Galanthamine nasal spray and preparation method thereof

Abstract

The invention discloses a galanthamine nasal spray and a preparation method thereof. The galanthamine nasal spray is prepared from the following raw and auxiliary materials: galanthamine or galanthamine salt, a viscosity regulator, a pH regulator, a chelating agent, an absorption enhancer, an osmotic pressure regulator, a preservative and water, wherein the viscosity regulator is polyvinylpyrrolidone. The galanthamine nasal spray has proper viscosity, reasonable osmotic pressure and pH range, better flight stability and smaller spray area and plume angle, can effectively improve the deposition rate of galanthamine medicine in a nasal cavity olfactory region, and can effectively improve the delivery efficiency of nose-brain medicine, thereby improving the effect of treating Alzheimer's disease.

Description

Technical Field

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

[0002] Cholinesterase is a class of glycoproteins, mainly including acetylcholinesterase (true cholinesterase) and butyrylcholinesterase (pseudocholinesterase), of which butyrylcholinesterase accounts for only 20% in normal brain tissue, while acetylcholinesterase accounts for 80% (Cai ZY et al., Beijing: Science Press, 2016: 5-20.). Cholinesterase is mainly present in the synaptic cleft and nerve cells of cholinergic nerve endings, and is widely involved in physiological processes such as cognition, learning and memory, and synaptic plasticity. As an important part of the central nervous system, the cholinergic nervous system is closely related to the brain's learning, memory, cognition and other functions, and its functional degeneration often develops into degenerative diseases of the central nervous system. Alzheimer's disease is currently the most common degenerative disease of the central nervous system, and the current main explanation for the disease is the cholinesterogenic hypothesis. According to the commonly used drug recommendations 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 type of drugs used to treat mild and moderate Alzheimer's disease.

[0003] Galantamine hydrobromide is a reversible, selective and competitive cholinesterase inhibitor with the dual effects of inhibiting acetylcholinesterase and regulating nicotinic acetylcholine receptors. The drug is a first-line drug for the treatment of mild and moderate Alzheimer's disease. The main site of Alzheimer's disease is the central nervous system, and drugs for the treatment of central nervous system diseases need to reach an effective concentration in the brain to produce therapeutic effects. However, existing cholinesterase inhibitors, including galantamine, mainly use three dosage forms: oral, injection and transdermal patch. All three types of preparations need to be absorbed through the peripheral blood circulation and pass through the blood-brain barrier to reach the disease site. Oral drugs are difficult to swallow, have obvious first-pass effects, and have low bioavailability. Increasing the dosage of the drug will produce obvious peripheral side effects, such as abdominal pain, vomiting, etc. In addition, for Alzheimer's patients with poor memory and bad mood, it is difficult to ensure the compliance of oral drugs. Long-term use of injections can easily cause severe muscle and vascular damage, and can easily lead to common complications such as pain and bleeding. Although transdermal patches have been developed for the existing similar therapeutic drugs donepezil and rivastigmine, new solutions are urgently needed due to problems such as limited absorption and allergic reactions. Currently, the existing routes of administration and drug preparations have not been able to effectively solve the problem of drugs having difficulty passing through the blood-brain barrier to reach the brain. Therefore, exploring new ways to deliver cholinesterase inhibitors such as galantamine to the brain is of great clinical significance for improving the treatment of Alzheimer's disease.

[0004] Due to the existence of the blood-brain barrier, the treatment of neurodegenerative diseases is difficult. Among the current clinically used drugs, almost 100% of macromolecular drugs and about 98% of small molecule drugs are difficult to penetrate the blood-brain barrier into the central nervous system (Gao H et al., Pharm Res, 2013, 30 (10), 2485-2498.). Nasal administration preparations are preparations that deliver drugs to the nasal cavity and absorb them through the nasal mucosa to exert local or systemic therapeutic effects. The nasal cavity can be roughly divided into three areas: the vestibule, the respiratory area, and the olfactory area. The nose-to-brain transport of drugs is mainly completed by the olfactory area, involving the olfactory nerve pathway, the trigeminal nerve pathway, etc. This drug delivery route has the characteristics of high safety, good compliance, and bypassing the blood-brain barrier to directly enter the brain. Therefore, for central nervous system drugs that cannot penetrate the blood-brain barrier, nasal olfactory administration is expected to improve the brain targeting of drugs. At present, there is no relevant literature reporting that galanthamine used for the treatment of Alzheimer's disease has been developed into a nasal administration preparation. Summary of the invention

