A phenylcynonarine hydrochloride nasal spray, a preparation method thereof and application thereof

Abstract

The present application relates to phenylol nonylate hydrochloride nasal spray and its preparation method, the nasal spray contains phenylol nonylate hydrochloride 0.1-5%, benzyl alcohol 0.1-10% and polyethylene glycol 400 0-25% in mass-volume ratio. The nasal spray of the present application is highly efficient into the brain through olfactory nerve, low-dose drug efficacy, and low irritation to nasal mucosa, reduces cost, reduces side effects, safe and effective, good stability of preparation, can improve the compliance and safety of swallowing population.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a phenylcyclononyl hydrochloride nasal spray, its preparation method, and its application. Background Technology

[0002] Motion sickness, also known as motion sickness, refers to what people commonly call "car sickness, seasickness, airsickness," etc., including astronaut sickness occurring under microgravity conditions. It is a series of physiological reactions caused by various factors leading to a misperception of motion. Motion sickness typically manifests as cold sweats, paleness, nausea and vomiting, loss of appetite, non-vertigo dizziness, and spatial disorientation. Motion sickness is not a pathological condition in the strict sense, but rather a normal physiological response to real or virtual motion stimuli. It mainly occurs in individuals with a complete vestibular system. However, if an individual is exposed to motion sickness stimuli for a prolonged period of time, it can further induce psychological and cognitive impairments, and even seriously affect travel and work.

[0003] Currently, the most commonly used drugs for treating motion sickness are anticholinergic drugs. However, most anticholinergic drugs have adverse reactions such as drowsiness, blurred vision, or dizziness. Phenycyclononyl hydrochloride is a new Class I centrally acting anticholinergic drug with strong pharmacological effects and few adverse reactions, showing broad application prospects. Phenycyclononyl hydrochloride crosses the blood-brain barrier and enters the brain, competitively binding to and blocking the agonistic effects of acetylcholine on nicotinic and cholinergic receptors, effectively preventing and inhibiting symptoms of autonomic dysfunction such as nausea and vomiting caused by motion sickness. Currently, the main dosage form of phenylcyclononyl hydrochloride on the market domestically and internationally is tablets. For people with motion sickness, severe vertigo can cause difficulty swallowing. Nasal sprays, administered through the nose, are absorbed and have a rapid onset of action, providing a convenient alternative for those who cannot tolerate oral medication. Summary of the Invention

[0004] The purpose of this invention is to provide a nasal spray containing 0.1-5% phenylcyclononyl hydrochloride, 0.1-10% benzyl alcohol, and 0-25% polyethylene glycol 400 by mass-volume ratio.

[0005] In a preferred embodiment of the present invention, the nasal spray contains 0.1-5% phenylcyclononyl hydrochloride, 0.1-10% benzyl alcohol, and 10-20% polyethylene glycol 400 by mass-volume ratio.

[0006] In a preferred embodiment of the present invention, the mass ratio of benzyl alcohol to polyethylene glycol 400 in the nasal spray is 0.1-10:0-25, preferably 0.5-5:10-20.

[0007] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 0.5-3% phenylcyclononyl hydrochloride, 0.5-5% benzyl alcohol, and 5-25% polyethylene glycol 400.

[0008] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 1-2% phenylcyclononyl hydrochloride, 0.5-5% benzyl alcohol, and 10-20% polyethylene glycol 400.

[0009] In a preferred embodiment of the present invention, the nasal spray contains 2% phenylcyclononyl hydrochloride, 5% benzyl alcohol, and 10% polyethylene glycol 400 by mass-volume ratio.

[0010] In a preferred embodiment of the present invention, the nasal spray contains 2% phenylcyclononyl hydrochloride, 5% benzyl alcohol, and 20% polyethylene glycol 400 by mass-volume ratio.

[0011] In a preferred embodiment of the present invention, the nasal spray contains 2% phenylcyclononyl ester hydrochloride and 4% benzyl alcohol by mass-volume ratio.

[0012] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 1% phenylcyclononyl hydrochloride, 0.9% benzyl alcohol, and 10% polyethylene glycol 400.

[0013] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 1% phenylcyclononyl hydrochloride, 0.5% benzyl alcohol, and 20% polyethylene glycol 400.

[0014] In a preferred embodiment of the present invention, the nasal spray further contains an acid-base regulator.

