Phencynonate hydrochloride nasal spray as well as preparation method and application thereof

Abstract

The invention relates to a phencynonate hydrochloride nasal spray and a preparation method thereof, and the nasal spray contains 0.1-5% of phencynonate hydrochloride, 0.1-10% of benzyl alcohol and 0-25% of polyethylene glycol 400 in terms of mass volume ratio. The nasal spray disclosed by the invention efficiently enters the brain through the olfactory region nerves, exerts the drug effect at a low dosage, has low irritation to nasal mucosa, reduces the cost and side effects, is safe and effective, has good preparation stability, and can improve the compliance of swallowing people and the medication safety.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine, and specifically relates to a phencyclnonate hydrochloride nasal spray, a preparation method thereof and an application thereof. Background Art

[0002] Motion sickness, also known as motion sickness, refers to what people usually call "car sickness, seasickness, airsickness", etc., including space sickness that occurs in microgravity conditions. It is a series of physiological reactions caused by various factors that lead to the human body's incorrect perception of motion status. Motion sickness usually manifests itself as cold sweat, pale face, nausea and vomiting, anorexia, non-vertigo dizziness, spatial disorientation and other symptoms. Motion sickness is not a pathological state in the strict sense, but a normal physiological response to real or virtual motion stimulation. It mainly occurs in individuals with a complete vestibular system. However, if an individual is exposed to a motion sickness stimulation environment for a long time, it will further induce psychological and cognitive disorders, and even seriously affect travel and work.

[0003] At present, the most commonly used drugs for the treatment of motion sickness are anticholinergic drugs, but most anticholinergic drugs have adverse reactions such as drowsiness, blurred vision or dizziness. Phencynonate hydrochloride is a new central anticholinergic class I drug with strong pharmacological effects and few adverse reactions, and has broad application prospects. Phencynonate hydrochloride enters the brain through the blood-brain barrier and blocks the stimulatory effect of acetylcholine on nicotinic receptors and nicotinic receptors by competitive binding, which can effectively prevent and inhibit the symptoms of autonomic dysfunction such as nausea and vomiting caused by motion sickness. At present, the dosage forms of phencyclnonate hydrochloride on the market at home and abroad are mainly tablets. For people with motion sickness, when the dizziness is severe, they will have difficulty swallowing. The nasal spray is administered through the nose and has a rapid onset of absorption, providing a convenient alternative for people who cannot tolerate oral motion sickness. Summary of the invention

[0004] The invention aims to provide a phencyclonate hydrochloride nasal spray, which contains 0.1-5% of phencyclonate hydrochloride, 0.1-10% of benzyl alcohol and 0-25% of polyethylene glycol 400 in terms of mass volume ratio.

[0005] In a preferred technical solution of the present invention, the nasal spray contains 0.1-5% of phencyclnonate hydrochloride, 0.1-10% of benzyl alcohol and 10-20% of polyethylene glycol 400 in terms of mass volume ratio.

[0006] In the preferred technical solution 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 the preferred technical solution of the present invention, the nasal spray contains 0.5-3% of phencyclonate hydrochloride, 0.5-5% of benzyl alcohol, and 5-25% of polyethylene glycol 400, calculated by mass volume ratio.

[0008] In the preferred technical solution of the present invention, the nasal spray contains 1-2% of phencyclnonate hydrochloride, 0.5-5% of benzyl alcohol and 10-20% of polyethylene glycol 400 in terms of mass volume ratio.

[0009] In the preferred technical solution of the present invention, the nasal spray contains 2% of phencyclnonate hydrochloride, 5% of benzyl alcohol and 10% of polyethylene glycol 400 in terms of mass volume ratio.

[0010] In the preferred technical solution of the present invention, the nasal spray contains 2% of phencyclnonate hydrochloride, 5% of benzyl alcohol and 20% of polyethylene glycol 400 in terms of mass volume ratio.

[0011] In the preferred technical solution of the present invention, the nasal spray contains 2% of phencyclnonate hydrochloride and 4% of benzyl alcohol in terms of mass volume ratio.

[0012] In the preferred technical solution of the present invention, the nasal spray contains 1% of phencyclnonate hydrochloride, 0.9% of benzyl alcohol and 10% of polyethylene glycol 400 in terms of mass volume ratio.