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

[0006] A galanthamine nasal spray is prepared from raw and auxiliary materials including the following components: galanthamine or galanthamine salt, viscosity regulator, pH regulator, chelating agent, absorption promoter, osmotic pressure regulator, preservative, and water;

[0007] The concentration of each component in the galanthamine nasal spray is as follows: galanthamine or galanthamine salt 20mg / mL-30mg / mL, viscosity regulator 5mg / mL-20mg / mL, chelating agent 2mg / mL-8mg / mL, absorption enhancer 1mg / mL-5mg / mL, osmotic pressure regulator 3mg / mL-8mg / mL, preservative 0.05mg / mL-0.5mg / mL, pH adjuster in an amount such that the pH of the galanthamine nasal spray is 5.5-6.5;

[0008] The viscosity modifier is polyvinyl pyrrolidone.

[0009] In some embodiments, the polyvinyl pyrrolidone is polyvinyl pyrrolidone K90.

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

[0011] In some embodiments, the concentration of the viscosity modifier in the galanthamine nasal spray is 12 mg / mL-17 mg / mL.

[0012] In some embodiments, the concentration of the viscosity modifier in the galanthamine nasal spray is 13 mg / mL-16 mg / mL.

[0013] In some embodiments, the concentration of the viscosity modifier in the galanthamine nasal spray is 14 mg / mL-16 mg / mL.

[0014] In some embodiments, the concentration of the viscosity modifier in the galanthamine nasal spray is 14.5 mg / mL-15.5 mg / mL.

[0015] In some embodiments, the concentration of the viscosity modifier in the galanthamine nasal spray is 14.8 mg / mL-15.2 mg / mL.

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

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

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

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

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

[0021] In some embodiments, the concentration of the absorption enhancer in the galanthamine nasal spray is 2 mg / mL-4 mg / mL.

[0022] In some embodiments, the concentration of the absorption enhancer in the galanthamine nasal spray is 2 mg / mL-3 mg / mL.

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

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

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

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

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

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

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

[0030] In some embodiments, the concentration of the chelating agent in the galanthamine nasal spray is 4.5 mg / mL-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 galanthamine nasal spray is 0.08 mg / mL-0.2 mg / mL.

[0033] In some of the embodiments, the concentration of each component in the galanthamine nasal spray is as follows: galanthamine or galanthamine salt 23mg / mL-27mg / mL, viscosity regulator 14mg / mL-16mg / mL, chelating agent 3mg / mL-7mg / mL, absorption enhancer 2mg / mL-3mg / mL, osmotic pressure regulator 5mg / mL-7mg / mL, preservative 0.08mg / mL-0.15mg / mL, pH adjuster in an amount such that the pH of the galanthamine nasal spray is 5.5-6.5.

[0034] In some of the embodiments, the concentration of each component in the galanthamine nasal spray is as follows: galanthamine or galanthamine salt 24mg / mL-26mg / mL, viscosity regulator 14.5mg / mL-15.5mg / mL, chelating agent 4mg / mL-6mg / mL, absorption enhancer 2.2mg / mL-2.8mg / mL, osmotic pressure regulator 5mg / mL-7mg / mL, preservative 0.08mg / mL-0.15mg / mL, pH adjuster in an amount such that the pH of the galanthamine nasal spray is 5.5-6.5.

[0035] In some embodiments, the galanthamine salt is galanthamine 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 galanthamine nasal spray, which comprises the following technical scheme.

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

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

[0043] 2) dissolving the absorption enhancer and preservative in the solution of step 1);

[0044] 3) dissolving the galanthamine or galanthamine salt in the solution of step 2);

[0045] 4) dissolving the osmotic pressure regulator in the solution of step 3);

[0046] 5) adding the viscosity modifier to the solution of step 4), leaving it to stand for 5-7 hours, and then shaking it thoroughly to dissolve;

[0047] 6) filtering and sterilizing the solution obtained in step 5) to obtain the galanthamine nasal spray.

