A nasal spray acting on the central nervous system, its preparation method and application

Abstract

The present invention discloses a nasal spray acting on the central nervous system, its preparation method and application; the nasal spray of the central nervous system drug comprises a central nervous system drug or a pharmaceutically acceptable salt thereof, an absorption enhancer and excipients; after administration, the drug in the nasal spray of the central nervous system drug of the present invention is directly delivered to the olfactory region through the nasal cavity, bypassing the blood-brain barrier, taking effect quickly, improving the bioavailability of the drug in the brain, reducing the dosage, and being used for treating central nervous system diseases; moreover, the nasal spray of the central nervous system drug has an appropriate viscosity, can effectively increase the deposition of the drug in the olfactory region, improve the nasal-brain delivery efficiency, and effectively treat central nervous system diseases.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to a nasal spray acting on the central nervous system, a preparation method thereof, and an application thereof. Background Art

[0002] As a non-invasive drug delivery route, the nasal drug delivery system has the advantages of no first-pass effect, rapid onset of action, bypassing the blood-brain barrier, and convenient drug administration, and has great clinical application potential and market prospects in the fields of nasal local, systemic, and central nervous system drug administration.

[0003] Due to the special physiological structure of the nasal cavity, drugs can be directly absorbed through the nose and enter the brain to take effect. The olfactory region of the nose is the only part of the central nervous system directly exposed to the external environment, and is considered to be the most direct and rapid way for drugs to bypass the blood-brain barrier and enter the cerebrospinal fluid. The central processes of the mucosal olfactory cells form olfactory nerve fibers, which then gather to form olfactory filaments, pass through the sieve holes of the cribriform plate of the ethmoid bone, enter the anterior cranial fossa, pass through the dura mater, arachnoid mater, and pia mater, and terminate at the olfactory bulb, communicating with the cerebrospinal fluid, forming the olfactory nerve pathway, which is also an important pathway for drugs to directly enter the brain through the olfactory region. In addition, drugs can also enter the supporting cells or cell gaps around the olfactory nerve through cell channel transport, cell bypass channel transport, etc., and are transported into the brain. The nasal drug delivery system can directly deliver drugs to the brain tissue through the nasal-brain pathway, with rapid onset of action, strong brain targeting, high bioavailability, reduced drug dosage, avoidance of gastrointestinal reactions, good patient compliance, and good safety, and has significant advantages and great clinical application prospects in the treatment of central nervous system diseases, especially suitable for the intracerebral delivery of drugs such as anti-Parkinson's disease, anti-Alzheimer's disease, anti-migraine, sedative, and analgesic drugs.

[0004] For a nasal spray acting on the central nervous system, the absorption of drugs in the olfactory region directly affects its therapeutic effect. The area of the olfactory mucosa is extremely small (1-5 cm 2 ), accounting for only 3%-5% of the total nasal cavity area. If the drug delivery efficiency is to be improved, promoting the absorption of drugs at the nasal mucosa site is the key point and difficulty in the research and development of this type of nasal spray. Summary of the Invention

[0005] The purpose of the first aspect of the present invention is to provide a pharmaceutical composition.

[0006] The purpose of the second aspect of the present invention is the preparation method of the above composition.

[0007] The purpose of the third aspect of the present invention is to provide the application of the above pharmaceutical composition.

[0008] The purpose of the fourth aspect of the present invention is to provide the application of dodecyl-β-D-maltoside as an absorption promoter in the preparation of a pharmaceutical preparation acting on the central nervous system.

[0009] The technical solution adopted by the present invention is as follows:

[0010] In the first aspect of the present invention, a pharmaceutical composition is provided, comprising a central nervous system drug and an absorption enhancer; the absorption enhancer is at least one of dodecyl-β-D-maltoside, tetradecyl-β-D-maltoside, chitosan, sucrose laurate, carboxymethyl chitosan, and sodium taurocholate.

[0011] Preferably, the central nervous system drug comprises at least one of a neurodegenerative disease drug, a migraine drug, an analgesic drug, a sedative drug, and an epilepsy drug.

[0012] Preferably, the neurodegenerative disease comprises at least one of Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[0013] Preferably, the drug for treating the central nervous system comprises at least one of rivastigmine, rizatriptan, sumatriptan, zolmitriptan, dexmedetomidine, diazepam, pramipexole, memantine, donepezil, lidocaine, butorphanol, alprazolam, demoxepam, flumazenil, midazolam, lorazepam, or a pharmaceutically acceptable salt thereof.

[0014] Among them, pramipexole, etc. are drugs for treating Parkinson's disease, rivastigmine, memantine, donepezil, etc. are drugs for treating Alzheimer's disease, sumatriptan, rizatriptan, zolmitriptan, etc. are drugs for treating migraine, lidocaine, dexmedetomidine, butorphanol, etc. are analgesic and sedative drugs, and diazepam, alprazolam, demoxepam, flumazenil, midazolam, lorazepam, etc. are benzodiazepine drugs for sedation and epilepsy.

[0015] Preferably, the absorption enhancer is dodecyl-β-D-maltoside.

[0016] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0017] Preferably, the excipient comprises at least one of a suspending agent, an antioxidant, a wetting agent, an antibacterial agent, a pH regulator, and an osmotic pressure regulator.

[0018] Preferably, the suspending agent is at least one of microcrystalline cellulose-sodium carboxymethylcellulose RC591 or CL611, carbomer 934, and carbomer 940.

[0019] Preferably, the microcrystalline cellulose-sodium carboxymethylcellulose comprises microcrystalline cellulose-sodium carboxymethylcellulose RC591, CL611, etc.

[0020] Preferably, the carbomer comprises carbomer 934, carbomer 940, etc.

[0021] Preferably, the suspending agent is microcrystalline cellulose - sodium carboxymethyl cellulose RC591.

[0022] Preferably, the antioxidant is at least one of ascorbic acid, ascorbyl palmitate, and sodium metabisulfite.

[0023] Preferably, the antioxidant is sodium metabisulfite.

[0024] Preferably, the wetting agent can be at least one of polysorbate and poloxamer.

[0025] Preferably, the wetting agent can be polysorbate.

[0026] Preferably, the polysorbate is polysorbate 80.

[0027] Preferably, the bacteriostatic agent is at least one of benzalkonium chloride, benzalkonium bromide, quaternary ammonium salts, cetrimide, phenoxyethanol, sodium benzoate, and phenethyl alcohol.

[0028] Preferably, the bacteriostatic agent is benzalkonium chloride.

[0029] Preferably, the pH regulator is used to adjust the pH of the pharmaceutical composition to 4.0 - 7.0.

[0030] Preferably, the pH regulator is at least one of citric acid / sodium citrate, phosphates, citric acid monohydrate, and sodium hydroxide.

[0031] Preferably, the phosphates include but are not limited to sodium dihydrogen phosphate / disodium hydrogen phosphate, potassium dihydrogen phosphate / dipotassium hydrogen phosphate, etc.

[0032] Preferably, the osmotic pressure regulator is used to adjust the osmotic pressure of the pharmaceutical composition to 270 - 350 mOsm / kg.

[0033] Preferably, the content of the osmotic pressure regulator is 0% - 1.5%.

[0034] Preferably, the osmotic pressure regulator is glycerol, glucose, mannitol, lactose, dextran, sorbitol, and inorganic salts such as sodium chloride.