[0013] In the preferred technical solution of the present invention, the nasal spray contains 1% of phencyclnonate hydrochloride, 0.5% of benzyl alcohol and 20% of polyethylene glycol 400, calculated by mass volume ratio.

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

[0015] In the preferred technical scheme of the present invention, the acid-base regulator is selected from any one 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, Na2HPO4 / NaH2PO4 or a combination thereof.

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

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

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

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

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

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

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

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

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

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

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

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

[0028] In the preferred technical solution of the present invention, the content of the absorption enhancer is 0.1-5% by mass volume ratio.

[0029] In the preferred technical solution of the present invention, the nasal spray contains 0.1-5% of phencyclnonate hydrochloride, 0.1-15% of benzyl alcohol, 1-5% of propylene glycol and 10-20% of polyethylene glycol 400 in terms of mass volume ratio.

[0030] In the preferred technical solution of the present invention, the nasal spray contains 2% of phencyclnonate hydrochloride, 5% of benzyl alcohol, 10% of polyethylene glycol 400, and 5% of propylene glycol, calculated by mass volume ratio.

[0031] In the preferred technical solution of the present invention, the nasal spray contains 1% of phencyclnonate hydrochloride, 0.9% of benzyl alcohol, 10% of polyethylene glycol 400 and 1% of propylene glycol, calculated by mass volume ratio.

[0032] In the preferred technical solution of the present invention, the nasal spray contains 1% of phencyclnonate hydrochloride, 0.9% of benzyl alcohol, 10% of polyethylene glycol 400, and 0.25% of DDM in terms of mass volume ratio.

[0033] In the preferred technical solution of the present invention, the nasal spray contains 1% of phencyclnonate hydrochloride, 0.9% of benzyl alcohol, 10% of polyethylene glycol 400, and 0.1% of DDM in terms of mass volume ratio.

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

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

[0036] In the preferred technical solution of the present invention, the dissolution temperature of phencyclonate hydrochloride is 15°C

[0037] -50°C, preferably 20°C -40°C.

[0038] In a preferred technical solution of the present invention, the nasal spray contains 0.1-5% of phencyclnonate hydrochloride, 0.1-10% of benzyl alcohol and 10-20% of polyethylene glycol 400 in terms of mass volume ratio.

[0039] In the preferred technical solution 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 the preferred technical solution of the present invention, the nasal spray contains 0.5-3% of phencyclonate hydrochloride, 0.5-5% of benzyl alcohol, and 5-25% of polyethylene glycol 400, calculated by mass volume ratio.

[0041] In the preferred technical solution of the present invention, the nasal spray contains 1-2% of phencyclnonate hydrochloride, 0.5-5% of benzyl alcohol and 10-20% of polyethylene glycol 400 in terms of mass volume ratio.

[0042] In the preferred technical solution of the present invention, the nasal spray contains 2% of phencyclnonate hydrochloride, 5% of benzyl alcohol and 10% of polyethylene glycol 400 in terms of mass volume ratio.

[0043] In the preferred technical solution of the present invention, the nasal spray contains 2% of phencyclnonate hydrochloride, 5% of benzyl alcohol and 20% of polyethylene glycol 400 in terms of mass volume ratio.

[0044] In the preferred technical solution of the present invention, the nasal spray contains 2% of phencyclnonate hydrochloride and 4% of benzyl alcohol in terms of mass volume ratio.

[0045] In the preferred technical solution of the present invention, the nasal spray contains 1% of phencyclnonate hydrochloride, 0.9% of benzyl alcohol and 10% of polyethylene glycol 400 in terms of mass volume ratio.

[0046] In the preferred technical solution of the present invention, the nasal spray contains 1% of phencyclnonate hydrochloride, 0.5% of benzyl alcohol and 20% of polyethylene glycol 400, calculated by mass volume ratio.

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

[0048] In the preferred technical scheme of the present invention, the acid-base regulator is selected from any one 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, Na2HPO4 / NaH2PO4 or a combination thereof.

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

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

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

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

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

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

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

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

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

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

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

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

[0061] In the preferred technical solution of the present invention, the content of the absorption enhancer is 0.1-5% by mass volume ratio.

[0062] In the preferred technical solution of the present invention, the nasal spray contains 0.1-5% of phencyclnonate hydrochloride, 0.1-15% of benzyl alcohol, 1-5% of propylene glycol and 10-20% of polyethylene glycol 400 in terms of mass volume ratio.

