, and significantly improve the in vivo bioavailability. Through the pretreatment of low-speed shearing and the homogenization under low pressure, the stiripentol nanocrystals prepared at the same time have small particle size, narrow distribution, good stability, less amount of stabilizer, are safe and effective, and the area under the plasma concentration-time curve is increased by 4.04 times compared with the commercially available dry suspension, and the daily dose can be relatively reduced, ensuring the compliance of patients; moreover, through lyophilization for solidification, the stiripentol nanocrystals are more stable, which is beneficial to storage and transportation, and the obtained freeze-dried powder of nanocrystals can be rapidly redissolved and can maintain the original particle size and dispersibility;

[0024] (2) The preparation method provided by the present invention has a simple process, the process is controllable, and it is easy to scale up the process and industrial production. Description of the Drawings

[0025] Figure 1 PXRD pattern of stiripentol nanocrystals prepared in Example 1;

[0026] Figure 2 In vitro dissolution curves of stiripentol nanocrystals, physical mixture of stiripentol, and stiripentol API prepared in Example 1 in water. Detailed Description of the Invention

[0027] For those specific technologies or conditions not specified in the present invention, they shall be carried out according to the technologies or conditions described in the literature in this field or according to the product specifications. For reagents or instruments whose manufacturers are not specified, they are all conventional products that can be obtained through commercial purchase.

[0028] The reagent information used in this example is as follows:

[0029] 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; Hydroxypropyl methylcellulose, abbreviated as HMPC, CAS No.: 9004-65-3; Polyvinylpyrrolidone, abbreviated as PVP, CAS No.: 9003-39-8; Polyvinylpyrrolidone K30, 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.

[0030] Both the first stabilizer and the second stabilizer used in the present invention are of pharmaceutical excipient grade.

[0031] The commercially available stiripentol dry suspension was purchased from Biocodex.

[0032] The methods for characterizing the properties of stiripentol nanosuspensions and nanomicelles are as follows:

[0033] 1) Determination of Size, PDI, and Zeta

[0034] Using a Malvern laser particle size analyzer, after suspending STP nanocrystalline powder in water, the particle size (Size), polydispersity index (PDI), and Zeta potential value were measured. Experimental conditions: the solute was STP, the refractive index was 1.578, the solvent was water, the refractive index was 1.330, the temperature was 25 °C, the equilibration time was 60 s, and parallel measurements were performed 3 times. The average value was obtained, and that was it.

[0035] 2) X-ray diffraction method (PXRD)

[0036] The STP nanocrystalline powder, excipients, and physical mixture powder were evenly spread on the sample cell respectively. After pressing the surface flat with a cover glass, the sample holder was fixed on the PXRD for testing. Measurement conditions: the anode target was a Cu-Kα target, the tube voltage was 40 kV, the tube current was 40 mA, the scanning speed was 0.1 s / step, the scanning step size was 0.02° per step, and the scanning range was from 4° to 50° (2θ).

[0037] To make the objectives, technical solutions, and advantages of the present invention clearer, the following further describes in detail the specific implementation manners of the present invention in combination with specific embodiments and the accompanying drawings.

[0038] STP: Stiripentol.

[0039] PM: The physical mixture of stiripentol was prepared by mixing stiripentol with a first stabilizer, a second stabilizer, and a lyoprotectant in a certain proportion.

[0040] The instrument and equipment involved in the examples are described as follows: freeze dryer (FreeZone) from Labconco Corporation, USA, high-pressure homogenizer (AH-NANO) from ATS Industrial Systems Co., Ltd.

[0041] The present invention uses an anti-solvent method combined with a high-pressure homogenization method to prepare a stiripentol nanocrystalline suspension, and uses freeze-drying to solidify the stiripentol nanosuspension to prepare stiripentol nanocrystals, with the average micelle particle size and PDI as evaluation indicators.

