Aprepitant nanocrystalline composition as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine, and particularly relates to an aprepitant nanocrystalline composition and a preparation method and application thereof.The aprepitant and a sucrose solution are mixed, a stabilizer is added to obtain a solution to be ground, the solution to be ground is ground through a wet grinding process, and the aprepitant nanocrystalline composition is obtained; uniformly mixing the suspension with a spray drying protective agent and a flow aid to obtain a mixed solution, and drying and curing the mixed solution by adopting a spray dryer to obtain the aprepitant nanocrystal composition in the form of a dry suspension, and directly spray-drying the suspension, uniformly mixing the suspension with a skeleton agent and an adhesive, adding water to a constant volume, carrying out vacuum degassing, and carrying out pre-freezing and freeze-drying to obtain the freeze-dried orally disintegrating tablet type aprepitant nanocrystal composition.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical technology, and particularly relates to an aprepitant nanocrystal composition, a preparation method thereof, and an application thereof. Background Art

[0002] Cancer, as one of the world's largest public health problems, seriously threatens human life and health. With the progress of cancer treatment, the mortality rate of cancer patients has been continuously decreasing. Chemotherapy, as the main method for cancer treatment, its associated nausea and vomiting (Chemo-induced nausea and vomiting, CNIV) are one of the most common and painful adverse reactions in patients receiving anti-tumor treatment, and also the main limiting factor for cancer patients to choose chemotherapy. CNIV is divided into acute (0 - 24 hours after chemotherapy) and delayed (more than 24 hours after chemotherapy). Symptom-oriented treatment for CNIV is usually ineffective, so prevention becomes more important for CNIV, especially delayed nausea and vomiting. Substance P (SP) belongs to the mammalian tachykinin family and is widely distributed in the central nervous system and peripheral nervous system (mainly sensory neurons and enteric neurons), participating in the regulation of sensation, movement, emotion, etc., and is closely related to the pathogenesis of pain transmission and mental diseases such as anxiety and depression. Studies on cisplatin-induced CNIV have shown that in the acute phase, it is mainly mediated by 5-HT3, while in the delayed phase, it is mainly caused by the high affinity of SP acting on neurokinin-1 (NK-1). Therefore, 5-HT3 antagonists (5-HT3 receptor antagonist, 5-HT3-RA) are often used to prevent acute vomiting, and NK-1 receptor antagonists (neurokinin-1 receptor antagonist, NK-1-RA) are used to prevent delayed vomiting. For the prevention of nausea and vomiting caused by commonly used highly and moderately emetogenic chemotherapy drugs (such as cisplatin, cyclophosphamide, doxorubicin, cytarabine), NK-1-RA, 5-HT3-RA, and glucocorticoids are often used in combination clinically. In March 2003, the US FDA first announced the approval of aprepitant (APT) as an NK-1-RA in combination with other antiemetics for the prevention of acute and delayed CNIV. Compared with the traditional treatment regimen, the application of aprepitant has increased the response rate of acute and delayed CNIV by 20%, making up for the deficiencies of the traditional treatment regimen to a certain extent. However, when taking the medicine, there are still children, the elderly with difficulty in swallowing, or patients who do not cooperate with taking the medicine. Summary of the Invention

[0003] In view of the above-mentioned children, the elderly with difficulty in swallowing, or patients who do not cooperate with taking the medicine, this application provides an aprepitant nanocrystalline composition. The specific solution is as follows:

[0004] 1. A preparation method of aprepitant nanocrystal composition, the steps of which include:

[0005] Mix aprepitant with a sucrose solution, add a stabilizer to obtain a solution to be ground, and grind the solution to be ground through a wet grinding process to obtain the aprepitant nanocrystal composition.

[0006] 2. The method according to item 1, wherein, in the solution to be ground, the concentration of aprepitant is 2 mg / mL to 50 mg / mL.

[0007] 3. The method according to item 1, wherein the mass ratio of aprepitant to the stabilizer is 1:4 to 10:1.

[0008] 4. The method according to item 1, wherein the mass ratio of aprepitant to sucrose is 1:1.

[0009] 5. The method according to item 1, wherein the average particle size of aprepitant is 200 - 500 nm.

[0010] 6. The method according to item 1, wherein the stabilizer is selected from one or more of cellulose derivatives, ionic surfactants, non-ionic surfactants, and crystallization inhibitors.

[0011] 7. The method according to item 6, wherein the stabilizer is selected from one or more of HPMC-E5, Tween-80, PVPK30, F68, SDS, and HPC-SL.

[0012] 8. The method according to item 6, wherein the stabilizer is HPMC-E5 and SDS or HPC-SL and SDS.

[0013] 9. The method according to item 1, wherein when performing wet grinding, the grinding time is 10 - 600 min.

[0014] 10. The method according to item 1, wherein when performing wet grinding, the dosage of grinding beads is 10 mL - 600 mL.

[0015] 11. The method according to item 1, wherein when performing wet grinding, the rotation speed is 600 - 6000 rpm.

[0016] 12. The method according to item 1, wherein the steps further include:

[0017] Mix the suspension with a spray drying protective agent and a glidant uniformly to obtain a mixed solution, and use a spray dryer to dry and solidify the mixed solution to obtain the aprepitant nanocrystal composition in the form of a dry suspension.

[0018] 13. The method according to item 12, wherein the spray-dried protective agent is selected from one or more of trehalose, sucrose, lactose, vitamin E polyethylene glycol succinate (TPGS), mannitol, and hydroxypropyl-β-cyclodextrin (H-β-CD).

[0019] 14. The method according to item 12, wherein the mass ratio of aprepitant to the spray-dried protective agent is 1:10 to 10:1.