[0063] In the preferred technical solution of the present invention, the nasal spray contains 2% of phencyclnonate hydrochloride, 5% of benzyl alcohol, 10% of polyethylene glycol 400, and 5% of propylene glycol, calculated by mass volume ratio.

[0064] In the preferred technical solution of the present invention, the nasal spray contains 1% of bencylonate hydrochloride, 0.9% of benzyl alcohol, 10% of polyethylene glycol 400 and 1% of propylene glycol in terms of mass volume ratio.

[0065] In the preferred technical solution of the present invention, the nasal spray contains 1% of phencyclnonate hydrochloride, 0.9% of benzyl alcohol, 10% of polyethylene glycol 400, and 0.25% of DDM in terms of mass volume ratio.

[0066] In the preferred technical solution of the present invention, the nasal spray contains 1% of phencyclnonate hydrochloride, 0.9% of benzyl alcohol, 10% of polyethylene glycol 400, and 0.1% of DDM in terms of mass volume ratio.

[0067] Another object of the present invention is to provide an application of phencyclnonate hydrochloride nasal spray in preventing or treating motion sickness.

[0068] In the preferred technical solution of the present invention, the motion sickness is any one of carsickness, airsickness and seasickness.

[0069] Unless otherwise specified, the present invention adopts high performance liquid chromatography to efficiently separate and detect the contents of phencyclnonate hydrochloride and related substances in the nasal spray of the present invention.

[0070] Table 1 Phencynonyl hydrochloride content determination method

[0071] Chromatographic columns C18 (4.6mm×250mm, 5μm) Mobile phase 0.01 mol / L sodium acetate solution (pH 4.5)-methanol (35:65) Detection wavelength 220nm Flow rate 1.0mL / min Column temperature 40℃ Injection volume 20μL Run time 30min Injection concentration 40 μg / mL

[0072] Table 2 Determination methods of related substances

[0073] Chromatographic columns C18 (4.6mm×250mm, 5μm) Mobile phase 0.01 mol / L sodium acetate solution (pH 4.5)-methanol (35:65) Detection wavelength 220nm Flow rate 1.0mL / min Column temperature 40℃ Injection volume 20μL Run time 50min Injection concentration 800 μg / mL

[0074] Compared with the prior art, the present invention has the following beneficial effects:

[0075] 1. The present invention scientifically screens and optimizes the components (such as benzyl alcohol, propylene glycol, polyethylene glycol 400, etc.) and proportions of bencyclonate hydrochloride nasal spray, effectively solves the bencyclonate hydrochloride dissolution problem, realizes bencyclonate hydrochloride high concentration dissolution, avoids drug precipitation, and improves the stability of the preparation. The blood-brain barrier is the biggest obstacle to the absorption of drugs for treating central nervous system diseases. The present invention improves bencyclonate hydrochloride injection into a nasal spray, which can bypass the blood-brain barrier using the nasal physiological structure, nasal mucosa and its abundant blood vessels, directly reaching the brain disease of central nervous system diseases, and makes full use of the abundant blood vessels under the nasal mucosa to improve the absorption of drugs, realizes nasal brain targeting central nervous system administration, and improves the blood-brain barrier pass rate of drugs. In addition, nasal administration does not require professional environment and medical staff to realize administration, can be administered by patients themselves, and is non-invasive, does not leave wound surface, and patients have high medication compliance. The phencyclnonate hydrochloride nasal spray of the present invention has the advantages of safety and effectiveness, high bioavailability, good stability, rapid onset of effect, convenient use, better cost, economical medication, good patient compliance, etc.

[0076] 2. The preparation method of the phencyclnonate hydrochloride nasal spray of the present invention has the advantages of simple operation, high production efficiency, green environmental protection, and easy industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0077] Figure 1 The irritation of the phencyclnonate hydrochloride nasal spray to rat nasal mucosa was investigated. DETAILED DESCRIPTION

[0078] The above contents of the present invention are further described in detail below by way of examples. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies implemented based on the above contents of the present invention belong to the scope of the present invention. The following examples further describe the beneficial effects of the present invention, and the examples are only for illustrative purposes and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by ordinary technicians in the field according to the present invention are also included in the scope of the present invention.

