Solution-type quetiapine composition for transnasal administration and use thereof

Abstract

The present invention pertains to the technical field of pharmaceutical preparations, and provides a novel solution-type quetiapine composition for transnasal administration. In the provided composition, quetiapine is completely dissolved therein in the form of a solution and administered transnasally. Compared with oral dosage forms on the market, the provided quetiapine solution-type transnasal preparation has particularly useful pharmacokinetic and pharmacodynamic profiles. Compared with other disclosed transnasal nano-emulsion forms, the composition of the present invention still has surprising pharmacokinetic and pharmacodynamic profiles, shows good clinical application prospects, and is expected to meet unmet clinical needs. On this basis, the present invention also provides a further improved high-saturation dissolution concentration technical solution and a further improved good chemical stability technical solution for preparing the quetiapine solution-type transnasal preparation.

Description

In the present disclosure, the balance means adding corresponding components to 100%. The meanings of the abbreviations in the present disclosure are in accordance with the common understanding of the industry, and some terms are annotated as follows: I.N.: intranasal administration; P.O.: oral administration; I.V.: intravenous injection; I.P.: intraperitoneal injection; HS-15: polyethylene glycol-15 hydroxystearate; HP-P-CD: hydroxypropyl-P-cyclodextrin; PEG 3350: polyethylene glycol 3350; PEG 400: polyethylene glycol 400; EDTA: edetate; EDTA-2Na: disodium edetate, also known as disodium ethylenediaminetetraacetate; EDTA-2K:    dipotassium edetate, also known as dipotassium ethylenediaminetetraacetate; DMA: N,N-dimethylacetamide. The present disclosure will be further explained below in conjunction with the accompanying drawings and specific examples. Example A: Animal pharmacokinetic study and pharmacodynamic study on the solution-type intranasal administration composition of the present disclosure Example 1 Pharmacokinetic study in beagle dogs 1. Purpose of the experiment The purpose of this experiment is to evaluate and compare the pharmacokinetic profiles of the solution-type intranasal administration composition of the present disclosure with those of oral tablets and injections after administration to beagle dogs. 2. Test substances The codes for the types of test substances are as follows: Code Group Drug Concentration (calculated as free base) Administration Mode Administration Volume Administration Dose A Nasal spray 1 92.5 mg / mL Intranasal spray 100 pL / spray, 3 sprays in total 27.75 mg / dog B Nasal spray 2 92.3 mg / mL Intranasal spray 100 pL / spray, 3 sprays in total 27.75 mg / dog C Quetiapine fumarate tablet 25 mg / tablet Oral 1 tablet / dog 25 mg / dog D Injection 2.5 mg / mL Intravenous injection 1 mL / kg 25 mg / dog The formulation compositions of test substances A and B are as follows: Quetiapine fumarate Benzyl alcohol Propylene glycol PEG 3350 Tween 20 Pectin Anhydrous ethanol 0.1 M citric acid solution A 10.6% 9.3% 4.7% 4.7% 1.4% / 18.5% Balance B 10.6% 9.3% 4.6% 4.6% 1.4% 0.7% 18.3% Balance “ / ” indicates no addition of the corresponding component in the preparation. Preparation method for the test substances A and B: the individual components were weighed, mixed uniformly, dissolved to clarify, then filled into a medium borosilicate glass vial, and assembled with a quantitative nasal spray pump to obtain the final product. The quetiapine fumarate tablet in Group C was purchased from Hunan Dongting Pharmaceutical Co., Ltd. through a regular commercial channel. The injection in Group D was prepared by dissolving quetiapine fumarate in normal saline. 3. Experimental method 3.1 Experimental animals Eight healthy adult Beagle dogs, male, weighing between 6.5 kg and 9.5 kg. 3.2 Experimental administration The animals were randomly divided into 4 groups with 2 dogs per group. Except for one random group which was administered the injection of test substance D via intravenous injection, the other three groups were administered test substances A, B and C in a crossover manner over a total of three periods. A 7-day washout was implemented prior to switching the test substance in each cycle. Taking into account the tablet strength and the saturation solubility of the nasal spray, the dosage in this test was set at 25 mg per dog for the oral group and the intravenous injection group, and 27.75 mg per dog for the nasal spray group. When calculating pharmacokinetic parameters, the doses were normalized to an equivalent dose for comparison. 3.3 Blood sample collection and processing 1 mL of blood was collected from the forelimb vein and anticoagulated with EDTA-K2 (the blood sample was placed in an ice bath after collection), then centrifuged at 3200 g for 10 minutes at 4°C within 2 hours to separate the plasma, and the plasma was stored at -80°C until testing. Sampling time point: Oral group C: before administration (0 hours), and 25 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours and 12 hours after administration. Nasal spray groups A and B, and intravenous injection group D: before administration (0 hours), and 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 4 hours, 8 hours and 12 hours after administration. 3.4 Analysis method and results The drug concentration in the plasma of Beagle dogs at different time points after administration was measured, and the plasma concentration-time curves were plotted. The main pharmacokinetic parameters were calculated using WinNonlin 8.3 software as follows: Cmax Tmax F A Nasal spray 1 1343 ± 492 ng / mL 0.0973 ± 0.0342 h 104 ± 28% B Nasal spray 2 1374 ± 768 ng / mL 0.125 ± 0.070 h 99.5 ± 32.2% C Quetiapine 70.7 ± 43.8 ng / mL 0.889 ± 0.414 h 16.3 ± 7.5% fumarate tablet The results demonstrated that the solution-type nasal spray preparation of the present disclosure exhibited a significantly shortened time to peak Tmax compared to the marketed tablet, and the maximum plasma concentration Cmax and bioavailability F were significantly increased by approximately 20-fold and 6-fold, respectively. Example 2 Pharmacodynamic study in a rat model of hyperlocomotion induced by methamphetamine 1. Purpose of the experiment The purpose of this experiment is to evaluate and compare the pharmacodynamic effects of the solution-type intranasal administration composition of the present disclosure with those of oral quetiapine preparation in the rat model of hyperlocomotion induced by methamphetamine. 