Ramelteon solution nasal spray and application thereof

Abstract

The invention provides the stable ramelteon solution nasal spray, the medicine is atomized and then absorbed by the nasal mucosa to enter body fluid circulation, the problem of low bioavailability caused by the first-pass effect of the liver during oral administration of ramelteon is solved, meanwhile, the ramelteon solution nasal spray takes effect faster and is obviously superior to an oral preparation, the osmotic pressure conforms to the acceptable range of a human body, and the ramelteon solution nasal spray is free of irritation and has a good application prospect. The medicine is safer and is suitable for long-term treatment of chronic diseases. The ramelteon solution nasal spray provided by the invention is simple in preparation process, suitable for industrial production and low in production cost.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a ramelteon solution nasal spray and application thereof. BACKGROUND

[0002] Ramelteon, molecular formula C 16 H 21 NO2, molecular weight 259.343, chemical name (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide, structural formula as follows:

[0003]

[0004] Ramelteon is a melatonin receptor agonist, which can selectively agonize melatonin type 1 and type 2 receptors (MT1, MT2) mainly concentrated in the hypothalamus, increase slow-wave sleep (SWS) and rapid eye movement sleep (REW), and thus reduce insomnia.

[0005] However, due to the first-pass metabolism of ramelteon in the liver, the oral bioavailability of ramelteon is only 1.8%, and since ramelteon is mainly metabolized by CYP1A2, CYP2C subfamily and CYP3A4 also participate in the metabolism, so it can be expected that the oral preparation has high inter-individual difference and significant drug-drug interactions. For example, fluvoxamine maleate (a strong CYP1A2 inhibitor) can significantly increase the blood concentration and systemic exposure of ramelteon. In addition, compared with healthy volunteers, the systemic exposure of ramelteon in patients with liver dysfunction will also be increased (AUC increased by 8 to 10.7 times). When taken with a high-fat meal, the AUC of ramelteon is increased by 31% compared with fasting administration, but the C max is decreased by 22% and the T max is delayed, which seriously affects the effect of the product on accelerating sleep.

[0006] And through nasal mucosa administration, the first-pass effect when orally administered can be avoided, and it directly enters the blood circulation, has rapid onset, improves bioavailability, and ensures the therapeutic effect.

[0007] Patent CN110996938A discloses a ramelteon intranasal administration nasal spray solution, but the applicant finds that the osmotic pressure of the nasal spray solution exceeds 500 mOsmol / kg, and too high osmotic pressure can cause stinging at the administration site when administered nasally, and long-term use can cause damage to the nasal mucosa and nasal cilia, which cannot be used for the treatment of insomnia and other chronic diseases. At the same time, according to the FDA's published inactive ingredients after approval (https: / / www.accessdata.fda.gov / scripts / cder / iig / index.cfm), it is found that sulfobutyl ether-beta-cyclodextrin in the prescription is not approved for nasal use, and the use of cyclodextrin and its derivatives in large quantities has local and systemic toxicity, which can easily cause changes in the histological characteristics of the nasal cavity and the frequency of ciliary beating, and also has hemolytic toxicity and cytotoxicity, with high safety risk.

[0008] Therefore, it is necessary to provide a ramelteon nasal spray with reduced irritation during nasal administration and improved safety for patients. SUMMARY

[0009] To solve the above technical problems, the present application provides a ramelteon solution nasal spray, which comprises the following components:

[0010] Ramelteon, absorption enhancer, surfactant, osmotic pressure regulator, solvent.

[0011] According to an embodiment of the present application, the content of ramelteon is 0.005% to 5.0%, preferably 0.01% to 3.0%, for example 0.05%, 0.1%, 0.2%, 0.5%, 0.8%, 1.0%, 2.0%.

[0012] According to an embodiment of the present application, the absorption enhancer is selected from any one, two or more of polyethylene glycol-6 methyl ether, n-dodecyl beta-D-maltoside, sulfobutyl-beta-cyclodextrin sodium, preferably n-dodecyl beta-D-maltoside.

