Ramelteon suspension nasal spray and application thereof

Abstract

According to the stable ramelteon suspension nasal spray, medicine is atomized and then absorbed through nasal mucosa to enter body fluid circulation, the problem that the bioavailability is low due to the first-pass effect of the liver when ramelteon is orally taken is solved, meanwhile, the ramelteon suspension nasal spray takes effect faster and is obviously superior to an oral preparation, osmotic pressure conforms to the acceptable range of a human body, and the ramelteon suspension nasal spray is free of irritation and free of toxic and side effects. The medicine is safer and is suitable for long-term treatment of chronic diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a rametamide suspension nasal spray and its application. Background Technology

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

[0003]

[0004] Ramelteline is a melatonin receptor agonist that selectively activates melatonin receptors type 1 and type 2 (MT1 and MT2) primarily in the hypothalamus, increasing slow-wave sleep (SWS) and rapid eye movement (REW) sleep, thereby reducing insomnia. Ramelteline is currently the first non-addictive insomnia treatment not listed under special regulations, and its tablet form has been approved in countries such as Japan and the United States.

[0005] However, due to the extensive first-pass metabolism of rameltein in the liver, its oral bioavailability is only 1.8%. Furthermore, since rameltein is primarily metabolized via CYP1A2, with CYP2C subgroups and CYP3A4 also involved, significant inter-individual variability and significant drug-drug interactions are expected with its oral formulation. For example, fluvoxamine maleate (a potent CYP1A2 inhibitor) can significantly increase the plasma concentration and systemic exposure of rameltein. In addition, compared to healthy volunteers, patients with hepatic impairment also show increased systemic exposure to rameltein (AUC increased 8 to 10.7 times). When taken with a high-fat meal, the AUC of rameltein is 31% higher than when administered on an empty stomach, but C... max Reduced by 22% and T max Delaying the process severely impacts the product's ability to accelerate sleep onset.

[0006] Nasal administration avoids the first-pass effect of oral administration, allowing the drug to enter the bloodstream directly, resulting in rapid onset of action, improved bioavailability, and guaranteed therapeutic efficacy.

[0007] Patent CN110996938A discloses a nasal spray solution for intranasal administration of ramelteamide. However, the applicant discovered that the osmotic pressure of this nasal spray solution exceeds 500 mOsmol / kg. Excessively high osmotic pressure can cause stinging at the administration site during nasal administration, and long-term use may damage the nasal mucosa and nasal cilia, making it unsuitable for the treatment of chronic diseases such as insomnia. Furthermore, according to the FDA's list of approved inactive ingredients (https: / / www.accessdata.fda.gov / scripts / cder / iig / index.cfm), sulfobutyl ether-β-cyclodextrin in the formulation is not approved for nasal use. Large doses of cyclodextrin and its derivatives have local and systemic toxicity, easily leading to changes in nasal histological characteristics and ciliary beating frequency. They also exhibit hemolytic toxicity and cytotoxicity, posing a high safety risk.

[0008] Therefore, it is necessary to provide a rametamide nasal spray that reduces the irritation of nasal administration and improves patient safety. Summary of the Invention

[0009] To address the aforementioned technical problems, the present invention provides a ramelteline nasal suspension spray, which comprises the following components:

[0010] Rametamide, suspending agent, surfactant, osmotic pressure regulator, solvent.

[0011] According to an embodiment of the present invention, the ramelteinamide is ramelteinamide micro powder; preferably, the ramelteinamide micro powder D 90 The size ranges from 1μm to 30μm, preferably from 5μm to 25μm, such as 10μm, 14μm, 15μm, 20μm, and 25μm.

[0012] According to embodiments of the present invention, the content of rameltein is 0.05% to 2.0%, preferably 0.1% to 1.0%, for example 0.2%, 0.5%, or 0.8%.

[0013] According to an embodiment of the present invention, the suspending agent is selected from any one, two or more of sodium carboxymethyl cellulose, hydroxyethyl methyl cellulose, sodium carboxymethyl starch, hydroxypropyl methyl cellulose, and microcrystalline cellulose-sodium carboxymethyl cellulose.