[0035] Preferably, the pharmaceutical composition comprises: 0.01% - 50% w / w of a drug or its pharmaceutically acceptable salt; and / or, 1% - 3% w / w of a suspending agent; and / or, 0.1% - 3% w / w of an antioxidant; and / or, 0.05% - 0.5% w / w of an absorption enhancer; and / or, 0.005% - 0.03% w / w of a wetting agent; and / or, 0.005% - 0.03% w / w of a bacteriostatic agent, with the balance being water.

[0036] Preferably, the pramipexole composition comprises: 0.01% to 2.5% w / w of pramipexole or a pharmaceutically acceptable salt thereof, and 0.05% to 0.5% w / w of an absorption enhancer.

[0037] Preferably, the rizatriptan composition comprises: 0.05% to 5% w / w of rizatriptan or a pharmaceutically acceptable salt thereof, and 0.05% to 0.5% w / w of an absorption enhancer.

[0038] Preferably, the zolmitriptan composition comprises: 5% to 25% w / w of zolmitriptan or a pharmaceutically acceptable salt thereof; 1.0% to 2% w / w of a suspending agent; 0.2% to 3% w / w of an antioxidant; 0.05% to 0.5% w / w of an absorption enhancer; 0.005% to 0.03% w / w of a wetting agent; 0.005% to 0.03% w / w of an antibacterial agent.

[0039] Preferably, the sumatriptan composition comprises: 5% to 20% w / w of sumatriptan or a pharmaceutically acceptable salt thereof, and 0.05% to 0.5% w / w of an absorption enhancer.

[0040] Preferably, the dexmedetomidine composition comprises: 0.1% to 2% w / w of dexmedetomidine or a pharmaceutically acceptable salt thereof, and 0.05% to 0.5% w / w of an absorption enhancer.

[0041] Preferably, the butorphanol composition comprises: 10 to 50% w / w of butorphanol or a pharmaceutically acceptable salt thereof, and 0.05% to 0.5% w / w of an absorption enhancer.

[0042] Preferably, the rivastigmine composition comprises: 0.6% to 6% w / w of rivastigmine or a pharmaceutically acceptable salt thereof; 1.0% to 2% w / w of a suspending agent; 0.2% to 3% w / w of an antioxidant; 0.05% to 0.5% w / w of an absorption enhancer; 0.005% to 0.03% w / w of a wetting agent; 0.005% to 0.03% w / w of an antibacterial agent.

[0043] Preferably, the memantine hydrochloride composition comprises: 0.5% to 10% w / w of memantine hydrochloride, and 0.05% to 0.5% w / w of an absorption enhancer.

[0044] Preferably, the donepezil composition comprises: 5% to 25% w / w of donepezil or a pharmaceutically acceptable salt thereof, and 0.05% to 0.5% w / w of an absorption enhancer.

[0045] Preferably, the pharmaceutical composition further comprises water.

[0046] Preferably, the drug comprises the drug and / or its micropowder.

[0047] Preferably, the particle size d of the micronized drug 90 is 2 - 20 μm.

[0048] Preferably, the dosage form of the pharmaceutical composition is powder, tablet, granule, capsule, emulsion, solution, suspension, or spray.

[0049] Preferably, the administration method of the pharmaceutical composition is nasal administration.

[0050] Preferably, the acceptable delivery volume of the nasal spray is 100 - 200 μL.

[0051] In the second aspect of the present invention, a preparation method of the above pharmaceutical composition is provided, which includes uniformly mixing a central nervous system drug, an absorption enhancer, and an excipient with water to obtain the pharmaceutical composition.

[0052] Preferably, the method further includes filling the pharmaceutical composition into a nasal spray bottle device to obtain a central nervous system drug nasal spray.

[0053] In the third aspect of the present invention, an application of the pharmaceutical composition described in the first aspect of the present invention in the preparation of a drug for treating central nervous system diseases is provided.

[0054] In the fourth aspect of the present invention, an application of dodecyl - β - D - maltoside in the preparation of an absorption enhancer for treating central nervous system diseases or a drug for treating the central nervous system is provided.

[0055] Preferably, the drug for treating central nervous system diseases includes at least one of drugs for neurodegenerative diseases, drugs for treating migraine, analgesic drugs, sedative drugs, and antiepileptic drugs.

[0056] Preferably, the neurodegenerative diseases include at least one of Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[0057] Preferably, the drug includes at least one of rivastigmine, rizatriptan, sumatriptan, zolmitriptan, dexmedetomidine, diazepam, pramipexole, memantine, donepezil, lidocaine, butorphanol, alprazolam, demoxepam, flumazenil, midazolam, lorazepam, or a pharmaceutically acceptable salt thereof.

[0058] Among them, pramipexole, etc. are drugs for treating Parkinson's disease, rivastigmine, memantine, donepezil, etc. are drugs for treating Alzheimer's disease, sumatriptan, rizatriptan, zolmitriptan, etc. are drugs for treating migraine, lidocaine, dexmedetomidine hydrochloride, butorphanol, etc. are analgesic and sedative drugs, and diazepam, alprazolam, demoxepam, flumazenil, midazolam, lorazepam, etc. are benzodiazepine drugs for sedation and epilepsy.

[0059] The beneficial effects of the present invention are as follows:

[0060] The present invention provides a nasal spray acting on the central nervous system, using dodecyl-β-D-maltoside as a drug absorption promoter, and compounding a suspending agent, an antioxidant, a wetting agent, an antibacterial agent, etc., to improve the stability of the drug in the liquid preparation. After administration, the preparation can achieve drug absorption through two pathways: 1) Part of the drug is delivered to the olfactory region, bypassing the blood-brain barrier and reaching the brain directly, with rapid onset of action; 2) Part of the drug is rapidly absorbed into the blood through the nasal mucosa in the respiratory region, enters the systemic circulation, and enters the brain through the blood-brain barrier to take effect. Among them, the nasal-brain pathway bypasses the blood-brain barrier and reaches the brain directly, which can significantly improve the drug absorption efficiency in the brain, with rapid onset of action and reduced dosage. The above preparation has an appropriate viscosity, which can effectively increase the deposition of the drug in the olfactory region. The addition of the absorption promoter further promotes the absorption of the drug deposited in the olfactory region, greatly improving the nasal-brain delivery efficiency and the bioavailability of the drug in the brain. Brief Description of the Drawings

[0061] Figure 1 Plasma concentration-time curve of pramipexole nasal spray in the brain.

[0062] Figure 2 Plasma concentration-time curve of rizatriptan nasal spray in the brain.

[0063] Figure 3 Plasma concentration-time curve of zolmitriptan nasal spray in the brain.

[0064] Figure 4 Plasma concentration-time curve of sumatriptan nasal spray in the brain.

[0065] Figure 5 Plasma concentration-time curve of dexmedetomidine nasal spray in the brain.

[0066] Figure 6 Plasma concentration-time curve of rivastigmine nasal spray in the brain.

[0067] Figure 7 Plasma concentration-time curve of memantine hydrochloride nasal spray in the brain.

[0068] Figure 8 Plasma concentration-time curve of donepezil nasal spray in the brain. Detailed Embodiments

[0069] The following will clearly and completely describe the concept and technical effects of the present invention in combination with the embodiments to fully understand the purpose, features, and effects of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative efforts shall fall within the scope of protection of the present invention.

[0070] The particle size d of the drug fine powder used in this example 90 is 2 - 20 μm.

