An agomelatine sublingual spray and a preparation method and application thereof

Abstract

The application discloses an agomelatine sublingual spray and a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations, and comprises pharmaceutically acceptable adjuvants and agomelatine drug-loaded micelles dispersed therein; wherein the agomelatine drug-loaded micelles take an amphiphilic compound as a carrier, agomelatine is loaded in the micelles to form a stable micelle system, the micelle system is directly used as a spray, or is mixed with pharmaceutically acceptable adjuvants to be prepared into a sublingual spray. The agomelatine sublingual spray is prepared by combining the drug-loaded micelle technology with the sublingual spray administration mode, and effectively solves the problem of low oral bioavailability of agomelatine caused by poor solubility, serious liver first-pass effect and the like. The agomelatine sublingual spray prepared by the application has good liver safety, and can reduce frequent liver function detection caused by oral administration of drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an agomelatine sublingual spray, its preparation method, and its application. Background Technology

[0002] Agomelatine is a novel antidepressant that combines melatonin MT1 / MT2 receptor agonist activity with 5-HT2C receptor antagonist activity. Clinically, it is primarily used to treat major depressive disorder in adults. Compared to traditional antidepressants, agomelatine can improve sleep quality and circadian rhythms, exert its antidepressant effect by regulating central neurotransmitter levels, and has advantages such as improving anxiety symptoms and cognitive function, thus possessing significant clinical application value.

[0003] However, the main marketed dosage form of agomelatine is currently oral tablets. Due to its poor water solubility, agomelatine is significantly affected by the first-pass effect in the liver after oral administration, resulting in an absolute bioavailability of only 3%–5%. Clinically, higher doses are usually required to achieve therapeutic effects. Official clinical review data (EMA package insert) clearly indicates that in patients taking agomelatine, the risk of serum transaminase (ALT and / or AST) levels exceeding three times the upper limit of normal increases significantly with increasing dose. In the 25 mg dose group, this risk occurred in 1.4%; however, when the dose increased to 50 mg, the incidence rapidly rose to 2.5%. This safety concern necessitates mandatory liver function monitoring at weeks 3, 6, 12, and 24 of treatment, significantly increasing the medical burden on patients. Furthermore, gastrointestinal adverse reactions are frequent after oral administration of agomelatine; clinical statistics show that adverse reactions such as nausea, dizziness, and diarrhea occur in 5% to 10% of cases. Therefore, developing a novel formulation that can circumvent the first-pass effect and significantly improve safety has become an urgent problem to be solved in this field.

[0004] Sublingual administration involves placing medication under the tongue mucosa for direct absorption into the systemic circulation. Compared to oral administration, it offers significant advantages: the sublingual mucosa lacks a keratinized layer, has a short penetration pathway, and is richly vascularized, facilitating rapid absorption and onset of action for lipophilic drugs; it also avoids the first-pass effect in the liver and gastrointestinal degradation, significantly improving bioavailability and reducing related side effects; furthermore, it is simple to administer, has good compliance, and is suitable for individuals with swallowing difficulties, as well as the elderly and children. It also avoids the risk of patients with mental illness hiding medication. Currently, the mainstream dosage forms are sublingual tablets and sublingual sprays. The latter, because it does not require disintegration and dissolution, and the fine droplets increase the contact area, it can reduce interference from saliva during swallowing, achieving faster and more efficient mucosal absorption. Therefore, the use of sublingual sprays holds promise for improving the current clinical challenges of agomelatine and bringing a breakthrough in the treatment of patients with depression.

[0005] While sublingual administration bypasses the first-pass effect, agomelatine's strong hydrophobicity makes it difficult to achieve effective therapeutic concentrations within a small spray volume (0.1 mL-0.2 mL). Furthermore, poorly soluble drugs readily precipitate in aqueous carriers, leading to poor formulation stability and limited mucosal absorption, thus hindering the full realization of the advantages of sublingual administration. Currently, there are no sublingual formulations that can effectively improve the solubility and bioavailability of agomelatine. Therefore, developing a sublingual spray of agomelatine based on highly dispersible solubilization technology, relying on formulation methods to improve the solubility and mucosal absorption of agomelatine, achieving sublingual administration, and avoiding gastrointestinal side effects and hepatic first-pass effects, is of significant clinical importance. Summary of the Invention

