Nasal nemonade dry powder inhalation and preparation method thereof

Abstract

The invention discloses nemoraxen nasal dry powder inhalation and a preparation method thereof, and belongs to the field of pharmaceutical preparations. The nasal dry powder inhalation is prepared from the following components: nemorexant, beta-cyclodextrin and poloxamer. The preparation method comprises the following steps: co-grinding and mixing the nemorexant micro powder with part of beta-cyclodextrin and all poloxamer in the prescription; and mixing the formed mixture with the residual beta-cyclodextrin. According to the invention, through development of a nasal dry powder inhalation prescription, a new dosage form of the nemorexant is provided, so that the compliance and convenience of a patient in use are improved, the delivery efficiency of the medicine is improved, the onset time is shortened, and the bioavailability of the medicine is improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a nemorexant nasal powder aerosol and a preparation method thereof. Background Art

[0002] Insomnia is a common disease, which is characterized by difficulty in initiating or maintaining sleep and accompanied by symptoms such as irritability or fatigue when awake. Insomnia can occur at all ages. A recent MATA analysis found that the incidence of insomnia in China is 15%, and young people are more likely to suffer from insomnia than the elderly. The reason may be the change in work and rest patterns and greater stress among young people nowadays. Insomnia can lead to daytime dysfunction, affecting normal study, life and work, and ultimately resulting in a decline in the quality of life and causing a series of psychophysiological diseases. For example, the risk of suffering from anxiety disorder and depression in insomnia patients is 7 times that of normal people. In addition, insomnia can also increase the risk of suffering from cardiovascular and cerebrovascular diseases and is related to metabolic disorders including obesity and diabetes.

[0003] The etiology and pathogenesis of insomnia are still not very clear so far. The generally accepted etiological hypothesis is the 3P hypothesis, including predisposing factors, precipitating factors and perpetuating factors. Brain structures such as the brainstem reticular formation, neurons in the pontine tegmentum, paraventricular nucleus of the thalamus, hypothalamus, raphe nucleus, and solitary tract nucleus in humans are involved in the regulation of sleep-wakefulness. In terms of the research on the pathogenesis, there is a two-way relationship between sleep and the secretion activity of the hypothalamic-pituitary-adrenal axis (HPA axis). Neurotransmitters in the central nervous system are closely related to sleep, such as 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA) and glutamate (Glu), dopamine (DA) and norepinephrine (NE), etc. In addition, inflammatory factors, melatonin, endogenous sleep-promoting substances (such as prostaglandin D-2 (PGD2) and adenosine), active cytokines, sleep-related genes, etc. are also closely related to the sleep rhythm.

[0004] Currently, the drugs used to treat insomnia mainly include benzodiazepines and non-benzodiazepines. Benzodiazepines have anticonvulsant, anxiolytic, sedative and muscle relaxant effects. Commonly used ones currently include estazolam, lorazepam, clonazepam tablets, etc. Non-benzodiazepines are a new type of sedative-hypnotic drugs, and representative drugs include zolpidem, zopiclone, zaleplon, etc. All sedative-hypnotic drugs have side effects, and may produce side effects such as dizziness, morning drowsiness, memory loss, trance, etc. after taking the medicine.

[0005] On January 10, 2022, the US Food and Drug Administration (FDA) approved the 25mg and 50mg tablets of Quviviq (daridorexant) for the treatment of adult sleep disorders. It is a novel dual orexin receptor antagonist. The results of numerous clinical trials of Quviviq (daridorexant) show that it is significantly effective for mild to moderate adult sleep disorders, with mild side effects such as drowsiness and dizziness the next day, and mild withdrawal symptoms after drug discontinuation. The recommended dose of daridorexant is a 50mg tablet once a night, orally administered within 30 minutes before going to bed at night.