[0014] According to an embodiment of the present invention, the content of the suspending agent is 1.0% to 15.0%, for example 2.0%, 2.5%, 3.0%, 5.0%, 8.0%, or 10.0%.

[0015] According to an embodiment of the present invention, the surfactant is selected from any one, two or more of polysorbate, poloxamer, polyethylene glycol (15)-hydroxystearate (HS-15), and sorbitan trioleate; preferably, the surfactant is selected from polysorbate-80, poloxamer 407, and HS-15.

[0016] According to embodiments of the present invention, the content of the surfactant is 0-0.5%, preferably 0.01%-0.1%, for example 0.005%, 0.008%, 0.01%, 0.02%, or 0.03%.

[0017] According to an embodiment of the present invention, the osmotic pressure regulator is selected from any one, two or more of sodium chloride, glycerol, anhydrous glucose, propylene glycol, potassium chloride, sorbitol, and mannitol; preferably, the osmotic pressure regulator is selected from glycerol.

[0018] According to an embodiment of the present invention, the content of the osmotic pressure regulator is 1.0%-5.0%, preferably 1.5%-4.0%, for example 1.8%, 2.4%, or 3.0%.

[0019] According to an embodiment of the present invention, the solvent is selected from water, such as purified water.

[0020] According to an embodiment of the present invention, the ramelteamide nasal spray optionally further comprises a pH adjuster; preferably, the pH adjuster is selected from any one, two, 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. According to an embodiment of the present invention, the pH adjuster comprises citric acid and sodium citrate; preferably, the content of citric acid is 0.2% to 0.6%; preferably, the content of sodium citrate is 0.2% to 0.6%; for example, 0.2% citric acid, for example, 0.35% sodium citrate.

[0021] According to an embodiment of the present invention, the content of the pH adjuster is 0.1%-1.0%, preferably 0.2%-0.6%, for example 0.2%, 0.35%, or 0.55%.

[0022] According to an embodiment of the present invention, the pH value of the ramelteilamide suspension nasal spray is 4 to 7, preferably 5 to 7, for example 5.0, 5.3, 5.5, 5.8, 6.0, 6.3, 6.5, 6.8, 7.0.

[0023] According to an embodiment of the present invention, 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 and phenethyl alcohol.

[0024] According to an embodiment of the present invention, the content of the preservative is 0%-0.1%, for example 0.01%, 0.02%, 0.03%, 0.05%, 0.06%, or 0.08%.

[0025] According to an embodiment of the present invention, the rametamide suspension nasal spray optionally further comprises any one, two or more of a chelating agent and a fragrance.

[0026] According to an embodiment of the present invention, the chelating agent is selected from disodium ethylenediaminetetraacetate; preferably, the content of the chelating agent is 0% to 1.0%, more preferably 0.01% to 0.4%.

[0027] According to an embodiment of the present invention, the fragrance agent is selected from phenylethanol; preferably, the content of the fragrance agent is 0% to 1.0%, more preferably 0.01% to 0.05%. According to an embodiment of the present invention, the rameltein nasal spray suspension comprises the following components:

[0028] Rametamide, suspending agent, surfactant, pH adjuster, osmotic pressure adjuster, water.

[0029] According to an embodiment of the present invention, the rameltetinamide nasal spray suspension comprises the following components:

[0030] Rametamide, suspending agent, surfactant, pH adjuster, osmotic pressure regulator, preservative, water.

[0031] According to an embodiment of the present invention, the rameltetinamide nasal spray suspension comprises the following components:

[0032] The composition of ramelteamide micro powder is 0.05%–2.0%, suspending agent is 1.0%–15.0%, osmotic pressure regulator is 1.0%–5.0%, surfactant is 0.01%–0.1%, pH regulator is 0.2%–0.6%, and the balance is water.

[0033] According to an embodiment of the present invention, the rameltetinamide nasal spray suspension comprises the following components:

[0034] The composition of ramelteamide micro powder is 0.05%–2.0%, suspending agent is 1.0%–15.0%, osmotic pressure regulator is 1.0%–5.0%, surfactant is 0.01%–0.1%, pH regulator is 0.2%–0.6%, preservative is 0%–0.1%, and the balance is water.