[0006] The purpose of this invention is to provide an agomelatine sublingual spray, its preparation method, and its application. By altering the route of administration, it aims to fundamentally circumvent the first-pass effect of the liver, avoiding the risk of dose-related liver injury and gastrointestinal adverse reactions associated with agomelatine tablets. This invention achieves high solubility and physical stability of agomelatine in a micro-liquid carrier by constructing a highly dispersed micellar drug-loaded solubilization system. This invention not only ensures that the drug can rapidly and efficiently enter systemic circulation through the sublingual mucosa, significantly improving bioavailability, but also maintains clinical efficacy while substantially reducing the dosage. This overcomes the safety bottleneck of agomelatine and provides a safer and more efficient formulation option for its clinical application.

[0007] To achieve the above objectives, the present invention provides the following technical solution: This invention provides an agomelatine sublingual spray, comprising pharmaceutically acceptable excipients and agomelatine drug-loaded micelles dispersed therein. The agomelatine drug-loaded micelles use an amphiphilic compound as a carrier, with agomelatine encapsulated within the micelles to form a stable micelle system. This micelle system can be used directly as a spray or mixed with pharmaceutically acceptable excipients to formulate a sublingual spray.

[0008] Preferably, the amphiphilic compound is polyethylene glycol 15-hydroxystearic acid (HS-15).

[0009] Preferably, the mass ratio of agomelatine to the amphiphilic compound is 1:5 to 1:30.

[0010] The present invention further provides a method for preparing the above-mentioned agomelatine sublingual spray, comprising the following steps: (1) Weigh out the amphiphilic compound and agomelatine, heat the amphiphilic compound to a molten state and then add agomelatine, mix well to obtain a mixture; (2) Add solvent to the mixture and promote the formation of micelles of amphiphilic compounds by physical means, so that agomelatine is loaded into the micelles to obtain an agomelatine drug-loaded micelle solution; (3) The obtained drug-loaded micelle solution is filtered through a filter membrane and filled into a spray device to obtain agomelatine sublingual spray; or, pharmaceutically acceptable excipients and preservatives are added to the obtained drug-loaded micelle solution, mixed evenly, and then a pH adjuster is added to adjust the pH of the system to 3.0-6.0; finally, it is filtered through a filter membrane and filled into a spray device to obtain agomelatine sublingual spray, which can be stored for a long time.

[0011] Preferably, the solvent used is an aqueous solvent selected from at least one of purified water, water for injection, physiological saline, and phosphate-buffered saline (PBS), with purified water being the most preferred.

[0012] Preferably, the agomelatine exists in a micelle loading state formed by polyethylene glycol 15-hydroxystearic acid, with an average particle size of 5 nm to 30 nm as determined by dynamic light scattering, a polydispersity index (PDI) of ≤0.3, and a zeta potential of -10 mV to 0 mV.

[0013] Preferably, the physical means of promoting the formation of micelles from the amphiphilic compound includes at least one of thin-film hydration, dialysis, temperature control, and isothermal shaking treatment. More preferably, isothermal shaking treatment is performed after the addition of solvent to allow the system to reach micelle formation and solubilization equilibrium. The conditions for the isothermal shaking treatment are: temperature 30℃~45℃, rotation speed 50r / min~200r / min, and treatment time 24h~72h; more preferably, the conditions for the isothermal shaking treatment are: temperature 37℃, rotation speed 100r / min, and treatment time 48h.

[0014] Preferably, the spraying device is a single-dose, dual-dose, or multi-dose device.

[0015] Preferably, the agomelatine sublingual spray is reconstituted into a drug-loaded solution by adding a diluent as needed before use. The diluent is one of water, physiological saline, and buffer solution.

[0016] Preferably, the pharmaceutically acceptable excipients include at least one of isotonic modifiers, flavoring agents, stabilizers, and absorption enhancers. The isotonic regulator includes at least one of sodium chloride, mannitol, sorbitol, glycerol, glucose, and xylitol, at a dosage of 0.5%–1% (w / v); the flavoring agent includes at least one of sucralose, aspartame, acesulfame potassium, sodium saccharin, steviol glycosides, and pharmaceutically acceptable flavorings, preferably peppermint, lemon, or orange flavorings, at a dosage of 0.01%–5% (w / v); the stabilizer includes at least one of sodium sulfite, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, glycine, citric acid, tartaric acid, ascorbic acid, and ethylenediaminetetraacetic acid, at a dosage of 0.1%–1% (w / v); the absorption promoter includes at least one of polysorbate 20, polysorbate 80, polyoxyethylene castor oil, sodium lauryl sulfate, azone, poloxamer 188, oleic acid, oleate, chitosan, ethanol, and propylene glycol.