[0015] In a preferred embodiment of the present invention, the acid-base regulator is selected from any one or a combination of hydrochloric acid, sodium hydroxide, citric acid, sodium citrate, malate, lactic acid, sodium lactate, potassium lactate, triethanolamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, phosphate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, HAc (acetic acid) / NaAc (sodium acetate), citric acid / sodium citrate, NaHCO3 / H2CO3, and Na2HPO4 / NaH2PO4.

[0016] In a preferred embodiment of the present invention, the nasal spray has a pH of 3.5-6.0, preferably 4.0-5.5.

[0017] In a preferred embodiment of the present invention, the nasal spray optionally contains a preservative.

[0018] In a preferred embodiment of the present invention, the preservative is selected from any one or a combination of benzalkonium bromide, benzalkonium chloride, benzoic acid, sodium benzoate, methylparaben, ethylparaben, propylparaben, butylparaben, sorbic acid, ethanol, glycerin, phenol, cresol, and chlorobutanol.

[0019] In a preferred embodiment of the present invention, the preservative contained in the nasal spray is 0-0.05%, preferably 0.01-0.02%.

[0020] In a preferred embodiment of the present invention, the nasal spray optionally contains an osmotic pressure regulator.

[0021] In a preferred embodiment of the present invention, the osmotic pressure regulator is selected from any one or a combination of sodium chloride, lactose, glucose, dextran, sorbitol, and mannitol.

[0022] In a preferred embodiment of the present invention, the content of the osmotic pressure regulator is 0.2-0.8% by mass-volume ratio.

[0023] In a preferred embodiment of the present invention, the nasal spray optionally contains a stabilizer.

[0024] In a preferred embodiment of the present invention, the stabilizer is selected from any one or a combination of disodium edetate, ethylene glycol tetraacetic acid, and EDTA.

[0025] In a preferred embodiment of the present invention, the nasal spray contains 0-0.5% stabilizer, preferably 0.1-0.3%.

[0026] In a preferred embodiment of the present invention, the nasal spray optionally contains an absorption enhancer.

[0027] In a preferred embodiment of the present invention, the absorption promoter is selected from any one or a combination of propylene glycol, dodecyl maltodextrin (DDM), tetradecyl maltodextrin (TDM), polyethylene glycol-15-hydroxystearate (HS-15), hydroxypropyl-β-cyclodextrin (HP-β-CD), and cyclodextrin.

[0028] In a preferred embodiment of the present invention, the content of the absorption promoter is 0.1-5% by mass-volume ratio.

[0029] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 0.1-5% phenylcyclononyl hydrochloride, 0.1-15% benzyl alcohol, 1-5% propylene glycol, and 10-20% polyethylene glycol 400.

[0030] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 2% phenylcyclononyl hydrochloride, 5% benzyl alcohol, 10% polyethylene glycol 400, and 5% propylene glycol.

[0031] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 1% phenylcyclononyl hydrochloride, 0.9% benzyl alcohol, 10% polyethylene glycol 400, and 1% propylene glycol.

[0032] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 1% phenylcyclononyl hydrochloride, 0.9% benzyl alcohol, 10% polyethylene glycol 400, and 0.25% DDM.

[0033] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 1% phenylcyclononyl hydrochloride, 0.9% benzyl alcohol, 10% polyethylene glycol 400, and 0.1% DDM.

[0034] Another object of the present invention is to provide a method for preparing a phenylcyclononyl hydrochloride nasal spray, wherein the nasal spray contains 0.1-5% phenylcyclononyl hydrochloride, 0.1-10% benzyl alcohol, and 0-25% polyethylene glycol 400 by mass-volume ratio. The nasal spray specifically includes the following steps: weighing the required amount of benzyl alcohol, adding water to 40-80% of the spray volume, mixing evenly, then adding the required amount of phenylcyclononyl hydrochloride, stirring evenly, then adding the required amount of other components, stirring until completely dissolved, adjusting the pH of the system to 3.5-6.0 with an acid-base adjuster, and adding water to make up the volume to obtain the final product.

[0035] In a preferred embodiment of the present invention, water is added to 65-85% of the spray, preferably 70-80%.

[0036] In a preferred embodiment of the present invention, the dissolution temperature of phenylcyclononyl hydrochloride is 15°C.