[0071] Example 1 Pramipexole Nasal Spray

[0072] 1. Preparation of Pramipexole Nasal Spray

[0073] The proportion ranges of each component in Pramipexole Nasal Spray are shown in Table 1:

[0074] Table 1 Prescription composition of Pramipexole Nasal Spray

[0075]

[0076]

[0077] Use the prescription shown in Table 2 to prepare Pramipexole Nasal Spray for subsequent experiments;

[0078] Table 2 Preferred prescription composition of Pramipexole Nasal Spray

[0079]

[0080] The specific preparation steps are as follows:

[0081] S1: Dissolve 0.2 g of disodium hydrogen phosphate and 10.0 g of potassium dihydrogen phosphate in sufficient water to prepare 1000 mL of phosphate buffer solution.

[0082] S2: Weigh 2.0 g of sodium hydroxide into a beaker, add water to dilute and dissolve it to 50 ml to obtain 1 M sodium hydroxide solution.

[0083] S3: Add the prescribed amount of Pramipexole Hydrochloride and an appropriate amount of purified water, and stir mechanically at 500 - 1000 rpm to dissolve the drug.

[0084] S4: Measure the pH of the solution in step S3, add an appropriate amount of sodium hydroxide (1N) solution to the solution, and adjust the pH to 5.0 ± 0.5.

[0085] S5: Add an appropriate amount of phosphate buffer solution to the solution in step S4, mix well, measure the pH of the solution. If the pH does not meet the required value, add an appropriate amount of sodium hydroxide (1N) solution to adjust the pH.

[0086] S6: Dissolve the prescribed amount of dodecyl - β - D - maltoside in an appropriate amount of water, add it to the solution in step S5, mix well, add phosphate buffer solution to make up the volume of the solution, and mix the resulting solution well.

[0087] S7: Filter the solution obtained in step S6 through 0.45 μm and 0.22 μm fin filters for 10 minutes, and fill it into the spray device.

[0088] 2. In vitro evaluation of pramipexole nasal spray

[0089] 1) Detect the content, related substances, osmotic pressure, pH, spray performance, etc. of the prepared pramipexole nasal spray. The results are shown in Table 3.

[0090] Table 3 Quality evaluation of pramipexole nasal spray

[0091]

[0092] The results show that this preparation meets the requirements of the nasal preparations section in the Chinese Pharmacopoeia 2020 edition.

[0093] 2) Investigation of delivery dose uniformity

[0094] According to the FDA guidelines and the requirements of the Chinese Pharmacopoeia 2020 edition, investigate the delivery dose uniformity of pramipexole nasal spray, and detect the delivery doses of 10 bottles of the same batch of samples. The results are shown in Table 4.

[0095] Table 4 Delivery dose uniformity of pramipexole nasal spray

[0096]

[0097]

[0098] The results show that the delivery doses of the first spray and the last spray (the 60th spray) in 10 times are 98.264% and 98.52% of the labeled amount respectively, which can stably deliver the drug and meet the requirements of the Chinese Pharmacopoeia 2020 edition and the FDA guidelines.

[0099] 3. Pharmacokinetic study of pramipexole nasal spray

[0100] Conduct a pharmacokinetic study on pramipexole nasal spray with or without dodecyl-β-D-maltoside (DDM) to evaluate the brain delivery performance of pramipexole nasal spray and the absorption-promoting effect of DDM on the drug.

[0101] Among them, the prescription design of the nasal spray (without DDM) is shown in Table 5.

[0102] Table 5 Prescription design of pramipexole nasal spray without DDM

[0103]

[0104] Prepare pramipexole nasal spray without DDM according to the above prescription. The preparation method is the same as the preparation method of pramipexole nasal spray in the previous text. The experimental animals and the administration method are the same as above. The results are as Figure 1as shown in Table 6;

[0105] Table 6 Levodopa content in rat brain tissue (n = 3)

[0106]

[0107] The results showed that the addition of DDM significantly promoted the absorption of pramipexole, increasing C max from 8.53 ng / mL to 10.06 ng / mL and increasing the brain AUC 0-8h from 697 ng / mL·min to 792 ng / mL·min.

[0108] Example 2 Rizatriptan Nasal Spray

[0109] 1. Preparation of Rizatriptan Nasal Spray

[0110] The prescription composition of rizatriptan nasal spray is shown in Table 7:

[0111] Table 7 Prescription composition of rizatriptan nasal spray

[0112]

[0113] The rizatriptan nasal spray was prepared using the prescription shown in Table 8 for subsequent experiments;

[0114] Table 8 Preferred prescription composition of rizatriptan nasal spray

[0115]

[0116]

[0117] Preparation process of rizatriptan nasal spray:

[0118] S1: Dissolve 0.2 g of disodium hydrogen phosphate and 10.0 g of potassium dihydrogen phosphate in sufficient water to prepare 1000 mL of phosphate buffer solution.

[0119] S2: Weigh 2.0 g of sodium hydroxide into a beaker, add water and dilute to dissolve to 50 ml to obtain 1 M sodium hydroxide solution.

[0120] S3: Weigh 70.04 g of citric acid monohydrate into a beaker, add water and dilute to dissolve, and make up the volume with water to 200 mL to obtain citric acid monohydrate (5 M) solution;

[0121] S4: Add the prescribed amount of purified water to the citric acid monohydrate (5 M) solution and mix well, add the prescribed amount of rizatriptan, and stir to dissolve the drug.

[0122] S5: Measure the pH of the solution in step S4, add an appropriate amount of sodium hydroxide (1N) solution to the solution, and adjust the pH to 5.0 ± 0.5.

[0123] S6: Add an appropriate amount of phosphate buffer solution to the solution in step S5. After mixing well, measure the pH of the solution. If the pH does not meet the required value, add an appropriate amount of sodium hydroxide (1M) solution to adjust the pH.

[0124] S7: Dissolve the prescribed amount of dodecyl-β-D-maltoside in an appropriate amount of water, add it to the solution in step S6, mix well, add phosphate buffer solution to make up the volume of the solution, and mix the resulting solution well.

[0125] S8: Filter the solution obtained in step S7 through 0.45 μm and 0.22 μm filters for 10 minutes, and fill it into a spray device.

[0126] 2. In vitro evaluation of rizatriptan nasal spray

[0127] 1) Detect the content, related substances, osmotic pressure, pH, spray performance, etc. of the prepared rizatriptan nasal spray. The results are shown in Table 9.

[0128] Table 9 Quality evaluation of rizatriptan nasal spray

[0129]

[0130] The results show that this preparation meets the requirements of the nasal preparations section in the Chinese Pharmacopoeia 2020 edition.

[0131] 2) Investigation of delivery dose uniformity

[0132] According to the FDA guidelines and the requirements of the Chinese Pharmacopoeia 2020 edition, detect the delivery doses of 10 vials of the same batch of samples. The results are shown in Table 10.

[0133] Table 10 Delivery dose uniformity of rizatriptan nasal spray

[0134]

[0135] The results show that the delivery doses of the first spray and the last spray (the 60th spray) in 10 times are 98.59% and 98.70% of the labeled amount respectively, which can stably deliver the drug and meet the requirements of the Chinese Pharmacopoeia 2020 edition and the FDA guidelines.