[0017] Preferably, the preservative includes at least one selected from benzalkonium bromide, hydroxyphenyl esters, benzoic acid, sorbic acid, chlorhexidine acetate, o-phenylphenol, and sodium thiosulfate; the pH adjuster includes at least one selected from hydrochloric acid, sodium hydroxide, citric acid, citrate, phosphoric acid, phosphate, and phosphate buffer. More preferably, the preservative is benzalkonium bromide; the pH adjuster is a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution with a molar ratio of 1:1.3, and the amount of preservative added is 0.02% to 0.5% (w / v).

[0018] The present invention also provides the use of the above-mentioned agomelatine sublingual spray in the preparation of a medicament for treating depression and insomnia.

[0019] Compared with existing formulations, the beneficial effects of the present invention are as follows: (1) The structure constructed in this invention has a small particle size and high stability, and can exhibit good release characteristics in cerebrospinal fluid release experiments. It is suitable for poorly soluble drugs that exert therapeutic effects in the central nervous system.

[0020] (2) This invention combines drug-loaded micelle technology with sublingual spray administration, effectively solving the problem of low oral bioavailability of agomelatine due to poor solubility and severe first-pass effect in the liver. Studies have shown that the agomelatine sublingual spray prepared by this invention has a high level of in vivo exposure. Even when the dosage of the sublingual spray (0.25 mg / kg) is only 1 / 10 of that of commercially available oral tablets (2.5 mg / kg), its AUC is still higher than that of oral administration.

[0021] (3) After administration of the agomelatine sublingual spray prepared in this invention, no significant abnormalities were observed in blood biochemical indicators, and no significant toxic damage to major organs was found in histopathological examination, indicating that the preparation has good liver safety. It can reduce the need for frequent liver function tests due to oral medications.

[0022] (4) The agomelatine sublingual spray prepared by the present invention improves the convenience of medication for patients, and is especially suitable for patients with difficulty swallowing or a tendency to hoard medicine. Attached Figure Description

[0023] Figure 1 The equilibrium solubility diagram of agomelatine; Figure 2 The particle size distribution of the agomelatine-loaded solution; Figure 3 Transmission electron microscopy image of agomelatine loading solution; Figure 4 The in vitro release curve of agomelatine loading solution in cerebrospinal fluid; Figure 5 To assess the dilution stability of agomelatine loading solutions; Figure 6 To assess the storage stability of agomelatine loading solutions; Figure 7 To assess the spray stability of agomelatine-loaded solutions; Figure 8 The time-pharmacy curves of agomelatine in plasma after oral administration of agomelatine suspension and sublingual administration of sublingual spray (low-dose group); Figure 9 HE-stained sections of the liver from the group receiving sublingual agomelatine administration; Figure 10 HE-stained sections of the liver from the group receiving oral agomelatine. Detailed Implementation

[0024] The present invention will be further described below with reference to specific embodiments, but this should not be construed as limiting the present invention. Any modifications or substitutions made to the methods, steps, and conditions of the present invention without departing from the spirit and substance thereof are within the scope of the present invention. Unless otherwise specified, the experiments, techniques, reagents, or materials used in the embodiments are all commercially available.

[0025] Example 1 Agomelatine drug-loaded micelle formulation ratio screening: To screen the optimal formulation ratio of agomelatine drug-loaded micelles, different mass ratios of agomelatine to HS-15 were screened using equilibrium solubility as the evaluation index, providing a basis for determining the subsequent formulation.

[0026] Weigh HS-15 according to the proportions of 2%, 5%, 10%, 15%, 20%, 25%, 30%, and 40% (w / v). Heat HS-15 to a molten state, add a certain amount of agomelatine and mix well. Then add 10 mL of purified water and place in a 37°C constant temperature shaker. Shake at 100 r / min for 48 h to allow the system to reach dissolution equilibrium.

[0027] After equilibration, the samples were filtered to remove undissolved agomelatine. The supernatant was appropriately diluted, and the concentration of agomelatine was determined by UV-Vis spectrophotometry. The equilibrium solubility of agomelatine in each group was calculated based on the standard curve. Each experiment was performed in triplicate, and the results are expressed as mean ± standard deviation (Mean ± SD).