[0013] According to an embodiment of the present application, the content of the absorption enhancer is 0.01% to 0.2%, preferably 0.05% to 0.15%, for example 0.1%.

[0014] According to an embodiment of the present application, the surfactant is selected from any one, two or more of polysorbate 80, poloxamer, vitamin E succinate polyethylene glycol ester, sorbitan trioleate, polyethylene glycol (15)-hydroxystearate (HS-15), methoxypolyethylene glycol-b-poly D,L-lactide; preferably, any one, two or more of vitamin E succinate polyethylene glycol ester, poloxamer 407, polyethylene glycol (15)-hydroxystearate.

[0015] According to embodiments of the present application, the surfactant is present in an amount of 0.5% to 15%, preferably 1% to 12%, for example 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%.

[0016] According to embodiments of the present application, the osmotic pressure regulator is selected from any one, two or more of sodium chloride, glycerin, dextrose, potassium chloride, sorbitol, mannitol, propylene glycol; preferably glycerin.

[0017] According to embodiments of the present application, the osmotic pressure regulator is present in an amount of 0.5% to 5.0%, preferably 0.8% to 4.0%, for example 1.0%, 1.2%, 1.5%, 1.8%, 2.0%, 2.5%, 3.0%.

[0018] According to embodiments of the present application, the solvent is selected from water, for example purified water.

[0019] According to embodiments of the present application, the ramelteon solution nasal spray optionally further comprises a pH adjusting agent.

[0020] According to embodiments of the present application, the pH adjusting agent is selected from one or more of citric acid, sodium citrate, hydrochloric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, boric acid and salts thereof, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.

[0021] According to embodiments of the present application, the pH adjusting agent comprises citric acid and sodium phosphate; preferably, the citric acid is present in an amount of 0.2% to 0.6%; preferably, the sodium phosphate is present in an amount of 0.2% to 0.6%; for example citric acid 0.2%, for example sodium phosphate 0.5%.

[0022] According to embodiments of the present application, the pH adjusting agent is present in an amount of 0.1% to 1.0%, preferably 0.2% to 0.8%, for example 0.2%, 0.5%, 0.7%.

[0023] According to embodiments of the present application, the pH of the ramelteon solution nasal spray is 4 to 7, preferably 5 to 7, for example 5.5, 5.8, 6.0, 6.3, 6.5, 6.8, 7.0.

[0024] According to embodiments of the present application, the ramelteon solution nasal spray comprises the following components:

[0025] Ramelteon 0.1% to 5.0%, surfactant 0.1% to 10.0%, osmotic pressure regulator 0.5% to 5.0%, pH adjusting agent 0.3% to 0.6%, absorption enhancer 0.01% to 0.2%, and the balance water.

[0026] According to an embodiment of the present application, the ramelteon solution nasal spray comprises the following components:

[0027] Ramelteon 0.1% - 5.0%, surfactant 0.1% - 10.0%, osmotic pressure regulator 0.5% - 5.0%, n-dodecyl β-D-maltoside 0.01% - 0.2%, and the balance being water.

[0028] According to an embodiment of the present application, the ramelteon solution nasal spray comprises the following components:

[0029] Ramelteon 0.1% - 5.0%, surfactant 0.1% - 10.0%, osmotic pressure regulator 0.5% - 5.0%, pH regulator 0.3% - 0.6%, n-dodecyl β-D-maltoside 0.01% - 0.2%, and the balance being water.

[0030] According to an embodiment of the present application, the ramelteon solution nasal spray optionally further comprises a preservative; preferably, the preservative is selected from any one, two or more of potassium sorbate, benzalkonium chloride, phenyl ethanol, and benzyl alcohol.

[0031] According to an embodiment of the present application, the preservative is present in an amount of 0% - 0.1%, for example, 0.01%, 0.02%, 0.03%, 0.05%, 0.06%, 0.08%.

[0032] According to an embodiment of the present application, the ramelteon suspension nasal spray optionally further comprises any one, two or more of a chelating agent, a fragrance.