2. Test substances The codes for the types of test substances are as follows: Code Group Drug Concentration Administration Mode Administration Volume Administration Dose A High-dose intranasal group 60 mg / mL Intranasal 0.167 mL / kg 10 mg / kg B Oral group 3 mg / mL Intragastric 3.333 mL / kg 10 mg / kg C Low-dose intranasal group 60 mg / mL Intranasal 0.025 mL / kg 1.5 mg / kg D Vehicle control group 0 mg / mL Intranasal 0.167 mL / kg 0 mg / kg The formulation compositions of the test substances are as follows: Code Quetiapine fumarate Benzyl alcohol Propylene glycol PEG 3350 Purified water A 7% 7.5% 12% 2.5% Balance B 0.35% 0.5% 12% 2.5% Balance C 7% 7.5% 12% 2.5% Balance D 0% 7.5% 12% 2.5% Balance Preparation method for each test substance: the individual components were weighed, mixed uniformly and dissolved until clear to obtain the final product. 3. Experimental method 3.1 Experimental animals Forty 7-week-old SD rats, with 10 rats in each group, were randomly divided into 4 groups, corresponding to each test substance respectively. The rats were acclimated to the experimental environment for one day prior to the test, and brought into the laboratory one hour in advance on the test day for further acclimatization. 3.2 Experimental administration On the test day, animals in different group were administered test substances A, B, C or D in conscious state via corresponding modes of administration. Immediately after administration, methamphetamine modeling was performed (via intraperitoneal injection). The methamphetamine was administered at a dose of 3 mg / kg to induce hyperactivity in the animals. 3.3 Phenomena, locomotor activity testing and recording Any-maze software recorded the distance the animals moved every five minutes to assess the levels of locomotor activity. Before administration, the animals were placed in an observation box to detect their locomotor activity for 60 minutes. After administration according to their groups, the animals were returned to the observation box and continuously observed and recorded for 90 minutes. The distance (in meters) the animals moved in the observation box was counted every 5 minutes, and abnormal phenomena such as toxic reactions or deaths of the animals during the experiment were promptly recorded. On the day following the experiment, a cage-side observation was conducted to record the status of the experimental animals in each group, and to determine whether the activity level returned to normal, whether there were animals suffering from hyperactivity or hypoactivity, and whether there were the phenomena such as toxic reactions. 3.4 Data collection Statistical analysis was performed using Prism software. Two-way ANOVA followed by Bonferroni's multiple comparisons test was used to compare the locomotor distance of animals in each group at different time points, while one-way ANOVA was applied to compare the total locomotor distance. A p-value < 0.05 was considered statistically significant. 4. Experimental results The data are as illustrated in FIG. 1. From 0 to 60 minutes after the start of the test, there was no statistical difference in the total distance moved among the four groups of animals. After 60 minutes of acclimation, drug administration was started. From 65 to 110 minutes after the start of the test, the high-dose intranasal group of test substance A significantly reduced the distance the animals moved every 5 minutes compared with the control group of test substance D. At 85 minutes and from 105 to 110 minutes after the start of the test, the distance moved by the animals in every 5 minutes was significantly reduced in the oral group of test substance C compared with the control group of test substance D. The data are as illustrated in FIG. 2. From 60 to 150 minutes after the start of the test, the total distance moved by the animals in the high-dose intranasal group of test substance A was significantly reduced compared with the control group of test substance D. However, there was no significant difference in the total distance moved by the animals in the oral group of test substance C compared with the blank group of test substance D. Cage-side observations during the experiment and on the day following the experiment showed no decrease in body weight, no adverse mental status, and no abnormal activity in the animals. The results demonstrated that the high-dose intranasal group significantly inhibited the methamphetamine-induced hyperlocomotor activity in rats, including the distance moved per 5 minutes and the total distance moved, and provided a significant advantage in rapid onset of action, and prolonged, stable inhibition. The oral group was able to inhibit hyperlocomotor activity only at certain time points, with a slower onset, weaker degree of inhibition, and shorter duration. Moreover, there was no significant difference in total movement distance from the control group. Furthermore, the intranasal group also exhibited favorable safety profiles. Example B: Study on the solubilization of quetiapine in the solution-type intranasal administration composition of the present disclosure 1. Determination of saturation solubility The present disclosure first tested the saturation solubility of quetiapine fumarate in common solvents, as follows: Solvent Saturation solubility (mg / mL) Water 4.0 Anhydrous ethanol 4.6 Propylene glycol 8.8 PEG 400 4.9 Phosphate buffer, pH 4.5 5.7 Acetate buffer, pH 4.5 6.7 Citrate buffer, pH 4.5 5.7 Citrate buffer, pH 5.5 5.0 Citrate buffer, pH 6.5 7.4 The above tests demonstrated that the saturation solubility of quetiapine fumarate in water was very low (4.0 mg / mL), and the saturation solubility in other common solvents such as ethanol was also low. The saturation solubility was higher at a moderately reduced pH, and the optimal pH for the solution-type preparation ranged from 4.5 to 6.5. However, even if the pH value was controlled at a low level, the saturation solubility of quetiapine fumarate was still at a low level, which could not meet the requirements of the solution-type preparation for intranasal delivery. 2. Saturation solubility with the addition of ethanol, propylene glycol, PEG 400, Tween 20 and Span 20 The present disclosure further tested the following formulation solvents, with the saturation solubility of quetiapine fumarate as follows: Solvent Saturation solubility (mg / mL) 19.8 wt% ethanol 11.7 12 wt% propylene glycol 5.2 20 wt% PEG 400 7.6 2.5 wt% Tween 20 4.4 22.9 wt% Span 20 7.5 The experiment with the above formulation solvents demonstrated that although the addition of ethanol, propylene glycol, PEG 400, Tween 20, and Span 20 to the aqueous solution had a certain improvement on the saturation solubility of quetiapine fumarate, the improvement was limited and still failed to meet the requirements for the solution-type preparation for intranasal delivery. 