[0028] Experimental results are as follows Figure 1 As shown in the figure, the results indicate that the equilibrium solubility of agomelatine gradually increases with the increase of HS-15 concentration. When the HS-15 concentration reaches 15% (w / v), the equilibrium solubility of agomelatine reaches a relatively high level; further increasing the HS-15 concentration to 20%–40% (w / v) does increase the equilibrium solubility of agomelatine, but the increase is small. Considering the solubilizing effect of agomelatine, the amount of excipients, and the economics of the formulation, a mass ratio of 1:8 for agomelatine to HS-15 was ultimately determined as the optimal formulation condition for subsequent experiments.

[0029] Example 2 Preparation of agomelatine loading solution: Accurately weigh 10 mg of agomelatine and 80 mg of HS-15. Place HS-15 in a clean container and heat it to 40°C until it is completely melted. Add agomelatine to the molten HS-15 and stir thoroughly to obtain a homogeneous mixture.

[0030] Add 4 mL of purified water to the above mixture for hydration to ensure thorough dispersion of the molten system. Then, place the resulting system in a constant-temperature shaker and shake at 37°C and 100 rpm for 48 hours to allow agomelatine to be fully encapsulated in the micelle system formed by HS-15. Once the system reaches dissolution equilibrium, the agomelatine-loaded micelle solution is obtained.

[0031] The resulting drug-loaded micelle solution was clear and transparent, with no visible insoluble matter, and could be used for the subsequent preparation of agomelatine sublingual spray.

[0032] Example 3 Characterization of agomelatine loading solution: The agomelatine-loaded micelle solution prepared in Example 2 was analyzed using dynamic light scattering (DLS) to determine its average particle size, polydispersity index (PDI), and zeta potential. Before measurement, the sample was appropriately diluted with purified water and mixed thoroughly. The measurement was performed at 25°C, with each sample measured in triplicate, and the average value was taken as the final result. The results showed that the average particle size of the prepared agomelatine-loaded micelles was approximately 11.68 ± 0.11 nm, the polydispersity index (PDI) was 0.134 ± 0.053, and the zeta potential was -3.40 ± 0.71 mV, indicating that the obtained micelles had small particle size and uniform particle size distribution, and the system exhibited good dispersibility and stability. The results are as follows: Figure 2 As shown.

[0033] An appropriate amount of the agomelatine-loaded micelle solution prepared in Example 2 was dropped onto a copper grid and allowed to stand for adsorption for about 1 to 2 minutes. Excess liquid was then removed. The micelles were negatively stained with 2% (w / v) phosphotungstic acid solution for 30 seconds, allowed to air dry at room temperature, and then their microstructure was observed and photographed under a transmission electron microscope. The results showed that the agomelatine-loaded micelles exhibited a nearly spherical or spherical structure, were uniformly dispersed, and showed no obvious aggregation. The particle size was consistent with the results determined by dynamic light scattering, indicating that the prepared micelles possessed good morphological characteristics and stability. The results are as follows: Figure 3 As shown.

[0034] Example 4 In vitro release behavior of agomelatine loading solution: The in vitro release behavior of agomelatine-loaded micelles was investigated using dynamic dialysis.

[0035] Artificial cerebrospinal fluid (aCSF) was prepared as a release medium, consisting of: 0.72% (w / v) sodium chloride, 0.02% (w / v) potassium chloride, 0.05% (w / v) magnesium sulfate, 0.22% (w / v) sodium bicarbonate, 0.02% (w / v) calcium chloride, and 0.40% (w / v) D-glucose. The pH was adjusted to 7.4 and then aseptically processed for later use.

[0036] 2 mL of a 2 mg / mL agomelatine-loaded micelle solution was precisely measured and placed into a dialysis bag with a molecular weight cutoff of 3.5 kDa. The bag was then sealed at both ends and placed in a release system containing 5 mL of artificial cerebrospinal fluid. An equivalent concentration of free agomelatine solution was used as a control group to compare drug release behavior.

[0037] The release experiment was conducted in a 37°C constant-temperature shaker at a shaking speed of 250 r / min. At 0, 1, 2, 4, 6, 8, 10, 12 and 24 h, 2 mL of the release medium was aspirated and simultaneously replenished with an equal volume of fresh artificial cerebrospinal fluid preheated to 37°C to maintain a constant volume of the release system.

