Aprepitant nanosuspension pharmaceutical composition and preparation method thereof

Abstract

The invention discloses an aprepitant nano suspension pharmaceutical composition and a preparation method thereof. The aprepitant nano suspension pharmaceutical composition comprises aprepitant, a space stabilizer, an electrostatic stabilizer and water, the steric stabilizer is selected from one or more of poloxamer F188, poloxamer F407 and polyvinylpyrrolidone K30, and the steric stabilizer is selected from one or more of poloxamer F188, poloxamer F407 and polyvinylpyrrolidone K30; the electrostatic stabilizer is lauryl sodium sulfate or PCM. By selecting a specific stabilizer and a preparation method, subcutaneous injection of aprepitant is realized, the stability of the medicine is remarkably improved, and the medicine loading capacity is increased. In addition, according to the method, the preparation process is simplified, the formula screening time is shortened, and therefore the overall preparation time is shortened.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an aprepitant nanosuspension pharmaceutical composition and a preparation method thereof. Background Art

[0002] Aprepitant is an NK-1 receptor antagonist developed by Merck & Co., Inc. in the United States. The oral capsule Emend was launched in 2003 for the prevention of chemotherapy-induced vomiting. It is often used in combination with other drugs for chemotherapy-related nausea and vomiting in specific patients. Aprepitant is a selective NK-1 receptor antagonist with low affinity for other antiemetic drug targets. Preclinical applications have shown that it can inhibit vomiting caused by chemotherapy drugs and enhance the antiemetic activity of other drugs.

[0003] Its raw material has poor solubility and low bioavailability. The injection has clinical advantages, but the poor solubility of aprepitant limits its development. The prodrug fosaprepitant dimeglumine lyophilized powder injection developed by Merck has many defects, such as poor prodrug stability, harsh storage conditions, high cost, pain at the injection site, and potential safety hazards. The aprepitant fat emulsion injection developed by HERON also has many problems, such as many excipients that can easily cause hypersensitivity reactions, sodium oleate is irritating, low-temperature storage is required, and the large volume of the liquid medicine is inconvenient to use. Therefore, it is still necessary to develop an injection that is safe, small in size, easy to use, and can be stored and transported at room temperature. Summary of the invention

[0004] The purpose of the present invention is to provide an aprepitant nanosuspension pharmaceutical composition and a preparation method thereof in order to solve the above problems. The nanosuspension of the present invention is a type of stabilizer that prepares the drug into nanoparticles, thereby forming a "pure" drug particle colloidal dispersion system. As a new type of sustained-release preparation for injection, the nanosuspension can significantly improve the bioavailability of poorly soluble active ingredients of drugs and improve their solubility. By controlling the drug particle size, the release rate of the drug can also be adjusted to achieve long-term sustained release. In addition, since the nanosuspension does not require a carrier material to "encapsulate" the drug, a higher drug loading can be achieved. The reduction of excipients in the formula also helps to alleviate pain at the injection site.

[0005] The present invention achieves the above-mentioned purpose through the following technical solutions:

[0006] An aprepitant nanosuspension pharmaceutical composition, comprising aprepitant, a steric stabilizer, an electrostatic stabilizer and water;

[0007] The steric stabilizer is selected from one or more of poloxamer F188, poloxamer F407, and polyvinyl pyrrolidone K30; the electrostatic stabilizer is sodium dodecyl sulfate or PCM; the PCM is a eutectic mixture of stearic acid and lauric acid, and the preparation method is: lauric acid and stearic acid with a mass ratio of 4:1 are melt-mixed uniformly at 60° C., and cooled at room temperature to obtain PCM.

[0008] A further solution is that according to some embodiments of the present invention, the mass ratio of aprepitant to the steric stabilizer is 1:(0.07-0.21), preferably 1:(0.11-0.18), preferably 1:(0.13-0.15), and most preferably 1:0.145.

[0009] The mass ratio of the aprepitant to the electrostatic stabilizer is 1:(0.07-0.21), preferably 1:(0.11-0.18), preferably 1:(0.13-0.15), and most preferably 1:0.145.

[0010] The mass ratio of the steric stabilizer to the electrostatic stabilizer is 1:(0.5-2), preferably 1:(0.6-1.5).

[0011] The ratio of aprepitant to water is 2.1:300.