3. Basic formulation design for solubilization and buffer screening Preparation B1 (acetate buffer pair) B2 (phosphate buffer pair) B3 (citrate buffer pair) Quetiapine fumarate 5.2% 5.2% 5.2% mPEG 350 20% 20% 20% PEG 400 15% 15% 15% Propylene glycol 6% 6% 6% Ethanol 6% 6% 6% Buffer, pH 4.5 Balance Saturation solubility (mg / mL) 16.96 19.96 20.83 Preparation method: the individual components were weighed according to the formulation table, mixed, and dissolved sufficiently but were not completely dissolved. After standing, the supernatant was separated and collected, and precipitation occurred approximately 3 hours later. After standing for 4 days, the saturation solubility of quetiapine in the supernatant was analyzed and determined (calculated as free base). The experimental process and results demonstrated that the above preparations had a certain improvement on the saturation solubility of quetiapine fumarate, but the improvement was limited and still failed to meet the requirements for the solution-type preparation for intranasal delivery. It also demonstrated that different types of buffer salts had no obvious effect on saturation solubility, but exerted a certain influence on dissolution rate, with citric acid buffer pair being relatively superior. 4. Study on the effect of adding Tween 20 and PEG 3350 on stabilization and precipitation prevention Preparation B4 B5 B6 B7 Quetiapine fumarate 5% 5% 5% 5% Anhydrous ethanol 19.8% 19.8% 19.8% 19.8% Propylene glycol 5% 5% 5% 5% PEG 3350 20% 20% 25% 30% Tween 20 1.5% 3% 1.5% 1.5% 0.1 M citric acid Balance Preparation method: the individual components were weighed according to the formulation table, mixed, and dissolved sufficiently but were not completely dissolved. After standing, the supernatant was separated and collected. No precipitation occurred during 14 days of high and low temperature cycling, as well as after storage at room temperature for 4 months (low temperature: 2°C to 8°C; high temperature: 50°C). The experimental process and results demonstrated that Tween 20 and PEG 3350 both had a good stabilizing effect on the formulation solution, thereby preventing precipitation. 5. Study on the effect of adding surfactant and cyclodextrin on solubilization Preparation B8 B9 B10 Quetiapine fumarate 5% 5% 5% HS-15 1.5% / / HP-P-CD / 5% 5% Tween 20 2.5% / / PEG 400 20% 20% 20% Propylene glycol 12% 12% 12% Citrate buffer pair, pH 5.0 Balance Saturation solubility (mg / mL) 15.04 28.87 26.61 “ / ” indicates no addition of this component in the preparation. Preparation method: the individual components were weighed according to the formulation table, mixed, and dissolved sufficiently but were not completely dissolved. After standing, the supernatant was separated and collected. The saturation solubility of quetiapine in the supernatant was analyzed and determined (calculated as free base). The experimental process and results demonstrated that the addition of cyclodextrin (HP-P-CD) had a certain improvement on the saturation solubility of quetiapine fumarate, but the improvement was still limited. Surfactants had only limited improvement on the saturation solubility of quetiapine fumarate. Further experiments also demonstrated that the addition of PEG 400 and surfactants was able to stabilize the formulation and prevent precipitation. 6. Study on the effect of adding DMA on solubilization Preparation B11 B12 B13 B14 Quetiapine fumarate 5.2% 5% 6.6% 6.0% DMA 10% 10% 10% 10% PEG 400 15% 17% 17% 17% Propylene glycol 12% / / / Anhydrous ethanol 19.8% 19% 19% 19% 0.1 M citric acid Balance Saturation solubility (mg / mL) 45.18 43.68 57.40 52.81 Recording of dissolution phenomenon Slight precipitation    at 2°C to 8°C for 1 day, and no precipitation    at room temperature for 5 days No precipitation at either 2°C to 8°C or room temperature for 5 days Precipitation     at 2°C to 8°C for 2 days, and a small amount of crystal precipitation     at room temperature for 2 days A small amount of precipitation at either 2°C to 8°C or room temperature for 1 day “ / ” indicates no addition of this component in the preparation. Preparation method: the individual components were weighed according to the formulation table, heated, and dissolved sufficiently. Quetiapine fumarate in each formulation was completely dissolved within 60 minutes on average. The saturation solubility of quetiapine in the solution was analyzed and determined (calculated as free base). The experimental process and results demonstrated that the addition of DMA significantly improved the saturation solubility of quetiapine fumarate, making it suitable for nasal spray administration. An active ingredient concentration greater than 50 mg / mL for nasal spray administration was able to significantly reduce the frequency of administration and thus reduce the corresponding nasal irritation. 7. Study on the effect of adding benzyl alcohol on solubilization Preparation B15 B16 Quetiapine fumarate 6.6% 8.2% Anhydrous ethanol 19.8% 19.8% Benzyl alcohol 5% 10% PEG 3350 20% 20% Tween 20 1.5% 1.5% 0.1 M citric acid Balance Saturation solubility (mg / mL) 57.65 70.87 Preparation method: the individual components were weighed according to the formulation table, mixed, and dissolved sufficiently. The saturation solubility of quetiapine in the solution was analyzed and determined (calculated as free base). The clear supernatant from each formulation showed no precipitation after three months of storage at room temperature. Preparation B17 B18 B19 B20 B21 B22 Quetiapine fumarate 7% 7% 5% 7% 5% 6.7% Propylene glycol 12% 12% 12% 12% 5% N / A PEG 3350 5% 5% 5% N / A 20% 20% Benzyl alcohol 5% 5% N / A 5% N / A 5% Tween 20 1.5% 1.5% 1.5% 1.5% 1.5% 1.5% Anhydrous ethanol 10% N / A N / A N / A 19.8% 19.8% 0.1 M citric acid Balance 59.5% 61.5% Balance Balance Balance PEG 400 N / A N / A N / A 15% N / A N / A Purified water N / A Balance Balance N / A N / A N / A Recording of dissolution phenomenon Completely dissolved after stirring at room temperature for 10 minutes Completely dissolved after heating and stirring at 50°C for 10 minutes Not dissolved after heating and stirring at 50°C for 1 hour Completely dissolved after heating and stirring at 50°C for approximately 20 minutes Not dissolved after heating and stirring at 50°C for 1 hour