[0033] According to an embodiment of the present application, the chelating agent is selected from disodium ethylenediaminetetraacetate; preferably, the chelating agent is present in an amount of 0% - 1.0%, preferably 0.01% - 0.4%.

[0034] According to an embodiment of the present application, the fragrance is selected from phenyl ethanol; preferably, the fragrance is present in an amount of 0% - 1.0%, preferably 0.01% - 0.05%.

[0035] According to an embodiment of the present application, the ramelteon solution nasal spray comprises the following components:

[0036] Ramelteon 0.01% - 3.0% (for example, 0.2%)

[0037] Surfactant (for example, vitamin E succinate polyethylene glycol ester) 4.0% - 10.0%

[0038] Osmotic pressure regulator (for example, glycerol) 1.2% - 2.0% (for example, 1.5%)

[0039] pH regulator 0.1% - 1.0% (for example, 0.7%)

[0040] Absorption enhancer (e.g., n-dodecyl β-D-maltoside) 0.01% to 0.2% (e.g., 0.01%)

[0041] The balance is water.

[0042] According to embodiments of the application, the pH adjusting agent consists of citric acid 0.2%, sodium phosphate dibasic 0.5%.

[0043] According to embodiments of the application, the rimegepant solution nasal spray comprises the following components:

[0044] Rimegepant 0.2%, vitamin E polyethylene glycol succinate 4.0%, glycerin 1.5%, citric acid 0.2%, sodium phosphate dibasic 0.5%, absorption enhancer (e.g., polyethylene glycol-6 monomethyl ether, n-dodecyl β-D-maltoside) 0.01%, the balance being water.

[0045] According to embodiments of the application, the rimegepant solution nasal spray comprises the following components:

[0046] Rimegepant 0.2%, vitamin E polyethylene glycol succinate 4.0%, glycerin 1.2% to 2.0% (e.g., 1.5%), citric acid 0.2%, sodium phosphate dibasic 0.5%, n-dodecyl β-D-maltoside 0.01%, the balance being water.

[0047] According to embodiments of the application, the rimegepant solution nasal spray comprises the following components:

[0048] Rimegepant 0.2%, surfactant (e.g., vitamin E polyethylene glycol succinate, poloxamer 407, polyethylene glycol (15)-hydroxystearate) 4.0%, glycerin 1.2% to 2.0%, citric acid 0.2%, sodium phosphate dibasic 0.5%, n-dodecyl β-D-maltoside 0.01%, the balance being water.

[0049] According to embodiments of the application, the rimegepant solution nasal spray comprises the following components:

[0050] Rimegepant 0.2%, vitamin E polyethylene glycol succinate 4.0% to 10.0%, glycerin 1.5%, citric acid 0.2%, sodium phosphate dibasic 0.5%, n-dodecyl β-D-maltoside 0.01%, the balance being water.

[0051] According to embodiments of the application, the rimegepant solution nasal spray comprises the following components:

[0052] Ramelteon 0.2%, Vitamin E succinate polyethylene glycol 4.0%, Glycerin 1.5%, Citric acid 0.2%, Sodium phosphate dibasic 0.5%, n-Dodecyl beta-D-maltoside 0.01%, and the balance of water.

[0053] According to an embodiment of the present application, the ramelteon solution nasal spray comprises the following components:

[0054] Ramelteon 0.2%, Vitamin E succinate polyethylene glycol 4.0%, Glycerin 1.5%, Citric acid 0.2%, Sodium phosphate dibasic 0.5%, n-Dodecyl beta-D-maltoside 0.01%, and the balance of water.

[0055] According to an embodiment of the present application, the content is a mass percentage.

[0056] The present application also provides a preparation method of the above-mentioned ramelteon solution nasal spray, which comprises the following steps:

[0057] Mixing, stirring, and filtering the ramelteon, absorption promoter, surfactant, osmotic pressure regulator, solvent, and optional pH regulator, preservative, chelating agent, and fragrance, to obtain the ramelteon solution nasal spray.

