Galantamine Nasal Spray and its Preparation Method

Abstract

This invention discloses a galantamine nasal spray and its preparation method. The galantamine nasal spray is prepared from raw materials comprising the following components: galantamine or galantamine salt, viscosity modifier, pH adjuster, chelating agent, absorption enhancer, osmotic pressure regulator, preservative, and water, wherein the viscosity modifier is polyvinylpyrrolidone. This galantamine nasal spray has suitable viscosity, reasonable osmotic pressure and pH range, good flight stability, and a small spray area and plume angle, which can effectively improve the deposition rate of galantamine in the nasal olfactory region and effectively enhance the naso-brain drug delivery efficiency, thereby improving its therapeutic effect on Alzheimer's disease.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and in particular relates to a galantamine nasal spray and its preparation method. Background Technology

[0002] Cholinesterases are a class of glycoproteins, mainly comprising acetylcholinesterase (true cholinesterase) and butyrylcholinesterase (pseudocholinesterase). Butyrylcholinesterase accounts for only 20% of normal brain tissue, while acetylcholinesterase accounts for 80% (Cai ZY et al., Beijing: Science Press, 2016: 5-20.). Cholinesterases are primarily found in the synaptic cleft and nerve cells of cholinergic nerve endings, and are widely involved in physiological processes such as cognition, learning, memory, and synaptic plasticity. The cholinergic nervous system, as an important component of the central nervous system, is closely related to the brain's learning, memory, and cognitive functions; its functional decline often leads to central nervous system degenerative diseases. Alzheimer's disease is currently the most prevalent central nervous system degenerative disease, and the current primary explanation for its pathogenesis is the cholinesterase hypothesis. According to the recommended medications in the "Guidelines for the Diagnosis and Treatment of Alzheimer's Disease (2020 Edition)" and the "Guidelines for the Diagnosis and Treatment of Mental Disorders (2020 Edition)," cholinesterase inhibitors such as rivastigmine and galantamine are the only types of drugs used to treat mild to moderate Alzheimer's disease.

[0003] Galantamine hydrobromide is a reversible, selective, and competitive cholinesterase inhibitor with dual effects: inhibiting acetylcholinesterase and regulating nicotinic acetylcholine receptors. It is a first-line treatment for mild to moderate Alzheimer's disease. Alzheimer's disease primarily affects the central nervous system, and drugs treating central nervous system diseases require effective concentrations in the brain to be effective. However, existing cholinesterase inhibitors, including galantamine, are mainly administered orally, by injection, or through transdermal patches. All three formulations require absorption through peripheral blood circulation and crossing the blood-brain barrier to reach the disease site. Oral medications are difficult to swallow, have a significant first-pass effect, and low bioavailability. Increasing the dosage produces significant peripheral side effects such as abdominal pain and vomiting. Furthermore, for Alzheimer's patients with pre-existing memory and mood problems, adherence to oral medications is difficult to maintain. Long-term use of injectable medications can easily cause severe muscle and vascular damage, leading to common complications such as pain and bleeding. Although transdermal patches have been developed for existing similar treatments such as donepezil and rivastigmine, limited absorption and allergic reactions necessitate new solutions. Currently, existing administration routes and drug formulations have not effectively addressed the challenge of drugs crossing the blood-brain barrier to reach the brain. Therefore, exploring novel brain delivery methods for cholinesterase inhibitors such as galantamine is of significant clinical importance for improving the treatment of Alzheimer's disease.

[0004] Due to the presence of the blood-brain barrier, the treatment of neurodegenerative diseases is challenging. Currently, almost 100% of macromolecular drugs and about 98% of small molecule drugs in clinical use cannot cross the blood-brain barrier to enter the central nervous system (Gao H et al., Pharm Res, 2013, 30(10), 2485-2498). Nasal delivery formulations are preparations that deliver drugs to the nasal cavity and are absorbed through the nasal mucosa to exert local or systemic effects. The nasal cavity can be roughly divided into three regions: the vestibule, the respiratory region, and the olfactory region. The naso-brain transport of drugs is mainly completed in the olfactory region, involving the olfactory nerve pathway, the trigeminal nerve pathway, etc. This drug delivery route has the characteristics of high safety, good compliance, and direct entry into the brain by bypassing the blood-brain barrier. Therefore, for central nervous system drugs that cannot cross the blood-brain barrier, nasal olfactory delivery is expected to improve the brain targeting of the drugs. Currently, there is no relevant literature reporting the development of galantamine, used for the treatment of Alzheimer's disease, into a nasal delivery formulation. Summary of the Invention

[0005] Based on this, the present invention provides a galantamine nasal spray, comprising the following technical solutions.