[0038] The concentration of agomelatine in the release medium at each time point was determined by ultraviolet spectrophotometry, and the cumulative release rate was calculated. In vitro release curves were plotted, and the results are shown in [Figure number missing]. Figure 4 .

[0039] Example 5 Stability study of agomelatine-loaded micelle solutions: (1) Dilution stability study The agomelatine-loaded micelle solution prepared in Example 2 was diluted with sterile water, physiological saline, phosphate-buffered saline (PBS), and artificial cerebrospinal fluid (aCSF), respectively. The diluted samples were stored at room temperature, and their average particle size was measured using dynamic light scattering (DLS) at 1, 2, 6, 10, 14, and 24 hours to evaluate the dilution stability of the drug-loaded micelles. The results are shown below. Figure 5 See Table 1.

[0040] Table 1. Stability of agomelatine loading solution in water, PBS, physiological saline and cerebrospinal fluid.

[0041] Depend on Figure 5 As shown in Table 1, after being diluted with sterile water, physiological saline, PBS and artificial cerebrospinal fluid, the average particle size of agomelatine-loaded micelles did not change significantly within 24 hours. The particle size remained in the range of about 12nm to 17nm at each time point, and no obvious increase in particle size or aggregation was observed.

[0042] The average particle size in sterile water ranged from 13.10 nm to 15.04 nm; in physiological saline, it ranged from 13.00 nm to 14.85 nm; in PBS, it ranged from 12.59 nm to 13.94 nm; and in artificial cerebrospinal fluid, it ranged from 12.48 nm to 17.03 nm. The small variation in particle size across groups indicates that different dilution media have minimal impact on the size of the drug-loaded micelles.

[0043] The above results indicate that the agomelatine-loaded micelles prepared in this invention have good dilution stability and can maintain a relatively stable particle size distribution after dilution in different aqueous media, providing a good stability basis for its subsequent formulation applications.

[0044] (2) Storage stability study The agomelatine-loaded micelle solution prepared in Example 2 was stored at 4°C in the dark. The average particle size was measured by dynamic light scattering (DLS) on the 7th and 14th days of storage, and the stability of the micelle system was observed.

[0045] The results showed that the average particle sizes of agomelatine-loaded micelles stored at 4℃ for 7 days and 14 days were 9.27±0.11 nm and 10.05±0.22 nm, respectively. The particle size changes were minimal, and the particle size distribution remained uniform, with no significant increase in particle size or aggregation observed. The particle size distribution of the drug-loaded micelles at 14 days is shown in the figure. Figure 6 .

[0046] The above results indicate that the agomelatine-loaded micelles prepared in this invention exhibit good physical stability within 14 days of storage at 4°C, and their particle size distribution remains stable, providing experimental basis for the preservation and application of subsequent formulations.

[0047] (3) Stability test of spray performance The agomelatine-loaded micelle solution prepared in Example 2 was filled into a metered spray apparatus and sprayed out according to normal usage. The sprayed samples were collected, and their average particle size was determined using dynamic light scattering (DLS). The average particle size was compared with that of the drug-loaded micelles before spraying to evaluate the effect of the spraying process on the stability of the drug-loaded micelles. The results are shown in [Figure Number]. Figure 7 .

[0048] The test results showed that the average particle size of the agomelatine-loaded micelles after spraying was 13.32±0.04nm. Compared with before spraying, the particle size did not change significantly, the particle size distribution remained uniform, and no obvious particle size increase or aggregation was observed.

[0049] The above results indicate that the spraying process did not significantly affect the particle size and dispersion state of the agomelatine-loaded micelles, demonstrating that the agomelatine-loaded micelles prepared in this invention have good spray performance stability and can maintain the integrity of the micelle structure during spray administration, providing experimental evidence for its application as a sublingual spray formulation.

[0050] Example 6 Pharmacokinetics of agomelatine loading solution: To evaluate the in vivo pharmacokinetic characteristics of the agomelatine sublingual spray of this invention, pharmacokinetic studies were conducted using SD rats.