[0136] 3. Pharmacokinetic study of rizatriptan nasal spray

[0137] Conduct a pharmacokinetic study on rizatriptan nasal spray with and without dodecyl-β-D-maltoside (DDM) to evaluate the brain delivery performance of rizatriptan nasal spray and the absorption-promoting effect of DDM on the drug.

[0138] The prescription designs of the nasal sprays (without DDM) and nasal sprays (1 / 2 DDM) are shown in Tables 11 - 12.

[0139] Table 11 Prescription Design of Sumatriptan Nasal Spray without DDM

[0140]

[0141] Table 12 Prescription Design of Sumatriptan Nasal Spray with 1 / 2 DDM

[0142]

[0143] Prepare the sumatriptan nasal spray without DDM and the sumatriptan nasal spray with 1 / 2 DDM according to the above prescriptions. The preparation method is the same as that of the sumatriptan nasal spray in the previous text.

[0144] The experimental animals and the administration method are the same as above, and the results are as Figure 2 shown in Table 13;

[0145] Table 13 Sumatriptan Content in Rat Brain Tissue (n = 3)

[0146]

[0147] The results show that the addition of DDM (dodecyl - β - D - maltoside) significantly promoted the absorption of sumatriptan, increasing C max from 555 ng / mL to 755 ng / mL and increasing the brain AUC 0-6h from 22632 ng / mL·min to 28779 ng / mL·min. In addition, the Cmax and AUC0 - 6h of the sumatriptan nasal spray with 1 / 2 DDM are between those of the sumatriptan nasal spray and the sumatriptan nasal spray without DDM, indicating that the absorption - promoting effect of DDM on sumatriptan is concentration - dependent.

[0148] Example 3 Zolmitriptan Nasal Spray

[0149] 1. Preparation of Zolmitriptan Nasal Spray

[0150] The proportion ranges of the components in the zolmitriptan nasal spray are shown in Table 14:

[0151] Table 14 Prescription Composition of Zolmitriptan Nasal Spray

[0152]

[0153]

[0154] Prepare the zolmitriptan nasal spray using the prescription shown in Table 15 for subsequent experiments:

[0155] Table 15 Composition of the preferred zolmitriptan nasal spray prescription

[0156]

[0157] The specific preparation steps are as follows:

[0158] S1: Perform air-flow pulverization on the zolmitriptan raw material to obtain zolmitriptan fine powder;

[0159] S2: Put the prescribed amount of purified water and wetting agent into the liquid preparation tank, set the stirring speed to 15 Hz, stir for 5 min, then add the prescribed amount of zolmitriptan fine powder, set the stirring speed to 30 Hz, and stir for 10 min to obtain Solution A.

[0160] S3: Dissolve the pH regulator, osmotic pressure regulator, antioxidant, absorption promoter, and bacteriostatic agent in appropriate amounts of purified water respectively to obtain Solution B, Solution D, Solution E, Solution F, and Solution G.

[0161] S4: Add an appropriate amount of purified water into the liquid preparation tank, lower the tank lid, set the stirring speed to 30 Hz (about 1 m / s), start stirring, and uniformly add the suspending agent into the liquid preparation tank. After the addition of the suspending agent is completed, keep the stirring speed unchanged, set the emulsifying speed to 50 Hz, emulsify for 60 min, then turn off the emulsification, add Solution B and Solution D into the liquid preparation tank through the feeding port. After the feeding is completed, continue to stir for 15 min until evenly dispersed; keep the stirring speed unchanged, set the emulsifying speed to 50 Hz, and emulsify for 30 min to obtain Solution C.

[0162] S5: After mixing Solution C, Solution E, Solution F, Solution G, and Solution A evenly, set the pressure of the liquid preparation tank to -0.08 Mpa, the stirring speed to 50 Hz, stir for 30 min until evenly mixed, then stop stirring to obtain the zolmitriptan suspension.

[0163] The method also includes filling the zolmitriptan suspension into a high-density polyethylene nasal spray bottle and installing a medicinal spray pump to obtain the zolmitriptan nasal spray.

[0164] 2. In vitro evaluation of the zolmitriptan nasal spray

[0165] 1) Detect the content of the prepared zolmitriptan nasal spray, and examine its viscosity, osmotic pressure, pH, sedimentation stability, spray performance, etc. The results are shown in Table 16.

[0166] Table 16 Quality evaluation of the zolmitriptan nasal spray

[0167]

[0168]

[0169] The results showed that the preparation met the requirements under nasal preparations in the Chinese Pharmacopoeia 2020 edition.

[0170] 2) Investigation of delivery dose uniformity

[0171] According to the FDA guidelines and the requirements of the Chinese Pharmacopoeia 2020 edition, the delivery dose uniformity of sumatriptan nasal spray was investigated, and the delivery doses of 10 bottles of the same batch of samples were detected. The results are shown in Table 17.

[0172] Table 17 Delivery dose uniformity of sumatriptan nasal spray

[0173]

[0174] The results showed that the 10 delivery doses were 98.29% of the labeled amount, which could stably deliver the drug and met the requirements of the Chinese Pharmacopoeia 2020 edition and the FDA guidelines.

[0175] 3. Pharmacokinetic study of sumatriptan nasal spray

[0176] A pharmacokinetic study was conducted on pramipexole nasal spray with or without dodecyl-β-D-maltoside (DDM) to evaluate the brain delivery performance of sumatriptan nasal spray and the absorption-promoting effect of DDM on the drug.

[0177] The prescription design of the nasal spray (without DDM) is shown in Table 18.

[0178] Table 18 Prescription design of sumatriptan nasal spray without DDM

[0179]

[0180] Prepare sumatriptan nasal spray without DDM according to the above prescription, and the preparation method is the same as that of sumatriptan nasal spray in the previous text.

[0181] The experimental animals and the administration method were the same as above, and the results are as Figure 3 shown in

[0182] Table 19 Content of sumatriptan in rat brain tissue (n = 3)

[0183]

[0184]

[0185] The results showed that the addition of DDM (dodecyl-β-D-maltoside) significantly promoted the absorption of sumatriptan, increasing Cmax from 869 ng / mL to 1273 ng / mL and the AUC0-6h of sumatriptan in the brain from 3367 ng / mL·h to 4840 ng / mL·h.

[0186] Example 4 Sumatriptan Nasal Spray

[0187] 1. Preparation of Sumatriptan Nasal Spray

[0188] The proportion ranges of the components in sumatriptan nasal spray are shown in Table 20:

[0189] Table 20 Prescription Composition of Sumatriptan Nasal Spray

[0190]

[0191] The sumatriptan nasal spray was prepared using the prescription shown in Table 21 for subsequent experiments;

[0192] Table 21 Preferred Prescription Composition of Sumatriptan Nasal Spray

[0193]

[0194] The specific preparation steps are as follows:

[0195] S1: Dissolve 0.2 g of disodium hydrogen phosphate and 10.0 g of potassium dihydrogen phosphate in sufficient water to prepare 1000 mL of phosphate buffer solution.

[0196] S2: Weigh 2.0 g of sodium hydroxide into a beaker, add water to dilute and dissolve it to 50 ml to obtain 1 M sodium hydroxide solution.

[0197] S3: Weigh 70.04 citric acid monohydrate into a beaker, add water to dilute and dissolve it, and make up the volume with water to 200 mL to obtain citric acid monohydrate (5 M) solution;

[0198] S4: Add the required amount of water in the prescription to the citric acid monohydrate (5 M) solution and mix well, then add the required amount of sumatriptan in the prescription and stir to dissolve the drug.