[0079] Example 1 Preparation of Phencynonate Hydrochloride Nasal Spray of the Present Invention

[0080] Composition of Phencynonate Hydrochloride Nasal Spray:

[0081] Components Dosage(g) Phencynonate hydrochloride 20 Benzyl alcohol 50 PEG400 100

[0082] The preparation of phencyclonate hydrochloride nasal spray comprises the following steps:

[0083] Add the required amount of benzyl alcohol to 500 ml of water and mix well. Add the required amount of benzyl alcohol hydrochloride and mix well. Then add PEG400 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 the volume to 1000 mL to prepare a colorless and clear benzyl alcohol hydrochloride nasal spray.

[0084] Example 2 Preparation of Phencynonate Hydrochloride Nasal Spray of the Present Invention

[0085] Composition of Phencynonate Hydrochloride Nasal Spray:

[0086] Components Dosage(g) Phencynonate hydrochloride 20 Benzyl alcohol 50 PEG400 200

[0087] The preparation of phencyclonate hydrochloride nasal spray comprises the following steps:

[0088] Add the required amount of benzyl alcohol to 500 ml of water and mix well. Add the required amount of phencyclonate hydrochloride and stir to mix well. Then add PEG 400 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 prepare a colorless and clear phencyclonate hydrochloride nasal spray.

[0089] Example 3 Preparation of Phencynonate Hydrochloride Nasal Spray of the Present Invention

[0090] Composition of Phencynonate Hydrochloride Nasal Spray:

[0091] Components Dosage(g) Phencynonate hydrochloride 20 Benzyl alcohol 40

[0092] The preparation of phencyclonate hydrochloride nasal spray comprises the following steps:

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

[0094] Example 4 Preparation of Phencynonate Hydrochloride Nasal Spray of the Present Invention

[0095] Composition of Phencynonate Hydrochloride Nasal Spray:

[0096] Components Dosage(g) Phencynonate hydrochloride 20 Benzyl alcohol 50 PEG400 100

[0097] The preparation of phencyclonate hydrochloride nasal spray comprises the following steps:

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

[0099] Example 5 Preparation of Phencynonate Hydrochloride Nasal Spray of the Present Invention

[0100] Composition of Phencynonate Hydrochloride Nasal Spray:

[0101] Components Dosage(g) Phencynonate hydrochloride 10 Benzyl alcohol 9 PEG400 100

[0102] The preparation of phencyclonate hydrochloride nasal spray comprises the following steps:

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

[0104] Example 6 Preparation of Phencynonate Hydrochloride Nasal Spray of the Present Invention

[0105] Composition of Phencynonate Hydrochloride Nasal Spray:

[0106] Components Dosage(g) Phencynonate hydrochloride 10 Benzyl alcohol 5 PEG400 200

[0107] The preparation of phencyclonate hydrochloride nasal spray comprises the following steps:

[0108] Add the required amount of benzyl alcohol to 500 ml of water and mix well, add the required amount of phencyclonate hydrochloride and stir to mix well, then add the required amount of PEG400 and stir to mix well, adjust the pH of the spray to 5.0 with an appropriate amount of citric acid / sodium citrate, add water to make the volume to 1000 mL, and prepare a colorless and clear phencyclonate hydrochloride nasal spray.

[0109] Example 7 Preparation of Phencynonate Hydrochloride Nasal Spray of the Present Invention

[0110] Composition of Phencynonate Hydrochloride Nasal Spray:

[0111] Components Weight(g) Phencynonate hydrochloride 20 Benzyl alcohol 50 PEG400 100 Propylene glycol 50

[0112] The preparation of phencyclonate hydrochloride nasal spray comprises the following steps:

[0113] Add the required amount of benzyl alcohol to 500 ml of water and mix well. Add the required amount of benzyl alcohol 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 the volume to 1000 mL to prepare a colorless and clear benzyl alcohol hydrochloride nasal spray.

[0114] Example 8 Preparation of Phencynonate Hydrochloride Nasal Spray of the Present Invention

[0115] Composition of Phencynonate Hydrochloride Nasal Spray:

[0116]

[0117]

[0118] The preparation of phencyclonate hydrochloride nasal spray comprises the following steps:

[0119] Add the required amount of benzyl alcohol to 500 ml of water and mix well. Add the required amount of phencyclonate 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 the volume to 1000 mL to prepare a colorless and clear phencyclonate hydrochloride nasal spray.