[0006] A galantamine nasal spray is prepared from raw materials comprising the following components: galantamine or galantamine salt, viscosity modifier, pH modifier, chelating agent, absorption enhancer, osmotic pressure regulator, preservative, and water;

[0007] The concentrations of each component in the galantamine nasal spray are as follows: galantamine or galantamine salt 20 mg / mL-30 mg / mL, viscosity modifier 5 mg / mL-20 mg / mL, chelating agent 2 mg / mL-8 mg / mL, absorption promoter 1 mg / mL-5 mg / mL, osmotic pressure regulator 3 mg / mL-8 mg / mL, preservative 0.05 mg / mL-0.5 mg / mL, and pH adjuster as needed to make the pH of the galantamine nasal spray 5.5-6.5;

[0008] The viscosity modifier is polyvinylpyrrolidone.

[0009] In some embodiments, the polyvinylpyrrolidone is polyvinylpyrrolidone K90.

[0010] In some embodiments, the absorption enhancer is dodecyl-β-D-maltodextrin.

[0011] In some embodiments, the viscosity modifier is present at a concentration of 12 mg / mL to 17 mg / mL in the galantamine nasal spray.

[0012] In some embodiments, the viscosity modifier is present at a concentration of 13 mg / mL to 16 mg / mL in the galantamine nasal spray.

[0013] In some embodiments, the viscosity modifier is present at a concentration of 14 mg / mL to 16 mg / mL in the galantamine nasal spray.

[0014] In some embodiments, the viscosity modifier is present at a concentration of 14.5 mg / mL to 15.5 mg / mL in the galantamine nasal spray.

[0015] In some embodiments, the viscosity modifier is present at a concentration of 14.8 mg / mL to 15.2 mg / mL in the galantamine nasal spray.

[0016] In some embodiments, the viscosity modifier is present at a concentration of 15 mg / mL in the galantamine nasal spray.

[0017] In some embodiments, the concentration of galantamine or galantamine salt in the galantamine nasal spray is 22 mg / mL to 28 mg / mL.

[0018] In some embodiments, the concentration of galantamine or galantamine salt in the galantamine nasal spray is 23 mg / mL to 27 mg / mL.

[0019] In some embodiments, the concentration of galantamine or galantamine salt in the galantamine nasal spray is 24 mg / mL to 26 mg / mL.

[0020] In some embodiments, the concentration of galantamine or galantamine salt in the galantamine nasal spray is 25 mg / mL.

[0021] In some embodiments, the absorption enhancer is present at a concentration of 2 mg / mL to 4 mg / mL in the galantamine nasal spray.

[0022] In some embodiments, the absorption enhancer is present at a concentration of 2 mg / mL to 3 mg / mL in the galantamine nasal spray.

[0023] In some embodiments, the concentration of the absorption enhancer in the galantamine nasal spray is 2.2 mg / mL to 2.8 mg / mL.

[0024] In some embodiments, the absorption enhancer is present at a concentration of 2.5 mg / mL in the galantamine nasal spray.

[0025] In some embodiments, the concentration of the osmotic pressure regulator in the galantamine nasal spray is 5 mg / mL to 7 mg / mL.

[0026] In some embodiments, the concentration of the osmotic pressure regulator in the galantamine nasal spray is 5.5 mg / mL to 6.5 mg / mL.

[0027] In some embodiments, the concentration of the osmotic pressure regulator in the galantamine nasal spray is 6 mg / mL.

[0028] In some embodiments, the concentration of the chelating agent in the galantamine nasal spray is 3 mg / mL to 7 mg / mL.