[0042] Example 1

[0043] Preparation of stiripentol nanocrystals

[0044] Weigh 3 parts of the first stabilizer HPMC, 20 parts of the second stabilizer HPC, and 3 parts of the lyoprotectant sucrose, add them to 100 ml of pure water, place them on a magnetic stirrer, and stir at 200 rpm until completely dissolved. Under the condition of an ultrasonic power of 250 w, dissolve them in water respectively to obtain an aqueous phase. Weigh 20 parts of the STP raw material drug, dissolve it in 8 ml of isopropanol, and according to the volume ratio of the organic phase to the aqueous phase of 4:100, inject the organic phase into the aqueous phase at a speed of 6 mL / min under the conditions of a stirring speed of 1000 r / min and a temperature of 0 °C to obtain a crude suspension. Add the above crude suspension into a high-pressure homogenizer (HPH), and under the condition of a homogenization power of 1000 bar in the high-pressure homogenizer, after 6 cycles of high-pressure homogenization, obtain the stiripentol nanocrystal suspension, place it at room temperature for 24 h, pre-freeze it at -80 °C for 6 h, and then freeze-dry it to obtain the powdered stiripentol nanocrystals. The prepared stiripentol nanocrystals have a particle size of 466.5 nm and a PDI of 0.275.

[0045] The characterization results of the stiripentol nanocrystals prepared in Example 1 are as follows:

[0046] As Figure 1 shown, the STP raw material drug and the physical mixture of pharmaceutical excipients have diffraction peaks at the same positions and corresponding numbers. The diffraction peak intensity of the STP nanocrystals is weak, but the peak positions are the same, indicating that although the drug in the nanocrystals appears in a crystalline state, 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 has decreased.

[0047] In order to better explore the bioavailability characteristics of stiripentol nanocrystals, in vitro dissolution studies and bioavailability evaluations were carried out, and the specific contents are as follows:

[0048] (1) In vitro dissolution studies

[0049] The dissolution curve of STP nanocrystals was determined by the small cup method. The determination conditions were as follows: the dissolution medium was water, the volume of the dissolution medium was 250 mL, the rotation speed was 100 rpm / min, and the temperature was 37.0 °C. Weigh 3 samples each of STP, the physical mixture, and the STP nanocrystal powder sample (equivalent to 10 mg of STP), accurately weigh them, and simultaneously put them into the dissolution cups. Start timing from 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 min respectively. Each time, draw 5 mL and immediately supplement 5 mL of the dissolution medium. Filter through a 0.45 μm pore size filter membrane, take the filtrate as the test sample, and use ultraviolet spectrophotometry to measure the absorbance at a wavelength of 270 nm.

[0050] The preparation process of the STP physical mixture was as follows: take 20 parts of the stiripentol raw material drug, 3 parts of HPMC, 20 parts of HPC, and 3 parts of sucrose, and mix them evenly to obtain it.

[0051] The results are as Figure 2 shown. As a poorly soluble drug, the dissolution of STP is slow. After being made into nanocrystals, the dissolution curve is significantly accelerated. Taking the cumulative dissolution rate of 90% as the evaluation index, the time for nanocrystals is 32 min, the physical mixture of drug and excipient is about 90 min, and the raw material drug is about 190 min. It can be seen that the dissolution behavior of the STP nanocrystals of the present invention shows rapid dissolution in water, and the dissolution rate of the STP nanocrystals is significantly higher than that of the STP raw material and the physical mixture of STP.

[0052] (2) Bioavailability

[0053] (2.1) Administration regimen and blood sample treatment

[0054] Weigh an appropriate amount of STP nanocrystal powder, accurately weigh it, and use 0.5% sodium carboxymethylcellulose as the dispersion solvent to prepare a suspension with a concentration of 100 mg / mL. Adult Wistar rats (weighing 200 ± 10 g) are adaptively fed for one week, fasted for 12 h before administration, and on the second day, 0.2 mL of the STP nanocrystal suspension (STP dose is 100 mg / kg) is injected into the tail vein. After administration, 0.5 mL of whole blood is taken from the orbital venous plexus under anesthesia at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 h, and anticoagulated with heparin (50 units / mL). Immediately centrifuge at 3000 r / min for 5 min to separate the plasma, and store it at -20 °C for extraction.