[0035] According to an embodiment of the present invention, the rameltetinamide nasal spray suspension comprises the following components:

[0036] Rametamide 0.05%–2.0%, suspending agent (e.g., microcrystalline cellulose-sodium carboxymethyl cellulose) 2.0%–3.0%, osmotic pressure regulator (e.g., glycerin) 1.8%–3.0%, surfactant (e.g., polysorbate 80, poloxamer 407, HS-15) 0.01%–0.1%, pH regulator (e.g., a combination of citric acid and sodium citrate) 0.2%–0.6%, preservative (e.g., benzalkonium chloride) 0%–0.1%, balance being water.

[0037] According to an embodiment of the present invention, the rameltetinamide nasal spray suspension comprises the following components:

[0038] Rametamide 0.05%–2.0%, microcrystalline cellulose-sodium carboxymethyl cellulose 2.0%–3.0%, surfactant (e.g., polysorbate 80, poloxamer 407, HS-15) 0.01%–0.1%, citric acid 0.2%, sodium citrate 0.35%, glycerin 2.4%, preservative (e.g., benzalkonium chloride) 0%–0.1%, balance being water.

[0039] According to an embodiment of the present invention, the rameltetinamide nasal spray suspension comprises the following components:

[0040] Rametamide 0.2%, Sodium Carboxymethyl Cellulose 2.0%, Polysorbate 80 0.01%, Citric Acid 0.2%, Sodium Citrate 0.35%, Glycerin 2.4%, Benzalkonium Chloride 0.02%, Balance: Water.

[0041] According to an embodiment of the present invention, the content is a mass percentage.

[0042] The present invention also provides a method for preparing the above-mentioned rameltetinamide nasal suspension spray, the preparation method comprising the following steps:

[0043] (1) Preparation of drug suspension: Dissolve the surfactant in an appropriate amount of solvent by stirring, then add ramelteamide, and then shear to obtain drug suspension;

[0044] (2) Suspension matrix: The suspending agent is stirred and sheared to obtain a suspension matrix;

[0045] (3) Osmotic pressure regulator solution: Dissolve the osmotic pressure regulator in an appropriate amount of solvent to obtain an osmotic pressure regulator solution;

[0046] (4) Mix the drug suspension, suspension matrix, osmotic pressure regulator solution and optional preservative, chelating agent and fragrance, add solvent to the prescription amount, adjust the pH to 4-7, stir, and obtain the suspension nasal spray.

[0047] According to an embodiment of the present invention, in step (1), shearing is performed by a high-shear dispersion emulsifier; preferably, the shearing speed is 4000rpm-6000rpm, for example 5500rpm; and the shearing time is 5min-30min, for example 15min.

[0048] According to an embodiment of the present invention, in step (2), stirring is performed by a mixer; preferably, the stirring speed is 200 rpm to 300 rpm, for example 250 rpm; preferably, the stirring time is 5 min to 30 min, for example 15 min.

[0049] According to an embodiment of the present invention, in step (2), shearing is performed by a high-shear dispersion emulsifier; preferably, the shearing speed is 4000rpm-6000rpm, for example 5000rpm; and the shearing time is 5min-30min, for example 10min.

[0050] According to an embodiment of the present invention, in step (4), the pH is adjusted to 5 to 7, for example, 5.0, 5.3, 5.5, 5.8, 6.0, 6.3, 6.5, 6.8, or 7.0.

[0051] According to an embodiment of the present invention, in step (4), the stirring speed is 200 rpm to 300 rpm, for example, 250 rpm. According to an embodiment of the present invention, in step (4), the stirring time is 5 min to 30 min, for example, 10 min or 15 min.

[0052] According to an embodiment of the present invention, in step (4), the mixing process is carried out by an electric mixer.

[0053] According to an embodiment of the present invention, in step (4), the suspension nasal spray is optionally filled into a nasal spray bottle.