[0012] In a further embodiment, the concentration of aprepitant is 7 mg / mL, the concentration of the steric stabilizer is (0.5-1.5) mg / mL, and the concentration of the electrostatic stabilizer is (0.5-1.5) mg / mL.

[0013] In a further embodiment, the aprepitant is a nanocrystal, and the D50 of the aprepitant nanocrystal is less than 150 nm, preferably less than 100 nm, and more preferably less than 80 nm. The small particle size of the aprepitant nanosuspension is more conducive to product stability and to improving its dissolution rate.

[0014] In a further embodiment, the D50 absolute value of the potential of the aprepitant nanosuspension is (20-50) mV, preferably (25-40), and more preferably (25-35) mV. The small particle size of the aprepitant nanosuspension is more conducive to product stability and to improving its dissolution rate.

[0015] Another aspect of the present invention also provides a method for preparing an aprepitant nanosuspension pharmaceutical composition, comprising the following steps:

[0016] Step (1), mixing a steric stabilizer, an electrostatic stabilizer and water to obtain a mixed solution;

[0017] Step (2), adding aprepitant to the mixed solution of step (1) to obtain a primary suspension;

[0018] Step (3) The initial suspension described in step (2) is homogenized to obtain a pharmaceutical composition containing aprepitant.

[0019] A further solution is that the pressure during homogenization in step (3) is 400-1200 bar, and the homogenization time is 1-4 min.

[0020] In another aspect, the present invention provides an aprepitant suspension subcutaneous injection, comprising the above-mentioned pharmaceutical composition or the pharmaceutical composition prepared by the above-mentioned method.

[0021] In another aspect, the present invention also provides an aprepitant lyophilized powder injection, comprising:

[0022] (1) the above-mentioned pharmaceutical composition or the pharmaceutical composition prepared by the above-mentioned method;

[0023] (2) lyoprotectants;

[0024] The lyophilization protective agent is selected from one or more of sucrose, lactose, mannitol and glucose.

[0025] In a further embodiment, the lyophilized powder injection is prepared by adding a lyophilization protective agent to the above-mentioned pharmaceutical composition of the present invention and subjecting the mixture to freeze-drying;

[0026] The weight ratio of the aprepitant to the lyoprotectant is 1:(0-7.14), preferably 1:(1.42-4.28), and more preferably 1:(1.42-2.86).

[0027] The weight ratio of aprepitant to mannitol is 1:(0-3.57), preferably 1:(0.71-2.14), and more preferably 1:(0.71-1.43).

[0028] The weight ratio of aprepitant to glucose is 1:(0-3.57), preferably 1:(0.71-2.14), and more preferably 1:(0.71-1.43).

[0029] The last aspect of the present invention also provides the use of the above-mentioned pharmaceutical composition or the pharmaceutical composition prepared by the above-mentioned method or the above-mentioned lyophilized powder injection in the preparation of a drug for preventing and / or treating chemotherapy-induced nausea and vomiting, and / or postoperative nausea and vomiting.

[0030] The beneficial effects of the present invention are:

[0031] The aprepitant nanosuspension pharmaceutical composition and preparation method thereof of the present invention realizes subcutaneous injection of aprepitant by selecting a specific stabilizer and preparation method, significantly improves the stability of the drug, and increases the drug loading. In addition, the method simplifies the preparation process, shortens the time for formula screening, and thus reduces the overall preparation time.

[0032] The nanosuspension prepared by the present invention can be stored and transported at room temperature, which further reduces the cost of production, storage and transportation because the need for special temperature control is reduced. Compared with the existing aprepitant injection on the market, the preparation of the present invention has obvious advantages in reducing the amount of excipients, which not only reduces the cost, but also reduces the irritation of the injection site, reduces the risk of hypersensitivity, and improves the safety of patients. In addition, due to the small volume of the drug, it is more convenient to use, and the preparation of the present invention has a longer duration, which reduces the frequency of administration, thereby improving the compliance of patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0034] Figure 1 This is a scanning electron microscope image of the present invention;

[0035] Among them: a. API, b. physical mixture, c. nanosuspension;

[0036] Figure 2 This is the differential scanning calorimetry diagram of the present invention.

[0037] Figure 3 This is the FTIR result diagram of the present invention.

[0038] Figure 4 This is the release test result of the present invention.