[0037] -50℃, preferably 20℃-40℃.

[0038] In a preferred embodiment of the present invention, the nasal spray contains 0.1-5% phenylcyclononyl hydrochloride, 0.1-10% benzyl alcohol, and 10-20% polyethylene glycol 400 by mass-volume ratio.

[0039] In a preferred embodiment of the present invention, the mass ratio of benzyl alcohol to polyethylene glycol 400 in the nasal spray is 0.1-10:0-25, preferably 0.5-5:10-20.

[0040] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 0.5-3% phenylcyclononyl hydrochloride, 0.5-5% benzyl alcohol, and 5-25% polyethylene glycol 400.

[0041] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 1-2% phenylcyclononyl hydrochloride, 0.5-5% benzyl alcohol, and 10-20% polyethylene glycol 400.

[0042] In a preferred embodiment of the present invention, the nasal spray contains 2% phenylcyclononyl hydrochloride, 5% benzyl alcohol, and 10% polyethylene glycol 400 by mass-volume ratio.

[0043] In a preferred embodiment of the present invention, the nasal spray contains 2% phenylcyclononyl hydrochloride, 5% benzyl alcohol, and 20% polyethylene glycol 400 by mass-volume ratio.

[0044] In a preferred embodiment of the present invention, the nasal spray contains 2% phenylcyclononyl ester hydrochloride and 4% benzyl alcohol by mass-volume ratio.

[0045] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 1% phenylcyclononyl hydrochloride, 0.9% benzyl alcohol, and 10% polyethylene glycol 400.

[0046] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 1% phenylcyclononyl hydrochloride, 0.5% benzyl alcohol, and 20% polyethylene glycol 400.

[0047] In a preferred embodiment of the present invention, the nasal spray further contains an acid-base regulator.

[0048] In a preferred embodiment of the present invention, the acid-base regulator is selected from any one or a combination of hydrochloric acid, sodium hydroxide, citric acid, sodium citrate, malate, lactic acid, sodium lactate, potassium lactate, triethanolamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, phosphate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, HAc (acetic acid) / NaAc (sodium acetate), citric acid / sodium citrate, NaHCO3 / H2CO3, and Na2HPO4 / NaH2PO4.

[0049] In a preferred embodiment of the present invention, the nasal spray has a pH of 3.5-6.0, preferably 4.0-5.5.

[0050] In a preferred embodiment of the present invention, the nasal spray optionally contains a preservative.

[0051] In a preferred embodiment of the present invention, the preservative is selected from any one or a combination of benzalkonium bromide, benzalkonium chloride, benzoic acid, sodium benzoate, methylparaben, ethylparaben, propylparaben, butylparaben, sorbic acid, ethanol, glycerin, phenol, cresol, and chlorobutanol.

[0052] In a preferred embodiment of the present invention, the preservative contained in the nasal spray is 0-0.05%, preferably 0.01-0.02%.

[0053] In a preferred embodiment of the present invention, the nasal spray optionally contains an osmotic pressure regulator.

[0054] In a preferred embodiment of the present invention, the osmotic pressure regulator is selected from any one or a combination of sodium chloride, lactose, glucose, dextran, sorbitol, and mannitol.

[0055] In a preferred embodiment of the present invention, the content of the osmotic pressure regulator is 0.2-0.8% by mass-volume ratio.

[0056] In a preferred embodiment of the present invention, the nasal spray optionally contains a stabilizer.

[0057] In a preferred embodiment of the present invention, the stabilizer is selected from any one or a combination of disodium edetate, ethylene glycol tetraacetic acid, and EDTA.

[0058] In a preferred embodiment of the present invention, the nasal spray contains 0-0.5% stabilizer, preferably 0.1-0.3%.

[0059] In a preferred embodiment of the present invention, the nasal spray optionally contains an absorption enhancer.

[0060] In a preferred embodiment of the present invention, the absorption promoter is selected from any one or a combination of propylene glycol, dodecyl maltodextrin (DDM), tetradecyl maltodextrin (TDM), polyethylene glycol-15-hydroxystearate (HS-15), hydroxypropyl-β-cyclodextrin (HP-β-CD), and cyclodextrin.

[0061] In a preferred embodiment of the present invention, the content of the absorption promoter is 0.1-5% by mass-volume ratio.