[0006] The Chinese Sleep Research Society and other institutions released the "2022 White Paper on National Healthy Sleep in China". The white paper survey shows that 42% of the elderly take more than half an hour to fall asleep, and the insomnia rate is as high as 21%. Not sleeping well has become a common pain point for the elderly. Unfortunately, daridorexant tablets are not suitable for the elderly with swallowing difficulties.

[0007] CN106414439A discloses a class of piperidine derivatives as orexin receptor antagonists, which have obvious inhibitory effects on OX1 and OX2 GPCR receptors. In the research, it is found that when they are prepared into solid pharmaceutical compositions, there are deficiencies such as low dissolution rate and dissolution degree, low bioavailability and high in vivo half-life. For insomnia drugs, a long half-life obviously has an adverse effect, such as producing a residual effect the next day, thus causing adverse consequences to patients.

[0008] Both CN104321059A and PCT / CN02021087262 disclose solid pharmaceutical preparations of dual orexin receptor antagonists, which are inconvenient for administration to patients with swallowing difficulties.

[0009] In addition, the solid preparation of daridorexant not only has low bioavailability, but also food has a certain impact on its absorption. The clinical trials of the original preparation Quviviq have shown that in healthy subjects, high-fat and high-calorie diets delay Tmax by 1.3 hours and reduce Cmax by 16%.

[0010] How to improve the bioavailability and administration convenience of daridorexant is an urgent problem to be solved. Summary of the Invention

[0011] In order to overcome the deficiencies of the prior art, the present invention aims to provide a nasal powder aerosol of daridorexant and its preparation method. This dosage form is convenient and effective, and can significantly improve the onset time of the drug compared with oral tablets. To achieve the purpose of the present invention, the following technical solutions are adopted by the present invention:

[0012] On the one hand, the present invention provides a nemorexant nasal powder aerosol, comprising nemorexant fine powder and a carrier, wherein the carrier is β-cyclodextrin and poloxamer, and the mass ratio of β-cyclodextrin to poloxamer is 1-9:1, preferably 1-6:1, more preferably 4-6:1.

[0013] Preferably, the particle size of the nemorexant fine powder in the nasal powder aerosol is D90: 70-110 μm, more preferably 90-110 μm.

[0014] Another object of the present invention is to provide a method for preparing the above-mentioned nemorexant nasal powder aerosol, comprising the following steps:

[0015] (1) Co-grind and mix the nemorexant fine powder with a part of β-cyclodextrin and all of the poloxamer in the prescription;

[0016] (2) Sieve and mix the mixture formed in step (1) with the remaining β-cyclodextrin.

[0017] Preferably, the part of β-cyclodextrin in step (1) accounts for 75%-85% of the total amount of β-cyclodextrin in the prescription.

[0018] Preferably, the nasal powder aerosol is a drug for treating insomnia.

[0019] Based on this, the present invention provides the application of the nemorexant nasal powder aerosol in the preparation of a drug for treating insomnia.

[0020] The present invention also provides a nemorexant capsule, comprising a capsule shell and the nemorexant nasal powder aerosol inside the capsule shell.

[0021] The present invention also provides a nasal device for a powder preparation, comprising a capsule for storing the powder preparation, and the capsule contains the nemorexant nasal powder aerosol. The capsule can be pre-installed in the nasal device, and the fine powder prepared in step (2) is filled into the capsule of the nasal device; or the fine powder prepared in step (2) is first filled into the capsule, and then the capsule is placed in the nasal device.

[0022] As a typical embodiment, the nasal device is a dry powder inhaler.

[0023] Preferably, the nasal device for the powder preparation is used to administer to only one nostril of an individual.