[0029] In some embodiments, the concentration of the chelating agent in the galantamine nasal spray is 4 mg / mL to 6 mg / mL.

[0030] In some embodiments, the concentration of the chelating agent in the galantamine nasal spray is 4.5 mg / mL to 5.5 mg / mL.

[0031] In some embodiments, the concentration of the chelating agent in the galantamine nasal spray is 5 mg / mL.

[0032] In some embodiments, the concentration of the preservative in the galantamine nasal spray is 0.08 mg / mL to 0.2 mg / mL.

[0033] In some embodiments, the concentrations of the components in the galantamine nasal spray are as follows: galantamine or galantamine salt 23 mg / mL-27 mg / mL, viscosity modifier 14 mg / mL-16 mg / mL, chelating agent 3 mg / mL-7 mg / mL, absorption enhancer 2 mg / mL-3 mg / mL, osmotic pressure regulator 5 mg / mL-7 mg / mL, preservative 0.08 mg / mL-0.15 mg / mL, and pH adjuster as needed to make the pH of the galantamine nasal spray 5.5-6.5.

[0034] In some embodiments, the concentrations of the components in the galantamine nasal spray are as follows: galantamine or galantamine salt 24 mg / mL-26 mg / mL, viscosity modifier 14.5 mg / mL-15.5 mg / mL, chelating agent 4 mg / mL-6 mg / mL, absorption enhancer 2.2 mg / mL-2.8 mg / mL, osmotic pressure regulator 5 mg / mL-7 mg / mL, preservative 0.08 mg / mL-0.15 mg / mL, and pH adjuster as needed to make the pH of the galantamine nasal spray 5.5-6.5.

[0035] In some embodiments, the galantamine salt is galantamine hydrobromide.

[0036] In some embodiments, the pH adjuster is disodium hydrogen phosphate.

[0037] In some embodiments, the chelating agent is disodium ethylenediaminetetraacetate.

[0038] In some embodiments, the osmotic pressure regulator is sodium chloride.

[0039] In some embodiments, the preservative is benzalkonium chloride.

[0040] The present invention also provides a method for preparing the above-mentioned galantamine nasal spray, including the following technical solution.

[0041] A method for preparing the above-mentioned galantamine nasal spray includes the following steps:

[0042] 1) Dissolve the pH adjuster and chelating agent in water;

[0043] 2) Dissolve the absorption promoter and preservative in the solution from step 1);

[0044] 3) Dissolve the galantamine or galantamine salt in the solution from step 2);

[0045] 4) Dissolve the osmotic pressure regulator in the solution from step 3);

[0046] 5) Add the viscosity modifier to the solution in step 4), let it stand for 5-7 hours, and then shake it thoroughly to dissolve;

[0047] 6) Filter the solution obtained in step 5) to remove bacteria, and you will get the Galantamine nasal spray.

[0048] In their research on galantamine nasal spray, the inventors discovered that, due to the narrow area at the top of the superior nasal meatus, droplets from traditional nasal sprays are difficult to reach and deposit in the nasal olfactory region, thus affecting their naso-brain delivery efficiency. Further research revealed that the type and concentration of viscosity modifiers significantly influence the spray performance of the resulting galantamine nasal spray. By selecting a suitable viscosity modifier and adjusting its specific viscosity, the deposition rate of the drug in the nasal olfactory region can be improved. Ultimately, this invention uses polyvinylpyrrolidone (preferably K90) as a viscosity modifier, combined with galantamine or galantamine salts and a certain amount of absorption enhancers and other excipients to prepare a galantamine nasal spray. With the synergistic effect of the components at specific concentrations, the galantamine nasal spray prepared by this invention exhibits suitable viscosity, reasonable osmotic pressure and pH range, good flight stability, and appropriate spray area and plume angle. After being sprayed through a nasal spray device, the droplet size distribution, spray pattern, and spray morphology are optimized for deposition in the olfactory region, facilitating drug adhesion to the vestibule and posterior vestibule deep within the nasal cavity. This effectively increases the deposition rate of galantamine in the olfactory region, enhances drug bioavailability in the targeted area, and results in a galantamine nasal spray with high naso-brain drug delivery efficiency, thereby improving its efficacy in treating Alzheimer's disease. At the same dosage, the galantamine nasal spray prepared according to this invention is significantly more effective than commercially available galantamine hydrobromide tablets in treating Alzheimer's disease via nasal spray administration. The galantamine nasal spray of this invention can achieve better therapeutic effects more quickly, leading to faster memory recovery in patients. Attached Figure Description

[0049] Figure 1 The osmotic pressure of each formulation of galantamine nasal spray.