[0020] 15. The method according to item 12, wherein the mass ratio of aprepitant to the glidant is 10:1 to 50:1.

[0021] 16. The method according to item 1, wherein the step further comprises:

[0022] Directly spray-drying the suspension, mixing it evenly with a skeleton agent and a binder, adding water to make up the volume, performing vacuum degassing, followed by pre-freezing and freeze-drying to obtain the aprepitant nanocrystal composition in the form of a freeze-dried orally disintegrating tablet.

[0023] 17. The method according to item 16, wherein the skeleton agent is selected from one or more of mannitol, maltodextrin, lactose, erythritol, glycine, and trehalose.

[0024] 18. The method according to item 16, wherein the binder is selected from gelatin, pullulan, xanthan gum, gum arabic, dextran, hydroxypropyl methylcellulose (HPMC), and polyvinylpyrrolidone (PVP).

[0025] 19. The method according to item 16, wherein the mass ratio of aprepitant to the skeleton agent is 10:1 to 1:1.

[0026] 20. The method according to item 16, wherein the mass ratio of aprepitant to the binder is 10:1 to 1:1.

[0027] 21. An aprepitant nanocrystal composition prepared by the method according to any one of items 1-20.

[0028] 22. An aprepitant nanocrystal composition, which includes aprepitant, sucrose, and a stabilizer, and the aprepitant nanocrystal composition is prepared by a micro-media milling method such that the average particle size of the aprepitant is 200-500 nm.

[0029] 23. The aprepitant nanocrystal composition according to item 21 or 22, which further includes a spray-dried protective agent and a glidant.

[0030] 24. The aprepitant nanocrystal composition according to item 21 or 22, further comprising a matrix agent and a binder.

[0031] 25. The aprepitant nanocrystal composition according to item 21 or 22, wherein the dosage form of the aprepitant nanocrystal composition is one or more of a suspension, a dry suspension, and a freeze-dried orally disintegrating tablet.

[0032] 26. Use of the aprepitant nanocrystal composition prepared by the method according to any one of items 1 - 20 or the aprepitant nanocrystal composition according to any one of items 21 - 25 in the preparation of a drug for preventing acute and delayed nausea and vomiting (CNIV).

[0033] Beneficial effects:

[0034] The present application provides an aprepitant nanocrystal composition, its preparation method and application. The aprepitant nanocrystals formed after grinding by a grinder have an aprepitant particle size of 200 - 400 nm. The nanocrystal composition composed of aprepitant with this particle size can be prepared into a suspension, a dry suspension, and an orally disintegrating tablet. The aprepitant is prepared into a nanocrystal suspension by wet media grinding. Utilizing the advantages of the particle size and specific surface area of the nanocrystals, the gastrointestinal wall adhesion of the drug is enhanced, the residence time of the drug in the gastrointestinal tract is prolonged, and the bioavailability is improved. At the same time, in response to the imperfect development of the swallowing function of children and infants and the relatively high sensitivity of the trachea, conventional oral dosage forms such as tablets and capsules may cause swallowing difficulties for child patients. Therefore, dosage forms such as suspensions, oral liquids, and syrups are more suitable for children. Young children are prone to severe coughing and difficulty breathing when taking thin liquids orally, and may even experience asphyxia in severe cases. On the one hand, the present application prepares aprepitant into a nanocrystal dry suspension powder, which is reconstituted with water or other suitable fluids for administration, increasing the compliance of child patients. On the other hand, the feasibility of preparing an orally disintegrating tablet based on aprepitant nanocrystals is explored. Due to the special nature of the orally disintegrating tablet dosage form, the orally disintegrating tablet rapidly disintegrates after contacting saliva, does not require drinking water when taken, is easy for patients to swallow, and can reduce the risk of coughing during oral administration, being particularly suitable for child patients. Description of the Drawings

[0035] The drawings are used to better understand the present application and do not constitute an improper limitation to the present application. Among them:

[0036] Figure 1 Shows the relevant data measured in Examples 1 to 6;

[0037] Figure 2 Shows the various values of the aprepitant nanocrystal suspension prepared in Example 24;

[0038] Figure 3Shows the change in particle size of aprepitant nanocrystal suspension after storage at different temperatures;

[0039] Figure 4 Shows the dissolution of the aprepitant nanocrystal suspension and aprepitant raw material drug prepared in Example 24;

[0040] Figure 5 Shows the electron micrographs of the products prepared with different spray dryers;

[0041] Figure 6 Shows the dissolution of the aprepitant nanocrystal dry suspension, aprepitant raw material drug, and physical mixture of excipients prepared in Example 25;

[0042] Figure 7 Shows the flowability of the dry suspension under the influence of glidants;

[0043] Figure 8 Shows the drug release of the dry suspension under the influence of glidants;

[0044] Figure 9 Shows the flowability of the dry suspension under the influence of sodium stearyl fumarate;

[0045] Figure 10 Shows the drug release of the dry suspension under the influence of sodium stearyl fumarate;

[0046] Figure 11 Shows the electron micrograph of the dry suspension;

[0047] Figure 12 Shows the dissolution of the aprepitant nanocrystal dry suspension and aprepitant raw material drug prepared in Example 26;

[0048] Figure 13 Shows the appearance of the orally disintegrating tablets prepared in Comparative Example 1;

[0049] Figure 14 Shows the appearance of the orally disintegrating tablets prepared with different matrix formers. Among them, the tablets in column A from left to right are the appearances of the orally disintegrating tablets prepared in Examples 27, 28, and 29, and the tablets in column B from left to right are the appearances of the orally disintegrating tablets prepared in Examples 30, 31, and 32;

[0050] Figure 15 Shows the appearance of the orally disintegrating tablets prepared with different binders. Among them, the tablets in column A from left to right are the appearances of the orally disintegrating tablets prepared in Examples 33 to 36, and the tablets in column B from left to right are the appearances of the orally disintegrating tablets prepared in Examples 37, 38, and 39;

[0051] Figure 16 Shows the dissolution of the aprepitant orally disintegrating tablets prepared in Example 33;

[0052] Figure 17 The drug-time curve is shown. Detailed implementation manners

[0053] The following detailed implementation manners more specifically illustrate the exemplary embodiments of the present application. In the following description, it should be understood that the following specific implementation manners do not have a restrictive meaning, and other embodiments can be expected to be implemented without departing from the scope and spirit of the present application.