[0199] S5: Measure the pH of the solution in step S4, add an appropriate amount of sodium hydroxide (1 M) solution to the solution, and adjust the pH to 5.0 ± 0.5.

[0200] S6: Add an appropriate amount of phosphate buffer solution to the solution in step S5, mix well, measure the pH of the solution, and if the pH does not meet the required value, add an appropriate amount of sodium hydroxide (1 M) solution to adjust the pH.

[0201] S7: Dissolve the prescribed amount of dodecyl-β-D-maltoside in an appropriate amount of water, add it to the solution obtained in step S6, mix evenly, add phosphate buffer to make up the volume of the solution, and mix the resulting solution evenly.

[0202] S8: After filtering the solution obtained in step S7 through 0.45 μm and 0.22 μm fin filters for 10 minutes, fill it into a nasal spray device.

[0203] 2. In vitro evaluation of sumatriptan nasal spray

[0204] 1) Detect the content, related substances, osmotic pressure, pH, spray performance, etc. of the prepared sumatriptan nasal spray. The results are shown in Table 22.

[0205] Table 22 Quality evaluation of sumatriptan nasal spray

[0206]

[0207] The results show that this preparation meets the requirements of the nasal preparations section in the Chinese Pharmacopoeia 2020 edition.

[0208] 2) Investigation of delivery dose uniformity

[0209] According to the FDA guidelines and the requirements of the Chinese Pharmacopoeia 2020 edition, detect the delivery doses of 10 vials of the same batch of samples. The results are shown in Table 23.

[0210] Table 23 Delivery dose uniformity of sumatriptan nasal spray

[0211]

[0212] The results show that its 10 delivery doses are 98.44% of the labeled amount, and it can stably deliver the drug, meeting the requirements of the Chinese Pharmacopoeia 2020 edition and the FDA guidelines.

[0213] 3. Pharmacokinetic study of sumatriptan nasal spray

[0214] Conduct a pharmacokinetic study on sumatriptan nasal spray with and without dodecyl-β-D-maltoside (DDM) to evaluate the brain delivery performance of sumatriptan nasal spray and the absorption-promoting effect of DDM on the drug.

[0215] The prescription design of the nasal spray (without DDM) is shown in Table 24.

[0216] Table 24 Prescription design of sumatriptan nasal spray without DDM

[0217]

[0218] Prepare sumatriptan nasal spray without DDM according to the above prescription, and the preparation method is the same as that of sumatriptan nasal spray in the previous text.

[0219] The experimental animals and the administration method are the same as above, and the results are as Figure 4 shown in Table 25;

[0220] Table 25 Sumatriptan content in rat brain tissue (n = 3)

[0221]

[0222] The results showed that the addition of DDM (dodecyl-β-D-maltoside) significantly promoted the absorption of sumatriptan, increasing the Cmax in brain tissue from 16.08 ng / mL to 20.13 ng / mL and increasing the AUC 0-8h of sumatriptan in the brain from 3875 ng / mL·min to 4719 ng / mL·min. In addition, the addition of DDM significantly promoted the absorption of sumatriptan in the brain, increasing the peak time from 90 min to 60 min.

[0223] Example 5 Dexmedetomidine Hydrochloride Nasal Spray

[0224] 1. Preparation of Dexmedetomidine Hydrochloride Nasal Spray

[0225] The proportion range of each component in dexmedetomidine hydrochloride nasal spray is shown in Table 26:

[0226] Table 26 Prescription composition of dexmedetomidine hydrochloride nasal spray

[0227]

[0228] Prepare dexmedetomidine hydrochloride nasal spray using the prescription shown in Table 27 for subsequent experiments;

[0229] Table 27 Preferred prescription composition of dexmedetomidine hydrochloride nasal spray

[0230]

[0231] The specific preparation steps are as follows:

[0232] S1: Dissolve 0.2 g of disodium hydrogen phosphate and 10.0 g of potassium dihydrogen phosphate in sufficient water to prepare 1000 mL of phosphate buffer solution.

[0233] S2: Weigh 2.0 g of sodium hydroxide into a beaker, add water to dilute and dissolve it to 50 ml to obtain 1 M sodium hydroxide solution.

[0234] S3: Add the prescribed amount of purified water and dexmedetomidine hydrochloride, and stir to dissolve the drug.

[0235] S4: Measure the pH of the solution in step S3, add an appropriate amount of sodium hydroxide (1N) solution to the solution, and adjust the pH to 5.0 ± 0.5.

[0236] S5: Add an appropriate amount of phosphate buffer solution to the solution in step S4. After mixing well, measure the pH of the solution. If the pH does not meet the required value, add an appropriate amount of sodium hydroxide (1M) solution to adjust the pH.

[0237] S6: Dissolve the prescribed amount of dodecyl-β-D-maltoside in an appropriate amount of water, add it to the solution in step S5, mix well, add phosphate buffer solution to make up the volume of the solution, and mix the resulting solution well.

[0238] S7: Filter the solution obtained in step S6 through 0.45 μm and 0.22 μm filters for 10 minutes, and then fill it into a nasal spray device to obtain the product.

[0239] 2. In vitro evaluation of dexmedetomidine hydrochloride nasal spray

[0240] 1) Detect the content, related substances, osmotic pressure, pH, spray performance, etc. of the prepared dexmedetomidine hydrochloride nasal spray. The results are shown in Table 28.

[0241] Table 28 Quality evaluation of dexmedetomidine nasal spray

[0242]

[0243] The results show that this preparation meets the requirements of the nasal preparations section in the Chinese Pharmacopoeia 2020 Edition.

[0244] 2) Investigation of delivery dose uniformity

[0245] According to the FDA guidelines and the requirements of the Chinese Pharmacopoeia 2020 Edition, detect the delivery doses of 10 vials of the same batch of samples. The results are shown in Table 29.

[0246] Table 29 Delivery dose uniformity of dexmedetomidine hydrochloride nasal spray

[0247]

[0248] The results show that the 10 delivery doses are 98.36% of the labeled amount, and it can stably deliver the drug, meeting the requirements of the Chinese Pharmacopoeia 2020 Edition and the FDA guidelines.

[0249] 3. Pharmacokinetic study of dexmedetomidine hydrochloride nasal spray

[0250] A pharmacokinetic study was conducted on dexmedetomidine hydrochloride nasal spray with and without dodecyl-β-D-maltoside (DDM) to evaluate the brain delivery performance of dexmedetomidine hydrochloride nasal spray and the absorption-promoting effect of DDM on the drug.

[0251] Among them, the prescription designs of nasal spray (without DDM) and nasal spray (1 / 2 DDM) are shown in Table 30 and Table 31.

[0252] Table 30 Prescription design of dexmedetomidine hydrochloride nasal spray without DDM

[0253]

[0254] Table 31 Prescription design of dexmedetomidine hydrochloride nasal spray with 1 / 2 DDM

[0255]

[0256]

[0257] Prepare dexmedetomidine hydrochloride nasal spray without DDM and dexmedetomidine hydrochloride nasal spray with 1 / 2 DDM according to the above prescriptions, and the preparation method is the same as that of dexmedetomidine hydrochloride nasal spray in the previous text.