[0050] Figure 2 Viscosity values ​​for each formulation of galantamine nasal spray.

[0051] Figure 3 pH values ​​for each formulation of galantamine nasal spray.

[0052] Figure 4 The spray particle size distribution of galantamine nasal sprays prepared for each formulation.

[0053] Figure 5 The spray plume angle (A) and spray area (B) of the galantamine nasal sprays prepared for each formulation.

[0054] Figure 6 Distribution results of galantamine nasal sprays prepared for each formulation in NGI aerodynamic tests.

[0055] Figure 7This is a 3D-printed nasal cavity model connected to NGI.

[0056] Figure 8 Results of nasal deposition distribution for each formulation of galantamine nasal spray: A represents the percentage of deposition in the olfactory region of the nasal cavity; B represents the nasal deposition distribution.

[0057] Figure 9 The cruise duration (A) and the proportion of cruise duration (B) of each group of rats in the target area are shown in the water maze test. Detailed Implementation

[0058] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments are merely illustrative of the present invention and should not be construed as limiting the invention.

[0059] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention.

[0060] The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product, or device that includes a series of steps is not limited to the steps or modules listed, but may optionally include steps not listed, or may optionally include other steps inherent to such process, method, product, or device.

[0061] In this invention, "multiple" refers to two or more. "And / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A alone, A and B simultaneously, or B alone. The character " / " generally indicates that the preceding and following related objects have an "or" relationship.

[0062] The following are specific examples.

[0063] Example 1

[0064] The raw materials and their dosages for the galantamine nasal spray provided in this embodiment are shown in Table 1 below:

[0065] Table 1

[0066]

[0067]

[0068] Galantamine nasal sprays were prepared according to the raw materials and dosages shown in Tables 1 and 2, with 10 formulations as shown in Table 2. The concentration of the active ingredient was 25 mg / mL. Other excipients and their concentrations are shown in Table 1.

[0069] Table 2 Prescription Proportions

[0070] prescription Viscosity modifier concentration (mg / mL) Viscosity modifier <![CDATA[P1]]> 10 Polyvinylpyrrolidone K90 <![CDATA[P2]]> 12.5 Polyvinylpyrrolidone K90 <![CDATA[P3]]> 15 Polyvinylpyrrolidone K90 <![CDATA[P4]]> 17.5 Polyvinylpyrrolidone K90 <![CDATA[P5]]> 20 Polyvinylpyrrolidone K90 <![CDATA[P6]]> 6 Sodium carboxymethyl cellulose <![CDATA[P7]]> 7 Sodium carboxymethyl cellulose <![CDATA[P8]]> 8 Sodium carboxymethyl cellulose <![CDATA[P9]]> 9 Sodium carboxymethyl cellulose <![CDATA[P 10 ]]> 10 Sodium carboxymethyl cellulose

[0071] Its preparation method includes the following steps:

[0072] 1) Add disodium hydrogen phosphate to deionized water to a final concentration of 1 mg / ml and disodium ethylenediaminetetraacetate to a final concentration of 5 mg / ml;

[0073] 2) Add dodecyl-β-D-maltodextrin to the solution in step 1) to a final concentration of 2.5 mg / mL and benzalkonium chloride to a final concentration of 0.1 mg / mL;

[0074] 3) Add galantamine hydrobromide to the solution in step 2) to a final concentration of 25 mg / mL, and dissolve completely;

[0075] 4) Add sodium chloride to the solution in step 3) to a final concentration of 6 mg / mL;

[0076] 5) Add an appropriate amount of viscosity modifier to the solution in step 4), let it stand for 5-7 hours, and then shake it thoroughly to dissolve;

[0077] 6) Sterilize the solution obtained in step 5) by passing it through a 0.22 μm filter membrane to obtain the galantamine nasal spray; store at 4°C.