[0058] According to an embodiment of the present application, the preparation method comprises the following steps:

[0059] (1) Placing the ramelteon and surfactant in a container, adding an appropriate amount of solvent-1 to dissolve, to obtain solution 1;

[0060] (2) Placing the absorption promoter, osmotic pressure regulator, pH regulator, and an appropriate amount of solvent in a container, stirring and dissolving, to obtain solution 2;

[0061] (3) Removing the solvent-1 in solution 1, adding solution 2, dissolving, and adding the remaining solvent, to obtain the ramelteon solution nasal spray.

[0062] According to an embodiment of the present application, in step (1), the solvent-1 is selected from solvents capable of sufficiently dissolving the ramelteon and surfactant, such as ethanol.

[0063] According to an embodiment of the present application, in step (3), the solvent-1 can be removed by a rotary evaporator.

[0064] According to an embodiment of the present application, in step (3), the solution nasal spray is optionally filled into a nasal spray bottle.

[0065] According to an embodiment of the present application, the preparation method comprises the following steps:

[0066] (1) Put ramelteon and surfactant into a container, add an appropriate amount of solvent-1 to dissolve, and obtain solution 1;

[0067] (2) Put absorption promoter, osmotic pressure regulator, pH regulator and part of purified water into a container, stir and dissolve, and obtain solution 2;

[0068] (3) Put solution 1 into a rotary evaporator, recover and remove solvent-1; after the complete removal of solvent-1, add solution 2, shake and dissolve, and then add the remaining purified water after complete dissolution, to obtain the ramelteon solution nasal spray.

[0069] The application also provides use of the above-mentioned ramelteon suspension nasal spray in the preparation of a drug for treating and / or preventing diseases such as sleep onset disorder leading to insomnia, insomnia, jet lag syndrome, etc.

[0070] The application also provides a method for treating and / or preventing diseases, which comprises administering a therapeutically effective amount of the above-mentioned ramelteon suspension nasal spray to a treatment subject, and the diseases are sleep onset disorder leading to insomnia, insomnia, jet lag syndrome, etc.

[0071] Advantages

[0072] The application provides a stable ramelteon solution nasal spray, which is atomized after the drug is absorbed into the body fluid circulation through the nasal mucosa, solves the problem of low bioavailability of ramelteon oral due to the first-pass effect of the liver, has a faster onset, is obviously superior to oral preparations, and has a permeability pressure meeting the human acceptable range, no irritation, is safer, and is suitable for long-term treatment of long-term chronic diseases. The ramelteon solution nasal spray provided by the application has a simple preparation process, is suitable for industrialized production, and has low production cost. DETAILED DESCRIPTION

[0073] The technical solutions of the application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively and explain the application, and should not be interpreted as limiting the scope of protection of the application. Any technology realized based on the above-mentioned content of the application is covered in the scope of protection intended by the application.

[0074] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0075] Example 1: Investigation of the influence of different absorption promoters on bioavailability

[0076] Preparation method of prescription 1-3:

[0077] (1) Put the prescription amount of ramelteon and vitamin E succinate polyethylene glycol into a tomato-shaped bottle, add an appropriate amount of ethanol to dissolve, and obtain solution 1;

[0078] (2) Add the prescription amount of absorption promoter, glycerol, citric acid, sodium hydrogen phosphate into the prescription amount of 70% purified water, stir and dissolve to obtain solution 2;

[0079] (3) Place solution 1 on a rotary evaporator, recover and remove ethanol at 40°C; after complete removal of ethanol, add solution 2, shake and dissolve, and then add the remaining 30% purified water, mix uniformly, and filter through a 0.22 μm filter membrane to obtain a liquid medicine;

[0080] (4) Fill the liquid medicine into a nasal spray bottle to obtain the nasal spray.