Completely dissolved after heating and stirring at 50°C for approximately 20 minutes Dissolved concentration (mg / mL) Approximately 60 Approximately 60 < 43 Approximately 60 < 43 58 “N / A” indicates no addition of this component in the preparation. Preparation method: the individual components were weighed according to the formulation table, mixed, and dissolved sufficiently. The dissolution phenomenon was recorded, and the dissolved concentration was estimated (calculated as free base). The experimental process and results demonstrated that the addition of benzyl alcohol significantly improved the saturation solubility of quetiapine fumarate to more than 50 mg / mL, making it suitable for nasal spray administration. Furthermore, the saturation solubility is positively correlated with the amount of benzyl alcohol used. Compared with DMA, the addition of benzyl alcohol can achieve a higher saturation solubility while avoiding the drawback of severe nasal irritation caused by DMA. 8. Extended study on the effect of adding benzyl alcohol on solubilization Preparation B23 B24 B25 B26 B27 B28 Quetiapine fumarate 9.5% 9.7% 13.4% 13.3% 9.7% 13% Propylene glycol 5% 5% 5% 5% 5% 5% PEG 3350 15% 15% 5% 5% 15% 5% Benzyl alcohol 10% 10% 10% 10% 10% 10% Tween 20 1.5% 1.5% 1.5% 1.5% 1.5% 1.5% Pectin / 0.25% / 0.25% 0.5% 0.5% Anhydrous ethanol 19.8% 19.8% 19.8% 19.8% 19.8% 19.8% 0.1 M citric acid Balance Saturation solubility (mg / mL) 82.61 84.70 116.26 115.22 84.43 112.61 “ / ” indicates no addition of this component in the preparation. Preparation method: the individual components were weighed according to the formulation table, mixed, and dissolved sufficiently. The saturation solubility of quetiapine in the solution was analyzed and determined (calculated as free base). The clear supernatant from each formulation showed no crystal precipitation during 14 days of high and low temperature cycling, and after three months of storage at room temperature (low temperature: 2°C to 8°C; high temperature: 50°C). The experimental process and results demonstrated that on the basis of benzyl alcohol addition, a significantly enhanced saturation solubility of quetiapine was achieved. The additional addition of pectin at various levels was also able to maintain a relatively high saturation solubility. When PEG 3350 was reduced from 15% to 5% in the formulation, the saturation solubility showed a remarkable increasing trend, which may be attributed to the excessive levels of PEG 3350 occupying solubility capacity in the formulation. The possible reason for the increase in the solubility of the above formulation is that benzyl alcohol, propylene glycol and ethanol form a mixed system with stronger solubilization ability. Tween 20 and PEG 3350 mainly play a stabilizing role in the formulation, inhibiting quetiapine from precipitating under high and low temperature conditions. 9. Additional formulations with good solubilization effects prepared and validated in other embodiments Based on the findings from the aforementioned solubilization studies, the amount of organic solvents used was reduced, and the following nasal spray preparations of solution-type quetiapine composition for intranasal administration were further prepared, all of which had a good high active ingredient concentration (the concentration in the table was estimated based on the complete dissolution of quetiapine fumarate, and the estimated concentration was calculated as free base). Preparation B29 B30 B31 B32 B33 B34 Quetiapine fumarate 7% 7% 6.5% 6.5% 6.5% 7% Propylene glycol 6% 6% 6% 6% 6% 6% PEG 3350 5% 5% N / A N / A 5% 5% Benzyl alcohol 5% 5% 5% 5% 5% 5% Tween 20 0.5% N / A 0.5% N / A N / A N / A 0.1 M citric acid 50% 50% 50% 50% 50% 1% PEG 400 N / A N / A 15% 15% 10% N / A Purified water Balance Dissolved concentration (mg / mL) 61 61 56 56 56 61 “N / A” indicates no addition of this component in the preparation. Preparation method: the individual components were weighed according to the formulation table, mixed, and dissolved sufficiently. The resulting clear solution was filled into a medium borosilicate glass vial, and assembled with a quantitative nasal spray pump to obtain the final product. Example C: Study on the chemical stability of the solution-type intranasal administration composition of the present disclosure 1. Basic formulation design and stability study Preparation C1 C2 C3 C4 Quetiapine fumarate 7% 5% 5% 7% Propylene glycol 6% 6% 6% 12% Benzyl alcohol 5% 5% 5% 7.5% PEG 3350 5% 2.5% 2.5% 2.5% Water Balance Citric acid monohydrate 1% 0.6% 0.4% N / A pH 3.9 4.1 4.2 4.9 “N / A” indicates no addition of this component in the preparation. Preparation method: the individual components were weighed according to the formulation table, mixed and dissolved until clear. The resulting solution was filled into a medium borosilicate glass vial, and assembled with a quantitative nasal spray pump to obtain the final product. H: The chemical stability of the above preparation (impurity G: ; impurity ) was investigated at 40°C and 75% RH. The analytical test data were as follows: Preparation Day 0 Day 12 Day 40 Total Impurities, % Total Impurities, % Impurity G, % Impurity H, % Cl 0.14 0.80 1.02 0.08 C2 0.14 0.67 0.66 0.12 C3 0.15 0.61 0.47 0.15 C4 0.14 0.35 0.13 0.11 The results demonstrated that the above solution-type intranasal administration composition, which was prepared to increase saturation solubility, had good chemical stability. 2. Study on formulation stability with addition of a surfactant and an antioxidant Based on the aforementioned C4 formulation, surfactants polyethylene glycol-15 hydroxystearate (HS-15) and Tween 80 were introduced. The pH of the solution was adjusted using NaOH to investigate their effect on the chemical stability of the formulation. Preparation C5 C6 C7 C8 C9 Quetiapine fumarate 7% 7% 7% 7% 7% Propylene glycol 12% 12% 12% 12% 12% Benzyl alcohol 7.5% 7.5% 7.5% 7.5% 7.5% PEG 3350 2.5% 2.5% 2.5% 2.5% 2.5% Water Balance HS-15 / 1.5% / / / Tween 80 / / 1% / 0.5% Sodium sulfite / / / 1% 1% Initial pH 4.9 4.8 4.9 5.8 5.9 pH adjusted with NaOH solution to: 5.0 5.0 4.5 5.1 4.2 “ / ” indicates no addition of this component in the preparation. Preparation method: the individual components were weighed according to the formulation table, mixed and dissolved until clear. The pH was adjusted using NaOH solution. The resulting solution was filled into a medium borosilicate glass vial, and assembled with a quantitative nasal spray pump to obtain the final product. The above formulations were subjected to long-term (25°C, 75% RH) and accelerated (40°C, 