[0078] Example 2

[0079] Take Example 1 according to P1-P 10 The viscosity, osmotic pressure and pH of the prepared galantamine nasal spray were measured.

[0080] Viscosity testing uses the rotational viscosity method. A viscometer (Bolefeld, Canada) was used with a No. 20 rotor. 15 mL of different formulations of galantamine nasal spray were poured into the test cup for viscosity testing. The testing speed was 20 rpm / min, and the testing time was 1 min. The instrument automatically recorded the viscosity data. Three consecutive tests were performed for the same formulation to calculate the mean and standard deviation of the results.

[0081] According to the requirements of the Chinese Pharmacopoeia, the osmotic pressure of nasal sprays should be between 280-380 mOsmol / kg. This invention utilizes a STY-1A osmotic pressure analyzer (Tianjin Tianfa Technology Co., Ltd., Tianjin) to measure the osmotic pressure of P1-P... 10The osmolarity of the galantamine nasal spray prepared according to the prescription was determined. A standard osmolarity solution with a calibration range of 100-500 mOsmol / kg was used. 0.1 mL of each prescription test solution was added to an EP tube, and the osmolarity value of the galantamine nasal spray was measured.

[0082] Using a Mettler Toledo FE28 pH meter (Zurich, Switzerland), take the standard pH calibration solution (calibration range pH = 2-9), add 5 mL of each prescription test solution to an EP tube, and determine the pH value of galantamine nasal spray.

[0083] Test results are as follows Figure 1-3 As shown, P1-P 10 The osmotic pressure of the formulated galantamine nasal spray was generally between 280-380 mOsmol / kg, and the pH value was between 5.5-6.5, which meets the pH requirements for nasal administration. Furthermore, the viscosity of the solution increased with increasing content of polyvinylpyrrolidone K90 and sodium carboxymethyl cellulose.

[0084] Example 3

[0085] Take Example 1 according to P1-P 10 Each 10 mL of the prepared galantamine nasal spray was filled into a nasal spray device (nasal spray device VP7, Apta Pharmaceutical Co., Ltd., China, delivery volume 100 μL / pump). The filled spray was used to test the uniformity of spray particles and other properties.

[0086] Using a HELOS laser particle size analyzer (Synpatek, Germany), the nasal spray module was selected and adjusted to a vertical position. An R4 lens was chosen (detecting particle sizes of 0.5 / 1.8-350 μm), with a trigger pressure of 60 N, a measurement time of 300 ms, and a detection distance of 30 mm. The measurement mode was spray mode to determine P1-P. 10 The spray particle size.

[0087] The results of the spraying process comparison of galantamine nasal sprays prepared according to different formulations are as follows: Figure 4 As shown, the nasal spray process can be roughly divided into three stages: the formation stage, the stabilization stage, and the dissipation stage. The formation stage is the initial stage of atomization, during which the droplet concentration rapidly increases, and the particle size also increases accordingly. During the stabilization stage, the particle size reaches its peak and remains stable. During the dissipation stage, the droplet concentration decreases, and the particle size fluctuates significantly. To reduce the possibility of drug entering the lungs, the spray droplet size should be greater than 10 μm. At the same time, excessively large spray droplets are prone to flowing out of the nasal cavity, which is not conducive to nasal absorption. The results show that the galantamine nasal spray prepared by P1-P3 has a spray droplet size in the range of 10-300 μm, which is more conducive to drug delivery to the olfactory region.

[0088] Example 4

[0089] Due to the complex physiological structure of the nasal cavity, further exploration of the spray performance of nasal sprays is needed to more comprehensively evaluate their delivery performance. This embodiment tests the spray performance of galantamine nasal spray.

[0090] pass The online droplet testing system determined the spray pattern and spray morphology of each formulation of galantamine nasal spray, with a trigger distance of 6 cm.