[0039] Figure 5 This is a He staining section diagram of the present invention.

[0040] Figure 6 This is the content determination result of substance P of the present invention. DETAILED DESCRIPTION

[0041] To make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be described in detail below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other implementation methods obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.

[0042] Example 1

[0043] Aprepitant nanocrystal suspension injection was prepared using polyvinyl pyrrolidone K30 as a steric stabilizer and sodium lauryl sulfate as an electrostatic stabilizer. The specific formulation composition and dosage are as follows:

[0044] Prescription 1 (100 sticks)

[0045] Aprepitant 2.1g

[0046] Polyvinylpyrrolidone K30 0.3g

[0047] Sodium dodecyl sulfate 0.3g

[0048] Add 300ml water for injection

[0049] Prescription 2 (100 sticks)

[0050] Aprepitant 2.1g

[0051] Polyvinylpyrrolidone K30 0.3g

[0052] PCM 0.3g

[0053] Add 300ml water for injection

[0054] Prescription 1 Preparation process:

[0055] (1) Preparation of initial grinding solution: Dissolve 0.3 g polyvinyl pyrrolidone K30 and 0.3 g sodium lauryl sulfate in water for injection and stir until completely dissolved. Add 2.1 g aprepitant API and disperse evenly to prepare the initial suspension.

[0056] (2) Pour the above initial suspension into a high-pressure homogenizer and start homogenization at a homogenization pressure of 866 bar.

[0057] (3) After homogenizing for 3 minutes, the average particle size of the suspension was tested to be less than 100 nm, thereby obtaining an aprepitant nanosuspension.

[0058] (4) The nanosuspension was further diluted with water for injection to about 7 mg / mL to prepare aprepitant nanosuspension injection.

[0059] Preparation process of prescription 2: same as prescription 1

[0060] Example 2

[0061] Aprepitant nanocrystal suspension injection was prepared using polyvinyl pyrrolidone K30 as a steric stabilizer and sodium lauryl sulfate as an electrostatic stabilizer. The specific formulation composition and dosage are as follows:

[0062] Prescription 1 (100 sticks)

[0063] Aprepitant 2.1g

[0064] Polyvinylpyrrolidone K30 0.2g

[0065] Sodium dodecyl sulfate 0.4g

[0066] Add 300ml water for injection

[0067] Preparation process: same as recipe 1 in Example 1.

[0068] Prescription 2 (100 sticks)

[0069] Aprepitant 2.1g

[0070] Polyvinylpyrrolidone K30 0.2g

[0071] PCM 0.4g

[0072] Add 300ml water for injection

[0073] Preparation process: same as recipe 1 in Example 1.

[0074] Example 3

[0075] Aprepitant nanocrystal suspension injection was prepared using polyvinyl pyrrolidone K30 as a steric stabilizer and sodium dodecyl sulfate as an electrostatic stabilizer. The specific formulation composition and dosage are as follows:

[0076] Prescription 1 (100 sticks)

[0077] Aprepitant 2.1g

[0078] Polyvinylpyrrolidone K30 0.24g

[0079] Sodium dodecyl sulfate 0.36g

[0080] Add 300ml water for injection

[0081] Preparation process: same as recipe 1 in Example 1.

[0082] Prescription 2 (100 sticks)

[0083] Aprepitant 2.1g

[0084] Polyvinylpyrrolidone K30 0.24g

[0085] PCM 0.36g

[0086] Add 300ml water for injection

[0087] Preparation process: same as recipe 1 in Example 1.

[0088] Example 4

[0089] Aprepitant nanosuspension stability test. Generally speaking, for a three-dimensionally stable nanosuspension, the absolute value of the zeta potential of the physical stabilization system should be at least 20 mV, and for an electrostatically stable nanosuspension, it should be 30 mV. The present application uses a three-dimensional stabilizer and an electrostatic stabilizer, combined with a high-pressure homogenization method, so that the potential of the preparation has reached the range required for the stability of the suspension.

[0090] Taking the first prescription of Example 1 as an example, the effect of homogenization time on potential was tested:

[0091] Table 1 Homogenization time test

[0092]

[0093] It can be seen from the above table that with the increase of homogenization time, the potential shows a trend of first decreasing and then increasing. The reason for the decrease is that with the increase of time, the materials in the system are in more uniform contact, resulting in a decrease in free charge in the system, thereby reducing the potential; the reason for the subsequent increase is that with the increase of time, the number of homogenizations gradually increases, the system temperature rises sharply, the nanoparticles are prone to fusion and aggregation, and the particle size distribution is uneven, resulting in an increase in the potential.