[0081] Table 1 Composition of Formulations 1-3

[0082]

[0083] Rat pharmacokinetic test:

[0084] Select 24 adult rats, 16 males and 8 females (non-lactation period), and divide them into a nasal spray group (nasal spray of formulations 1-3) and an oral (gavage) group Four groups, 6 rats in each group (male to female ratio of 2:1), are administered at a dose of 8 mg / kg, and the main pharmacokinetic parameters of the test animals, including half-life, peak time, maximum blood concentration and AUC, are determined 0～t The determination results are shown in Table 2.

[0085] Table 2 Pharmacokinetic parameters of formulations 1-3

[0086]

[0087]

[0088] As shown in Table 2, the pharmacodynamic effect time, half-life and maximum blood concentration of the solution nasal spray provided by the application are all superior to those of the oral group, and the bioavailability of the solution nasal spray of each formulation is significantly higher than that of the oral group.

[0089] Table 3 pH results of formulations 1-3

[0090] Group Formulation 1 Formulation 2 Formulation 3 pH 5.76 5.80 6.08

[0091] Example 2 Investigation of the influence of different doses of osmotic pressure adjusting agents on osmotic pressure

[0092] Prepare formulations 1, 4-5 according to Example 1, and determine the osmotic pressure of the formulations.

[0093] Table 4 Composition of formulations 1, 4-5

[0094]

[0095] Table 5: Osmotic pressure detection results of prescription 1, 4-5

[0096] Group Formulation 1 Formulation 4 Formulation 5 Osmolarity (mOsm / kg) 306.00 285.00 348.00

[0097] As shown in the results of Table 4, the osmotic pressure of the solution nasal spray provided by the present application is close to the normal human osmotic pressure of 280-310 mOsm / kg, is non-irritating, does not damage the nasal mucosa and nasal cilia, and has good safety.

[0098] Example 3: Investigation of the effect of different surfactants on content

[0099] Prescription 1, 6-7 were prepared according to Reference Example 1, and the content of ramelteon in the prescription was determined.

[0100] Table 6: Composition of prescription 1, 6-7

[0101]

[0102] Table 7: Content determination results of prescription 1, 6-7

[0103] Group Formulation 1 Formulation 6 Formulation 7 API content 97.5％ 93.8％ 90.7％

[0104] Example 4: Screening of surfactant dosage

[0105] Prescription 1, 8-9 were prepared according to Reference Example 1, and the content of ramelteon in the prescription was determined.

[0106] Table 8: Composition of prescription 1, 8-9

[0107]

[0108]

[0109] Table 9: Content determination results of prescription 1, 8-9

[0110] Group Formulation 1 Formulation 8 Formulation 9 API content 97.5％ 2.1％ 99.8％

[0111] From the above results, it can be seen that the addition of a surfactant in the prescription can significantly improve the solubility of the drug in the liquid.

[0112] Example 5: Screening of osmotic pressure regulator type

[0113] Prescription 5, 10-11 were prepared according to Reference Example 1, and the content of ramelteon in the prescription was determined.

[0114] Table 10: Composition of prescription 5, 10-11

[0115]

[0116] Table 11 osmotic pressure detection results of prescription 5, 10-11

[0117]

[0118]

[0119] Example 6 study on surfactant addition mode

[0120] Prescription 1 and 12 have the same composition, wherein prescription 1 is prepared according to the process of example 1, and prescription 12 is prepared by the following process steps:

[0121] 1) Add the prescription amount of ramelteon, vitamin E succinate polyethylene glycol, n-dodecyl β-D-maltoside, glycerol, citric acid, sodium hydrogen phosphate into the prescription amount of purified water, and stir for 240 min using a magnetic stirrer at 400 rpm;

[0122] 2) After stirring, filter using a 0.22 μm filter membrane to obtain a medicinal liquid;

[0123] 3) Fill the medicinal liquid into a nasal spray bottle to obtain the product.

[0124] After the above prescription 1 and 12 are prepared, the content of ramelteon in the prescription is determined.

[0125] Table 12 content results of prescription 1 and 12

[0126] Group Formulation 1 Formulation 12 Content 97.5％ 16.4％

[0127] Example 7 stability investigation

[0128] The sample of prescription 1 is placed in a stability test box for accelerated testing, and the properties, API content and related impurities of the sample are detected at 0 month, 3 months and 6 months, respectively, to investigate the stability of the product. The results are shown in Table 13.