75% RH) testing. The analytical test data were as follows: Preparation Total Impurity Content (%) Content of Impurity G (%) Day 0 25°C 40°C 25°C 40°C Day 38 Day 38 Day 38 Day 38 C5 0.07 0.09 0.17 ND 0.09 C6 0.06 0.09 0.14 ND 0.07 C7 0.07 0.11 0.39 0.04 0.18 C8 The total impurity content in C8 and C9 reached 0.84% and 2.09% respectively after 7 days of accelerated storage, and therefore no further testing was conducted. C9 “ND” means not detected. The results demonstrated that the stability of the formulation with the addition of surfactants HS-15 and Tween 80 was controllable and did not cause a significant increase in related substances. However, the introduction of the antioxidant sodium sulfite not only failed to improve the stability, but also unexpectedly led to a sharp decline in the stability of the formulation. The use of NaOH to adjust the pH did not destroy the chemical stability. When the pH was appropriately increased, the formation of hydrolyzed impurity G was inhibited and the chemical stability was improved. 3. Study on formulation stability with introduction of an organic base Increasing the pH of the formulation was found to inhibit the growth of impurity G. An attempt was made to introduce the organic base meglumine to increase the pH value of the formulation so as to enhance its stability. Preparation C10 C11 Quetiapine fumarate 7% 7% Propylene glycol 12% 12% Benzyl alcohol 7.5% 7.5% PEG 3350 2.5% 2.5% Water Balance Meglumine 0.25% 0.50% PH 5.1 5.3 Preparation method: the individual components were weighed according to the formulation table, mixed and dissolved until clear. The resulting solution was filled into a medium borosilicate glass vial, and assembled with a quantitative nasal spray pump to obtain the final product. The above formulations were subjected to 30-day long-term (25°C, 75% RH) and accelerated (40°C, 75% RH) testing. The analytical test data were as follows: Preparation Total Impurity Content (%) Content of Impurity G (%) Day 0 25°C 40°C 25°C 40°C Day 30 Day 30 Day 30 Day 30 C10 0.08 0.09 0.13 ND 0.05 C11 0.08 0.09 0.12 ND 0.04 “ND” means not detected. The results demonstrated that the use of organic base meglumine to increase pH was beneficial to inhibiting the formation of hydrolyzed impurity G, thereby improving chemical stability. 4. Extended study on formulation stability Firstly, stability studies were conducted with or without nitrogen filling, as well as the addition of or variation in the amount of the solubilizer HP-P-CD, the surfactant HS-15, and the stabilizer disodium edetate. The formulations were designed as follows: Preparation C12 C13 C14 C15 C16 C17 Quetiapine 7% 7% 7% 7% 7% 7% fumarate Propylene glycol 12% 12% 12% 12% 12% 12% Benzyl alcohol 7.5% 7.5% 7.5% 7.5% 7.5% 7.5% PEG 3350 2.5% 2.5% 2.5% 2.5% 2.5% 2.5% Water Balance Meglumine / 0.5% 0.5% 0.5% 0.5% 0.5% HS-15 / 3% 3% / / 3% Disodium edetate / / 0.05% / 0.05% 0.05% HP-P-CD / / / 5% 5% / Sodium bisulfite / / / / / 0.5% PH 5.0 5.4 5.3 5.4 5.5 5.2 “ / ” indicates no addition of this component in the preparation. Preparation method: (1) the individual components were weighed according to the formulation table, mixed and dissolved until clear. The resulting clear solution was filled into a medium borosilicate glass vial, and assembled with a quantitative nasal spray pump to obtain the final product. (2) Parallel formulations, C16-1 and C17-1, were additionally prepared for C16 and C17, respectively, with an extra incorporation of nitrogen filled protection. The above formulations were subjected to 24-day long-term (25°C, 75% RH) and accelerated (40°C, 75% RH) testing. The analytical test data were as follows: Preparation Total Impurity Content (%) Content of Impurity G (%) Day 0 25°C 40°C 25°C 40°C Day 24 Day 24 Day 24 Day 24 C12 0.08 0.08 0.14 ND 0.06 C13 0.08 0.09 0.12 ND 0.04 C14 0.07 0.08 0.11 ND 0.04 C15 0.07 0.10 0.11 ND 0.03 C16 0.08 0.08 0.15 ND 0.03 C16-1 0.08 N / A 0.14 N / A 0.03 C17 The total impurity content in C17 and C17-1 reached 0.62% and 0.38% respectively after 10 days of accelerated storage, and therefore no further testing was conducted. C17-1 “N / A” means not applicable. “ND” means not detected. The results demonstrate that the stability of the formulation with the addition of or variation in the amount of the solubilizer HP-P-CD, the surfactant HS-15, and the stabilizer disodium edetate was controllable and did not cause a significant increase in related substances. However, surprisingly, the introduction of the antioxidant sodium bisulfite not only failed to improve the antioxidant performance of quetiapine, but also unexpectedly led to a rapid decline in the stability of the formulation. The results also demonstrated that there was no obvious difference in the impurity growth rate and content between the two formulations with and without nitrogen filling, that is, stable formulations could be obtained with or without nitrogen filling. Based on above studies, the following formulations were further prepared, which are stable under long-term and accelerated test. The solution-type intranasal administration composition preparation used in further animal studies was also stable. Preparation C18 C19 C20 C21 C22 C23 C24 C25 C26 C27 C28 Quetiapine fumarate 0.25% 1.7% 6.7% 1.7% 6.7% 1.7% 6.7% 1.7% 6.7% 1.7% 6.7% Propylene glycol 12% 11% 11% / / / / 11% 11% 11% 11% Ethanol / / / 19.8% 19.8% / / / / / / Glycerol / / / / / 2.2% 2.2% / / / / Benzyl alcohol 1% 3.2% 7.5% 3.2% 7.5% 3.2% 7.5% 3.2% 7.5% 3.2% 7.5% PEG 3350 2.5% 5% 5% 5% 5% 5% 5% / / 5% 5% PEG 400 / / / / / / / 15% 15% / / Benzalkonium chloride 0.02% / / / / / / / / 0.02% 0.02% Meglumine 0.02% The pH value was adjusted with sodium hydroxide, meglumine, or citric acid. Water Balance pH 6.1 5.3   5.3   5-6    5-6   5-6 5-6 5-6 5-6   5-6 5-6 “ / ” indicates no addition of this component in the preparation. Preparation method: the individual components were weighed according to the formulation table, mixed and dissolved until clear. The resulting solution was filled into a medium borosilicate glass vial, and assembled with a quantitative nasal spray pump to obtain the final product. The present disclosure is not limited to the above optional implementations, and various other forms of products may be derived by any person based on the teachings of the present disclosure. The above specific implementations should not be understood as limiting the scope of protection of the present disclosure. The scope of protection of the present disclosure should be based on the definition in the claims, and the description can be used to interpret the claims.