[0024] The present invention studies and provides a nemorexan nasal powder aerosol, which is passively absorbed through the nasal mucosa of patients without the need for patients to cooperate with inhalation. At the same time, the administrator does not need to master professional techniques and can complete the administration within 30 seconds, with a success rate of over 90%. This has significant beneficial effects for the elderly with dysphagia. From the perspective of patients, nasal preparations also have several practical advantages: non-invasive, basically painless, easy to administer, and well tolerated. At the same time, the drug is absorbed quickly, takes effect rapidly, there is no hepatic first-pass metabolism, and as a small molecule drug, it has better nasal bioavailability.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0026] (1) The present invention provides a new dosage form of nemorexan nasal powder aerosol. Through comparison, it is found that compared with the oral administration route, this method can significantly improve the bioavailability and avoid the disadvantage of the administration being affected by food. At the same time, this preparation reduces the administration dose and helps to reduce side effects.

[0027] (2) Due to the large cohesive force between particles after the drug is micronized, it promotes the agglomeration of the powder, reduces the fluidity of the particles, and usually a suitable carrier needs to be added in the formulation design of the powder aerosol to improve the stability and delivery efficiency of the drug. Pharmaceutical excipients include sugars and amino acids, etc. However, different carriers also have their own defects. For example, lactose carriers are not suitable for patients with lactose intolerance, which will cause allergic reactions, and the particle size of lactose needs to be screened. A slight change in the particle size has an obvious impact on the pulmonary deposition rate; the inhalation product of arginine mixed with antibacterial drugs is likely to cause airway inflammation; when mannitol is prepared into fine powder, electrostatic phenomena may occur, and the ultra-fine powder is difficult to screen and easy to agglomerate.

[0028] The comparative test of the carrier of the present invention obtains a drug carrier suitable for the nemorexan nasal powder aerosol. Cyclodextrin acts as a filler, and at the same time, poloxamer is used to make the drug better dispersed, so as to achieve the purpose of increasing the delivery dose.

[0029] (3) The existing nemorexan is for oral administration, which brings inconvenience to patients with dysphagia. The nemorexan nasal powder aerosol provided by the present invention is for nasal administration, which can facilitate administration without any pain, increasing the compliance and convenience of medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The specification drawings forming a part of the present invention are used to provide a further understanding of the present invention. The schematic embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention.

[0031] Figure 1 It is a structural diagram of a nasal device for a powder preparation provided for Example 6 of the present invention.

[0032] Among them, 1 - device housing, 2 - capsule, 3 - capsule shell cutting device, 4 - blowing port, 5 - opening. Detailed implementation mode

[0033] The following combines the drawings and embodiments to further describe in detail the specific implementation mode of the present invention. The following embodiments are used to illustrate the present invention, but are not used to limit the scope of the present invention.

[0034] The present invention is further described below through specific embodiments.

[0035] Example 1, preparation of nemorexant nasal powder aerosol with different particle sizes

[0036] The following test materials are used:

[0037] Micronized nemorexant 1 (D90: 23 μm);

[0038] Micronized nemorexant 2 (D90: 73 μm);

[0039] Micronized nemorexant 3 (D90: 96 μm);

[0040] Micronized nemorexant 4 (D90: 112 μm);

[0041] Micronized nemorexant 5 (D90: 141 μm);

[0042] Micronized nemorexant 6 (D90: 235 μm);

[0043] Table 1 Prescriptions of Test Examples 1 to 6

[0044]

[0045] Preparation process:

[0046] The micronized nemorexant is weighed with a balance and filled into the capsules of the dry powder inhaler.

[0047] Detection method:

[0048] The spray geometry generated by the powder in the nasal powder aerosol device is an important feature, which determines the surface area of the nasal powder deposited in the nasal cavity. Suitable spray geometry features for the present invention include a spray angle falling within the range of 30 - 75°, and a plume width falling within the range of 20 - 50 mm.

[0049] The spray geometry is detected 6 cm away from the nozzle using an Oxford laser imager, and the spray angle and the spray width 6 cm away from the nozzle are recorded. The specific detection results are shown in Table 2.

[0050] Table 2 Spray Angles and Plume Widths of Test Examples 1 to 6

[0051] Test Example Spray Angle (°) Plume Width (mm) 1 18.31 13.2 2 33.31 20.3 3 52.5 35.7 4 58.6 38.5 5 28.21 17.6 6 21.22 15.1

[0052] From the data of Test Examples 1 to 6, it can be seen that when the D90 of micronized nemorensic is 70 - 110 μm, the spray angle and plume width are within the required ranges.