[0054] According to an embodiment of the present invention, in step (4), after obtaining the suspension nasal spray, it is optionally subjected to shearing treatment; preferably, shearing treatment is performed by a high shear dispersion emulsifier; preferably, the shearing speed is 4000rpm-6000rpm, for example 5000rpm; the shearing time is 5min-30min, for example 10min, 20min, 30min.

[0055] According to an embodiment of the present invention, the preparation method includes the following steps:

[0056] (1) Preparation of drug suspension: Dissolve the prescribed amount of surfactant in an appropriate amount of purified water by stirring, then add rameltein amine micro powder, and then use a high shear dispersion emulsifier to shear at 5500 rpm for 15 min to obtain drug suspension;

[0057] (2) Suspension matrix: The suspending agent is slowly added to an appropriate amount of purified water under the stirring of a mixer at 250 rpm and stirred for 15 min until no visible particles are visible. Then, a high shear dispersion emulsifier is used to shear at 5000 rpm for 10 min to obtain the suspension matrix.

[0058] (3) Osmotic pressure regulator solution: Dissolve the osmotic pressure regulator in an appropriate amount of purified water to obtain an osmotic pressure regulator solution;

[0059] (4) Mix the drug suspension, suspension matrix, osmotic pressure regulator solution, and optional preservative, chelating agent, and fragrance, add purified water to the prescribed amount, adjust the pH to 4-7, and stir at 250 rpm for 10 min to obtain the suspension nasal spray.

[0060] The present invention also provides the use of the above-mentioned rametamide suspension nasal spray in the preparation of medicaments for the treatment and / or prevention of diseases, such as sleep disturbances, insomnia, jet lag syndrome, etc., that cause insomnia.

[0061] The present invention also provides a method for treating and / or preventing a disease, the method comprising administering a therapeutically effective amount of the above-mentioned rameltetinamide suspension nasal spray to a subject, wherein the disease is sleep disturbances leading to insomnia, insomnia, jet lag syndrome, etc.

[0062] Beneficial effects

[0063] This invention provides a stable rameltetinamide suspension nasal spray, which atomizes the drug and allows it to be absorbed into the body fluid circulation through the nasal mucosa. This solves the problem of low bioavailability caused by the first-pass effect of the liver when rameltetinamide is taken orally. At the same time, it has a faster onset of action, is significantly better than oral formulations, and its osmotic pressure is within the acceptable range for the human body. It is non-irritating, safer, and suitable for long-term treatment of chronic diseases. Detailed Implementation

[0064] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0065] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0066] Example 1 investigated the effect of different surfactant dosages on the mixing uniformity of the nasal spray.

[0067] Preparation methods of prescriptions 1-3:

[0068] 1. Prepare ramelteamide micronized powder to D 90It is 14μm;

[0069] 2. Drug suspension: Dissolve the prescribed amount of surfactant in an appropriate amount of water, then add micronized ramelteamide, and shear at 5000 rpm for 15 minutes to obtain a drug suspension;

[0070] 3. Suspension matrix: Add microcrystalline cellulose-sodium carboxymethyl cellulose to an appropriate amount of purified water and stir with an electric stirrer at 250 rpm for 15 min. After stirring, use a high-shear dispersing emulsifier at 5000 rpm for 10 min to obtain the suspension matrix.

[0071] 4. Isotonic solution: Dissolve the prescribed amount of glycerol in an appropriate amount of purified water to obtain an isotonic glycerol solution;

[0072] 5. Mix the drug suspension, suspension matrix, and isotonic glycerol solution, and add citric acid, sodium citrate, and benzalkonium chloride. Add purified water to the weight limit and stir with a stirrer at 250 rpm for 10 min to obtain the nasal spray suspension, which is then filled into nasal spray bottles.

[0073] Prepare prescriptions 1-3 and determine the uniformity of the content of the prescription suspension.