[0091] The results are as follows Figure 5 As shown, with increasing viscosity, the spray area and plume angle of each formulation gradually decrease. The minimum cross-sectional area of ​​a normal adult nasal cavity is typically less than 400 mm². 2 Therefore, P3-P 10 The narrow aerosol formed by the formulated galantamine nasal spray reduces droplet collision and trapping in the nasal vestibule and ineffective deposition in the anterior nasal cavity, making it easier to deliver to the deeper olfactory region of the nasal cavity. However, when the plume angle is too small, the existing formulation results in poor atomization and dispersion, causing droplets to deposit prematurely in the anterior nasal cavity. Formulation P3 has a plume angle of 24.70° and a spray area of ​​366.8 mm² at 6 cm. 2 Based on the combined results of spray particle size, the galantamine nasal spray prepared with formulation P3 exhibits the best spray performance.

[0092] Example 5

[0093] New generation impactor (NGI) testing of galantamine nasal sprays prepared according to each formulation.

[0094] Preparation of galantamine nasal spray solution: according to P1-P in Example 1 10 Formulate and prepare a nasal spray containing galantamine hydrobromide. The drug solution was encapsulated in a nasal spray delivery device (the same device as in Example 3) for NGI experiments to test the drug delivery performance of each formulated galantamine nasal spray.

[0095] First, the NGI (Natural Genomic Inhaler) is checked for airtightness. If the airtightness is good, the instrument is installed. The inhalation device is connected horizontally and tightly to the simulated throat using the adapter. The vacuum pump is turned on, and the NGI system flow rate is set to 15 ± 5% L / min. In the seven-disc NGI equipped with a glass expander chamber (GEC), four sprays (400 μl each) of each prescription galantamine nasal spray are sprayed into the GEC. The drug solution in each disc (stage 1-7) and the micropore collector (moc) is collected and its concentration is measured. The final drug distribution results are expressed as a percentage. The operation is repeated three times in parallel, and the mean and standard deviation are obtained.

[0096] The results are as follows Figure 6 As shown, the drug in each prescription galantamine nasal spray is essentially retained in the GEC, with very small amounts entering the bronchi and alveoli (diameter <10 μm) represented by stages 2-7. The results indicate that through the P1-P of this invention... 10 The drug in the formulated galantamine nasal spray is deposited in the nasal cavity and does not enter the bronchi with a diameter of less than 10 μm, effectively preventing the drug from entering the lungs. This ensures efficient and accurate drug delivery and complies with the recommendation in the Chinese Pharmacopoeia (2020) that "the spray particle size for nasal spray formulations should not be less than 10 μm to reduce inhalation into the lungs or small bronchi." Therefore, the galantamine nasal spray prepared in this invention can be used as a nasal spray for targeted brain delivery of galantamine.

[0097] Example 6

[0098] To quantitatively test the distribution and deposition of nasal spray drugs in the nasal cavity, a 3D-printed human nasal cavity model was used to determine the deposition distribution and olfactory region percentage of each prescription. Based on the magnetic resonance imaging (MRI) scans of healthy adults, a human nasal cavity model was established and divided into five parts according to its physiological structure: the nasal vestibule (NV), inferior turbinate (INT), middle turbinate (MNT), superior nasal meatus (SNT), and pharynx (ORO). Its structure is as follows: Figure 7 As shown, the drug ratio in the SNT can be considered as the fraction of drug deposition in the olfactory region (ORF).

[0099] Nasal deposition test: The nasal spray device is connected to the NGI and sprayed perpendicularly to the nostrils. Each prescription is sprayed 4 times. The device is then split and the deposited drug in each part is dissolved with a quantitative amount of deionized water. The drug concentration is determined by high performance liquid chromatography and the deposition percentage is calculated.

[0100] The results are as follows Figure 8 As shown, consistent with the preferred results of Example 4, the galantamine nasal spray of the P3 formulation has the most suitable spray particle size, plume angle and spray area, thereby reducing the deposition distribution of the drug in the nasal vestibule and respiratory zone, and can effectively deliver the drug to the olfactory region located deep in the nasal cavity, with the highest olfactory drug deposition ratio of 23.85%, which can deliver more galantamine hydrobromide to the olfactory region of the nasal cavity, and then to the brain, thereby improving the therapeutic effect of the drug.