[0048] The inventor of the present invention found in the process of studying galanthamine nasal spray that, because the olfactory area is mainly located in the narrow area at the top of the upper nasal passage, the droplets produced by the traditional nasal spray are difficult to reach and deposit in the nasal olfactory area, thereby affecting its nose-brain delivery efficiency. The inventor has then done a lot of research and found that the type and concentration of the viscosity modifier have a great influence on the spray performance of the obtained galanthamine nasal spray. By selecting a suitable viscosity modifier and adjusting its specific viscosity, the deposition rate of the drug in the olfactory area of ​​the nasal cavity can be improved. Finally, the present invention uses polyvinyl pyrrolidone (preferably K90) as a viscosity modifier, and prepares a galanthamine nasal spray with auxiliary materials such as galanthamine or galanthamine salt and a certain amount of absorption promoter. Under the synergistic coordination of each component at a specific concentration, the galanthamine nasal spray prepared by the present invention has suitable viscosity, reasonable osmotic pressure and pH range, good flight stability, and suitable spray area and plume angle. After being sprayed through a nasal spray device, a droplet size distribution, spray pattern and spray form suitable for olfactory area deposition can be obtained, which is more conducive to the adhesion of the drug to the atrium and the back vestibule deep in the nasal cavity, effectively improving the deposition rate of the galanthamine drug in the nasal olfactory area, and improving the bioavailability of the drug in a fixed area, so that the obtained galanthamine nasal spray has a higher nose-brain drug delivery efficiency, thereby improving its effect in treating Alzheimer's disease. Under the same dose, the galanthamine nasal spray prepared by the present invention is significantly better than the currently commercially available product galanthamine hydrobromide tablets in the effect of nasal spray administration for treating Alzheimer's disease. The galanthamine nasal spray of the present invention can achieve better therapeutic effects more quickly, and make the patient's memory recover faster. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 Osmolarity of galantamine nasal spray prepared for each formulation.

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

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

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

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

[0054] Figure 6 Distribution results of galantamine nasal spray prepared for each formulation in the NGI aerodynamic test.

[0055] Figure 7A 3D printed nasal model connected to NGI.

[0056] Figure 8 The nasal deposition distribution results of galantamine nasal spray prepared for each prescription: A is the percentage of deposition in the nasal olfactory area; B is the nasal deposition distribution.

[0057] Fig. 9 The cruising time of rats in each group in the water maze test (A) and the proportion of the cruising time of rats in the target area (B). DETAILED DESCRIPTION

[0058] The technical scheme of the present invention is further illustrated by specific examples below. Those skilled in the art should understand that the examples are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0059] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0060] The terms "including" and "having" and any variations thereof of the present invention are intended to cover non-exclusive inclusions. For example, a process, method, device, product or equipment comprising a series of steps is not limited to the listed steps or modules, but may optionally include steps not listed, or may optionally include other steps inherent to these processes, methods, products or equipment.

[0061] In the present invention, the term "multiple" refers to two or more than two. "And / or" describes the association relationship of associated objects, indicating that three relationships may exist. For example, A and / or B can represent the following three situations: A exists alone, A and B exist at the same time, and B exists alone. The character " / " generally indicates that the associated objects are in an "or" relationship.

[0062] The following are specific embodiments.

[0063] Example 1

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

[0065] Table 1

[0066]

[0067]

[0068] According to the raw materials and dosages shown in Tables 1 and 2, galantamine nasal sprays of 10 prescriptions shown in Table 2 were prepared, with the main drug concentration being 25 mg / mL. Other excipients and their concentrations are shown in Table 1.

[0069] Table 2 Prescription ratio table

[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] The preparation method thereof comprises the following steps:

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

[0073] 2) adding dodecyl-β-D-maltoside 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) adding galantamine hydrobromide to the solution in step 2) to a final concentration of 25 mg / mL and dissolving the galantamine hydrobromide sufficiently;

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

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

[0077] 6) sterilizing the solution obtained in step 5) through a 0.22 μm filter membrane to obtain the galanthamine nasal spray; and storing at 4° C.

[0078] Example 2

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

[0080] The viscosity test uses the rotational viscosity method. Viscometer (Broughfield, Canada) was used with a No. 20 rotor. 15 mL of galantamine nasal spray of different formulations was poured into the test cup for viscosity test. The test speed was 20 rpm / min and the test time was 1 min. The instrument automatically recorded the viscosity data. The same formulation was tested three times in a row to calculate the mean and standard deviation of the results.

[0081] According to the requirements of the Chinese Pharmacopoeia, the osmotic pressure of nasal spray should be between 280-380 mOsmol / kg. The present invention uses STY-1A osmotic pressure measuring instrument (Tian Da Tian Fa Technology Co., Ltd., Tianjin) to measure P1-P 10The galanthamine nasal spray prepared by the prescription was subjected to osmotic pressure determination. The standard osmotic pressure solution calibration range was 100-500mOsmol / kg. 0.1mL of the test solution of each prescription was taken and added to the EP tube to determine the osmotic pressure value of the galanthamine nasal spray.