[0062] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 0.1-5% phenylcyclononyl hydrochloride, 0.1-15% benzyl alcohol, 1-5% propylene glycol, and 10-20% polyethylene glycol 400.

[0063] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 2% phenylcyclononyl hydrochloride, 5% benzyl alcohol, 10% polyethylene glycol 400, and 5% propylene glycol.

[0064] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 1% phenylcyclononyl hydrochloride, 0.9% benzyl alcohol, 10% polyethylene glycol 400, and 1% propylene glycol.

[0065] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 1% phenylcyclononyl hydrochloride, 0.9% benzyl alcohol, 10% polyethylene glycol 400, and 0.25% DDM.

[0066] In a preferred embodiment of the present invention, the nasal spray contains, by mass-volume ratio, 1% phenylcyclononyl hydrochloride, 0.9% benzyl alcohol, 10% polyethylene glycol 400, and 0.1% DDM.

[0067] Another object of the present invention is to provide the use of phenylcyclononyl hydrochloride nasal spray in the prevention or treatment of motion sickness.

[0068] In the preferred embodiment of the present invention, the motion sickness is any one of car sickness, airsickness, or seasickness.

[0069] Unless otherwise stated, this invention employs high performance liquid chromatography to efficiently separate and detect the content of phenylcyclononyl hydrochloride and related substances in the nasal spray of this invention.

[0070] Table 1. Methods for determining the content of phenylcyclononyl hydrochloride.

[0071] mobile phase 0.01 mol / L sodium acetate solution (pH 4.5) - methanol (35:65) Detection wavelength 220nm Flow rate 1.0 mL / min Column temperature 40℃ Injection volume 20μL Runtime 30min Injection concentration 40μg / mL

[0072] Table 2. Methods for determining related substances

[0073] mobile phase 0.01 mol / L sodium acetate solution (pH 4.5) - methanol (35:65) Detection wavelength 220nm Flow rate 1.0 mL / min Column temperature 40℃ Injection volume 20μL Runtime 50min Injection concentration 800 μg / mL

[0074] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0075] 1. This invention scientifically screens and optimizes the components (such as benzyl alcohol, propylene glycol, polyethylene glycol 400, etc.) and ratios of phenylcyclononyl hydrochloride nasal spray, effectively solving the dissolution problem of phenylcyclononyl hydrochloride, achieving high-concentration dissolution of phenylcyclononyl hydrochloride, avoiding drug precipitation, and improving the stability of the formulation. The blood-brain barrier is the biggest obstacle to the absorption of drugs for treating central nervous system diseases. This invention improves phenylcyclononyl hydrochloride injection into a nasal spray, which can utilize the physiological structure of the nasal cavity, the nasal mucosa, and its rich blood vessels to bypass the blood-brain barrier and directly reach the brain of central nervous system diseases. It also makes full use of the rich blood vessels under the nasal mucosa to enhance drug absorption, achieving nasal-brain targeted central nervous system drug delivery and improving the blood-brain barrier crossing rate. Furthermore, nasal administration does not require a professional environment or medical personnel, can be administered by the patient themselves, and is non-invasive, leaving no wounds, resulting in high patient compliance. The phenylcyclononyl hydrochloride nasal spray of the present invention has the advantages of being safe and effective, having high bioavailability, good stability, rapid onset of action, convenient use, lower cost, economical medication, and good patient compliance.

[0076] 2. The preparation method of the phenylcyclononyl hydrochloride nasal spray of the present invention has the advantages of simple operation, high production efficiency, green environmental protection, and easy industrial production. Attached Figure Description

[0077] Figure 1 The effects of the phenylcyclononyl hydrochloride nasal spray of the present invention on the nasal mucosa of rats were investigated. Detailed Implementation

[0078] The following embodiments further illustrate the above-described content of the present invention in detail. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. The following embodiments further describe the beneficial effects of the present invention. The embodiments are for illustrative purposes only and do not limit the scope of the present invention. Furthermore, obvious changes and modifications made by those skilled in the art based on the present invention are also included within the scope of the present invention.