[0054] Unless otherwise specified, in all cases, the numbers used in this specification and the claims to describe dimensions, quantities, and physical properties should be understood to be modified by the term "about". Therefore, unless otherwise stated, the numbers described in this specification and the claims are approximate values, and these approximate values can change according to the characteristics required by those skilled in the art using the methods proposed by the present invention. Numerical ranges expressed using end values include all the numbers within that range and any range within that range.

[0055] In the present application, "nanocrystal technology" is one of the most commonly used means in the strategy of reducing particle size, generally referring to directly nanosizing the active pharmaceutical ingredient without carriers or encapsulating materials, and the drug particles with a particle size less than 1 μm. As a drug delivery system, it can be further processed into various dosage forms such as suspensions, tablets, capsules, and freeze-dried powder injections. Compared with the active pharmaceutical ingredient, the saturated solubility and dissolution rate of nanocrystalline drugs are significantly increased, the biofilm adhesion is increased, the food effect can be reduced or even eliminated, and the bioavailability is improved.

[0056] In the present application, "orally disintegrating tablets" and "freeze-dried orally disintegrating tablets" both belong to orally disintegrating tablets (ODT), which are a new type of rapid-release solid preparation that is convenient for clinical use and has a rapid onset of efficacy. In the Chinese Pharmacopoeia, orally disintegrating tablets are defined as "tablets that can rapidly disintegrate or dissolve in the oral cavity without the need for water". Orally disintegrating films (ODFs), also called orally soluble films, have the same administration method and application range as ODTs and are a commonly used dosage form in clinics. Because oral disintegrating preparations can rapidly disintegrate and disperse in the oral cavity under anhydrous or low-water conditions and enter the digestive tract with the swallowing action, they are particularly suitable for children, the elderly with swallowing difficulties, or patients who do not cooperate with taking medicine.

[0057] In the present application, the "angle of repose" is also called the angle of repose. It is the smallest angle formed with the horizontal surface when the inclined plane makes the object placed on it in a critical state of sliding along the inclined plane. The angle of repose is generally measured by the injection method or the discharge method. The larger the angle of repose, the larger the friction coefficient, and the worse the fluidity of the powder.

[0058] Examples

[0059] Preparation of Aprepitant Nanocrystalline Suspension

[0060] Instruments and Reagents Source Aprepitant Shandong Weizhi Pharmaceutical Co., Ltd. Hydroxypropyl Methylcellulose (HPMC-E5) Shaanxi Tangyao Biotechnology Co., Ltd. Tween 80 Ruichengkang Pharmaceutical Technology (Shaanxi) Co., Ltd. Sucrose Tianjin Damao Chemical Reagent Factory Polyvinylpyrrolidone (PVP K30) Huzhou Shenhua High Polymer Materials Co., Ltd. Hydroxypropyl Cellulose (HPC-SL) Nippon Soda Co., Ltd. Poloxamer 188 (F68) Ruichengkang Pharmaceutical Technology (Shaanxi) Co., Ltd. IKA T18 Digital Display High-Speed Dispersing and Homogenizing Machine IKA Company, Germany ZNCL-BS Intelligent Constant Temperature Digital Display Heating and Temperature Adjusting Magnetic Stirrer Shanghai Hongyi Instrument and Equipment Co., Ltd. DF-101S Thermostatic Heating Magnetic Stirrer with Collector Gongyi Yuhua Instrument Co., Ltd. ZEN3700 Particle Size Analyzer Malvern Instruments Ltd. BT-9300S Laser Particle Size Analyzer Dandong Baite Instrument Co., Ltd. AH-2020 High Pressure Homogenizer Antos Nano Technology (Suzhou) Co., Ltd. Mini-Easy Nano Grinding Equipment Sichuan Ruichituowei Technology Co., Ltd.

[0061] Example 1

[0062] In a 10 mL vial, add APT and 0.5% HPMC-E5, stir and disperse evenly in a water bath at 40 °C, add 4 mL of zirconia beads with a diameter of 0.6 - 0.8 mm and a rotor, grind at a speed of 1100 rpm / min for 4 h to obtain a suspension, measure and record the particle size, particle size distribution (PDI), Zeta potential and sedimentation volume ratio of APT-NS in Table 1 or Figure 1 in it.

[0063] Example 2

[0064] The difference between this example and Example 1 is that Tween-80 is used instead of HPMC-E5, measure and record the particle size, particle size distribution (PDI), Zeta potential and sedimentation volume ratio of APT-NS in Table 1 or Figure 1 in it.

[0065] Example 3

[0066] The difference between this example and Example 1 is that PVP K30 is used instead of HPMC-E5, measure and record the particle size, particle size distribution (PDI), Zeta potential and sedimentation volume ratio of APT-NS in Table 1 or Figure 1 in it.

[0067] Example 4

[0068] The difference between this example and Example 1 is that F 68 is used instead of HPMC-E5, measure and record the particle size, particle size distribution (PDI), Zeta potential and sedimentation volume ratio of APT-NS in Table 1 or Figure 1 in it.