[0082] A Mettler-Toledo FE28 pH meter (Zurich, Switzerland) was used to calibrate the standard pH calibration solution in the range of pH = 2-9. 5 mL of each test solution was taken and added to the EP tube to determine the pH value of the galantamine nasal spray.

[0083] Test results such as Figure 1-3 As shown, P1-P 10 The osmotic pressure of the galanthamine nasal spray prepared by the prescription is basically between 280-380mOsmol / kg, and the pH value is between 5.5-6.5, which meets the pH value requirement range for nasal administration. And the viscosity of the drug solution increases with the increase of the content of polyvinylpyrrolidone K90 and sodium carboxymethylcellulose.

[0084] Example 3

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

[0086] With the laser particle size analyzer HELOS (Synpatek, Germany), select the nasal spray module, adjust it to the vertical position, select the R4 lens (detection particle size 0.5 / 1.8-350μm), the trigger pressure is 60N, the measurement time is 300ms, and the detection distance is 30mm. The measurement mode is the spray mode to measure P1-P 10 of spray particle size.

[0087] The spray process comparison results of the galantamine nasal spray prepared by each prescription are as follows Figure 4 As shown in the figure, the spray process of nasal spray can be roughly divided into three stages: formation period, stabilization period and dissipation period. The formation period is the beginning stage of atomization, the droplet concentration increases rapidly, and the particle size also increases accordingly; the particle size reaches a peak value and remains stable during the stabilization period; the droplet concentration decreases during the dissipation period, and the particle size fluctuates greatly. In order to reduce the possibility of drugs entering the lungs, the spray droplet size should be greater than 10μm; at the same time, too large spray droplets can easily cause droplets to flow out of the nasal cavity, which is not conducive to nasal absorption. The results show that the spray particle size of the galanthamine nasal spray prepared by P1-P3 is in the range of 10-300μm, which is more conducive to the olfactory delivery of drugs.

[0088] Example 4

[0089] Due to the complex physiological structure of the nasal cavity, the spray performance of nasal sprays still needs to be explored to more comprehensively evaluate the delivery performance of nasal sprays. This example tests the spray performance of galantamine nasal spray.

[0090] pass The droplet online testing system measured the spray pattern and spray form of the galanthamine nasal spray prepared with each prescription, and the trigger distance was 6 cm.

[0091] The results are as follows Figure 5 As shown in the figure, as the viscosity increases, the spray area and plume angle of each prescription gradually decrease. The minimum cross-sectional area of ​​the normal adult nasal cavity is usually less than 400mm 2 , so P3-P 10 The narrow spray aerosol formed by the galantamine nasal spray prepared by the prescription can reduce the collision and interception of spray droplets in the nasal vestibule and the ineffective deposition in the front of the nasal cavity, making it easier to be delivered to the olfactory area deep in the nasal cavity. However, when the plume angle is too small, the existing prescription will form a poor atomization and dispersion effect, causing the droplets to deposit in the front of the nasal cavity in advance. The plume angle of prescription P3 is 24.70°, and the spray area at 6cm is 366.8mm 2 ,Combining the spray particle size results, the spray performance of galantamine nasal spray prepared by prescription P3 is the best.

[0092] Example 5

[0093] New generation impactor (NGI) testing of galantamine nasal spray prepared according to various formulations.

[0094] Preparation of galantamine nasal spray solution: according to P1-P in Example 1 10 The drug solution was encapsulated in a nasal spray drug delivery device (the same device as in Example 3) to perform an NGI experiment to detect the drug delivery performance of the galanthamine nasal spray of each prescription.

[0095] First, the NGI was checked for air tightness. If the air tightness was good, the instrument was installed. The inhalation device was tightly connected to the simulated throat with an adapter in a horizontal manner, the vacuum pump was turned on, and the flow rate of the NGI system was set to 15±5% L / min. In the seven-disc NGI instrument equipped with a glass expansion chamber (GEC), 4 sips (volume 400μl) of each prescription galantamine nasal spray were sprayed toward the GEC, and the drug solution of each disk (stage1-7) and microporous collector (moc) was collected and its content was detected. The final drug distribution result was expressed as a percentage. The operation was repeated three times in parallel to obtain the mean and standard deviation.