[0053] Example 2: Preparation of nemorensic nasal powder aerosol with different carrier formulations

[0054] Inhalation powder aerosol prescription 1:

[0055] Composition Dosage per Capsule Active Ingredient Nemorexant 5 mg

[0056] Preparation process:

[0057] Grind and mix nemorensic with a mortar, weigh according to the prescription amount in the above table with a balance, and fill it into the capsules of a dry powder inhaler.

[0058] Inhalation nasal powder aerosol prescription 2:

[0059] Composition Dosage per Capsule Active Ingredient Nemorexant 5 mg Excipient Lactose 10 mg

[0060] Preparation process:

[0061] (1) Co-grind and mix nemorensic with 9 / 10 lactose using a mortar;

[0062] (2) Mix the mixture formed in step (1) with the remaining 1 / 10 lactose through a 60-mesh sieve;

[0063] (3) Weigh the fine powder obtained in step (2), weigh it with a balance, and fill it into the capsules of a dry powder inhaler. Inhalation nasal powder aerosol prescription 3:

[0064] Functional Structure Composition Dosage per Capsule Active Ingredient Nemorexant 5 mg Excipient β-Cyclodextrin 10 mg

[0065] Preparation process:

[0066] (1) Co-grind and mix nemorensic with 9 / 10 β-cyclodextrin using a mortar;

[0067] (2) Mix the mixture formed in step (1) with the remaining 1 / 10 β-cyclodextrin through a 60-mesh sieve; (3) Weigh the fine powder obtained in step (2), weigh it with a balance, and fill it into the capsules of a dry powder inhaler. Inhalation nasal powder aerosol prescription 4:

[0068] Functional Structure Composition Dosage per Capsule Active Ingredient Nemorexant 5 mg Excipient Mannitol 10 mg

[0069] Preparation process:

[0070] (1) Co-grind and mix nemorensic with 9 / 10 mannitol using a mortar;

[0071] (2) Mix the mixture formed in step (1) with the remaining 1 / 10 mannitol through a 60-mesh sieve.

[0072] (3) Weigh the fine powder obtained in step (2), and after weighing with a balance, fill it into the capsules of a dry powder inhaler. Inhaled nasal powder aerosol prescription 5:

[0073] Functional Structure Composition Dosage per Capsule Active Ingredient Nemorexant 5 mg Excipient Lactose: Poloxamer = 1:1 5 mg:5 mg

[0074] Preparation process:

[0075] (1) Co-grind and mix nemorubicin with 4 / 5 lactose and all poloxamer in a mortar.

[0076] (2) Mix the mixture formed in step (1) with the remaining 1 / 5 lactose through a 60-mesh sieve.

[0077] (3) Weigh the fine powder obtained in step (2), and after weighing with a balance, fill it into the capsules of a dry powder inhaler. Inhaled nasal powder aerosol prescription 6:

[0078] Functional Structure Composition Dosage per Capsule Active Ingredient Nemorexant 5 mg Excipient β-Cyclodextrin: Poloxamer = 1:1 5 mg:5 mg

[0079] Preparation process:

[0080] (1) Co-grind and mix nemorubicin with 4 / 5 β-cyclodextrin and all poloxamer in a mortar.

[0081] (2) Mix the mixture formed in step (1) with the remaining 1 / 5 β-cyclodextrin through a 60-mesh sieve.

[0082] (3) Weigh the fine powder obtained in step (2), and after weighing with a balance, fill it into the capsules of a dry powder inhaler.

[0083] Inhaled nasal powder aerosol prescription 7:

[0084] Functional Structure Composition Dosage per Capsule Active Ingredient Nemorexant 5 mg Excipient Mannitol: Poloxamer = 1:1 5 mg:5 mg

[0085] Preparation process:

[0086] (1) Co-grind and mix nemorubicin with 4 / 5 mannitol and all poloxamer in a mortar.