[0079] Example 1: Preparation of the phenylcyclononyl hydrochloride nasal spray of the present invention

[0080] Composition of phenylcyclononyl hydrochloride nasal spray:

[0081] Benzyl nonyl hydrochloride 20 benzyl alcohol 50 PEG400 100

[0082] The preparation of phenylcyclononyl ester hydrochloride nasal spray includes the following steps:

[0083] Add the required amount of benzyl alcohol to 500 mL of water and mix well. Add the required amount of phenylcyclononyl hydrochloride and mix well. Then add PEG400 and stir until well mixed. Adjust the pH of the spray to 4.0 with an appropriate amount of citric acid / sodium citrate. Add water to make up to 1000 mL to obtain a colorless and clear phenylcyclononyl hydrochloride nasal spray.

[0084] Example 2: Preparation of the phenylcyclononyl hydrochloride nasal spray of the present invention

[0085] Composition of phenylcyclononyl hydrochloride nasal spray:

[0086] Benzyl nonyl hydrochloride 20 benzyl alcohol 50 PEG400 200

[0087] The preparation of phenylcyclononyl ester hydrochloride nasal spray includes the following steps:

[0088] Add the required amount of benzyl alcohol to 500 mL of water and mix well. Add the required amount of phenylcyclononyl hydrochloride and stir until well mixed. Then add PEG 400 and stir until well mixed. Adjust the pH of the spray to 4.5 with an appropriate amount of citric acid / sodium citrate. Add water to make up to 1000 mL to obtain a colorless and clear phenylcyclononyl hydrochloride nasal spray.

[0089] Example 3: Preparation of the phenylcyclononyl hydrochloride nasal spray of the present invention

[0090] Composition of phenylcyclononyl ester hydrochloride nasal spray:

[0091] Benzyl nonyl hydrochloride 20 benzyl alcohol 40

[0092] The preparation of phenylcyclononyl ester hydrochloride nasal spray includes the following steps:

[0093] Add the required amount of benzyl alcohol to 500 ml of water and mix well. Add the required amount of phenylcyclononyl hydrochloride and stir to mix well. Adjust the pH of the spray to 4.5 with an appropriate amount of citric acid / sodium citrate. Add water to make up to 1000 mL to obtain a colorless and clear phenylcyclononyl hydrochloride nasal spray.

[0094] Example 4: Preparation of the phenylcyclononyl hydrochloride nasal spray of the present invention

[0095] Composition of phenylcyclononyl ester hydrochloride nasal spray:

[0096] Benzyl nonyl hydrochloride 20 benzyl alcohol 50 PEG400 100

[0097] The preparation of phenylcyclononyl ester hydrochloride nasal spray includes the following steps:

[0098] Add the required amount of benzyl alcohol to 500 mL of water and mix well. Add the required amount of phenylcyclononyl hydrochloride and stir until well mixed. Then add PEG400 and stir until well mixed. Adjust the pH of the spray to 3.5 with an appropriate amount of citric acid / sodium citrate. Add water to make up to 1000 mL to obtain a colorless and clear phenylcyclononyl hydrochloride nasal spray.

[0099] Example 5: Preparation of the phenylcyclononyl hydrochloride nasal spray of the present invention

[0100] Composition of phenylcyclononyl hydrochloride nasal spray:

[0101] Benzyl nonyl hydrochloride 10 benzyl alcohol 9 PEG400 100

[0102] The preparation of phenylcyclononyl ester hydrochloride nasal spray includes the following steps:

[0103] Add the required amount of benzyl alcohol to 500 mL of water and mix well. Add the required amount of phenylcyclononyl hydrochloride and stir until well mixed. Then add the required amount of PEG400 and stir until well mixed. Adjust the pH of the spray to 4.9 with an appropriate amount of citric acid / sodium citrate. Add water to a final volume of 1000 mL to obtain a colorless and clear phenylcyclononyl hydrochloride nasal spray.

[0104] Example 6: Preparation of the phenylcyclononyl hydrochloride nasal spray of the present invention

[0105] Composition of phenylcyclononyl hydrochloride nasal spray:

[0106] Benzyl nonyl hydrochloride 10 benzyl alcohol 5 PEG400 200

[0107] The preparation of phenylcyclononyl ester hydrochloride nasal spray includes the following steps:

[0108] Add the required amount of benzyl alcohol to 500 mL of water and mix well. Add the required amount of phenylcyclononyl hydrochloride and stir until well mixed. Then add the required amount of PEG400 and stir until well mixed. Adjust the pH of the spray to 5.0 with an appropriate amount of citric acid / sodium citrate. Add water to make up to 1000 mL to obtain a colorless and clear phenylcyclononyl hydrochloride nasal spray.