[0094] Table 2 Homogenization pressure test

[0095]

[0096]

[0097] It can be seen from the above table that with the increase of homogenization pressure, the potential tends to decrease. The reason is that with the increase of pressure, the particle size of the particles continues to decrease, and the contact area with the charge continues to increase, resulting in a decrease in the free charge in the system, thereby causing the potential to decrease.

[0098] The potential of the formulation 2 of Example 1 is similar to that of the formulation 1, and the potential of the preparation has reached the range required for the stability of the suspension.

[0099] Example 5

[0100] The aprepitant nanosuspension sample was prepared by the method of Example 1 and divided into two groups, each with 3 parts, which were stored at 4°C and 25°C, respectively. Samples were taken at 0, 1, 2, 3, 5, 7, 14, 21, and 30 days, and the particle size, PDI, and potential of the samples were measured. The physical stability was evaluated based on the changes. The results are as follows.

[0101] Table 3 Nanosuspension stability test results at 4°C

[0102]

[0103] Table 4 Nanosuspension stability test results at 25°C

[0104]

[0105] It can be seen from the table that under the conditions of 4°C and 25°C, the changes in particle size, PDI, potential and content of the nanosuspension are small, indicating that the nanosuspension has good stability.

[0106] As can be seen from Examples 4 and 5, the present application selects a specific stabilizer and preparation method, and obtains a stable aprepitant nanocrystal suspension injection by controlling the potential in the suspension; compared with the prior art (CN 117243900 A), no deflocculating agent is required, and the obtained nanosuspension has a smaller particle size (the particle size in the prior art is about 100 nm, and that in the present application is about 65 nm), and the stability is greatly extended (the nanosuspension prepared by the prior art only gives 10 days of stability data, and it is unknown whether it is stable thereafter, and the suspension of the present application gives 30 days of stability, and the stability is good).

[0107] The particle size of the second prescription in Example 1 is about 20% larger than that of the first prescription. At 4°C, the changes in the particle size, PDI, potential and content of the nanosuspension are small. Based on comprehensive considerations, the first prescription is selected as the final product.

[0108] Example 6: Preparation of lyophilized powder

[0109] In order to further improve the physical stability of the aprepitant nanosuspension, freeze-drying technology was used to prepare it into a lyophilized preparation for easy storage, transportation and use.

[0110] Freeze-drying was carried out using mannitol and glucose (1:1) as freeze-drying protective agents. The test results after reconstitution are shown in the figure below.

[0111] Table 5 Results of different dosages of freeze-drying protective agent

[0112]

[0113] The test results show that the particle size and PDI of the freeze-dried preparation prepared in this example have the smallest changes after reconstitution, and the appearance of the freeze-dried preparation is a loose, porous, uniform and fine white powder, which can be stably stored for a long time and has good redispersibility.

[0114] Example 7: Characterization of Suspension

[0115] 7.1 Morphological observation

[0116] The surface morphology of the nanosuspension was observed using a scanning electron microscope (SEM). The aprepitant bulk drug, physical mixture, and nanosuspension were diluted with purified water and dropped onto a glass plate, dried at room temperature, sprayed with gold in a vacuum environment, and observed and photographed at an accelerating voltage of 10 kV. The results are shown in Figure 1 ;

[0117] Experiments showed that the aprepitant raw material was in irregular plate shape, PVP-K30 was in spherical shape, and SDS was in regular block shape. The physical mixture of the three was a mixture of spheres, blocks and plates. The aprepitant nanosuspension lyophilized powder was in plate shape, similar to the raw material, indicating that the crystal form of aprepitant did not change during the preparation and lyophilization process.

[0118] 7.2 Differential Scanning Calorimetry (DSC) Analysis

[0119] DSC can detect potential changes in the physical state of aprepitant during the formulation process. Differential scanning calorimetry is used to test aprepitant API, nanosuspension, and physical mixture. Weigh 5-10 mg of the sample into an alumina pan, seal it, use a blank alumina pan as a reference, and heat the sample at a heating rate of 10°C / min in the temperature range of 25-350°C under nitrogen protection. Record and analyze the thermogram to determine the physical state of the sample.