[0258] The experimental animals and administration methods are the same as above, and the results are as Figure 5 shown in Table 32;

[0259] Table 32 Content of dexmedetomidine in rat brain tissue (n = 3)

[0260]

[0261] The results showed that the addition of DDM (dodecyl-β-D-maltoside) significantly promoted the absorption of dexmedetomidine hydrochloride, increased the Cmax of dexmedetomidine hydrochloride from 11.25 ng / mL to 13.88 ng / mL, and increased the AUC in the brain 0-8h from 2345 ng / mL·min to 2780 ng / mL·min. In addition, the Cmax and AUC of 1 / 2 DDM dexmedetomidine hydrochloride nasal spray 0-8h were between those of dexmedetomidine hydrochloride nasal spray and dexmedetomidine hydrochloride nasal spray without DDM, indicating that the absorption-promoting effect of DDM on dexmedetomidine hydrochloride was concentration-dependent. At the same time, the addition of DDM significantly accelerated the absorption of dexmedetomidine hydrochloride, and the peak time was increased from 60 min to 30 min.

[0262] Example 6 Butorphanol tartrate nasal spray

[0263] 1. Preparation of butorphanol tartrate nasal spray

[0264] The prescription composition of butorphanol tartrate nasal spray is shown in Table 33 as follows:

[0265] Table 33 Prescription composition of butorphanol tartrate nasal spray

[0266]

[0267] The subsequent experiments were carried out with the butorphanol tartrate nasal spray prepared according to the prescription shown in Table 34;

[0268] Table 34 Preferred prescription composition of butorphanol tartrate nasal spray

[0269]

[0270]

[0271] The preparation process of butorphanol tartrate nasal spray:

[0272] S1: Dissolve 0.2 g of disodium hydrogen phosphate and 10.0 g of potassium dihydrogen phosphate in sufficient water to prepare 1000 mL of phosphate buffer solution.

[0273] S2: Weigh 2.0 g of sodium hydroxide into a beaker, add water to dilute and dissolve it to 50 ml to obtain 1N sodium hydroxide solution.

[0274] S3: Add the purified water and butorphanol tartrate in the prescription amount, and stir to dissolve the drug.

[0275] S4: Measure the pH of the solution in step S3, add an appropriate amount of sodium hydroxide (1M) solution to the solution, and adjust the pH to 5.0 ± 0.5.

[0276] S5: Add an appropriate amount of phosphate buffer solution to the solution in step S4, mix well, measure the pH of the solution. If the pH does not meet the required value, add an appropriate amount of sodium hydroxide (1M) solution to adjust the pH.

[0277] S6: Dissolve the prescription amount of dodecyl-β-D-maltoside in an appropriate amount of water, add it to the solution in step S5, mix well, add phosphate buffer solution to make up the volume of the solution, and mix the obtained solution well.

[0278] S7: Filter the solution obtained in step S6 through 0.45 μm and 0.22 μm fin filters for 10 minutes, and then fill it into the nasal spray device to obtain the product.

[0279] 2. In vitro evaluation of butorphanol tartrate nasal spray

[0280] 1) Detect the content, related substances, osmotic pressure, pH, spray performance, etc. of the prepared butorphanol tartrate nasal spray, and the results are shown in Table 35.

[0281] Table 35 Quality Evaluation of Butorphanol Tartrate Nasal Spray

[0282]

[0283] The results showed that the preparation met the requirements of nasal preparations in the Chinese Pharmacopoeia 2020 Edition.

[0284] 2) Investigation of Delivery Dose Uniformity

[0285] According to the FDA guidelines and the requirements of the Chinese Pharmacopoeia 2020 Edition, the delivery doses of 10 bottles of samples from the same batch were detected, and the results are shown in Table 36.

[0286] Table 36 Delivery Dose Uniformity of Butorphanol Tartrate Nasal Spray

[0287]

[0288] The results showed that the delivery doses of the 10 bottles were 98.27% of the labeled amount, and the drug could be stably delivered, meeting the requirements of the Chinese Pharmacopoeia 2020 Edition and the FDA guidelines.

[0289] Example 7 Rivastigmine Nasal Spray

[0290] 1. Preparation of Rivastigmine Nasal Spray

[0291] The prescription composition of rivastigmine nasal spray is shown in Table 37:

[0292] Table 37 Prescription Composition of Rivastigmine Nasal Spray

[0293]

[0294] The preferred rivastigmine nasal spray was prepared using the prescription shown in Table 38 for subsequent experiments;

[0295] Table 38 Prescription Composition of Preferred Rivastigmine Nasal Spray

[0296]

[0297] Preparation process of rivastigmine nasal spray:

[0298] S1: The rivastigmine raw material was pulverized by a jet mill to obtain rivastigmine fine powder;

[0299] S2: The prescribed amount of purified water and wetting agent were added to the liquid preparation tank, the stirring speed was set to 15 Hz, and stirred for 5 min. Then the prescribed amount of rivastigmine fine powder was added, and the stirring speed was set to 30 Hz and stirred for 10 min to obtain Solution A.

[0300] S3: Dissolve the pH regulator, osmotic pressure regulator, antioxidant, absorption enhancer, and bacteriostatic agent in appropriate amounts of purified water respectively to obtain Solution B, Solution D, Solution E, Solution F, and Solution G.

[0301] S4: Add appropriate amounts of purified water to the liquid preparation tank, lower the tank lid, set the stirring speed to 30 Hz (about 1 m / s), start stirring, and uniformly add the suspending agent to the liquid preparation tank. After the addition of the suspending agent is completed, keep the stirring speed unchanged, set the emulsification rotation speed to 50 Hz, emulsify for 60 min, then turn off the emulsification, and add Solution B and Solution D to the liquid preparation tank through the feeding port. After the addition is completed, continue stirring for 15 min until evenly dispersed; keep the stirring speed unchanged, set the emulsification rotation speed to 50 Hz, and emulsify for 30 min to obtain Solution C.

[0302] S5: Mix Solution C, Solution E, Solution F, Solution G, and Solution A evenly, set the pressure of the liquid preparation tank to -0.08 Mpa and the stirring speed to 50 Hz, stir for 30 min until evenly mixed, then stop stirring to obtain the rivastigmine suspension.

[0303] The method further includes filling the rivastigmine suspension into a spraying device, and installing a medicinal spray pump under a nitrogen environment after filling to obtain the rivastigmine nasal spray.

[0304] 2. In vitro evaluation of rivastigmine nasal spray

[0305] 1) Detect the content of the prepared rivastigmine nasal spray, and examine its viscosity, osmotic pressure, pH, sedimentation stability, spraying performance, etc. The results are shown in Table 39.

[0306] Table 39 Quality evaluation of rivastigmine nasal spray

[0307]

[0308] The results show that this preparation meets the requirements of the nasal preparations in the Chinese Pharmacopoeia 2020 Edition.

[0309] 2) Investigation of delivery dose uniformity

[0310] According to the FDA guidelines and the requirements of the Chinese Pharmacopoeia 2020 Edition, investigate the delivery dose uniformity of the zolmitriptan nasal spray, and detect the delivery doses of 10 vials of the same batch of samples. The results are shown in Table 40.

[0311] Table 40 Delivery dose uniformity of rivastigmine nasal spray

[0312]

[0313] The results showed that the delivered dose of 10 vials was 98.29% of the labeled amount, and it could stably deliver the drug, meeting the requirements of the Chinese Pharmacopoeia 2020 Edition and FDA guidelines.