[0109] Example 7: Preparation of the phenylcyclononyl hydrochloride nasal spray of the present invention

[0110] Composition of phenylcyclononyl hydrochloride nasal spray:

[0111] Benzyl nonyl hydrochloride 20 benzyl alcohol 50 PEG400 100 Propylene glycol 50

[0112] The preparation of phenylcyclononyl ester hydrochloride nasal spray includes the following steps:

[0113] Add the required amount of benzyl alcohol to 500 mL of water and mix well. Add the required amount of phenylcyclononyl hydrochloride and stir until well mixed. Then add the required amount of PEG400 and propylene glycol and stir until well mixed. Adjust the pH of the spray to 4.0 with an appropriate amount of citric acid / sodium citrate. Add water to make up to 1000 mL to obtain a colorless and clear phenylcyclononyl hydrochloride nasal spray.

[0114] Example 8: Preparation of the phenylcyclononyl hydrochloride nasal spray of the present invention

[0115] Composition of phenylcyclononyl hydrochloride nasal spray:

[0116]

[0117]

[0118] The preparation of phenylcyclononyl ester hydrochloride nasal spray includes the following steps:

[0119] Add the required amount of benzyl alcohol to 500 mL of water and mix well. Add the required amount of phenylcyclononyl hydrochloride and stir to mix well. Then add the required amount of PEG400 and propylene glycol and stir to mix well. Adjust the pH of the spray to 4.0 with an appropriate amount of citric acid / sodium citrate. Add water to make up to 1000 mL to obtain a colorless and clear phenylcyclononyl hydrochloride nasal spray.

[0120] Example 9: Preparation of the phenylcyclononyl hydrochloride nasal spray of the present invention

[0121] Composition of phenylcyclononyl hydrochloride nasal spray:

[0122] Benzyl nonyl hydrochloride 10 benzyl alcohol 9 PEG400 100 DDM 2.5

[0123] The preparation of phenylcyclononyl ester hydrochloride nasal spray includes the following steps:

[0124] Add the required amount of benzyl alcohol to 500 mL of water and mix well. Add the required amount of phenylcyclononyl hydrochloride and stir to mix well. Then add the required amounts of PEG400 and DDM and stir to mix well. Adjust the pH of the spray to 4.0 with an appropriate amount of citric acid / sodium citrate. Add water to make up to 1000 mL to obtain a colorless and clear phenylcyclononyl hydrochloride nasal spray.

[0125] Example 10: Preparation of the phenylcyclononyl hydrochloride nasal spray of the present invention

[0126] Composition of phenylcyclononyl ester hydrochloride nasal spray:

[0127] Benzyl nonyl hydrochloride 10 benzyl alcohol 9 PEG400 100 DDM 1.0

[0128] The preparation of phenylcyclononyl ester hydrochloride nasal spray includes the following steps:

[0129] Add the required amount of benzyl alcohol to 500 mL of water and mix well. Add the required amount of phenylcyclononyl hydrochloride and stir to mix well. Then add the required amounts of PEG400 and DDM and stir to mix well. Adjust the pH of the spray to 4.0 with an appropriate amount of citric acid / sodium citrate. Add water to make up to 1000 mL to obtain a colorless and clear phenylcyclononyl hydrochloride nasal spray.

[0130] Example 11 Preparation of the phenylcyclononyl hydrochloride nasal spray of the present invention

[0131] Composition of phenylcyclononyl ester hydrochloride nasal spray:

[0132] Benzyl nonyl hydrochloride 10 benzyl alcohol 9 Sodium chloride 5.6

[0133] The preparation of phenylcyclononyl ester hydrochloride nasal spray includes the following steps:

[0134] Add the required amount of benzyl alcohol to 500 mL of water and mix well. Add the required amount of phenylcyclononyl hydrochloride and stir until well mixed. Add the required amount of sodium chloride and stir until well mixed. Adjust the pH of the spray to 4.0 with an appropriate amount of citric acid / sodium citrate. Add water to a final volume of 1000 mL to obtain a colorless and clear phenylcyclononyl hydrochloride nasal spray.