[0069] Example 5

[0070] The difference between this example and Example 1 is that SDS is used instead of HPMC-E5, measure and record the particle size, particle size distribution (PDI), Zeta potential and sedimentation volume ratio of APT-NS in Table 1 or Figure 1 in it.

[0071] Example 6

[0072] The difference between this example and Example 1 is that HPC-SL is used instead of HPMC-E5, measure and record the particle size, particle size distribution (PDI), Zeta potential and sedimentation volume ratio of APT-NS in Table 1 or Figure 1 in it.

[0073] Table 1 Effects of Different Stabilizers on D90, Zeta, and H / H0 of APT-NS

[0074] Stabilizer <![CDATA[D 90 (nm)]]> ζ (mV) <![CDATA[H / H0]]> Example 1 HPMC-E5 958±58.0 -22.5±0.424 0.63±0.03 Example 2 Tween-80 1160±170 -22.5±0.0707 0.28±0.06 Example 3 PVP K30 1320±141 24.6±0.0707 0.15±0.08 Example 4 F 68 1390±205 -9.86±0.339 0.36±0.05 Example 5 SDS 1020±199 -45.5±0.141 0.53±0.06 Example 6 HPC-SL 867±45.8 -21.3±0.276 0.58±0.09

[0075] As shown in Table 1 and Figure 1 as shown, HPMC-E5, HPC-SL, and SDS have smaller particle sizes and PDI under the same conditions compared to other stabilizers, and the stability of the system is better.

[0076] Example 7

[0077] The difference between this example and Example 1 is that the mass ratio of APT to HPMC-E5 is 1:2. The average particle size (PS), PDI, Zeta potential, and sedimentation volume ratio are measured and recorded in Table 2.

[0078] Example 8

[0079] The difference between this example and Example 1 is that the mass ratio of APT to HPMC-E5 is 1:1. The average particle size (PS), PDI, Zeta potential, and sedimentation volume ratio are measured and recorded in Table 2.

[0080] Example 9

[0081] The difference between this example and Example 1 is that the mass ratio of APT to HPMC-E5 is 2:1. The average particle size (PS), PDI, Zeta potential, and sedimentation volume ratio are measured and recorded in Table 2.

[0082] Example 10

[0083] The difference between this example and Example 1 is that the mass ratio of APT to HPMC-E5 is 5:1. The average particle size (PS), PDI, Zeta potential, and sedimentation volume ratio are measured and recorded in Table 2.

[0084] Example 11

[0085] The difference between this example and Example 6 is that the mass ratio of APT to HPC-SL is 2:1. The average particle size (PS), PDI, Zeta potential, and sedimentation volume ratio are measured and recorded in Table 2.

[0086] Example 12

[0087] The difference between this example and Example 6 is that the mass ratio of APT to HPC-SL is 5:1. The average particle size (PS), PDI, Zeta potential, and sedimentation volume ratio are measured and recorded in Table 2.

[0088] Table 2 Effects of HPMC-E5 and HPC-SL on Various Values of APT-NS

[0089]

[0090] The results showed that the APT-NS particle size of Example 12 was smaller and more stable than that of other ratios.

[0091] Example 13

[0092] Prior art shows that the combined use of cellulose derivative stabilizer and SDS can significantly reduce particle aggregation compared to the single application. Therefore, on the basis of Example 6, a certain amount of SDS was added to make APT:SDS = 50:1, and the particle size and distribution of NPT-NS were recorded in Table 3.

[0093] Example 14

[0094] The difference between this example and Example 13 is that APT:SDS = 100:1, and the particle size and distribution of NPT-NS were recorded in Table 3.

[0095] Example 15

[0096] The difference between this example and Example 13 is that APT:SDS = 200:1, and the particle size and distribution of NPT-NS were recorded in Table 3.

[0097] Table 3 Influence of the combined use of HPC-SL and SDS on various values of APT-NS

[0098] APT:SDS PS (nm) PDI <![CDATA[D 90 (nm)]]> ζ (mV) <![CDATA[H / H0]]> Example 13 50:1 503.8±9.76 0.153±0.034 901±44.50 -26.6±0.424 0.72±0.06 Example 14 100:1 320±10.39 0.157±0.044 541±26.92 -19.0±1.414 0.94±0.04 Example 15 200:1 458.6±3.54 0.380±0.006 1390±113.26 -18.9±0.495 0.80±0.07

[0099] As shown in Table 3, the effect of Example 14 was the best. At this time, the optimal feeding ratio of aprepitant to stabilizer in Example 14 was APT:HPC-SL:SDS = 100:20:1.

[0100] The orthogonal experimental design was used to investigate the influence of the media milling process on the particle size and distribution of APT-NS. The main factors were set as follows: milling time, amount of milling beads, content of APT in the coarse suspension, and rotation speed. Among them, the milling time at the first level was 60 min, the amount of milling beads was 100 mL, the APT content was 12.5%, and the rotation speed was 2500 rpm. The milling time at the second level was 90 min, the amount of milling beads was 120 mL, the APT content was 15%, and the rotation speed was 3000 rpm. The milling time at the third level was 120 min, the amount of milling beads was 150 mL, the APT content was 20%, and the rotation speed was 3500 rpm.

[0101] Example 16

[0102] Take 6.25 g of aprepitant raw material solution, 6.25 g of sucrose, 1.25 g of hydroxypropyl cellulose, and 62.5 mg of sodium dodecyl sulfate, dissolve them in pure water, and quantitatively adjust the system to 500 mL and stir to obtain a crude suspension with an aprepitant concentration of 12.5%. Take the crude suspension and place it in a grinding machine containing 100 mL of zirconia beads, and grind it at a speed of 2500 rpm for 60 min to obtain an aprepitant nanocrystal suspension.