[0129] Table 13 stability investigation results of prescription 1

[0130]

[0131] The results of Table 13 show that after 6 months of accelerated investigation, the sample content is stable and no API is precipitated, and the sample stability is good.

[0132] The above examples only express several embodiments of the present application, and the description is more specific, but it cannot be understood as limiting the scope of the patent of the present application. It should be noted that for ordinary skilled persons in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are all within the scope of protection of the present application. Therefore, the protection scope of the patent of the present application should be subject to the appended patent claims.

[0133] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, and the like made within the spirit and principle of the present application should be included in the scope of the present application.

Claims

1. A rameltein nasal spray solution, the rameltein nasal spray solution comprising the following components: Ramelotinib, absorption enhancer, surfactant, osmotic pressure regulator, solvent; The absorption enhancer is selected from n-dodecyl β-D-maltodextrin; The osmotic pressure regulator is selected from glycerol.

2. The rameltein nasal spray according to claim 1, characterized in that, The content of rameltein is 0.005% to 5.0%, preferably 0.01% to 3.0%; Preferably, the content of the absorption promoter is 0.01% to 0.2%, more preferably 0.05% to 0.15%; Preferably, the content of the osmotic pressure regulator is 0.5%-5.0%, more preferably 0.8%-4.0%.

3. The rameltein nasal spray according to claim 1 or 2, characterized in that, The surfactant is selected from any one, two or more of polysorbate 80, poloxamer, polyethylene glycol e-succinate, sorbitan trioleate, polyethylene glycol (15)-hydroxystearate (HS-15), and methoxy polyethylene glycol-b-polyD,L-lactide; preferably, it is selected from any one, two or more of polyethylene glycol e-succinate, poloxamer 407, and polyethylene glycol (15)-hydroxystearate. Preferably, the surfactant content is 0.5%-15%, more preferably 1%-12%; Preferably, the solvent is selected from water.

4. The rameltein nasal spray according to any one of claims 1-3, characterized in that, The ramelteilamide solution nasal spray optionally further includes a pH adjuster; Preferably, the pH adjuster is selected from one or more of citric acid, sodium citrate, hydrochloric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, boric acid and its salts, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. Preferably, the pH adjuster includes citric acid and sodium hydrogen phosphate; preferably, the content of citric acid is 0.2% to 0.6%; preferably, the content of sodium hydrogen phosphate is 0.2% to 0.6%. Preferably, the pH adjuster has a content of 0.1%-1.0%, more preferably 0.2%-0.8%; Preferably, the pH value of the rameltein nasal spray solution is 4-7, more preferably 6-7.

5. The rameltein nasal spray according to any one of claims 1-4, characterized in that, The rameltetinamide nasal spray comprises the following components: Rametamide 0.1%–5.0%, surfactant 0.1%–10.0%, osmotic pressure regulator 0.5%–5.0%, pH regulator 0.3%–0.6%, absorption promoter 0.01%–0.2%, balance being water; Preferably, the rameltein nasal spray comprises the following components: Rametamide 0.1%–5.0%, surfactant 0.1%–10.0%, osmotic pressure regulator 0.5%–5.0%, n-dodecyl β-D-maltodextrin 0.01%–0.2%, balance being water. Preferably, the rameltein nasal spray comprises the following components: Rametamide 0.1%–5.0%, surfactant 0.1%–10.0%, osmotic pressure regulator 0.5%–5.0%, pH regulator 0.3%–0.6%, n-dodecyl β-D-maltodextrin 0.01%–0.2%, balance being water.