[0101] Example 7

[0102] An Alzheimer's disease rat model was established to conduct an in vivo pharmacodynamic study on the preferred P3 formulation galantamine nasal spray. A commercially available galantamine hydrobromide tablet (Jinkang) solution at the same dose as the gavage administration was selected as a positive control.

[0103] Drug preparation: Preparation of galantamine oral (gavage) solution: Crush commercially available galantamine hydrobromide tablets (dosage: 5 mg / tablet) in a mortar and pestle, and then dissolve in physiological saline to prepare a 1.5 mg / mL suspension. The drug solution was administered to SD rats in the oral gavage group via gavage.

[0104] Model establishment: SD rats of similar weight were randomly divided into 4 groups of 6 rats each: Control group, Model group, PO group (oral administration group), and NS group (nasal spray group). After anesthetizing the rats in all groups except the Control group, Aβ was injected into the CA1 region of the hippocampus (3.0 mm from the anterior fontanelle, 3.5 mm lateral to the midline, and 4 mm deep) at a rate of 1 μL / min. 1-42 5 μL protein solution (containing 5 μg Aβ) 1-42 A rat model of Alzheimer's disease was established by injecting saline solution into both hippocampi of the rats. Rats in the control group were injected with an equal volume of saline solution in the same manner.

[0105] Administration: The PO group and NS were administered 1.8 mg / kg / day, while the Control and Model groups received an equal volume of normal saline daily. After 30 days of continuous administration, the Morris water maze test was performed.

[0106] Morris water maze test: A pool with a diameter of 1.6m and a depth of 1m is filled with water and divided into four equal sectors with the center as the intersection point. These sectors are labeled A, B, C, and D. Four markers of different shapes are fixed at the midpoint of the outer perimeter of each sector. A transparent platform with a diameter of 10cm (i.e., a hidden platform) is placed 2cm below the water surface at the isometric tangent of sector A, and sector A is defined as the target area. For four consecutive days, rats from each group are placed into the pool sequentially along the midpoint of the outer perimeter of each of the four sectors (A, B, C, and D). The rats are encouraged to swim and navigate in the pool by utilizing the feeling of weightlessness in the water. The fixed markers around the pool serve as indicators to guide the rats to find the platform (hidden platform). The spatial memory ability of each group of rats is evaluated by analyzing the time taken for each group of rats to find and land on the platform (navigation time) and the proportion of time spent navigating in the target area, using a video camera above the pool and animal behavior analysis software (SuperMaze, Shanghai Xinruan Company).

[0107] After four days of training and testing, the time it took for rats in each group to successfully locate the hidden platform in the pool decreased day by day. Figure 9As shown, the cruising time in the Model group was significantly longer than that in the Control group, indicating the successful establishment of the Alzheimer's disease rat model. The cruising times in both the PO and NS groups were significantly shorter than those in the Model group, indicating that the treated Alzheimer's model rats could better recognize the target area and remember the location of the hidden platform. Furthermore, the cruising time in the NS group was closer to that of the Control group than the PO group, demonstrating superior spatial memory ability. Comparing the four consecutive days of training tests, the cruising time and the ratio of cruising time to the target area in the NS group were closer to the performance of the Control group, indicating that intranasal administration of galantamine has a better therapeutic effect on Alzheimer's disease.

[0108] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0109] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A galantamine nasal spray, characterized in that, prepared from the following raw and auxiliary materials: galantamine or galantamine salt, viscosity regulator, pH regulator, chelating agent, absorption promoter, osmotic pressure regulator, preservative, water; The concentration of each component in the galantamine nasal spray is as follows: galantamine or galantamine salt 20 mg / mL-30 mg / mL, viscosity regulator 14 mg / mL-16 mg / mL, chelating agent 2 mg / mL-8 mg / mL, absorption promoter 1 mg / mL-5 mg / mL, osmotic pressure regulator 3 mg / mL-8 mg / mL, preservative 0.05 mg / mL-0.5 mg / mL, pH regulator appropriate amount to make the pH of the galantamine nasal spray 5.5-6.5; The viscosity regulator is polyvinylpyrrolidone K90; The absorption promoter is dodecyl-β-D-maltoside; The chelating agent is disodium ethylenediaminetetraacetate; The osmotic pressure regulator is sodium chloride.