[0055] Take 0.5 ml of plasma sample, add 1.5 ml of organic solvent, vortex for 5 min, centrifuge at 3000 r / min for 10 min, suck out the organic solvent, dry it under nitrogen, and repeat the solvent extraction 3 times. The dried product is dissolved in 0.1 ml of solvent, centrifuged, and the supernatant is aspirated for HPLC injection analysis.

[0056] (2.2) HPLC chromatographic analysis

[0057] The concentration of STP in plasma samples was determined by HPLC. Chromatographic column: Kromasil C18 column (10 nm - 5 μm, 4.6 mm × 250 mm) (Hanbon Science Technology Co., Ltd), mobile phase: methanol - acetonitrile - 1% acetic acid solution (50:10:40), detection wavelength: 270 nm, flow rate: 0.8 mL / min, column temperature: room temperature, injection volume: 20 μL. The internal standard is xanthone. Under these conditions, the chromatogram of peak separation is shown in the following figure. As can be seen from the figure, 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.

[0058] The results showed that after the rats were administered STP nanocrystal lyophilized powder via the gastrointestinal tract, the blood drug concentration was higher than that of the commercially available dry suspension, and the AUC 0-t increased by 4.04 times, and the relative bioavailability was significantly improved.

[0059] Example 2

[0060] Preparation of stiripentol nanocrystals

[0061] Weigh 5 parts of the first stabilizer HPMC, 30 parts of the second stabilizer HPC and 5 parts of the lyoprotectant sucrose, add them to 100 ml of pure water, and dissolve them in water respectively under the condition of an ultrasonic power of 200 w to obtain an aqueous phase. Weigh 30 parts of the STP raw material drug and dissolve it in 8 ml of isopropanol. According to the volume ratio of the organic phase to the aqueous phase of 6:100, under the conditions of a stirring speed of 600 r / min and a temperature of 25 °C, inject the organic phase into the aqueous phase at a speed of 2 mL / min to obtain a crude suspension. Add the above crude suspension into a high-pressure homogenizer (HPH). Under the condition of a homogenization power of 800 bar in the high-pressure homogenizer, after 14 cycles of high-pressure homogenization, a stiripentol nanocrystal suspension is obtained. Place it at room temperature for 24 h, pre-freeze it at -80 °C for 24 h, and then freeze-dry it to obtain powdery stiripentol nanocrystals. The prepared stiripentol nanocrystals have a particle size of 435.7 nm and a PDI of 0.456.

[0062] Example 3

[0063] Preparation of stiripentol nanocrystals

[0064] Weigh 10 parts of the first stabilizer HPMC, 40 parts of the second stabilizer HPC and 10 parts of the lyoprotectant sucrose, add them to 100 ml of pure water, and dissolve them in water respectively under the condition of an ultrasonic power of 450 w to obtain an aqueous phase. Weigh 50 parts of the STP raw material drug and dissolve it in 4 ml of isopropanol. According to the volume ratio of the organic phase to the aqueous phase of 8:100, under the conditions of a stirring speed of 200 r / min and a temperature of 50 °C, inject the organic phase into the aqueous phase at a speed of 10 mL / min to obtain a crude suspension. Add the above crude suspension into a high-pressure homogenizer (HPH). Under the condition of a homogenization power of 1200 bar in the high-pressure homogenizer, after 26 cycles of high-pressure homogenization, a stiripentol nanocrystal suspension is obtained. Place it at room temperature for 24 h, pre-freeze it at -80 °C for 12 h, and then freeze-dry it to obtain powdery stiripentol nanocrystals. The prepared stiripentol nanocrystals have a particle size of 422.6 nm and a PDI of 0.378.