6. The rameltein nasal spray according to any one of claims 1-5, characterized in that, The rameltein nasal spray optionally further includes a preservative; preferably, the preservative is selected from any one, two or more of potassium sorbate, benzalkonium chloride, phenylethanol and benzyl alcohol; preferably, the content of the preservative is 0%-0.1%; Preferably, the rameltetinamide nasal spray optionally further comprises any one, two or more of a chelating agent and a fragrance; preferably, the chelating agent is selected from disodium ethylenediaminetetraacetate; preferably, the content of the chelating agent is 0% to 1.0%; preferably, the fragrance is selected from phenylethanol; preferably, the content of the fragrance is 0% to 1.0%.

7. The rameltein nasal spray according to any one of claims 1-6, characterized in that, The rameltetinamide nasal spray comprises the following components: Rametamide 0.01%-3.0% Surfactant 4.0%-10.0% Osmotic pressure regulator 1.2%-2.0% pH adjuster 0.1%-1.0% Absorption enhancer 0.01%–0.2% The remainder is water; Preferably, the pH adjuster consists of 0.2% citric acid and 0.5% sodium hydrogen phosphate. Preferably, the rameltein nasal spray comprises the following components: Rametamide 0.2%, Vitamin E succinate polyethylene glycol 4.0%, Glycerin 1.5%, Citric acid 0.2%, Sodium hydrogen phosphate 0.5%, Absorption enhancer 0.01%, Balance: Water; Preferably, the rameltein nasal spray comprises the following components: Rametamide 0.2%, Vitamin E succinate polyethylene glycol 4.0%, Glycerin 1.2%-2.0%, Citric acid 0.2%, Sodium hydrogen phosphate 0.5%, n-dodecyl β-D-maltodextrin 0.01%, balance water; Preferably, the rameltein nasal spray comprises the following components: Rametamide 0.2%, surfactant 4.0%, glycerol 1.2%-2.0%, citric acid 0.2%, sodium hydrogen phosphate 0.5%, n-dodecyl β-D-maltose 0.01%, balance water; Preferably, the rameltein nasal spray comprises the following components: Rametamide 0.2%, Vitamin E succinate polyethylene glycol 4.0%-10.0%, Glycerin 1.5%, Citric acid 0.2%, Sodium hydrogen phosphate 0.5%, n-Dodecyl β-D-maltodextrin 0.01%, Balance: Water; Preferably, the rameltein nasal spray comprises the following components: Rametamide 0.2%, Vitamin E succinate polyethylene glycol 4.0%, Osmotic pressure regulator 1.5%-2.0%, Citric acid 0.2%, Sodium hydrogen phosphate 0.5%, n-dodecyl β-D-maltodextrin 0.01%, balance water; Preferably, the rameltein nasal spray comprises the following components: Rametamide 0.2%, Vitamin E succinate polyethylene glycol 4.0%, Glycerin 1.5%, Citric acid 0.2%, Sodium hydrogen phosphate 0.5%, n-dodecyl β-D-maltodextrin 0.01%, and the balance being water.

8. A method for preparing the rameltein nasal spray according to any one of claims 1-7, the method comprising the following steps: Rametamide, absorption enhancer, surfactant, osmotic pressure regulator, solvent, and optionally pH adjuster, preservative, chelating agent, and fragrance are mixed, stirred, and filtered to obtain the rametamide solution nasal spray.

9. The method for preparing the rameltein nasal spray according to claim 8, wherein the preparation method comprises the following steps: (1) Place rameltein and surfactant in a container, add an appropriate amount of solvent-1 to dissolve, and obtain solution 1; (2) Place the absorption promoter, osmotic pressure regulator, pH regulator and appropriate amount of solvent in a container, stir to dissolve, and obtain solution 2; (3) Remove solvent-1 from solution 1, add solution 2, dissolve, add the remaining solvent, and the rametamide solution nasal spray is obtained; Preferably, in step (1), solvent-1 is selected from solvents that can fully dissolve rameltein and surfactants, such as ethanol; preferably, in step (3), solvent-1 can be removed by a rotary evaporator.

10. The use of the rameltetinamide nasal spray according to any one of claims 1-7 in the preparation of a medicament for treating and / or preventing a disease, wherein the disease is sleep disturbances leading to insomnia, insomnia, jet lag syndrome, etc.

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