[0120] Example 9 Preparation of Phencynonate Hydrochloride Nasal Spray of the Present Invention

[0121] Composition of Phencynonate Hydrochloride Nasal Spray:

[0122] Components Weight(g) Phencynonate hydrochloride 10 Benzyl alcohol 9 PEG400 100 DDM 2.5

[0123] The preparation of phencyclonate hydrochloride nasal spray comprises the following steps:

[0124] Add the required amount of benzyl alcohol to 500 ml of water and mix well. Add the required amount of phencyclonate hydrochloride and stir to mix well. Then add the required amount 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 the volume to 1000 mL to prepare a colorless and clear phencyclonate hydrochloride nasal spray.

[0125] Example 10 Preparation of Phencynonate Hydrochloride Nasal Spray of the Present Invention

[0126] Composition of Phencynonate Hydrochloride Nasal Spray:

[0127] Components Weight(g) Phencynonate hydrochloride 10 Benzyl alcohol 9 PEG400 100 DDM 1.0

[0128] The preparation of phencyclonate hydrochloride nasal spray comprises the following steps:

[0129] Add the required amount of benzyl alcohol to 500 ml of water and mix well. Add the required amount of phencyclonate hydrochloride and stir to mix well. Then add the required amount 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 the volume to 1000 mL to prepare a colorless and clear phencyclonate hydrochloride nasal spray.

[0130] Example 11 Preparation of Phencynonate Hydrochloride Nasal Spray of the Present Invention

[0131] Composition of Phencynonate Hydrochloride Nasal Spray:

[0132] Components Weight(g) Phencynonate hydrochloride 10 Benzyl alcohol 9 Sodium chloride 5.6

[0133] The preparation of phencyclonate hydrochloride nasal spray comprises the following steps:

[0134] Add the required amount of benzyl alcohol to 500 ml of water and mix well. Add the required amount of phencyclonate hydrochloride and stir to mix well. Then add the required amount of sodium chloride 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 the volume to 1000 mL to prepare a colorless and clear phencyclonate hydrochloride nasal spray.

[0135] Test Example 1 Stability Study of Phencynonate Hydrochloride Nasal Spray of the Present Invention

[0136] Taking the prepared phencyclonate hydrochloride nasal spray of Example 11 and Example 5 as an example, it is placed in an ampoule bottle, and then placed under 60°C and strong light irradiation (4500±500) lx for 5 days, 10 days, and 30 days. After sampling, the properties, content and related substances are observed, and the results are shown in Table 3. The phencyclonate hydrochloride nasal spray of the present invention has good stability.

[0137] Table 3

[0138]

[0139]

[0140] Test Example 2 Investigation of the ciliary toxicity of the phencyclonate hydrochloride nasal spray of the present invention

[0141] Taking the phencyclonate hydrochloride nasal spray prepared in Example 1, Example 3, Example 5 and Example 7 as examples, the ciliary toxicity of the phencyclonate hydrochloride nasal spray prepared in the present invention was investigated.

[0142] Using bullfrog as animal model, after the spinal cord is destroyed, the oral palate mucosa is taken, blood clots and dirt are washed off, and the mucosa is divided into 3mm×3mm, with the cilia facing upward, and physiological saline is added as a negative control, and 1% sodium deoxycholate is added as a positive control. 100μL of the phencyclonate hydrochloride nasal spray prepared in Examples 1, 3, 5, and 7 are added respectively. Each group is repeated 3 times, and the movement of cilia is observed under a microscope. After observation, it is placed in a culture dish containing water, sealed, and taken out for observation at appropriate intervals. If it continues to swing, it is placed back in the culture dish after observation, and the swing start time and swing stop time are recorded. The time difference between the swing start time and the swing stop time is the ciliary continuous motion time (LTCM). If the cilia stop swinging, the cover glass is clamped with tweezers, the cilia are rinsed with physiological saline, and then placed under an optical microscope to observe whether the swing of the mucociliary can be restored. If the swing can be restored, the recovery swing time is recorded, and the LTCM is the sum of the continuous motion time and the recovery swing time.

[0143] The relative percentage of ciliary motion (PPV) = test sample LTCM / negative control LTCM. The results are shown in Table 4. As shown in Table 4, the mucosal surface of the phencyclnonate hydrochloride nasal spray exemplified by Example 1, Example 3, Example 5, and Example 7 of the present invention is intact, the relative percentage of ciliary motion is high, no ciliary toxicity is shown, and the safety and effectiveness are excellent.