[0314] 3. Pharmacokinetic study of rivastigmine nasal spray

[0315] A pharmacokinetic study was conducted on rivastigmine nasal spray with and without dodecyl-β-D-maltoside (DDM) to evaluate the brain delivery performance of rivastigmine nasal spray and the absorption-promoting effect of DDM on the drug.

[0316] Among them, the prescription designs of nasal spray (without DDM) and nasal spray (1 / 2 DDM) are shown in Table 41.

[0317] Table 41 Prescription design of rivastigmine nasal spray without DDM

[0318]

[0319] Table 42 Prescription design of 1 / 2 DDM rivastigmine nasal spray

[0320]

[0321] Prepare rivastigmine nasal spray without DDM and rivastigmine nasal spray with 1 / 2 DDM according to the above prescriptions, and the preparation method is the same as that of rivastigmine nasal spray in the previous text.

[0322] The experimental animals and administration methods are the same as above, and the results are as Figure 6 shown in Table 43;

[0323] Table 43 Rivastigmine content in rat brain tissue (n = 3)

[0324]

[0325] The results showed that the addition of DDM (dodecyl-β-D-maltoside) significantly promoted the absorption of rivastigmine, increasing the Cmax of rivastigmine in brain tissue from 841 ng / mL to 1645 ng / mL and the AUC 0-5h from 109092 ng / mL·min to 124150 ng / mL·min. In addition, the Cmax and AUC 0-5h of 1 / 2 DDM rivastigmine nasal spray were between those of rivastigmine nasal spray and rivastigmine nasal spray without DDM, indicating that the absorption-promoting effect of DDM on rivastigmine was concentration-dependent. At the same time, the addition of DDM significantly accelerated the absorption rate of rivastigmine, shortening the time to peak from 30 min to 15 min.

[0326] Example 8 Memantine hydrochloride nasal spray

[0327] 1. Preparation of Memantine Hydrochloride Nasal Spray

[0328] The prescription composition of memantine hydrochloride nasal spray is shown in Table 44 as follows:

[0329] Table 44 Prescription Composition of Memantine Hydrochloride Nasal Spray

[0330]

[0331] Prepare memantine hydrochloride nasal spray using the prescription shown in Table 45 for subsequent experiments;

[0332] Table 45 Optimized Prescription Composition of Memantine Hydrochloride Nasal Spray

[0333]

[0334]

[0335] Preparation process of memantine nasal spray:

[0336] S1: Dissolve 0.2 g of disodium hydrogen phosphate and 10.0 g of potassium dihydrogen phosphate in sufficient water to prepare 1000 mL of phosphate buffer solution.

[0337] S2: Weigh 2.0 g of sodium hydroxide into a beaker, add water to dilute and dissolve it to 50 ml to obtain 1 M sodium hydroxide solution.

[0338] S3: Add the prescribed amount of purified water and memantine hydrochloride, and stir to dissolve the drug.

[0339] S4: Measure the pH of the solution in step S3, add an appropriate amount of sodium hydroxide (1 M) solution to the solution, and adjust the pH to 5.0 ± 0.5.

[0340] S5: Add an appropriate amount of phosphate buffer solution to the solution in step S4, mix well, measure the pH of the solution. If the pH does not meet the required value, add an appropriate amount of sodium hydroxide (1 M) solution to adjust the pH.

[0341] S6: Dissolve the prescribed amount of dodecyl-β-D-maltoside in an appropriate amount of water, add it to the solution in step S5, mix well, add phosphate buffer solution to make up the volume of the solution, and mix the resulting solution well.

[0342] S7: Filter the solution obtained in step S6 through 0.45 μm and 0.22 μm fin filters for 10 minutes, and then fill it into a nasal spray device to obtain the product.

[0343] 2. In Vitro Evaluation of Memantine Hydrochloride Nasal Spray

[0344] 1) The content, related substances, osmotic pressure, pH, spray performance, etc. of the prepared memantine hydrochloride nasal spray were detected, and the results are shown in Table 46.

[0345] Table 46 Quality Evaluation of Memantine Hydrochloride Nasal Spray

[0346]

[0347] The results showed that the preparation met the requirements of the nasal preparations in the Chinese Pharmacopoeia 2020 Edition.

[0348] 3. Pharmacokinetic Study of Memantine Hydrochloride Nasal Spray

[0349] A pharmacokinetic study was carried out on memantine hydrochloride nasal spray with and without dodecyl-β-D-maltoside (DDM) to evaluate the brain delivery performance of memantine hydrochloride nasal spray and the absorption-promoting effect of DDM on the drug.

[0350] Among them, the prescription design of the nasal spray (without DDM) is shown in Table 47.

[0351] Table 47 Prescription Design of Memantine Hydrochloride Nasal Spray without DDM

[0352]

[0353] The memantine hydrochloride nasal spray without DDM was prepared according to the above prescription, and the preparation method was the same as that of the memantine hydrochloride nasal spray in the previous text.

[0354] The experimental animals and the administration method were the same as above, and the results are as Figure 7 shown in Table 48;

[0355] Table 48 Content of Memantine Hydrochloride in Rat Brain Tissue (n = 3)

[0356]

[0357]

[0358] The results showed that the addition of DDM (dodecyl-β-D-maltoside) significantly promoted the absorption of memantine hydrochloride, increased the peak concentration in the brain from 215 ng / mL to 310 ng / mL, and increased the AUC 0-12h from 794 ng / mL·h to 839 ng / mL·h. In addition, the addition of DDM significantly promoted the brain delivery of memantine hydrochloride, and increased Tmaxy from 60 min to 30 min.

[0359] Example 9 Donepezil Nasal Spray

[0360] 1. Preparation of Donepezil Nasal Spray

[0361] The prescription composition of donepezil nasal spray is shown in Table 49 as follows:

[0362] Table 49 Prescription composition of donepezil nasal spray

[0363]

[0364] The donepezil nasal spray was prepared using the prescription shown in Table 50 for subsequent experiments;

[0365] Table 50 Optimized prescription composition of donepezil nasal spray

[0366]

[0367] Preparation process of donepezil nasal spray:

[0368] S1: Dissolve 0.2 g of disodium hydrogen phosphate and 10.0 g of potassium dihydrogen phosphate in sufficient water to prepare 1000 mL of phosphate buffer solution.

[0369] S2: Weigh 2.0 g of sodium hydroxide into a beaker, add water to dilute and dissolve it to 50 ml to obtain 1 M sodium hydroxide solution.

[0370] S3: Add the prescribed amount of purified water and donepezil, and stir to dissolve the drug.

[0371] S4: Measure the pH of the solution in step S3, add an appropriate amount of sodium hydroxide (1 M) solution to the solution, and adjust the pH to 5.0 ± 0.5.

[0372] S5: Add an appropriate amount of phosphate buffer solution to the solution in step S4, mix well, measure the pH of the solution. If the pH does not meet the required value, add an appropriate amount of sodium hydroxide (1 M) solution to adjust the pH.

[0373] S6: Dissolve the prescribed amount of dodecyl-β-D-maltoside in an appropriate amount of water, add it to the solution in step S5, mix well, add phosphate buffer solution to make up the volume of the solution, and mix the resulting solution well.

[0374] S7: Filter the solution obtained in step S6 through 0.45 μm and 0.22 μm fin filters for 10 minutes, and then fill it into a nasal spray device to obtain the product.