Claims

1. A quetiapine composition for nasal administration, comprising quetiapine or a pharmaceutically acceptable salt thereof, wherein the composition is a solution.

2. The composition according to claim 1, wherein the mass percentage of quetiapine in the composition, calculated as free base, is from 0.22% to 11.7%, or from 4.3% to 11.7%,or, preferably, quetiapine is dissolved in the composition in the form of fumarate, and the mass percentage of the quetiapine fumarate in the composition is from 0.25% to 13.4%, from 0.25% to 5%, from 0.25% to 1.7%, from 5% to 13.4%, from 5% to 9.7%, from 5% to 7%, 0.25%, 1.7%, 5%, 5.2%, 6%, 6.5%, 6.6%, 6.7%, 7%, 8.2%, 9.5%, 9.7%, 13%, 13.3% or 13.4%.

3. The composition according to claim 1, wherein the composition further comprises one or a combination of two or more selected from a solubilizer, a cosolvent, a viscosity enhancer, a stabilizer, a preservative, a pH regulator and a pH buffer.

4. The composition according to claim 3, whereinthe solubilizer optionally comprises one or a combination of two or more selected from benzyl alcohol, DMA, cyclodextrin and a surfactant, wherein the cyclodextrin optionally comprises one or a combination of two or more selected from P-cyclodextrin, hydroxypropyl-P-cyclodextrin and sulfobutyl—P-cyclodextrin, and wherein the surfactant optionally comprises one or a combination of two or more selected from Tween, Span, Carbomer and polyethylene glycol-15 hydroxystearate;the cosolvent optionally comprises a saturated alcohol, and the saturated alcohol optionally comprises one or a combination of two or more selected from propylene glycol, ethanol and glycerol;the viscosity enhancer optionally comprises one or a combination of two or more selected from polyethylene glycol, pectin, cellulose, polyolefin and polyacrylic acid;the stabilizer optionally comprises edetate, and the edetate optionally comprises EDTA-2Na and / or EDTA-2K;the preservative optionally comprises benzalkonium chloride, benzalkonium bromide, benzethonium chloride, potassium sorbate, methyl paraben, ethyl paraben, propyl paraben,2024414252   02 Jun 2026butyl paraben, isopropyl paraben, isobutyl paraben, sodium propyl paraben and / or sodium methyl paraben;the pH regulator optionally comprises one or a combination of two or more selected from citric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide and meglumine; andthe pH buffer optionally comprises one or a combination of two or more selected from citrate buffer, phosphate buffer and acetate buffer.