[0074] Table 1 Composition of Prescriptions 1-3

[0075]

[0076] Table 2 Results of uniformity of suspension content in prescriptions 1-3

[0077] Group Average content (%) RSD (%) Prescription 1 95.7 2.70 Prescription 2 98.1 0.9 Prescription 3 97.9 0.8

[0078] As shown in Table 2, without the addition of polysorbate 80, the average content of the formulation was only 95.7%, which was low, and the RSD was as high as 2.7%, indicating poor content uniformity. When 0.01% (w / v) of polysorbate 80 was added, the average content of the formulation increased to 98.1%, and the RSD was only 0.9%. When the amount of polysorbate 80 increased to 0.1% (w / v), there was no significant change in the average content and content uniformity of the formulation.

[0079] Table 3 pH results of the suspension

[0080] Group pH Prescription 2 5.79

[0081] Example 2: Screening of Surfactant Types

[0082] Formulas 1-2 and 4-5 were prepared according to Example 1, and the uniformity of the content of the formula suspension and the uniformity of the delivery dose were determined.

[0083] Table 4 Composition of Prescriptions 1-2 and 4-5

[0084]

[0085] Table 5 Results of uniformity of suspension content in prescriptions 1-2 and 4-5

[0086] Group Average content (%) RSD (%) Prescription 1 95.7 2.70 Prescription 2 98.1 0.9 Prescription 4 97.7 1.1 Prescription 5 98.9 0.7

[0087] Table 6 Results of uniformity in delivery dosage of suspensions 1-2 and 4-5

[0088]

[0089] As can be seen from Tables 5-6, the addition of surfactants significantly improves the uniformity of dosage delivery during the formulation process.

[0090] Example 3: Screening of Osmotic Pressure Regulator Dosage

[0091] Formulas 2 and 6-7 were prepared according to Example 1, and the osmotic pressure of the formula suspensions was measured.

[0092] Table 7 Composition of Prescriptions 2 and 6-7

[0093]

[0094] Table 8. Osmotic pressure test results for prescriptions 2 and 6-7

[0095] Group Prescription 2 Prescription 6 Prescription 7 Osmotic pressure (mOsm) 298.00 266.00 333.00

[0096] Example 4: Screening of Osmotic Pressure Regulators

[0097] Formulas 2 and 8-9 were prepared according to Example 1, and the osmotic pressure of the formula suspensions was measured.

[0098] Table 9 Composition of Prescriptions 2 and 8-9

[0099]

[0100] Table 10. Osmolarity test results for prescriptions 2 and 8-9

[0101] Group Prescription 2 Prescription 8 Prescription 9 Osmotic pressure (mOsm) 298.00 467.00 161.00

[0102] As shown in Table 10, under the same dosage, the glycerol group can control the osmotic pressure of the drug solution within the range of human plasma osmotic pressure. Therefore, glycerol has good performance as an osmotic pressure regulator.

[0103] Example 5: Screening of Suspension Agents

[0104] Formulas 2 and 10-11 were prepared according to Example 1, and the mixing uniformity and sedimentation volume ratio of the formula suspensions in the mixing tank were measured.

[0105] Table 11 Composition of Prescriptions 2 and 10-11

[0106]

[0107] Table 12 Results of Mixing Homogeneity for Formulas 2 and 10-11

[0108]

[0109] Table 13 shows the sedimentation volume ratio results for prescriptions 2 and 10-11.

[0110]

[0111]

[0112] As shown in Table 12-13, under the same addition amount, the sample of Formulation 2 has a smaller RSD and a better sedimentation volume ratio.

[0113] Example 6 investigated the effect of different micronized particle sizes on the bioavailability of the nasal spray.

[0114] Formulas 2 and 12-13 with different API microparticle sizes were prepared according to Example 1, and the pharmacokinetic properties of the formulas in rats were determined.

[0115] Table 14 Composition of Prescriptions 2 and 12-13

[0116]

[0117] Rat pharmacokinetic studies:

[0118] Twenty-four adult rats (16 males and 8 females, non-perinatal) were selected and divided into four groups: a nasal spray group (prescriptions 2, 12-13), an oral group (ramelteamide tablets), and a control group (n=6 rats per group, with a male-to-female ratio of 1:2). The rats were administered the drug via nasal spray or oral (oral gavage) at a dose of 8 mg / kg, respectively. The main pharmacokinetic parameters of each experimental animal were determined: half-life, time to peak concentration, maximum plasma concentration, and AUC. 0～t The measurement results are shown in Table 13 below.