[0375] 2. In vitro evaluation of donepezil nasal spray

[0376] 1) Detect the content, related substances, osmotic pressure, pH, spray performance, etc. of the prepared donepezil nasal spray, and the results are shown in Table 51.

[0377] Table 51 Quality evaluation of donepezil nasal spray

[0378]

[0379]

[0380] The results showed that the preparation met the requirements of nasal preparations in the Chinese Pharmacopoeia 2020 edition.

[0381] 2) Investigation of delivery dose uniformity

[0382] According to the FDA guidelines and the requirements of the Chinese Pharmacopoeia 2020 edition, the delivery doses of 10 vials of the same batch of samples were detected, and the results are shown in Table 52.

[0383] Table 52 Delivery dose uniformity of donepezil nasal spray

[0384]

[0385] The results showed that the delivery dose for 10 times was 98.62% of the labeled amount, which could stably deliver the drug and met the requirements of the Chinese Pharmacopoeia 2020 edition and FDA guidelines.

[0386] 3. Pharmacokinetic study of donepezil nasal spray

[0387] A pharmacokinetic study was conducted on donepezil nasal spray with and without dodecyl-β-D-maltoside (DDM) to evaluate the brain delivery performance of donepezil nasal spray and the absorption-promoting effect of DDM on the drug.

[0388] The prescription design of the nasal spray (without DDM) is shown in Table 53.

[0389] Table 53 Prescription design of donepezil nasal spray without DDM

[0390]

[0391] The donepezil nasal spray without DDM was prepared according to the above prescription, and the preparation method was the same as that of the donepezil nasal spray in the previous text. The experimental animals and the administration method were the same as above, and the results are as Figure 8 shown in Table 54;

[0392] Table 54 Content of donepezil in rat brain tissue (n = 3)

[0393]

[0394] The results showed that the addition of DDM (dodecyl-β-D-maltoside) significantly promoted the absorption of donepezil, increased the Cmax of donepezil in the brain from 147 ng / mL to 283 ng / mL, and increased the AUC 0-4hIt increased from 11150 ng / mL·min to 15927 ng / mL·min. In addition, the addition of DDM significantly promoted the intracerebral delivery of donepezil, increasing the peak time from 9 min to 6 min.

[0395] The above specific embodiments have described the present invention in detail. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those of ordinary skill in the relevant technical field, various changes can be made without departing from the spirit of the present invention. In addition, without conflict, the embodiments of the present invention and the features in the embodiments can be combined with each other.

Claims

1. Use of a composition in the preparation of a drug for central nervous system diseases, wherein the composition consists of the following components: 5% to 25% w / w of zolmitriptan or a pharmaceutically acceptable salt thereof, 1% to 2% w / w of a suspending agent, 0.2% to 3% w / w of an antioxidant, 0.05% to 0.5% w / w of an absorption enhancer, 0.005% to 0.02% w / w of a wetting agent, 0.005% to 0.03% w / w of a bacteriostatic agent, an osmotic pressure regulator in an amount to adjust the osmotic pressure of the composition to 270 to 350 mOsm / kg, a pH regulator in an amount to adjust the pH of the composition to 4 to 7, and purified water, with the purified water added to 100%; The absorption enhancer is dodecyl-β-D-maltoside; The wetting agent is polysorbate 80; The bacteriostatic agent is benzalkonium chloride; The suspending agent is microcrystalline cellulose - sodium carboxymethylcellulose RC591; The antioxidant is sodium metabisulfite; The pH regulator is citric acid and sodium citrate; The administration method of the central nervous system drug is nasal administration; The dosage form of the central nervous system drug is a spray; 2. Use of a composition in the preparation of a drug for central nervous system diseases, wherein the composition consists of the following components: 0.6% to 6% w / w of rivastigmine or a pharmaceutically acceptable salt thereof, 1% to 2% w / w of a suspending agent, 0.2% to 3% w / w of an antioxidant, 0.05% to 0.5% w / w of an absorption enhancer, 0.005% to 0.02% w / w of a wetting agent, 0.005% to 0.03% w / w of a bacteriostatic agent, an osmotic pressure regulator in an amount to adjust the osmotic pressure of the composition to 280 to 350 mOsm / kg, a pH regulator in an amount to adjust the pH of the composition to 4 to 7, and purified water, with the purified water added to 100%; The absorption enhancer is dodecyl-β-D-maltoside; The wetting agent is polysorbate 80; The bacteriostatic agent is benzalkonium chloride; The suspending agent is microcrystalline cellulose - sodium carboxymethylcellulose RC591; The antioxidant is sodium metabisulfite; The pH regulator is citric acid and sodium citrate; The administration method of the central nervous system drug is nasal administration; The dosage form of the central nervous system drug is a spray; 3. The application according to claim 1 or 2, characterized in that, The drug is drug micropowder; 4. The application according to claim 3, characterized in that The particle size D of the micronized drug 90 is 2 to 20 μm.

5. A method for preparing a central nervous system drug composition, characterized in that, The preparation method includes the following steps: mixing the central nervous system drug, the absorption enhancer, the excipients and the purified water evenly to obtain the drug composition; the central nervous system drug composition consists of the following components: 5% to 25% w / w of zolmitriptan or a pharmaceutically acceptable salt thereof, 1% to 2% w / w of a suspending agent, 0.2% to 3% w / w of an antioxidant, 0.05% to 0.5% w / w of an absorption enhancer, 0.005% to 0.02% w / w of a wetting agent, 0.005% to 0.03% w / w of a bacteriostatic agent, an osmotic pressure regulator in an amount to adjust the osmotic pressure of the composition to 270 to 350 mOsm / kg, a pH regulator in an amount to adjust the pH of the composition to 4 to 7, and purified water, with the purified water added to 100%; The absorption enhancer is dodecyl-β-D-maltoside; The wetting agent is polysorbate 80; The bacteriostatic agent is benzalkonium chloride; The suspending agent is microcrystalline cellulose - sodium carboxymethylcellulose RC591; The pH regulator is citric acid and sodium citrate; The antioxidant is sodium metabisulfite.

6. A method for preparing a central nervous system pharmaceutical composition, characterized in that, The preparation method comprises the following steps: uniformly mixing a central nervous system drug, an absorption enhancer, an excipient and purified water to obtain a pharmaceutical composition; the central nervous system pharmaceutical composition consists of the following components: 0.6% - 6% w / w of rivastigmine or a pharmaceutically acceptable salt thereof, 1% - 2% w / w of a suspending agent, 0.2% - 3% w / w of an antioxidant, 0.05% - 0.5% w / w of an absorption enhancer, 0.005% - 0.02% w / w of a wetting agent, 0.005% - 0.03% w / w of a bacteriostatic agent, an osmotic pressure regulator in an amount to adjust the osmotic pressure of the composition to 280 - 350 mOsm / kg, a pH regulator in an amount to adjust the pH of the composition to 4 - 7, and purified water, with the purified water added to 100%; The absorption enhancer is dodecyl-β-D-maltoside; The wetting agent is polysorbate 80; The bacteriostatic agent is benzalkonium chloride; The suspending agent is microcrystalline cellulose - sodium carboxymethylcellulose RC591; The pH regulator is citric acid and sodium citrate; The antioxidant is sodium metabisulfite.

7. The preparation method according to claim 5 or 6, characterized in that, The method further comprises filling the pharmaceutical composition into a nasal spray device to obtain a nasal spray of the central nervous system drug.

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