[0144] Table 4

[0145] Group LTCM / min Is it reversible? Relative movement percentage (%) Normal 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] Test Example 3 Study on the nasal mucosal irritation effect of the phencyclonate hydrochloride nasal spray of the present invention

[0147] Taking the phencyclonate hydrochloride nasal spray prepared in Example 5 as an example, the irritation 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 of drug withdrawal was investigated.

[0148] Eighteen SD rats were randomly divided into three groups according to Table 3, with a body weight of 190-210 g, half of which were male and half were female:

[0149] Table 5

[0150] Group Number of animals Drug administration Dosage A1-A3 6 Normal saline 50μL B1-B3 6 1% Sodium deoxycholate 50μL C1-C3 6 Example 6 Phencynonate hydrochloride nasal spray 50μL

[0151] Each rat was administered 50 μL of the nasal spray of Example 5 into each nostril using a microsyringe once a day for 5 consecutive days. The rat was killed on the 6th day. The nasal mucosa attached to the nasal septum was removed, fixed with 4% paraformaldehyde, embedded in paraffin, stained with HE, and then pathological sections were prepared. The changes in the morphology of the mucosa were observed under an optical microscope. Figure 1 . The surface of the mucosa on both sides of the nasal concha cartilage of rats in the normal saline group was covered with normal pseudostratified columnar ciliated epithelium, most of the cells were closely arranged, and cilia were clearly visible on the surface; the cilia of rats in the 1% sodium deoxycholate group were completely shed after five days of administration, and the epithelial cells were degenerated and necrotic. There was no significant difference between the phencyclonate hydrochloride nasal spray group and the normal saline group. The cilia were clearly visible, and the cell morphology was normal and closely arranged. The results showed that the phencyclonate hydrochloride nasal spray group had weak irritation to the rat nasal mucosa and had good safety.

[0152] The above-described embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or changes made by those skilled in the art based on the present invention are within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. A phencyclonate hydrochloride nasal spray, wherein: Calculated by mass-volume ratio, the nasal spray contains 0.1-5% of phencyclonate hydrochloride, 0.1-10% of benzyl alcohol and 4000-25% of polyethylene glycol.

2. The nasal spray according to claim 1, wherein the nasal spray contains 0.1-5% of phencyclonate hydrochloride, 0.1-10% of benzyl alcohol and 0.05% of polyethylene glycol 400, based on the mass volume ratio. 10-20%.

3. The nasal spray according to any one of claims 1 to 2, wherein 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.

4. The nasal spray according to any one of claims 1 to 3, wherein the nasal spray contains 0.5-3% of phencyclonate hydrochloride, 0.5-5% of benzyl alcohol, and 5-25% of polyethylene glycol 400, based on mass volume ratio.

5. The nasal spray according to any one of claims 1 to 4, wherein the nasal spray contains 1-2% of phencyclonate hydrochloride, 0.5-5% of benzyl alcohol, and 10-20% of polyethylene glycol 400, based on mass volume ratio.

6. The nasal spray according to any one of claims 1 to 5, further comprising an acid-base regulator, preferably, 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, Na2HPO4 / NaH2PO4.

7. The nasal spray according to any one of claims 1 to 6, wherein the nasal spray optionally contains a preservative, preferably, the preservative is selected from any one of benzalkonium bromide, benzalkonium chloride, benzoic acid, sodium benzoate, methylparaben, ethylparaben, propylparaben, butylparaben, sorbic acid, ethanol, glycerol, phenol, cresol, chlorobutanol or a combination thereof.

8. The nasal spray according to any one of claims 1 to 7, wherein the nasal spray optionally contains an osmotic pressure regulator, preferably, the osmotic pressure regulator is selected from any one of sodium chloride, lactose, glucose, dextran, sorbitol, mannitol or a combination thereof.

9. The method for preparing the phencyclonate hydrochloride nasal spray according to any one of claims 1 to 8, comprising the following steps: weighing a required amount of benzyl alcohol, adding water to 40-80% of the spray, mixing evenly, adding a required amount of phencyclonate hydrochloride, stirring evenly, adding a required amount of other components, stirring until completely dissolved, adjusting the system pH to 3.5-6.0 with an acid-base regulator, and adding water to the fixed volume to obtain the product.

10. Use of the phencyclnonate hydrochloride nasal spray according to any one of claims 1 to 8 in preventing or treating motion sickness.

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