5. The composition according to claim 1, wherein the composition further comprises a solubilizer, a cosolvent, a viscosity enhancer and water,the solubilizer is benzyl alcohol, and the mass percentage of the benzyl alcohol in the composition is selected from 1% to 10%, from 1% to 9.3%, from 5% to 9.3%, 1%, 3.2%, 5%, 7.5% or 9.3%;the cosolvent is one or a combination of two or more selected from propylene glycol, ethanol and glycerol, preferably propylene glycol, the mass percentage of the propylene glycol in the composition is selected from 0% to 12%, from 4.6% to 12%, from 6% to 12%, 4.6%, 4.7%, 5%, 6%, 10%, 11% or 12%, the mass percentage of ethanol in the composition is selected from 0% to 20%, from 6% to 20%, from 0% to 19.8%, from 18.3% to 19.8%, 6%, 10%, 18.3%, 18.5% or 19.8%, and the mass percentage of glycerol in the composition is selected from 0% to 5%, from 0% to 3%, from 0% to 2.5%, from 0% to 2.2% or 2.2%; andthe viscosity enhancer is polyethylene glycol, preferably PEG 3350 or PEG 400, the mass percentage of PEG 3350 in the composition is selected from 0% to 20%, from 2.5% to 15%, from 5% to 15%, 2.5%, 4.6%, 4.7%, 5%, 15% or 20%, and the mass percentage of PEG 400 in the composition is selected from 0% to 15%, 10% or 15%.

6. The composition according to claim 5, wherein the composition further comprises one or a combination of two or more selected from a stabilizer, a preservative, a pH regulator and a pH buffer,wherein the stabilizer is EDTA-2Na, and the mass percentage of EDTA-2Na in the composition is selected from 0% to 0.1% or 0.05%;2024414252   02 Jun 2026the preservative is benzalkonium chloride, and the mass percentage of the benzalkonium chloride in the composition is selected from 0% to 0.02% or 0.02%;the pH regulator is one or a combination of two or more selected from citric acid, hydrochloric acid, sodium hydroxide and meglumine, and the pH regulator adjusts the pH value of the composition to from 4.1 to 6.0, from 4.5 to 6.0, from 5.0 to 6.0, and 4.1, 4.5, 4.9, 5.0, 5.1, 5.3 or 6.0; andthe pH buffer is a citrate buffer, a phosphate buffer or an acetate buffer.

7. An intranasal administration composition with improved dissolved concentration of quetiapine, wherein the composition comprises quetiapine or a pharmaceutically acceptable salt thereof, wherein the composition is a solution and further comprises a solubilizer;preferably, the solubilizer comprises one or a combination of two or more selected from benzyl alcohol, DMA, cyclodextrin and a surfactant;or preferably, the solubilizer comprises benzyl alcohol and / or DMA;or preferably, the solubilizer comprises benzyl alcohol, the mass percentage of benzyl alcohol in the composition is selected from 1% to 10%, from 3.2% to 10%, from 5% to 10%, from 5% to 9.3%, from 5% to 7.5%, 1%, 3.2%, 5%, 7.5%, 9.3% or 10%, and optionally, the mass ratio of benzyl alcohol to quetiapine in the composition is from 1: 0.8 to 1: 1.2.

8. The composition according to claim 7, whereinthe solubilizer in the composition may only comprise benzyl alcohol,or the solubilizer in the composition may only comprise benzyl alcohol and cyclodextrin,or the solubilizer in the composition may only comprise benzyl alcohol and the surfactant,or the solubilizer in the composition may only comprise benzyl alcohol, cyclodextrin and the surfactant.

9. The composition according to claim 7, wherein the composition further comprises a cosolvent, wherein the cosolvent optionally comprises saturated alcohol, the saturated alcohol optionally comprises one or a combination of two or more selected from propylene2024414252   02 Jun 2026glycol, ethanol and glycerol, and the saturated alcohol is preferably propylene glycol or a combination of propylene glycol and ethanol;and wherein the mass percentage of propylene glycol in the composition is selected from 0% to 12%, from 4.6% to 12%, from 6% to 12%, 4.6%, 4.7%, 5%, 6%, 10%, 11% or 12%;the mass percentage of ethanol in the composition is selected from 0% to 20%, from 6% to 20%, from 0% to 19.8%, from 18.3% to 19.8%, 6%, 10%, 18.3%, 18.5% or 19.8%; andthe mass percentage of glycerol in the composition is selected from 0% to 5%, from 0% to 3%, from 0% to 2.5%, from 0% to 2.2% or 2.2%.

10. The composition according to claim 7, wherein the composition further comprises a surfactant and / or polyethylene glycol, preferably further comprises one or a combination of two or more selected from Tween, PEG 3350 and PEG 400, the Tween comprises Tween 80 or Tween 20;wherein the mass percentage of PEG 3350 in the composition is selected from 0% to 20%, from 2.5% to 15%, from 5% to 15%, 2.5%, 4.6%, 4.7%, 5%, 15% or 20%;the mass percentage of PEG 400 in the composition is selected from 0% to 15%, 10% or 15%; andthe mass percentage of Tween in the composition is selected from 0% to 1.5%, 0.5%, 1%, 1.4% or 1.5%.

11. The composition according to claim 7, wherein the cyclodextrin comprises one or a combination of two or more selected from P-cyclodextrin, hydroxypropyl-P-cyclodextrin and sulfobutyl-P-cyclodextrin, and the mass percentage of cyclodextrin in the composition is selected from 0% to 10%, from 1% to 5%, or 5%.

12. The composition according to claim 7, wherein the dissolved concentration of quetiapine in the composition, calculated as free base, is from 4.3% to 11.7% or from 5.6% to 11.7% by mass;or, preferably, quetiapine is dissolved in the composition in the form of fumarate, and the mass percentage of quetiapine fumarate in the composition is from 5% to 13.4%, from2024414252   02 Jun 20265% to 9.7%, from 5% to 7%, 5%, 5.2%, 6%, 6.5%, 6.6%, 6.7%, 7%, 8.2%, 9.5%, 9.7%, 13%, 13.3% or 13.4%.