[0096] The results are as follows Figure 6 As shown in the figure, the galantamine nasal spray drugs of each prescription are basically retained in the GEC, and a very small amount enters the bronchus and alveoli represented by stage 2-7 (diameter <10μm). 10 The drugs in the galantamine nasal spray prepared by the prescription can be deposited in the nasal cavity and will not enter the bronchi with a diameter of less than 10 μm, which can effectively prevent the drugs from entering the lungs, ensuring efficient and accurate drug delivery, and complying with the recommendation in the Chinese Pharmacopoeia (2020) that "the spray particle size of nasal spray preparations should not be less than 10 μm to reduce inhalation into the lungs or microbronchial tubes". Therefore, the galantamine nasal spray prepared by the present invention can be used as a nasal spray for targeted brain delivery of galantamine.

[0097] Example 6

[0098] In order to quantitatively test the distribution and deposition of nasal spray drugs in the nasal cavity, the nasal deposition distribution of each prescription and the percentage of olfactory deposition were determined by 3D printing a human nasal cavity model. Based on the magnetic resonance imaging results of healthy adults, a human nasal cavity model was established. According to its physiological structure, it was divided into five parts: nasal vestibule (NV), inferior turbinate (INT), middle turbinate (MNT), superior nasal meatus (SNT), and pharynx (ORO). Its structure is as follows Figure 7 The drug ratio in SNT can be regarded as the drug deposition fraction in the olfactory region (ORF).

[0099] Nasal deposition test: Connect the nasal spray device to the NGI and spray perpendicular to the nostrils. Repeat the spray 4 times for each prescription. Split the device and use quantitative deionized water to dissolve the deposited drugs in each part. Determine the drug concentration by HPLC and calculate the deposition percentage.

[0100] The results are as follows Figure 8 As shown, consistent with the preferred results of Example 4, the galanthamine nasal spray of P3 prescription 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 area, and can effectively deliver the drug to the olfactory area deep in the nasal cavity, with the highest olfactory drug deposition ratio of 23.85%, which can deliver more galanthamine hydrobromide to the nasal olfactory area, and then to the brain, thereby improving the therapeutic effect of the drug.

[0101] Example 7

[0102] By constructing an Alzheimer's disease rat model, the in vivo pharmacodynamics of the preferred P3 prescription galantamine nasal spray was studied. The commercially available galantamine hydrobromide tablets (Jinkang) solution with the same dose as that of oral administration was selected as a positive control.

[0103] Drug preparation: Preparation of galantamine oral (oral gavage) solution: Grind the commercially available galantamine hydrobromide tablets (dose: 5 mg / tablet) in a mortar and pestle, and prepare a 1.5 mg / mL suspension solution with normal saline. The drug solution was administered to SD rats in the oral gavage group using an oral gavage needle.

[0104] Modeling: SD rats with similar body weight were randomly divided into 4 groups, 6 rats in each group, namely Control group, Model group, PO group (oral administration group), and NS group (nasal spray administration group). After anesthetizing the rats in the remaining groups except the Control group, Aβ was injected into the CA1 area of ​​the hippocampus of the rat brain (at -3.0mm from the anterior bregma, 3.5mm to the left and right of the raphe, and 4mm deep) at a rate of 1μL / min. 1-42 5 μL protein solution (containing 5 μg Aβ 1-42 The rat model of Alzheimer's disease was established by injecting the left and right hippocampus with the same volume of saline.

[0105] Drug administration: The PO group and NS were administered at a dose of 1.8 mg / kg / d, and the Control group and Model group were administered with an equal volume of normal saline daily. After 30 consecutive days of 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 of the circle as the intersection point. They are marked as areas ABCD, and four markers of different shapes are fixed at the midpoint of the periphery of each area. A transparent platform with a diameter of 10cm (i.e., a hidden platform) is placed 2cm below the water surface at the equiangular section of the sector of area A, and area A is defined as the target area. For four consecutive days, the experimental rats of each group were placed in the pool along the periphery midpoint of the four areas ABCD in turn. The sense of emptiness of the rats in the water was used to force the rats to swim and cruise in the pool. The fixed markers around the pool were used as instructions to guide the rats to find a platform where they could stand (hidden platform). The video recorder above the pool and the animal behavior analysis software (SuperMaze, Shanghai Xinruan Company) were used to analyze the time it took for each group of rats to find and log on to the platform (cruising time) and the proportion of the cruising time of each group of rats in the target area to evaluate the spatial memory ability of each group of rats.