[0103] Example 17

[0104] The difference between this example and Example 16 lies in the crude suspension with an aprepitant concentration of 15%. Take the crude suspension and place it in a grinding machine containing 120 mL of zirconia beads, and grind it at a speed of 3000 rpm for 60 min to obtain an aprepitant nanocrystal suspension.

[0105] Example 18

[0106] The difference between this example and Example 16 lies in the crude suspension with an aprepitant concentration of 20%. Take the crude suspension and place it in a grinding machine containing 150 mL of zirconia beads, and grind it at a speed of 3500 rpm for 60 min to obtain an aprepitant nanocrystal suspension.

[0107] Example 19

[0108] The difference between this example and Example 16 lies in the crude suspension with an aprepitant concentration of 15%. Take the crude suspension and place it in a grinding machine containing 100 mL of zirconia beads, and grind it at a speed of 3500 rpm for 90 min to obtain an aprepitant nanocrystal suspension.

[0109] Example 20

[0110] The difference between this example and Example 16 lies in the crude suspension with an aprepitant concentration of 20%. Take the crude suspension and place it in a grinding machine containing 120 mL of zirconia beads, and grind it at a speed of 2500 rpm for 90 min to obtain an aprepitant nanocrystal suspension.

[0111] Example 21

[0112] The difference between this example and Example 16 lies in the crude suspension with an aprepitant concentration of 12.5%. Take the crude suspension and place it in a grinding machine containing 150 mL of zirconia beads, and grind it at a speed of 3000 rpm for 90 min to obtain an aprepitant nanocrystal suspension.

[0113] Example 22

[0114] The difference between this example and Example 16 lies in the crude suspension with aprepitant concentration of 20%. Take the crude suspension and place it in a grinder containing 100 mL of zirconia beads, and grind it at a speed of 3000 rpm for 120 min to obtain aprepitant nanocrystal suspension.

[0115] Example 23

[0116] The difference between this example and Example 16 lies in the crude suspension with aprepitant concentration of 12.5%. Take the crude suspension and place it in a grinder containing 120 mL of zirconia beads, and grind it at a speed of 3500 rpm for 120 min to obtain aprepitant nanocrystal suspension.

[0117] Example 24 (optimal suspension)

[0118] The difference between this example and Example 16 lies in the crude suspension with aprepitant concentration of 15%. Take the crude suspension and place it in a grinder containing 150 mL of zirconia beads, and grind it at a speed of 2500 rpm for 120 min to obtain aprepitant nanocrystal suspension.

[0119] Table 4 Influence of various factors in the orthogonal experiment on the effect

[0120]

[0121] According to the data in Table 5, organize and calculate the scores of various values or factors in Examples 16 to 24, and calculate the relevant scores of k1, k2, and k3 and list them in Table 5, where

[0122] k1—the average value of the comprehensive scores of the first level of the four factors;

[0123] k2—the average value of the comprehensive scores of the second level of the four factors;

[0124] k3—the average value of the comprehensive scores of the second level of the four factors.

[0125] Table 5 Orthogonal experiment data processing

[0126]

[0127]

[0128] Based on Table 5, it is concluded that the range of the grinding time fraction is 31.29, the range of the grinding bead dosage fraction is 39.17, the range of the APT concentration fraction is 33.81, and the range of the rotation speed fraction is 2.32. That is, the optimal grinding time is 120 min, the optimal grinding bead dosage is 150 mL, the optimal APT concentration of the crude suspension is 15%, and the optimal rotation speed is 2500 rpm.

[0129] Experimental Example 1

[0130] As Figure 2 shown, the measured values of the aprepitant nanocrystal suspension prepared in Example 24 are as follows: the sedimentation volume ratio is 0.99 ± 0.01, the pH is 8.32 ± 0.27, the particle size is 199.25 ± 12.88 nm, the PDI is 0.148 ± 0.026, and the Zeta potential is -24.82 ± 1.28 mV.

[0131] Experimental Example 2

[0132] Examine the particle size changes of the aprepitant nanocrystal suspension prepared in Example 24 at 4 °C, room temperature, and 40 °C for 0, 3, 24, and 72 h. The results are as Figure 3 shown.

[0133] The nanocrystal suspension is a highly dispersed thermodynamically unstable system. Due to the non-uniformity of the particle size distribution in the suspension, as the storage time prolongs and the temperature increases, the particles in the system tend to grow, the Ostwald ripening phenomenon intensifies, the nanocrystal aggregation effect enhances, and the particle size increases. Therefore, to ensure its stability, it is considered to perform drying and solidification treatment on the suspension subsequently.

[0134] Experimental Example 3

[0135] Perform a dissolution test on the active pharmaceutical ingredient and the aprepitant nanocrystal suspension prepared in Example 24 of this application in a 2.2% sodium dodecyl sulfate solution. As Figure 4 shown, the dissolution rate of the suspension is significantly improved compared with that of the active pharmaceutical ingredient.

[0136] Preparation of aprepitant nanocrystal dry suspension

[0137] As mentioned in Experimental Example 2 above, the nanocrystal suspension belongs to a thermodynamically unstable system and is prone to aggregation and sedimentation after long-term storage. Therefore, to ensure the storage stability of the active ingredient, spray drying, freeze drying and other methods are now used to solidify the fluid into dry powder.