[0065] Example 4

[0066] 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 prepared stiripentol nanocrystals have a particle size of 379.2 nm and a PDI of 0.315.

[0067] Example 5

[0068] It is basically the same as Example 1, except that the organic solvent is DMSO. The prepared stiripentol nanocrystals have a particle size of 202.7 nm and a PDI of 0.781.

[0069] Example 6

[0070] It is basically the same as Example 1, except that the organic solvent is ethyl acetate. The prepared stiripentol nanocrystals have a particle size of 432.8 nm and a PDI of 0.553.

[0071] Example 7

[0072] It is basically the same as Example 1, except that the organic solvent is methanol. The prepared stiripentol nanocrystals have a particle size of 986.2 nm and a PDI of 0.456.

[0073] Example 8

[0074] It is basically the same as Example 1, except that the organic solvent is ethanol. The prepared stiripentol nanocrystals have a particle size of 953.9 nm and a PDI of 0.437.

[0075] Example 9

[0076] It is basically the same as Example 1, except that the organic solvent is acetonitrile. The prepared stiripentol nanocrystals have a particle size of 731.6 nm and a PDI of 0.572.

[0077] Example 10

[0078] 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 particle size range of the prepared stiripentol nanocrystals is 100 nm to 500 nm.

[0079] It was found during the experiment that compared with before lyophilization, the turbidity values of the stiripentol nanocrystal suspension increased after reconstitution after lyophilization, indicating that obvious aggregation of drug particles occurred, and the lyophilization process had a certain impact on the stability of the nanocrystals; the re-suspended STP nanocrystal powder after being placed at accelerated conditions (40 °C, RH 75%) for 10 days showed a tendency of decreasing turbidity values for the CMC, HEC, and MCC samples compared with 0 days after acceleration of lyophilization, indicating that the drug particles settled slightly faster, while the turbidity values of the MC, EC, HPC, CA, and HPMC samples increased, indicating that the drug particles might have aggregated; however, relatively speaking, the MC and HPC samples had the smallest turbidity changes, indicating better stability.

[0080] Comparative Example 1

[0081] It is basically the same as Example 1, except that the first stabilizer is different. Nine groups of tests are designed. Test 1 uses cetyltrimethylammonium bromide; Test 2 uses poloxamer 188; Test 3 uses polyvinylpyrrolidone; Test 4 uses tyloxapol; Test 5 uses gum arabic; Test 6 uses carbomer 974P; Test 7 uses lecithin; Test 8 uses Tween; Test 9 uses polyvinyl alcohol.

[0082] During the experiment, it was found that adding HPMC or SDS can better reduce the aggregation of drug crystals. The particle size of stiripentol is small and evenly dispersed. However, when adding cetyltrimethylammonium bromide, poloxamer 188, polyvinylpyrrolidone, tyloxapol, carbomer 974P, lecithin, polyvinyl alcohol, and Tween, a small amount of crystal aggregation occurred. Among them, the aggregation phenomenon of adding cetyltrimethylammonium bromide and gum arabic is relatively serious, and the crystal size is relatively large.

[0083] Comparative Example 2

[0084] It is basically the same as Example 1, except that the mass fraction of stiripentol raw material is different. Two groups of tests are designed. In Test 1, 15 parts of stiripentol raw material are weighed, and in Test 2, 55 parts of stiripentol raw material are weighed. Test 1: The particle size of stiripentol nanocrystals is 982.5 nm, and the PDI is 0.348; Test 2: The particle size of stiripentol nanocrystals is 957.8 nm, and the PDI is 0.372.