[0135] Experimental Example 1: Stability Study of the Phenylacetyl Nonyl Hydrochloride Nasal Spray of the Present Invention

[0136] Taking the phenylcyclononyl hydrochloride nasal sprays prepared in Examples 11 and 5 as examples, they were placed in ampoules and then placed under strong light irradiation (4500±500) lx at 60°C for 5 days, 10 days, and 30 days. Samples were taken and their properties, content, and related substances were observed. The results are shown in Table 3. The phenylcyclononyl hydrochloride nasal spray of the present invention exhibits good stability.

[0137] Table 3

[0138]

[0139]

[0140] Test Example 2: Ciliary toxicity study of the phenylcyclononyl ester hydrochloride nasal spray of the present invention

[0141] Using the phenylcyclononyl hydrochloride nasal sprays prepared in Examples 1, 3, 5 and 7 as examples, the ciliary toxicity of the phenylcyclononyl hydrochloride nasal sprays prepared in this invention was investigated.

[0142] Using bullfrogs as an animal model, the oral mucosa was harvested after the spinal cord was destroyed. Blood clots and debris were washed away, and the mucosa was divided into 3mm × 3mm sections with the ciliated side facing upwards. Physiological saline was added as a negative control, and 1% sodium deoxycholate as a positive control. 100 μL of phenylcyclononyl ester hydrochloride nasal spray prepared in Examples 1, 3, 5, and 7 was added to each section. Each group was repeated in triplicate, and ciliary movement was observed under a microscope. After observation, the sections were placed in a water-containing culture dish, sealed, and observed at appropriate intervals. If the movement continued, the sections were returned to the culture dish after observation, and the start and stop times of the movement were recorded. The time difference between the start and stop times was the duration of ciliary movement (LTCM). If the ciliary movement stopped, the coverslip was picked up with forceps, the cilia were rinsed with physiological saline, and then placed under an optical microscope to observe whether the movement of the mucosal cilia could be restored. If the movement could be restored, the recovery time was recorded, and the LTCM was the sum of the duration of movement and the recovery time.

[0143] The percentage of relative ciliary movement (PPV) = LTCM of the test sample / LTCM of the negative control. The results are shown in Table 4. As can be seen from Table 4, the phenylcyclononyl hydrochloride nasal sprays exemplified in Examples 1, 3, 5, and 7 of this invention have intact mucosal surfaces, high percentages of relative ciliary movement, and do not exhibit ciliary toxicity, demonstrating excellent safety and efficacy.

[0144] Table 4

[0145] physiological saline 364.33±6.92 yes 100±1.90 Positive control 10.13±3.13 no 2.78±0.10 Example 1 285.00±1.73 yes 78.58±0.48 Example 3 251.67±1.53 yes 69.01±0.42 Example 5 297.00±5.29 yes 81.89±1.46 Example 7 247.00±4.00 yes 68.11±1.10

[0146] Experimental Example 3: Study on the nasal mucosa irritation effect of the phenylcyclononyl hydrochloride nasal spray of the present invention.

[0147] Using the phenylcyclononyl hydrochloride nasal spray prepared in Example 5 as an example, the irritant effect of the flumazenil nasal spray of the present invention on the nasal mucosa of rats after continuous administration for 5 days and one week after drug withdrawal was investigated.

[0148] Eighteen SD rats were randomly divided into three groups according to Table 3, with a weight of 190–210g and half males and half females:

[0149] Table 5

[0150] A1-A3 6 physiological saline 50μL B1-B3 6 1% sodium deoxycholate 50μL C1-C3 6 Example 6: Phenylacetyl hydrochloride nasal spray 50μL

[0151] Each rat was administered 50 μL of the nasal spray from Example 5 via a microsyringe once daily for 5 consecutive days. Rats were sacrificed on day 6, and the nasal mucosa attached to the nasal septum was removed, fixed in 4% paraformaldehyde, embedded in paraffin, stained with hematoxylin and eosin (HE), and then prepared as pathological sections. Changes in mucosal morphology were observed under an optical microscope. Figure 1 In the saline group, the surface of the nasal turbinate cartilage mucosa on both sides of the rats was covered with normal pseudostratified columnar ciliated epithelium, with most cells tightly packed and cilia clearly visible on the surface. In the 1% sodium deoxycholate group, the cilia completely detached after five days of administration, and the epithelial cells underwent degeneration and necrosis. There was no significant difference between the phenylcyclononyl hydrochloride nasal spray group and the saline group; the cilia were clearly visible, and the cells had normal morphology and were tightly packed. The results indicate that the phenylcyclononyl hydrochloride nasal spray group had weak irritation to the rat nasal mucosa and good safety.