[0138]

[0139] Screening of spray drying protectants

[0140] Sugars, sugar alcohols, and hydroxyl-rich polymers are commonly used as stabilizers and supporters in spray drying to increase the physical stability of the active ingredient. In this study, six commonly used drying protectants including trehalose, sucrose, lactose, vitamin E polyethylene glycol succinate (TPGS), mannitol, and hydroxypropyl-β-cyclodextrin (H-β-CD) were screened at an inlet air temperature of 120 °C, a pump speed of 10%, and an atomization pressure of 30 - 40 mmHg. The addition amount was tentatively set at 200% of the mass of APT.

[0141] Taking the group without protective agent as the control group (None), the effects of different spray-drying protective agents on the yield, redissolved particle size, and stability after 3 hours of storage of APT-NCS were investigated. The results showed that the particle size of APT-NS before drying was 211.6 nm, and after drying, the particle size increased slightly to 229.8 nm, the PDI increased, and the D90 increased by about 100 nm. In addition, during the drying process, it was observed that the adhesion of the TPGS and mannitol groups to the instrument was relatively serious, and the product collected in the TPGS group was in the form of aggregated particles; the increase in the particle size and PDI of the sucrose group was relatively large, so it was not suitable as a protective agent. Trehalose, lactose, and H-β-CD had good protective effects on the particle size.

[0142] Furthermore, the particle morphologies of the products of trehalose, lactose, and H-β-CD as spray-drying protective agents and the control group without added protective agent were observed by scanning electron microscopy, and the results are as Figure 5 shown.

[0143] The particle sizes of each group were uneven. The particle diameter of the blank group was about 5 - 10 μm, and the surface wrinkles were obvious. After adding the protective agent, some particles gradually became plump, with cracks or holes on the surface, and the particle size of the particles increased slightly to 10 - 30 μm. This was because the surface of the droplets was instantaneously dried in the hot air stream, and excipients such as the protective agent provided a skeleton support. Except for the control group, there was no obvious difference in the SEM morphologies of the three groups of dried powders. However, it was found that after the H-β-CD group was stored at room temperature for 3 days, slight caking occurred in the powder, presumably related to the strong hygroscopicity of this excipient. Therefore, the effects of the addition amounts of trehalose and lactose on the various indexes of the dried products were further investigated.

[0144] Determination of Particle Size and Average Particle Size

[0145] Particle Size refers to the linear dimension of a single particle and is used to describe the size of the particle. It is usually described by the equivalent spherical diameter.

[0146] Average Particle Size is the statistical average of the particle sizes in a particle system, and its calculation method depends on the measurement method and physical meaning. Different defined average particle sizes have different "weights" for the particle population, and the core difference lies in the weighting parameters used in the statistics (such as quantity, volume, surface area, light intensity, etc.). In this study, a Malvern laser particle size analyzer was used to characterize the average particle size (Particle size, PS), D90, and particle size distribution (PDI) of aprepitant nanocrystals. An appropriate amount of aprepitant nanocrystals was diluted until there was a slight opalescence, and 1 mL was taken for measurement. The smaller the PDI, the narrower the particle size distribution of the system and the more stable it is.

[0147] Screening of the Dosage of Spray-Drying Protective Agent

[0148] The effects of different dosages of trehalose or lactose on the appearance, particle size, state, etc. of the spray-dried powder were observed and recorded in Tables 6 and 7.

[0149] Table 6 Effects of Trehalose Dosage on Various Indexes of Aprepitant for Oral Suspension

[0150]

[0151]

[0152] Note: " / " indicates no precipitation.

[0153] Table 7 Effects of Lactose Dosage on Various Indexes of Aprepitant for Oral Suspension

[0154] Dose Appearance Adhesion Yield (%) PS (nm) PDI <![CDATA[D 90 (nm)]]> Precipitation 0 White Powder ++ 74.29 216.48 0.233 471 / 100％ White Powder + 73.96 208.33 0.216 466 / 150％ White Powder + 73.56 203.95 0.214 410 / 200％ White Powder + 74.11 208.12 0.213 440 / 250％ White Powder + 73.33 203.37 0.219 396 / 300％ White Powder + 74.94 203.42 0.212 419 /

[0155] Note: " / " indicates no precipitation.

[0156] From the particle sizes of each group, it can be seen that when 100% trehalose and 100% lactose are added to the suspension to be sprayed, the particle sizes are 211.6 nm and 208.3 nm respectively. Dosages greater than this have a certain protective effect on the particle size and PDI. In addition, compared with the average particle size and PDI, lactose has a greater impact on D 90 , and adding lactose can, to a certain extent, reduce the slight wall sticking problem during the drying process of the suspension and improve the yield. Therefore, 150% lactose was selected as the spray drying protective agent for aprepitant nano-suspension.

[0157] Example 25

[0158] The aprepitant nano-crystal suspension prepared in Example 24 was mixed with the spray drying protective agent lactose. The instrument parameters were set as follows: pump speed 5%, atomization pressure 30 - 40 mmHg, and the mixed aprepitant nano-crystal suspension was spray-dried at 120 °C to obtain aprepitant nano-crystal for oral suspension.

[0159] Experimental Example 4

[0160] The dissolution tests of the aprepitant nano-crystal for oral suspension, aprepitant raw material drug, and physical mixture (PMs) of excipients prepared in Example 25 were carried out in a 2.2% sodium dodecyl sulfate solution. The results are as Figure 6 shown. More than 85% of the dry suspension was dissolved at 5 min. Preparing APT into a nano-dry suspension can significantly improve its dissolution rate. The dissolution of the PMs group was slightly faster than that of the raw material group, indicating that HPC-SL and SDS in the excipients have the ability to increase the dissolution rate of APT.