[0107] After four days of training and testing, the time it took each group of rats to successfully find the hidden platform in the pool decreased day by day. Fig. 9As shown in the figure, the cruising time of the Model group was significantly longer than that of the Control group, indicating that the Alzheimer's disease rat model was successfully established. The cruising time of the PO group and the NS group was significantly lower than that of the Model group, indicating that the treated Alzheimer's disease model rats were able to better recognize the target area and remember the location of the hidden platform; and the cruising time of the NS group rats was closer to that of the Control group than that of the PO group, showing a spatial memory ability superior to that of the PO group. Comparing the four consecutive days of training tests, the cruising time of the NS group and the cruising time ratio of the target area 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-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described 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 above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A galantamine nasal spray, characterized in that, The preparation is made of raw materials and auxiliary materials including the following components: galanthamine or galanthamine salt, viscosity regulator, pH regulator, chelating agent, absorption promoter, osmotic pressure regulator, preservative, water; The concentration of each component in the galanthamine nasal spray is as follows: galanthamine or galanthamine salt 20mg / mL-30mg / mL, viscosity regulator 5mg / mL-20mg / mL, chelating agent 2mg / mL-8mg / mL, absorption enhancer 1mg / mL-5mg / mL, osmotic pressure regulator 3mg / mL-8mg / mL, preservative 0.05mg / mL-0.5mg / mL, pH adjuster in an amount such that the pH of the galanthamine nasal spray is 5.5-6.5; The viscosity modifier is polyvinyl pyrrolidone.

2. The galanthamine nasal spray according to claim 1, characterized in that The polyvinyl pyrrolidone is polyvinyl pyrrolidone K90; and / or, The absorption enhancer is dodecyl-β-D-maltoside.

3. The galanthamine nasal spray according to claim 1 or 2, characterized in that The concentration of the viscosity regulator in the galanthamine nasal spray is 12 mg / mL-17 mg / mL, preferably 14 mg / mL-16 mg / mL, preferably 14.5 mg / mL-15.5 mg / mL, preferably 15 mg / mL.

4. The galanthamine nasal spray according to claim 1 or 2, characterized in that The concentration of the galanthamine or galanthamine salt in the galanthamine nasal spray is 22 mg / mL-28 mg / mL, preferably 23 mg / mL-27 mg / mL, preferably 24 mg / mL-26 mg / mL, and preferably 25 mg / mL.

5. The galanthamine nasal spray according to claim 1 or 2, characterized in that The concentration of the absorption enhancer in the galanthamine nasal spray is 2 mg / mL-4 mg / mL, preferably 2 mg / mL-3 mg / mL, preferably 2.5 mg / mL.

6. The galanthamine nasal spray according to claim 1 or 2, characterized in that The concentration of the osmotic pressure regulator in the galanthamine nasal spray is 5 mg / mL-7 mg / mL, preferably 5.5 mg / mL-6.5 mg / mL, preferably 6 mg / mL.

7. The galanthamine nasal spray according to claim 1 or 2, characterized in that The concentrations of the components in the galanthamine nasal spray are as follows: galanthamine or galanthamine salt 23 mg / mL-27 mg / mL, viscosity regulator 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 an appropriate amount of pH regulator to make the pH of the galanthamine nasal spray 5.5-6.

5.

8. The galanthamine nasal spray according to claim 7, characterized in that The concentrations of the components in the galanthamine nasal spray are as follows: galanthamine or galanthamine 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 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 an appropriate amount of pH regulator to make the pH of the galanthamine nasal spray 5.5-6.

5.

9. The galanthamine nasal spray according to claim 1 or 2, characterized in that The galanthamine salt is galanthamine hydrobromide; and / or, The pH regulator is disodium hydrogen phosphate; and / or, The chelating agent is disodium ethylenediaminetetraacetate; and / or, The osmotic pressure regulator is sodium chloride; and / or, The preservative is benzalkonium chloride.

10. A method for preparing the galanthamine nasal spray according to any one of claims 1 to 9, characterized in that: The steps include: 1) dissolving the pH adjuster and the chelating agent in water; 2) dissolving the absorption enhancer and preservative in the solution of step 1); 3) dissolving the galanthamine or galanthamine salt in the solution of step 2); 4) dissolving the osmotic pressure regulator in the solution of step 3); 5) adding the viscosity modifier to the solution of step 4), allowing to stand for 5-7 hours, and then shaking thoroughly to dissolve; 6) filtering and sterilizing the solution obtained in step 5) to obtain the galanthamine nasal spray.

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