[0120] Results Figure 2 Aprepitant has a sharp endothermic peak at 251°C, while the absorption peaks of aprepitant nanosuspension and physical mixture shifted to the left, indicating that the excipients will affect the melting point of aprepitant and the crystal form may have changed. Therefore, FTIR was performed for further verification.

[0121] 7.3 Fourier Transform Infrared (FTIR) Spectroscopy

[0122] To test whether the drug and excipients interact, appropriate amounts of aprepitant, physical mixture, and nanosuspension freeze-dried powder were mixed with potassium bromide powder and pressed into tablets. –1 The wave number range was scanned and FTIR analysis was performed.

[0123] Results Figure 3As can be seen from the figure, the infrared characteristic peak of the nanosuspension is similar to that of the aprepitant raw material and has not shifted, indicating that the crystal form of aprepitant has not changed during the preparation process.

[0124] 7.4. Determination of drug content

[0125] To test the content of the drug in the lyophilized preparation, 5 mg of aprepitant lyophilized powder was accurately weighed into a sample bottle, and 10 mL of ultrapure water was added, and ultrasonicated until completely reconstituted. The reconstituted suspension was diluted 10 times with methanol, centrifuged at 12000 rpm for 10 min, and the supernatant was taken and analyzed using the HPLC method. Three samples were prepared for each group, and the average content was calculated.

[0126] Table 6 Drug loading of nanosuspension and lyophilized powder

[0127]

[0128] 7.5 Saturation Solubility Test

[0129] Take an excess of aprepitant, physical mixture, and nanosuspension freeze-dried powder in a sample bottle, add an appropriate amount of purified water, and sonicate until the solution reaches saturation. Fix it on a constant temperature oscillator and oscillate for 3 days. After the solution is taken out, centrifuge it, take the supernatant, and determine the content by HPLC. Prepare three samples for each group.

[0130] Table 7 Determination of saturated solubility

[0131]

[0132] As shown in Table 7, the saturated solubility of the aprepitant raw material was 1.36±0.15 μg / mL, the saturated solubility of the physical mixture was 4.83±0.21 μg / mL, and the saturated solubility of the nanosuspension lyophilized powder was 17.12±2.68 μg / mL, indicating that the solubility of aprepitant was increased after the preparation was made.

[0133] 7.6 Release test

[0134] The release application of aprepitant nanosuspension adopts the rotating dialysis cell model with some modifications. The rotation speed is set to 100rpm and the temperature is 37±0.5℃. 0.5% SDS phosphate buffer solution (PH=7.4) is used as the dissolution medium, and the volume of the medium is 600mL. Take aprepitant nanosuspension lyophilized powder and aprepitant raw material (about 7mg) in an activated dialysis bag (molecular cutoff is 30000), tie it tightly and fix it on the stirring paddle, and put the stirring paddle into the dissolution medium. Take 1mL of samples at 0.17, 0.33, 0.50, 0.75, 1.00, 2.00, 4.00, 6.00, 8.00, 12.00, 24.00, 36.00, 48.00, 60.00, and 72.00h respectively (the same volume of dissolution medium is supplemented at the same time of sampling). After the dissolution is completed, the sample is centrifuged and the content of the supernatant after centrifugation is determined by HPLC.

[0135] Table 8 Cumulative release percentage

[0136]

[0137]

[0138] At 72 h, the cumulative release of aprepitant API and nanosuspension was 19.61±0.45% and 85.12±2.33%, respectively. Compared with aprepitant, the drug release of nanosuspension increased by 4.34 times, indicating that the nanoformulation had better release characteristics.

[0139] Example 8: Irritation Test

[0140] In order to explore whether aprepitant nanosuspension is irritating to the skin of the body or may cause more serious safety hazards, and to avoid other safety issues caused by medication, a preliminary safety test was conducted on mice. The mice were divided into 2 groups (6 mice in each group), (a) blank group (subcutaneous injection of normal saline), (b) nanosuspension group. 3 days after subcutaneous injection, the skin and subcutaneous tissue at the injection site were taken for pathological tissue sections to observe the skin morphology.