[0051] Healthy male SD rats were randomly divided into four groups, totaling 28 rats. The agomelatine suspension administered via gavage served as the control group, while the other three groups were designated as low-dose, medium-dose, and high-dose agomelatine-loaded solution groups, respectively. The suspension was prepared as follows: a 0.5% CMC-Na solution was prepared, and a precise amount of agomelatine powder (from Hansoh Pharmaceutical's agomelatine tablets) was accurately weighed and placed in a mortar. The powder was ground repeatedly with added solution and transferred to 50mL EP tubes. Each group was administered the drug according to the preset dosage and administration method: the low, medium, and high-dose groups received doses of 0.25 mg / kg, 0.5 mg / kg, and 1.0 mg / kg, respectively, via sublingual spray; the suspension dose was 2.5 mg / kg, administered orally via gavage.

[0052] Blood samples were collected via the orbital venous plexus at 0.08, 0.25, 0.50, 1.00, 2.00, 4.00, 6.00, and 12.00 h after drug administration. After centrifugation to separate the plasma, the concentration of agomelatine in the plasma was determined by high-performance liquid chromatography (HPLC). Plasma concentration-time curves were plotted based on the plasma drug concentrations at each time point. Figure 8 ) The results show that the agomelatine sublingual spray prepared in this invention can achieve stable in vivo exposure, and different dose groups have good dose-exposure relationships. Among them, the plasma drug concentration change trend of the preferred low-dose group has good consistency with the clinical pharmacokinetic data of commercially available agomelatine tablets, which can achieve pharmacokinetic bridging with clinical dosing regimens.

[0053] The results showed that agomelatine concentration peaked 10 minutes after administration, and the area under the curve (AUC) for sublingual administration was 1.56 times that for oral administration. Compared with commercially available formulations, formulating agomelatine into a sublingual spray will improve its bioavailability and reduce toxic side effects.

[0054] Example 7 Safety evaluation of agomelatine sublingual spray: (1) Blood biochemical index detection To evaluate the in vivo safety of the agomelatine sublingual spray of this invention, blood samples were collected from rats in each group after administration. Serum was separated and sent to a qualified third-party testing institution for blood biochemical analysis. The tested indicators included alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin (TBIL). The results are shown in Table 2.

[0055] Table 2 Serum Biochemical Indicators

[0056] Reference range: ALT: 21.53-61.75 U / L; TBIL: 2.57-36.85 μmol / L; ALP: 12.04-610.97 U / L.

[0057] As shown in Table 2, the ALT, TBIL, and ALP levels in the low-dose sublingual spray group were all within the normal reference range, and no obvious abnormalities were observed in any of the indicators. The ALT and ALP levels in the medium-dose sublingual spray group were slightly higher than those in the low-dose group, and the TBIL fluctuated relatively more, but no obvious abnormal changes were observed overall.

[0058] Compared with the sublingual spray group, the oral suspension group showed significantly higher levels of ALT and ALP. The mean ALT level was approximately 1.93 times that of the low-dose sublingual spray group, and the ALP level was also higher than that of the sublingual spray group. Meanwhile, the TBIL level was similar to that of the medium-dose sublingual spray group.

[0059] The above results indicate that, under the experimental conditions, compared with oral suspension administration, the agomelatine sublingual spray of the present invention has a smaller impact on liver function-related biochemical indicators, suggesting that sublingual administration can reduce the burden of drugs on the liver to a certain extent and has good liver safety.

[0060] (2) Histopathological observation of liver tissue—HE staining sections After the pharmacokinetic experiment, rats in each experimental group were sacrificed, and liver tissue was collected from each group. After fixation and dehydration, the liver tissue was sent to a qualified third-party testing institution for paraffin embedding, tissue sectioning, and hematoxylin-eosin staining. After staining, the tissue was observed under a microscope, and pathological images of the liver tissue were collected. The results are as follows: Figure 9 and Figure 10 As shown.

[0061] HE staining results showed that, compared with the oral suspension group, the liver tissue structure of the low-dose and medium-dose agomelatine sublingual spray groups remained intact, with regular hepatocyte arrangement and no obvious hepatocyte degeneration, necrosis, or inflammatory response. In the oral suspension group, some hepatocyte morphological changes were observed, along with hepatic sinusoidal dilation, significantly centrilobular vasodilation, erythrocyte aggregation, diffuse vacuolation of hepatocyte cytoplasm, hepatocyte necrosis and lysis, and nuclear pyknosis or rupture.

[0062] The above results indicate that the agomelatine sublingual spray prepared in this invention did not cause significant liver tissue pathological damage within the experimental dosage range. Combined with the serum biochemical index test results, this demonstrates that the preparation has good in vivo safety.