[0087] (2) Mix the mixture formed in step (1) with the remaining 1 / 5 mannitol through a 60-mesh sieve.

[0088] (3) Weigh the fine powder obtained in step (2), and after weighing with a balance, fill it into the capsules of a dry powder inhaler.

[0089] Inhaled nasal powder aerosol prescription 8:

[0090] Functional Structure Composition Dosage per Capsule Active Ingredient Nemorexant 5 mg Excipient β-Cyclodextrin: Mannitol = 1:1 5 mg:5 mg

[0091] Preparation process:

[0092] (1) Co-grind and mix nemoroxan with 4 / 5 β-cyclodextrin and all mannitol in a mortar.

[0093] (2) Mix the mixture formed in step (1) with the remaining 1 / 5 β-cyclodextrin through a 60-mesh sieve.

[0094] (3) Weigh the fine powder obtained in step (2), and after weighing with a balance, fill it into the capsules of a dry powder inhaler.

[0095] Examine the nemoroxan nasal powder aerosol prepared from Formulations 1-8 of Example 1. Use an inhaled powder aerosol delivery dose measuring device, which includes a base with a stainless-steel sieve for placing a filter paper, a sampling collection tube equipped with two sealed end caps, and a nozzle adapter to ensure the sealing between the sampling collection tube and the nozzle. This device can quantitatively collect the delivery dose of the inhaled powder aerosol.

[0096] Install a suitable adapter at the inlet end of the device to ensure that the nozzle port of the inhaler is flush with the sample collection tube mouth. Place a circular filter paper in the base and fix it at one end of the sampling collection tube. Connect the base port to a vacuum pump, connect the device, connect the inhaler to the instrument inlet, and check the airtightness. Adjust the flow rate (42 L / min) and the pumping time so that the air flow rate within the pumping time is 4.3 L. Take 1 capsule of this product, with the capsule cap facing up, quickly and vertically place it in the inhaler, press the buttons on both sides of the device with fingers to pierce both sides of the capsule, keep the buttons pressed, connect the adapter, release the buttons, turn on the vacuum pump, and after pumping for the specified time, remove the inhaler and the collection tube. Accurately measure 20 ml of 0.01 mol / L hydrochloric acid-disodium edetate solution and add it to the collection tube to completely dissolve the sample in the collection tube. Discard the solution made from the first capsule. After cleaning and drying the inhaler, take another 9 capsules and repeat the above operations respectively.

[0097] Determine by high performance liquid chromatography (General Principles 0512, Volume IV, Chinese Pharmacopoeia 2015 Edition). Use octadecylsilane chemically bonded silica gel as the filler (250 mm × 4.6 mm, 5 μm), use a methanol-water system as the mobile phase, containing a buffer: 20 mM potassium dihydrogen phosphate (KH2PO4), adjust the pH to 3.0, the flow rate is 1.0 ml per minute, the column temperature is 30 °C, the detection wavelength: 290 nm, and the tailing factor of the peak should not be greater than 1.5. Accurately measure 100 μl of the solution, inject it into the chromatograph, record the chromatogram, and calculate the delivery dose and average value of 10 capsules by the external standard method based on the peak area. The target value of the delivery dose per capsule is 5.0 mg.

[0098] Repeat the above process for 10 capsules for each formulation of the nemoroxan nasal powder aerosol

[0099] Table 3: Detection Results of Delivery Dose Uniformity for Prescriptions 1 - 8 (n = 10)

[0100]

[0101] The above test results show that: in Prescription 6, when β - cyclodextrin: poloxamer = 1:1, the average delivery dose is the highest. It can be seen that the delivery efficiency of the delivery dose under this prescription is the best.