[0141] He stained sections Figure 5 The morphology of pathological tissue sections was observed by He staining smears. The morphological characteristics of group b were similar to those of group a, and the stratum corneum of the two groups was relatively well preserved, the epidermal cells were relatively complete, the thickness was uniform, the layers were clear, the continuity was good, the morphology was normal, and no obvious abnormalities were found in the tissues, indicating that subcutaneous injection of the nanosuspension is relatively safe.

[0142] Example 9: Pharmacodynamics Experiment

[0143] 9.1 Animal Modeling and Drug Administration

[0144] Commonly used model animals such as rats, mice, guinea pigs and rabbits lack vomiting reflexes, so this application chooses to apply for rat vomiting behavior by observing alternative symptoms (such as simulated coughing, reflex taste aversion and pica, etc.). Many applications have proved that rats' ingestion of kaolin can effectively represent their nausea and vomiting reactions. When kaolin blocks were placed on the first day, the rats did not know whether kaolin was food, and based on their biological characteristics, they showed the behavior of ingesting kaolin; on the second day, the rats gradually adapted to the presence of kaolin, and realized that it was not food, and the food intake began to decrease; by the third day, the rats almost stopped ingesting kaolin, indicating that they had ignored the presence of kaolin, and the model establishment could be started at this time.

[0145] SD rats (weight 200-220g) were used for the pharmacodynamic application of chemotherapy emesis. All rats were housed in single cages at 25±2℃ and 45% relative humidity. After one week of adaptive feeding, kaolin and ordinary feed were fed for 3 days to adapt to the presence of kaolin. The rats were divided into 4 groups (6 rats in each group): (a) blank group (healthy animals), (b) model group (only modeling without drug administration), (c) positive control group (Aprepitant raw material group), (d) Aprepitant nanosuspension group.

[0146] 1 hour before the experiment (8:00am), each group of rats was given preventive medication. Rats in groups a and b were subcutaneously injected with equal amounts of saline. Rats in group c were gavaged for 3 consecutive days (12.6 mg / kg on the first day, 8.4 mg / kg on the second day, and 8.4 mg / kg on the third day). Rats in group d were subcutaneously injected with medication (29.4 mg / kg). 1 hour after medication (9:00am), the blank control group was intraperitoneally injected with 6 mg / kg saline, and the other groups were intraperitoneally injected with 6 mg / kg cisplatin solution. Rats in each group were fed with normal drinking water.

[0147] 9.2 General evaluation indicators

[0148] At 8:00am on the first day of modeling, specific indicators of rats were recorded, including kaolin intake, food intake, water intake, body weight, mental state, feces, and death. If there was any kaolin and feed debris, they were collected and weighed together. Recording was continued every 12 hours until the 3rd day after modeling.

[0149] Table 9 Test of kaolin intake (g)

[0150]

[0151] Table 10 Test of feed intake (g)

[0152]

[0153]

[0154] Table 11 Test of water intake (mL)

[0155]

[0156] It can be seen from Tables 9 to 11 that subcutaneous injection of nanosuspension can intervene in the pica behavior of rats after modeling, improve the behavior of weight loss in rats, and improve the problem of reduced feed intake and water intake after modeling. Compared with oral administration of raw materials, subcutaneous injection of nanosuspension has better efficacy and lasts longer.

[0157] 9.3 Determination of substance P content

[0158] Substance P is the key to causing nausea and vomiting and inhibiting gastric emptying. It can penetrate the blood-brain barrier and enter the brain tissue to participate in the pathological process of vomiting. Aprepitant, as an NK-1 receptor antagonist, can achieve an antiemetic effect by binding to NK-1 receptors to block substance P. Therefore, the content of substance P is one of the indicators to measure the therapeutic effect of chemotherapy vomiting drugs.

[0159] Blood was collected from the rats' tail vein at 24h and 72h, respectively. The plasma was centrifuged at 3000rpm for 10min at 4℃, and the serum was collected and stored in a -80℃ ultra-low temperature refrigerator. The serum substance P content was determined using the Elisa kit method. The operation was performed according to the kit instructions.