[0085] Comparative Example 3

[0086] It is basically the same as Example 1, except that the stirring speed and temperature are different in the preparation of the antisolvent. Two groups of tests are designed. In Test 1, the stirring speed is 1200 r / min; in Test 2, the temperature is 60 °C. Test 1: The particle size of stiripentol nanocrystals is 1182.3 nm, and the PDI is 0.448; Test 2: The particle size of stiripentol nanocrystals is 682.1 nm, and the PDI is 0.578.

[0087] Comparative Example 4

[0088] It is basically the same as Example 1, except that the high-pressure homogenization conditions are different. Two groups of tests are designed. In Test 1, the homogenization power is 1200 bar, and the high-pressure homogenization cycle is 4 weeks; in Test 2, the homogenization power is 600 bar, and the high-pressure homogenization cycle is 28 weeks. Test 1: The particle size of stiripentol nanocrystals is 1022.3 nm, and the PDI is 0.538; Test 2: The particle size of stiripentol nanocrystals is 1258.3 nm, and the PDI is 0.491.

[0089] Without conflict, the above-mentioned embodiments and the features in the embodiments in this article can be combined with each other.

[0090] The above are only the 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 principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A preparation method of stiripentol nanocrystals, characterized in that, the preparation method comprises the following steps: Step S1, preparation of stiripentol nanosuspension, Weigh the first stabilizer and the second stabilizer according to the dosage, dissolve them in water by ultrasonic wave to obtain an aqueous phase; weigh the stiripentol raw material drug, dissolve it in an organic solvent to obtain an organic phase; at a certain stirring speed and temperature, inject the organic phase into the aqueous phase at a preset ratio at a preset speed, and stir evenly to obtain a stiripentol nanosuspension; the volume ratio of the aqueous phase to the organic phase is 100:(4 - 8), the injection speed of the organic phase is 2 mL / min - 10 mL / min, the rotation speed of the stirring is 200 r / min - 1000 r / min, and the temperature is 0 - 50 °C; Step S2, preparation of stiripentol nanocrystals, Add a lyoprotectant to the stiripentol nanosuspension, after high-pressure homogenization, freeze-dry and solidify to obtain powdery stiripentol nanocrystals; the pressure of the high-pressure homogenization is 800 bar - 1200 bar, and the range of the homogenization cycle number of the high-pressure homogenization is 6 - 30 cycles; wherein, by mass parts, the stiripentol raw material drug is 20 - 50 parts, the first stabilizer is 3 - 10 parts, the second stabilizer is 20 - 40 parts, and the lyoprotectant is 1 - 10 parts; the first stabilizer is hydroxypropyl methylcellulose or sodium dodecyl sulfate; the second stabilizer is hydroxypropyl cellulose or methylcellulose; the lyoprotectant is sucrose or lactose; the organic solvent is any one of isopropanol, DMSO and ethyl acetate; the mass concentration of stiripentol in the organic phase is 2.5 mg / mL - 12.5 mg / mL.

2. The preparation method according to claim 1, characterized in that, the mass concentration of the first stabilizer in the aqueous phase is 0.03 mg / mL - 0.1 mg / mL.

3. The preparation method according to claim 2, characterized in that, the mass concentration of the second stabilizer is 0.2 mg / mL - 0.4 mg / mL.

4. The preparation method according to claim 3, characterized in that, in step S1, the ultrasonic dissolution power is 200 w - 450 w.

5. The preparation method according to claim 4, characterized in that, in step S2, the pre-freezing temperature of the freeze-drying is -20 °C - 80 °C, and the pre-freezing time is 6 - 24 hours.

6. A stiripentol nanocrystal prepared by the preparation method according to claim 5.

7. The stiripentol nanocrystal according to claim 6, characterized in that, the particle size of the stiripentol nanocrystal is 379.2 nm - 466.5 nm, and the PDI is 0.275 - 0.

553.

8. An anti-epileptic drug composition, characterized in that, it comprises stiripentol nanocrystals prepared by the preparation method according to any one of claims 1 - 5.

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