[0152] The above-described embodiments are merely preferred embodiments provided to fully illustrate the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims

1. A nasal spray containing phenylcyclononyl hydrochloride, wherein the nasal spray has a pH of 3.5-6.0, wherein, The nasal spray, by mass-volume ratio, consists of 1-2% phenylcyclononyl hydrochloride, 0.5-5% benzyl alcohol, 10-20% polyethylene glycol 400, with the balance being an acid-base adjuster and water. The mass ratio of benzyl alcohol to polyethylene glycol 400 in the nasal spray is 0.5-5:10-20.

2. The nasal spray as described in claim 1, wherein, by mass-volume ratio, the nasal spray comprises 2% phenylcyclononyl hydrochloride, 5% benzyl alcohol, 10% polyethylene glycol 400, and the balance being an acid-base adjuster and water.

3. The nasal spray as described in claim 1, wherein, by mass-volume ratio, the nasal spray comprises 2% phenylcyclononyl hydrochloride, 5% benzyl alcohol, 20% polyethylene glycol 400, and the balance being an acid-base adjuster and water.

4. The nasal spray as described in claim 1, wherein, by mass-volume ratio, the nasal spray comprises 1% phenylcyclononyl hydrochloride, 0.9% benzyl alcohol, 10% polyethylene glycol 400, and the balance being an acid-base adjuster and water.

5. The nasal spray as described in claim 1, wherein, by mass-volume ratio, the nasal spray comprises 1% phenylcyclononyl hydrochloride, 0.5% benzyl alcohol, 20% polyethylene glycol 400, and the balance being an acid-base adjuster and water.

6. The nasal spray according to any one of claims 1-5, wherein the pH of the nasal spray is 4.0-5.

5.

7. A nasal spray containing phenylcyclononyl hydrochloride, wherein the nasal spray has a pH of 4.0, wherein... By mass-volume ratio, the nasal spray consists of 1% phenylcyclononyl hydrochloride, 0.9% benzyl alcohol, 10% polyethylene glycol 400, 0.25% dodecyl maltodextrin, with the balance being citric acid-sodium citrate and water.

8. A nasal spray containing phenylcyclononyl ester hydrochloride, wherein the nasal spray has a pH of 4.0, By mass-volume ratio, the nasal spray consists of 1% phenylcyclononyl hydrochloride, 0.9% benzyl alcohol, 10% polyethylene glycol 400, 0.1% dodecyl maltodextrin, with the balance being citric acid-sodium citrate and water.

9. A method for preparing a phenylcyclononyl hydrochloride nasal spray according to any one of claims 1-5, specifically comprising the following steps: weighing the required amount of benzyl alcohol, adding water to 40-80% of the spray volume, mixing evenly, then adding the required amount of phenylcyclononyl hydrochloride, stirring evenly, then adding the required amount of other components, stirring until completely dissolved, adjusting the pH of the system to 3.5-6.0 with an acid-base adjuster, and adding water to make up to the final volume to obtain the final product.

10. The method for preparing the phenylcyclononyl hydrochloride nasal spray as described in claim 9, wherein water is added to 65-80% of the spray volume.

11. The method for preparing the phenylcyclononyl hydrochloride nasal spray as described in claim 10, wherein water is added to 70-80% of the spray volume.

12. The preparation method of the phenylcyclononyl hydrochloride nasal spray according to claim 9, wherein the dissolution temperature of phenylcyclononyl hydrochloride is 15℃-50℃.

13. The preparation method of phenylcyclononyl hydrochloride nasal spray according to claim 12, wherein the dissolution temperature of phenylcyclononyl hydrochloride is 20℃-40℃.

14. The use of the phenylcyclononyl hydrochloride nasal spray according to any one of claims 1-8 in the preparation of a medicament for the prevention or treatment of motion sickness.

15. The application as described in claim 14, wherein the motion sickness is any one of car sickness, airsickness, or seasickness.

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