[0161] Experimental Example 5

[0162] The stability and efficiency of powders in the processes of production, transportation, mixing, filling and storage are all affected by fluidity, which is an important influencing factor in powder technology and is closely related to product quality. Particle size, shape, specific surface area, moisture content, etc. will affect the fluidity of powders. The APT-NCS prepared in this application is fluffy and delicate, with a particle size of about 10 to 20 μm and poor fluidity, so it is considered to add a glidant to the preparation to improve fluidity. Hydrophobic glidants may affect drug release, so the hydrophilic glidants added thereto include colloidal silicon dioxide and sodium stearyl fumarate to examine the effect on powder fluidity.

[0163] 2% and 4% colloidal silicon dioxide were added to the suspension to be sprayed before spray drying to investigate the effect on the dissolution and powder flowability of APT-NCS. 200Pharma was mixed with the suspension to be sprayed before spray drying to investigate its powder fluidity and in vitro release. Figure 7 , Figure 8 As shown in the figure, adding 2% colloidal silicon dioxide before spray drying can slightly improve the fluidity of APT-NCS. However, when the addition amount is increased to 4%, the drug particles are over-wrapped by nano-silicon, the micro-convex structure disappears, the agglomeration between particles increases, and the repose angle increases.

[0164] Experimental Example 6

[0165] Sodium stearyl fumarate (SSF) is a commonly used hydrophilic glidant that can promote particle disaggregation. It is commonly used as a lubricant for tablets and capsules and is non-toxic and harmless. This application attempts to add sodium stearyl fumarate before spray drying to investigate its effect on the fluidity and in vitro dissolution of the dried powder. The results are as follows Figure 9 , Figure 10 As shown, adding 2% SSF (based on the solid content of the sample to be sprayed) before spray drying improved the angle of repose from 61.5° to 39.8° compared with the control group, and had no significant effect on the dissolution behavior.

[0166] Scanning electron microscopy was used to observe the microscopic morphology of spray-dried sodium stearyl fumarate powders with different ratios. Figure 11 As shown, as the amount of sodium stearyl fumarate increased, the roundness of the particles increased, the number of large-diameter particles increased, and the surface of the particles in the 2% SSF group showed obvious protrusions and became rough.

[0167] Example 26 (dry suspension is optimal)

[0168] After the aprepitant nanocrystal suspension prepared in Example 24 was uniformly mixed with the spray-drying protective agent lactose and the glidant, the mixed solution was dried and solidified by a spray dryer to obtain a dry suspension powder. The instrument parameters were set as follows: pump speed 5%, atomization pressure 30 - 40 mmHg, and temperature 120°C. In the dry suspension powder, the mass ratio of aprepitant to the drying protective agent was 1:1.5, the glidant used was sodium stearyl fumarate, and the mass ratio of aprepitant to the glidant in the dry suspension powder was 20:1

[0169] Experimental Example 7

[0170] The dissolution tests of the aprepitant nanocrystal dry suspension and aprepitant raw material drug prepared in Example 26 were carried out in a 2.2% sodium dodecyl sulfate solution. The results are as Figure 12 shown. The dry suspension had dissolved 95% at 15 min, while the raw material drug had a dissolution of less than 85%. Preparing APT into a nanocrystalline dry suspension can significantly improve its dissolution rate.

[0171] Preparation of aprepitant nanocrystal freeze-dried orally disintegrating tablets in Example 27

[0172] The pump speed was set at 5%, the drying gas flow rate was 100%, the inlet temperature was 120°C, and the atomization pressure was 30 - 40 mmHg. The aprepitant nanocrystal suspension prepared in Example 24 was directly spray-dried. The obtained product was placed in a beaker and mixed with 141 mg of mannitol, and purified water was added to make the volume up to 15 mL to obtain a mixed solution. After the mixed solution was degassed under vacuum, 500 μL was measured and injected into the blister. The freeze-drying program was set as follows: pre-freezing at -40°C for 2 h, evacuating to 350 mTorr and maintaining for 30 min, raising the temperature to -20°C in 2 h and maintaining for 3 h, raising the temperature to -10°C in 1 h and maintaining for 3 h, raising the temperature to 0°C in 2 h and maintaining for 3 h, raising the temperature to 20°C in 2 h and maintaining for 2 h. After completion, aprepitant freeze-dried orally disintegrating tablets were obtained, and the specification of the orally disintegrating tablets was 20 mg / tablet.

[0173] Example 28

[0174] The difference between this example and Example 27 is that mannitol was replaced by maltodextrin.

[0175] Example 29

[0176] The difference between this example and Example 27 is that mannitol was replaced by glycine.

[0177] Example 30

[0178] The difference between this example and Example 27 is that mannitol was replaced by lactose.

[0179] Example 31

[0180] The difference between this example and Example 27 is that mannitol is replaced by trehalose.

[0181] Embodiment 32

[0182] The difference between this example and Example 27 is that mannitol is replaced by erythritol.

[0183] Experimental Example 8

[0184] The appearance and disintegration time of the aprepitant nanocrystalline orally disintegrating tablets prepared in Examples 27 to 32 were observed, and the data were recorded in Table 8.

[0185] Table 8 Effect of skeleton agent on appearance, disintegration time and average particle size of orally disintegrating tablets

[0186]

[0187] Combined with Table 8, the effect of the skeleton agent on the particle size of nanocrystals is within an acceptable range, and the disintegration time is <4s. Figure 14 The orodisintegrating tablets in each group had uniform color, but the maltodextrin group had cracks; the glycine group had pitting on the surface and slight wall adhesion; the edges of the tablets in the lactose and trehalose groups were severely broken, while the erythritol group was relatively full; the mannitol group had the fullest tablet shape, uniform color, a slightly convex center, and a qualified appearance. Therefore, mannitol is the best choice as the skeleton agent for orodisintegrating tablets.