[0119] Table 15 Pharmacokinetic parameters of prescriptions 2 and 12-13

[0120]

[0121]

[0122] As shown in Table 15, the duration of action, half-life, and maximum blood concentration of the suspension nasal spray formulation prepared in this invention are all superior to those of the oral group, and the bioavailability of each nasal spray formulation is significantly higher than that of the oral group.

[0123] Example 7 investigated the effect of different suspending agent dosages on the viscosity of the nasal spray.

[0124] Formulas 2 and 14-15 were prepared according to Example 1, and the viscosity and droplet size distribution of the formulas were measured.

[0125] Table 16 Composition of Prescriptions 2 and 14-15

[0126]

[0127] Table 17 Viscosity test results for prescriptions 2 and 14-15

[0128] Group Prescription 2 Prescription 14 Prescription 15 Viscosity (mPa.s) 434.49 544.39 827.53

[0129] *Note: Viscosity: Viscosity (mPa.s) after shearing at a shear rate of 1000 1 / s for 5 min and at a shear rate of 0.1 1 / s for 10 s.

[0130] Table 18. Droplet size distribution results for formulations 2 and 14-15

[0131] Group x10 / μm x50 / μm x90 / μm Prescription 2 16.60 38.33 80.73 Prescription 14 18.89 43.53 92.35 Prescription 15 22.51 65.89 123.92

[0132] As shown in Tables 17-18 above, the suspension prepared by this invention has good viscosity, uniform droplet size, and good spraying effect.

[0133] Example 8 Screening of the stirring dispersion and shear emulsification time of the suspension matrix

[0134] Formula 16 was prepared according to Example 1. The stirring and shearing parameters in step (3) of the suspension matrix preparation step were adjusted, and the properties of the nasal spray suspension were tested.

[0135] Table 19 Results of stirring parameters and suspension properties in step (3)

[0136]

[0137] Table 20 Results of Shear Parameter and Suspension Properties in Step (3)

[0138]

[0139] According to the above results, in step (3) of the preparation of the suspension matrix, the suspension matrix (suspension agent solution) is stirred at 250 rpm for 15 min and then sheared at 5000 rpm for 10 min, and the suspension matrix can be completely swollen, thereby obtaining a uniform and delicate white nasal spray suspension.

[0140] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A ramelteline nasal suspension spray, wherein the ramelteline nasal suspension spray comprises the following components: Ramelteline, suspending agent, surfactant, osmotic pressure regulator, solvent; The osmotic pressure regulator is selected as glycerol; The suspending agent is selected from microcrystalline cellulose-sodium carboxymethyl cellulose.

2. The rameltetinamide nasal spray according to claim 1, characterized in that, The ramelteinamide is ramelteinamide micro powder; preferably, the ramelteinamide micro powder D 90 The range is from 1μm to 30μm; Preferably, the content of rameltein is 0.05% to 2.0%, more preferably 0.1% to 1.0%; Preferably, the content of the suspending agent is 1.0% to 15.0%; Preferably, the content of the osmotic pressure regulator is 1.0%-5.0%.

3. The rameltetinamide nasal spray according to claim 1 or 2, characterized in that, The surfactant is selected from any one, two or more of polysorbate, poloxamer, polyethylene glycol (15)-hydroxystearate, and sorbitan trioleate; preferably, the surfactant is selected from polysorbate-80, poloxamer 407, and HS-15. Preferably, the surfactant content is 0-0.5%, more preferably 0.01%-0.1%; Preferably, the solvent is selected from water.

4. The rameltein nasal spray suspension according to any one of claims 1-3, characterized in that, The rameltein nasal spray optionally further includes a pH adjuster; preferably, the pH adjuster is selected from any one, two 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 content of the pH adjuster is 0.1%-1.0%; preferably, the pH value of the rameltein nasal spray is 4-7; Preferably, 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 and phenethyl 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%.