2. The galantamine nasal spray of claim 1, wherein, The concentration of the viscosity regulator in the galantamine nasal spray is 14.5 mg / mL-15.5 mg / mL.

3. The galantamine nasal spray of claim 2, wherein, The concentration of the viscosity regulator in the galantamine nasal spray is 15 mg / mL.

4. The galantamine nasal spray of claim 1, wherein, The concentration of the galantamine or galantamine salt in the galantamine nasal spray is 22 mg / mL-28 mg / mL.

5. The nasal spray of galantamine according to claim 4, characterized in that, The concentration of the galantamine or galantamine salt in the galantamine nasal spray is 23 mg / mL-27 mg / mL.

6. The nasal spray of galantamine according to claim 5, characterized in that, The concentration of the galantamine or galantamine salt in the galantamine nasal spray is 24 mg / mL-26 mg / mL.

7. The nasal spray of galantamine according to claim 6, characterized in that, The concentration of the galantamine or galantamine salt in the galantamine nasal spray is 25 mg / mL.

8. The nasal spray of galantamine according to claim 1, characterized in that, The concentration of the absorption promoter in the galantamine nasal spray is 2 mg / mL-4 mg / mL.

9. The nasal spray of galantamine according to claim 8, characterized in that, The concentration of the absorption promoter in the galantamine nasal spray is 2 mg / mL-3 mg / mL.

10. The nasal spray of galantamine according to claim 9, characterized in that, The concentration of the absorption promoter in the galantamine nasal spray is 2.5 mg / mL.

11. The galantamine nasal spray of claim 1, wherein, The concentration of the osmotic pressure regulator in the galantamine nasal spray is 5 mg / mL-7 mg / mL.

12. The nasal spray of galantamine according to claim 11, characterized in that, The concentration of the osmotic pressure regulator in the galantamine nasal spray is 5.5 mg / mL-6.5 mg / mL.

13. The nasal spray of galantamine according to claim 12, characterized in that, The concentration of the osmotic pressure regulator in the galantamine nasal spray is 6 mg / mL.

14. The nasal spray of galantamine according to claim 1, characterized in that, The concentration of each component in the galantamine nasal spray is as follows: galantamine or galantamine salt 23 mg / mL-27 mg / mL, viscosity regulator 14 mg / mL-16 mg / mL, chelating agent 3 mg / mL-7 mg / mL, absorption promoter 2 mg / mL-3 mg / mL, osmotic pressure regulator 5 mg / mL-7 mg / mL, preservative 0.08 mg / mL-0.15 mg / mL, pH regulator appropriate amount to make the pH of the galantamine nasal spray 5.5-6.

5.

15. The nasal spray of galantamine according to claim 14, characterized in that, The concentration of each component in the galantamine nasal spray is as follows: galantamine or galantamine salt 24 mg / mL-26 mg / mL, viscosity regulator 14.5 mg / mL-15.5 mg / mL, chelating agent 4 mg / mL-6 mg / mL, absorption promoter 2.2 mg / mL-2.8 mg / mL, osmotic pressure regulator 5 mg / mL-7 mg / mL, preservative 0.08 mg / mL-0.15 mg / mL, pH regulator in an appropriate amount to make the pH of the galantamine nasal spray 5.5-6.

5.

16. The nasal spray of galantamine according to any one of claims 1-15, characterized in that, The galantamine salt is galantamine hydrobromide; and / or, The pH regulator is disodium hydrogen phosphate; and / or, The preservative is benzalkonium chloride.

17. A method of preparing the galantamine nasal spray of any one of claims 1-16, characterized in that, The method comprises the following steps: The pH regulator and chelating agent are dissolved in water; 2) The absorption promoter and preservative are dissolved in the solution of step 1); 3) The galantamine or galantamine salt is dissolved in the solution of step 2); 4) The osmotic pressure regulator is dissolved in the solution of step 3); 5) The viscosity regulator is added to the solution of step 4), left to stand for 5-7 hours, and then dissolved by shaking thoroughly; 6) The solution obtained in step 5) is filtered to sterilize, and the galantamine nasal spray is obtained.

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