[0188] Embodiment 33

[0189] The difference between this example and Example 27 is that 921 mg of pullulan is further added to the beaker.

[0190] Embodiment 34

[0191] The difference between this example and Example 33 is that pullulan is replaced by gelatin.

[0192] Embodiment 35

[0193] The difference between this example and Example 33 is that pullulan is replaced by dextran.

[0194] Embodiment 36

[0195] The difference between this example and Example 33 is that pullulan is replaced by polyvinylpyrrolidone VA64.

[0196] Embodiment 37

[0197] The difference between this example and Example 33 is that pullulan is replaced with yellow gelatin.

[0198] Embodiment 38

[0199] The difference between this example and Example 33 is that pullulan is replaced by arabic gum.

[0200] Example 39

[0201] The difference between this example and Example 33 is that pullulan is replaced by hypromellose.

[0202] Experimental Example 9

[0203] The orally disintegrating tablets of aprepitant nanocrystals prepared in Examples 33 to 39 were observed for appearance and disintegration time, and the data were recorded in Table 9.

[0204] Table 9 Effects of binders on the appearance, disintegration time and average particle size of orally disintegrating tablets

[0205]

[0206] Combined with Table 9, the effect of the binder on the particle size of the nanocrystals is within an acceptable range. Except that the finished product prepared with yellow gelatin and arabic gum is in a blocky form and does not disintegrate, the disintegration time of each group is < 4 s. As Figure 15 shown, the orally disintegrating tablets of the xanthan gum and PVP groups are prone to tablet detachment and have rough edges; the gelatin group and the HPMC-E5 group have cracked edges; the dextran group and the arabic gum group have tablet shrinkage; in contrast, pullulan is more suitable as a binder for freeze-dried orally disintegrating tablets.

[0207] Experimental Example 10

[0208] The dissolution tests of the aprepitant nanocrystal dry suspension prepared in Example 26 and the aprepitant orally disintegrating tablets prepared in Example 33 were carried out in a 2.2% sodium dodecyl sulfate solution. The results are as Figure 16 shown. The dissolution of the orally disintegrating tablets can reach more than 95% in 5 min, which is faster than that of the dry suspension. This is because of the special loose and porous matrix structure inside the freeze-dried orally disintegrating tablets, which can make the nanocrystals quickly disintegrate when encountering water and improve the dissolution rate.

[0209] Experimental Example 11 Bioavailability Experiment

[0210] Five male SD rats were selected as the test animals, with an average body weight of 200 ± 20 g. After fasting for 12 hours, they were administered by gavage, and blood was taken at certain time points. The aprepitant dry suspension prepared in Example 26 of this application, the freeze-dried orally disintegrating tablets prepared in Example 33 and the content of the commercially available aprepitant capsules were used as the administration groups, and the aprepitant raw material was used as the control group. Referring to the bioavailability test method, the relative bioavailability was calculated with AUC. The administration dose was based on the drug contained in the preparation, all being 30 mg / kg.

[0211] The best compartment model was determined to be a two-compartment model by fitting with DAS 2.0 software, and the weight value was W = 1 / cc. The AUC0-48h of aprepitant nanocrystalline dry suspension, freeze-dried orally disintegrating tablets and the content of the commercial capsule were 28.51 ± 1.62 μg·h / mL, 28.48 ± 2.19 μg·h / mL and 27.62 ± 2.83 μg·h / mL, respectively.

[0212] The pharmacokinetic parameters are shown in Table 1. The results show that the relative bioavailability of the aprepitant nanocrystalline dry suspension and freeze-dried orally disintegrating tablets prepared in this application were 103.22% and 103.11%, respectively. The concentration-time curve is shown in Figure 17 , and it can be seen from the figure that the absorption of the dry suspension and freeze-dried orally disintegrating tablets are both better than that of aprepitant raw material; there is no significant difference in the absorption of the dry suspension and freeze-dried orally disintegrating tablets compared with the marketed preparation.

[0213] The above are only the preferred embodiments of the present application, and are not intended to limit the present application in other forms. Any person skilled in the art may use the technical content disclosed above to make changes or modifications into equivalent embodiments with equivalent changes. However, any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present application without departing from the technical solution content of the present application still belong to the protection scope of the technical solution of the present application.

Claims

1. A preparation method of aprepitant nanocrystal composition, the steps of which include: Mix aprepitant with a sucrose solution, add a stabilizer to obtain a solution to be ground, and grind the solution to be ground through a wet grinding process to obtain the aprepitant nanocrystal composition.

2. The method according to claim 1, wherein In the solution to be ground, the concentration of aprepitant is 2 mg / mL to 50 mg / mL.

3. The method according to claim 1, wherein, The mass ratio of the aprepitant to the stabilizer is 1:4 to 10:

1.

4. The method according to claim 1, wherein, The mass ratio of the aprepitant to sucrose is 1:

1.

5. The method according to claim 1, wherein, The average particle size of the aprepitant is 200 - 500 nm.

6. The method according to claim 1, wherein The stabilizer is selected from one or more of cellulose derivatives, ionic surfactants, non-ionic surfactants, and crystallization inhibitors.

7. The method according to claim 6, wherein, The stabilizer is selected from one or more of HPMC-E5, Tween-80, PVPK30, F68, SDS, and HPC-SL.

8. The method according to claim 6, wherein, The stabilizer is HPMC-E5 and SDS or HPC-SL and SDS.

9. The method according to claim 1, wherein When performing wet grinding, the grinding time is 10 - 600 min.

10. The method according to claim 1, wherein, When performing wet grinding, the dosage of grinding beads is 10 mL - 600 mL.

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