5. The rameltetinamide nasal spray suspension according to any one of claims 1-4, characterized in that, The ramelteilamide suspension nasal spray comprises the following components: ramelteilamide, suspending agent, surfactant, pH adjuster, osmotic pressure adjuster, and water; Preferably, the rameltein nasal spray suspension comprises the following components: rameltein, suspending agent, surfactant, pH adjuster, osmotic pressure adjuster, preservative, and water.

6. The rameltetinamide nasal spray according to any one of claims 1-5, characterized in that, The ramelteamide suspension nasal spray comprises the following components: ramelteamide micro powder 0.05%–2.0%, suspending agent 1.0%–15.0%, osmotic pressure regulator 1.0%–5.0%, surfactant 0.01%–0.1%, pH regulator 0.2%–0.6%, and the balance being water; Preferably, the rameltein nasal suspension spray comprises the following components: rameltein 0.05%–2.0% micro powder, 1.0%–15.0% suspending agent, 1.0%–5.0% osmotic pressure regulator, 0.01%–0.1% surfactant, 0.2%–0.6% pH adjuster, 0%–0.1% preservative, and the balance being water. Preferably, the rameltein nasal spray suspension comprises the following components: rameltein 0.05%–2.0%, suspending agent 2.0%–3.0%, osmotic pressure regulator 1.8%–3.0%, surfactant 0.01%–0.1%, pH regulator 0.2%–0.6%, preservative 0%–0.1%, and the balance being water. Preferably, the rameltein nasal spray suspension comprises the following components: rameltein 0.05%–2.0%, microcrystalline cellulose-sodium carboxymethyl cellulose 2.0%–3.0%, surfactant 0.01%–0.1%, citric acid 0.2%, sodium citrate 0.35%, glycerin 2.4%, preservative 0%–0.1%, and the balance being water. Preferably, the rameltein nasal spray suspension comprises the following components: rameltein 0.2%, sodium carboxymethyl cellulose 2.0%, polysorbate 80 0.01%, citric acid 0.2%, sodium citrate 0.35%, glycerin 2.4%, benzalkonium chloride 0.02%, and the balance being water.

7. A method for preparing the rameltein nasal spray suspension according to any one of claims 1-6, the method comprising the following steps: (1) Preparation of drug suspension: Dissolve the surfactant in an appropriate amount of solvent by stirring, then add ramelteamide, and then shear to obtain drug suspension; (2) Suspension matrix: The suspending agent is stirred and sheared to obtain a suspension matrix; (3) Osmotic pressure regulator solution: Dissolve the osmotic pressure regulator in an appropriate amount of solvent to obtain an osmotic pressure regulator solution; (4) Mix the drug suspension, suspension matrix, osmotic pressure regulator solution and optional preservative, chelating agent and fragrance, add solvent to the prescription amount, adjust the pH to 4-7, stir, and obtain the suspension nasal spray.

8. The preparation method according to claim 7, characterized in that, In step (1), the process is performed by a high-shear dispersion emulsifier; preferably, the shearing speed is 4000 rpm-6000 rpm; preferably, the shearing time is 5 min-30 min. Preferably, in step (2), the mixing is carried out by a mixer; preferably, the mixing speed is 200 rpm-300 rpm; preferably, the mixing time is 5 min-30 min. Preferably, in step (2), the shearing process is performed using a high-shear dispersion emulsifier; preferably, the shearing speed is 4000rpm-6000rpm; and the shearing time is 5min-30min. Preferably, in step (4), the stirring speed is 200 rpm to 300 rpm; preferably, in step (4), the stirring time is 5 min to 30 min.

9. The use of the rameltetinamide nasal spray according to any one of claims 1-6 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.

10. A method for treating and / or preventing a disease, the method comprising administering to a subject a therapeutically effective amount of the ramelteamide nasal spray according to any one of claims 1-6, the disease being a sleep disorder, insomnia, jet lag syndrome, or the like that causing insomnia.

Images