[0102] Example 3: Preparation of Nemorexant Nasal Powder Aerosol with Different Prescription Proportions

[0103] On the basis of Prescription 6, optimize the proportion of β - cyclodextrin and poloxamer, and prepare nemorexant nasal powder aerosol of the following prescriptions with reference to Prescription 6.

[0104]

[0105] (1) Co - grind and mix 4 / 5 β - cyclodextrin, nemorexant and all poloxamer in a mortar;

[0106] (2) Mix the mixture formed in step (1) with the remaining 1 / 5 β - cyclodextrin through a 60 - mesh sieve;

[0107] (3) Weigh the fine powder obtained in step (2) and fill it into the capsules of a dry powder inhaler after weighing with a balance.

[0108] Examine the nemorexant nasal powder aerosol prepared from Prescriptions 9 - 13 in Example 3, and determine the delivery dose uniformity of the inhaled powder aerosol according to the above method. Repeat the above process for 10 capsules for each prescription of the nemorexant nasal powder aerosol

[0109] Table 4: Detection Results of Delivery Dose Uniformity for Prescriptions 9 - 13 (n = 10)

[0110]

[0111] The above test results show that: in Examples 11 and 12, when β - cyclodextrin: poloxamer = 4 - 6:1, the delivery efficiency of the delivery dose is the optimal.

[0112] Comparative Example 1: Preparation of Nemorexant Nasal Powder Aerosol with Different Processes

[0113] On the basis of Prescription 12, change the process. Preparation process: (1) Co - grind and mix nemorexant with all β - cyclodextrin and all poloxamer in a mortar, and mix through a 60 - mesh sieve; (2) Weigh the fine powder obtained in step (1) and fill it into the capsules of a dry powder inhaler after weighing with a balance.

[0114] Comparative Example 2: Preparation of Nemorexant Nasal Powder Aerosol with Different Processes

[0115] Based on Prescription 12, the process is changed. Preparation process: (1) Nemonapride and 4 / 5 β-cyclodextrin are ground and mixed together in a mortar; (2) The mixture formed in step (1) is mixed with the remaining 1 / 5 β-cyclodextrin and all poloxamer through a 60-mesh sieve; (3) Weigh the fine powder obtained in step (2), and after weighing with a balance, fill it into the capsules of a dry powder inhaler.

[0116] Examine the nemonapride nasal powder aerosol prepared in Comparative Examples 1 and 2, and determine the delivery dose uniformity of the inhaled powder aerosol according to the above method. The above process is repeated for 10 capsules of the nemonapride nasal powder aerosol for each prescription.

[0117] Table 5: Detection results of delivery dose uniformity for Comparative Examples 1-2 (n = 10)

[0118]

[0119] The above results show that the prescription process of Example 12 is superior to that of Comparative Example 1 and Comparative Example 2.

[0120] Example 4, In vivo pharmacokinetic evaluation of the nemonapride nasal powder aerosol of the present invention

[0121] Six male and six female Sprague-Dawley rats are divided into 2 groups and administered drugs respectively.

[0122] The first group is administered by intranasal instillation. The dose is administered according to the body weight of the rats: (1) Grasp the rats in the correct manner; (2) Use a syringe or pipette to drip a small amount of the drug (using water as a solvent) at the nostrils of the animals; (3) Note that the drug will disappear into the nostrils; (3) Repeat the above operations until the required amount is completed.

[0123] The second group is administered by gavage. The dose is administered according to the body weight of the rats: (1) Select an oral gavage needle of an appropriate size. The end of this needle is spherical to facilitate preventing entry into the trachea. (2) The required length should be measured starting from the corner of the animal's mouth when the animal is lifted. The spherical head of the gavage needle should reach the last rib of the animal. (3) Keep the animal's head and body in a straight line so that the esophagus can be straightened and the feeding tube can pass through more easily. (4) Insert the spherical tip of the needle into the animal's mouth and cover the tongue. After the needle is in place, pick up the needle and syringe and gently press on the upper jaw so that the animal's nose faces the ceiling. (5) Continue to insert the needle until the predetermined distance is reached. The needle should pass through easily and the animal should not gasp or choke. (6) Inject the drug, and it should flow into the stomach.