[0160] Table 12 Test of P substance content (ng / mL)

[0161]

[0162] Results Figure 6 Before modeling, there was no significant difference in the content of substance P in each group (P>0.05). After modeling, the content of substance P in rats in group b was significantly increased compared with that in the blank group (P<0.05), indicating that cisplatin modeling can cause an increase in the content of substance P in rats. As can be seen from the above figure, after subcutaneous injection, the content of substance P in rats in group d was significantly reduced and lasted for 3 days. The therapeutic effect and duration were stronger than those of the raw material drug.

[0163] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can easily think of changes or replacements within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims. It should also be noted that the various specific technical features described in the above-mentioned specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further explain various possible combinations. In addition, the various different embodiments of the present invention can also be combined arbitrarily, as long as they do not violate the concept of the present invention, they should also be regarded as the contents disclosed by the present invention.

Claims

1. An aprepitant nanosuspension pharmaceutical composition, characterized in that: including aprepitant, a steric stabilizer, an electrostatic stabilizer, and water; The steric stabilizer is selected from one or more of poloxamer F188, poloxamer F407, and polyvinyl pyrrolidone K30; the electrostatic stabilizer is sodium dodecyl sulfate or PCM.

2. The aprepitant nanosuspension pharmaceutical composition according to claim 1, characterized in that: The mass ratio of the aprepitant to the steric stabilizer is 1:(0.07-0.21); or 1:(0.11-0.18); or 1:(0.13-0.15); or 1:0.145; The mass ratio of the aprepitant to the electrostatic stabilizer is 1:(0.07-0.21); or 1:(0.11-0.18); or 1:(0.13-0.15); or 1:0.145; the mass ratio of the steric stabilizer to the electrostatic stabilizer is 1:(0.5-2); or 1:(0.6-1.5); The ratio of aprepitant to water is 2.1:

300.

3. The aprepitant nanosuspension pharmaceutical composition according to claim 1, wherein: The concentration of aprepitant is 7 mg / mL, the concentration of the steric stabilizer is (0.5-1.5) mg / mL, and the concentration of the electrostatic stabilizer is (0.5-1.5) mg / mL; The aprepitant is a nanocrystal, and the D50 of the aprepitant nanocrystal is less than 150 nm, or less than 100 nm, or less than 80 nm; The D50 absolute value of the potential of the aprepitant nanosuspension is (20-50) mV, or (25-40), or (25-35) mV.

4. A method for preparing an aprepitant nanosuspension pharmaceutical composition according to any one of claims 1 to 3, characterized in that: The following steps are involved: Step (1), mixing a steric stabilizer, an electrostatic stabilizer and water to obtain a mixed solution; Step (2), adding aprepitant to the mixed solution of step (1) to obtain a primary suspension; Step (3) The initial suspension described in step (2) is homogenized to obtain a pharmaceutical composition containing aprepitant.

5. An aprepitant nanosuspension pharmaceutical composition and a preparation method thereof as claimed in claim 4, characterized in that: The pressure during homogenization in step (3) is 400-1200 bar, and the homogenization time is 1-4 min.

6. An aprepitant suspension subcutaneous injection, comprising the pharmaceutical composition according to any one of claims 1 to 3 or the pharmaceutical composition prepared by the method according to any one of claims 4 to 5.

7. A lyophilized powder injection of aprepitant, characterized in that: include: (1) The pharmaceutical composition according to any one of claims 1 to 3 or the pharmaceutical composition prepared by the method according to any one of claims 4 to 5; (2) lyoprotectants; The freeze-drying protective agent is selected from one or more of sucrose, lactose, mannitol and glucose.

8. The aprepitant lyophilized powder injection according to claim 7, characterized in that: The weight ratio of the aprepitant to the lyoprotectant is 1:(0-7.14), or 1:(1.42-4.28), or 1:(1.42-2.86).

9. The aprepitant lyophilized powder injection according to claim 7, characterized in that: The weight ratio of aprepitant to mannitol is 1:(0-3.57), or 1:(0.71-2.14), or 1:(0.71-1.43); The weight ratio of aprepitant to glucose is 1:(0-3.57), or 1:(0.71-2.14), or 1:(0.71-1.43).

10. Use of the pharmaceutical composition according to any one of claims 1 to 3, or the pharmaceutical composition prepared by the method according to any one of claims 4 to 5, or the lyophilized powder injection according to any one of claims 7 to 9 in the preparation of a medicament for preventing and / or treating chemotherapy-induced nausea and vomiting, and / or postoperative nausea and vomiting.

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