[0063] The above description is merely an example and illustration of the concept of the present invention. Those skilled in the art can make various modifications or additions to the specific embodiments described or use similar methods to replace them, as long as they do not deviate from the concept of the invention or exceed the scope defined by the present invention, they shall all fall within the protection scope of the present invention.

Claims

1. An agomelatine sublingual spray, characterized in that, The product includes pharmaceutically acceptable excipients and agomelatine-loaded micelles dispersed therein; wherein the agomelatine-loaded micelles use an amphiphilic compound as a carrier, and agomelatine is encapsulated within the micelles to form a stable micelle system, which can be used directly as a spray or mixed with pharmaceutically acceptable excipients to form a sublingual spray.

2. The agomelatine sublingual spray according to claim 1, characterized in that, The mass ratio of agomelatine to the amphiphilic compound is 1:5 to 1:

30.

3. The agomelatine sublingual spray according to claim 1, characterized in that, The amphiphilic compound is 15-hydroxystearic acid polyethylene glycol ester.

4. A method for preparing the agomelatine sublingual spray according to any one of claims 1-3, characterized in that, Includes the following steps: (1) Weigh out the amphiphilic compound and agomelatine, heat the amphiphilic compound to a molten state and then add agomelatine, mix well to obtain a mixture; (2) Add solvent to the mixture and promote the formation of micelles of amphiphilic compounds by physical means, so that agomelatine is loaded into the micelles to obtain an agomelatine drug-loaded micelle solution; (3) The obtained drug-loaded micelle solution is filtered through a filter membrane and filled into a spray device to obtain agomelatine sublingual spray; or, pharmaceutically acceptable excipients and preservatives are added to the obtained drug-loaded micelle solution, mixed evenly, and then a pH adjuster is added to adjust the pH of the system to 3.0 to 6.0; finally, it is filtered through a filter membrane and filled into a spray device to obtain agomelatine sublingual spray.

5. The method for preparing agomelatine sublingual spray according to claim 4, characterized in that, The solvent used is an aqueous solvent, selected from at least one of purified water, water for injection, physiological saline, and phosphate buffer.

6. The method for preparing agomelatine sublingual spray according to claim 4, characterized in that, Agomelatine exists in a micelle loading state formed of 15-hydroxystearic acid polyethylene glycol ester, with an average particle size of 5nm to 30nm, a PDI of ≤0.3 for the drug-loaded micelles, and a Zeta potential of -10mV to 0mV.

7. The method for preparing agomelatine sublingual spray according to claim 4, characterized in that, The physical means of promoting the formation of micelles from amphiphilic compounds includes isothermal shaking treatment after the addition of solvent to bring the system to micelle formation and solubilization equilibrium; the conditions for isothermal shaking treatment are temperature 30℃~45℃, rotation speed 50r / min~200r / min, and treatment time 24h~72h.

8. The method for preparing agomelatine sublingual spray according to claim 4, characterized in that, The pharmaceutically acceptable excipients include at least one of isotonicity modifiers, flavoring agents, stabilizers, and absorption promoters; the isotonicity modifiers include at least one of sodium chloride, mannitol, sorbitol, glycerin, glucose, and xylitol; the flavoring agents include at least one of sucralose, aspartame, acesulfame potassium, sodium saccharin, steviol glycosides, and pharmaceutically acceptable flavorings, wherein the flavoring is peppermint, lemon, or orange flavoring; the stabilizers include at least one of sodium sulfite, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, glycine, citric acid, tartaric acid, ascorbic acid, and ethylenediaminetetraacetic acid; the absorption promoters include at least one of polysorbate 20, polysorbate 80, polyoxyethylene castor oil, sodium lauryl sulfate, azone, poloxamer 188, oleic acid, oleate, chitosan, ethanol, and propylene glycol. The preservative includes at least one of benzalkonium bromide, hydroxyphenyl esters, benzoic acid, sorbic acid, chlorhexidine acetate, o-phenylphenol, and sodium thiosulfate; the pH adjuster includes at least one of hydrochloric acid, sodium hydroxide, citric acid, citrate, phosphoric acid, phosphate, and phosphate buffer.

9. The use of the agomelatine sublingual spray according to any one of claims 1-3 in the preparation of a medicament for treating depression and insomnia.

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