[0124]

[0125] Under the condition that the intranasal administration dose is half of the oral administration dose, the T of intranasal administration and oral administrationmax The mean ratio is 0.5, C max Intranasal administration is slightly higher than oral administration, and the AUC 0-∞ Intranasal administration is similar to oral administration, indicating that intranasal administration has high bioavailability and rapid onset, which is faster than oral administration.

[0126] Example 5, a nemorexant capsule

[0127] It contains a capsule shell and a nemorexant nasal powder aerosol inside the capsule shell.

[0128] Example 6, a nasal device for powder preparations

[0129] As Figure 1 shown, it includes a device housing 1 and a capsule 2 for storing the powder preparation placed in the device housing 1. The capsule 2 contains a nemorexant nasal powder aerosol. The device housing 1 can adopt an existing structure, such as a dry powder inhaler like the Xsail respiratory power device.

[0130] The capsule can be pre-installed in the nasal device, and the fine powder prepared in step (2) of the example is filled into the capsule of the nasal device; or the fine powder prepared in step (2) is first filled into the capsule, and then the capsule is placed in the nasal device.

[0131] The nasal device for powder preparations is only administered to one nostril of an individual.

[0132] During use, the capsule shell of the capsule in the device housing 1 is cut by a capsule shell cutting device 3 to release the nemorexant nasal powder aerosol. The patient blows air through the mouthpiece 4, and the powder aerosol is blown into the nostril through the opening 5 at the top of the nasal device. As another implementation manner, in some nasal devices for powder preparations, the capsule shell cutting device 3 can adopt a needle-piercing structure to pierce the capsule shell and release the nemorexant nasal powder aerosol, which is a replacement of conventional technology.

[0133] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, 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 nemorexant nasal powder aerosol, characterized in that, It comprises nemorexant micronized powder and a carrier, wherein the carrier is β-cyclodextrin and poloxamer, and the mass ratio of β-cyclodextrin to poloxamer is 1-9:

1.

2. The nemorexant nasal powder aerosol according to claim 1, wherein The mass ratio of the β-cyclodextrin to the poloxamer is 1-6:

1.

3. The nemorexant nasal powder aerosol according to claim 1, wherein The mass ratio of the β-cyclodextrin to the poloxamer is 4-6:

1.

4. The nemorexant nasal powder aerosol according to claim 1, wherein, The particle size of the nemorexant micronized powder is D90: 70-110 μm.

5. The nemorexant nasal powder aerosol according to claim 1, characterized in that, The particle size of the nemorexant micronized powder is D90: 90-110 μm.

6. A preparation method of nemorexant nasal powder aerosol, characterized in that, The nemorexant nasal powder aerosol comprises nemorexant micronized powder and a carrier, wherein the carrier is β-cyclodextrin and poloxamer, and the mass ratio of β-cyclodextrin to poloxamer is 1-9:1; the preparation method comprises the following steps: (1) Co-grind and mix the nemorexant micronized powder with a part of the β-cyclodextrin and all of the poloxamer in the prescription; (2) Mix the mixture formed in step (1) with the remaining β-cyclodextrin.

7. The preparation method of nemorexant nasal powder aerosol according to claim 6, characterized in that, In step (1), the part of the β-cyclodextrin accounts for 75%-85% of the total amount of β-cyclodextrin in the prescription.

9. Use of the nemorexant nasal powder aerosol according to any one of claims 1-5 in the preparation of a drug for treating insomnia.

9. A nemorexant capsule, characterized in that, It comprises a capsule shell and the nemorexant nasal powder aerosol according to any one of claims 1-5.

10. A nasal device for a powder preparation, characterized in that, It includes a capsule for storing a powder preparation, and the capsule contains the nemorexant nasal powder aerosol according to any one of claims 1-5.

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