13. The composition according to any one of claims 7 to 12, wherein the composition further comprises water, and one or a combination of two or more selected from a viscosity enhancer, a stabilizer, a preservative, a pH regulator and a pH buffer.

14. A stable intranasal administration composition, wherein the composition is a solution comprising water and the following components:Component Mass Percentage Quetiapine or a pharmaceutically acceptable salt thereof (calculated as free base) 0.22%-11.7% Solubilizer 1%-10% Cosolvent 0%-20% Viscosity enhancer 0%-15%15. The composition according to claim 14, wherein the mass percentage of quetiapine in the composition, calculated as free base, is from 4.3% to 11.7%;or, preferably, quetiapine is dissolved in the composition in the form of fumarate, and the mass percentage of quetiapine fumarate in the composition is from 0.25% to 13.4%, from 0.25% to 5%, from 0.25% to 1.7%, from 5% to 13.4%, from 5% to 9.7%, from 5% to 7%, 0.25%, 1.7%, 5%, 5.2%, 6%, 6.5%, 6.6%, 6.7%, 7%, 8.2%, 9.5%, 9.7%, 13%, 13.3% or 13.4%;preferably,the solubilizer comprises one or a combination of two or more selected from benzyl alcohol, cyclodextrin, Tween and polyethylene glycol-15 hydroxystearate, the cyclodextrin optionally comprises hydroxypropyl-P-cyclodextrin, and the Tween optionally comprises Tween 80 and / or Tween 20;and wherein the mass percentage of benzyl alcohol in the composition is selected from 1% to 10%, from 1% to 9.3%, from 5% to 9.3%, 1%, 3.2%, 5%, 7.5% or 9.3%, the mass percentage of cyclodextrin in the composition is selected from 0% to 5% or 5%, the mass2024414252   02 Jun 2026percentage of Tween in the composition is selected from 0% to 1.4%, 1% or 1.4%, and the mass percentage of polyethylene glycol-15 hydroxystearate in the composition is selected from 0% to 3%, 1.5% or 3%;or preferably, the cosolvent comprises one or a combination of two or more selected from propylene glycol, ethanol and glycerol;and wherein the mass percentage of propylene glycol in the composition is selected from 0% to 12%, from 4.6% to 12%, from 6% to 12%, 4.6%, 4.7%, 6%, 11% or 12%, the mass percentage of ethanol in the composition is selected from 0% to 20%, from 0% to 19.8%, from 18.3% to 19.8%, 18.3%, 18.5% or 19.8%, and the mass percentage of glycerol in the composition is selected from 0% to 5%, from 0% to 3%, from 0% to 2.5%, from 0% to 2.2% or 2.2%;or preferably,the viscosity enhancer comprises polyethylene glycol and / or pectin, and the polyethylene glycol optionally comprises PEG 3350 and / or PEG 400;and wherein the mass percentage of PEG 3350 in the composition is selected from 0% to 5%, 2.5% to 5%, 2.5%, 4.6%, 4.7% or 5%, the mass percentage of PEG 400 in the composition is selected from 0% to 15% or 15%, and the mass percentage of pectin in the composition is selected from 0% to 1% or 0.7%.or preferably, the composition is free of sodium sulfite and sodium bisulfite ;or preferably, the composition consists of quetiapine fumarate, a solubilizer, a cosolvent, a viscosity enhancer and water,the solubilize is benzyl alcohol,the cosolvent is one or a combination of two or more selected from propylene glycol, ethanol and glycerol, preferably propylene glycol,the viscosity enhancer is PEG 3350 and / or PEG 400; andoptionally, one or a combination of two or more selected from benzalkonium chloride, a pH regulator and a pH buffer is further added to or not added to the composition.

16. The composition according to claim 14, wherein the composition further comprises any one or a combination of two or more selected from the following2024414252   02 Jun 2026components:Component Mass Percentage Stabilizer 0%-0.1% Preservative 0%-0.2% pH regulator An amount effective to adjust the pH of the composition to 4.1-6.

917. The composition according to claim 16, whereinthe stabilizer comprises edetate, the edetate comprises disodium edetate and / or dipotassium edetate, and the mass percentage of the disodium edetate in the composition is selected from 0% to 0.1% or 0.05%;the preservative comprises benzalkonium chloride, and the mass percentage of benzalkonium chloride in the composition is selected from 0% to 0.02% or 0.02%;the pH regulator comprises one or a combination of two or more selected from sodium hydroxide, potassium hydroxide, meglumine, citric acid and hydrochloric acid, and the pH regulator is added in an amount effective to adjust the pH of the composition to a value selected from 4.1 to 6.0, from 4.5 to 6.0, from 5.0 to 6.0, 4.1, 4.5, 4.9, 5.0, 5.1, 5.3 or 6.0, and wherein the mass percentage of meglumine in the composition is selected from 0% to 0.5%, 0.02%, 0.25% or 0.5%, and the citric acid is selected as a 1 M citric acid solution;preferably, a pH buffer is further added to or not added to the composition, and the pH buffer optionally comprises one or a combination of two or more selected from citrate buffer, phosphate buffer and acetate buffer.

18. A quetiapine nasal spray, comprising the composition according to any one of claims 1 to 17 and a quantitative nasal spray device for applying and delivering the composition into the nasal cavity, wherein a volume of the composition delivered per spray by the quantitative nasal spray device is selected from 25 pL to 200 pL, from 50 pL to 150 pL, 25 pL, 50 pL, 75 pL, 100 pL, 125 pL, 150 pL, 175 pL or 200 pL.

19. Use of the composition according to any one of claims 1 to 17 or the quetiapine nasal spray according to claim 18 in the manufacture of a medicament for treating mental2024414252   02 Jun 2026diseases.

20. A method for treating mental diseases, comprising administering a therapeutically effective amount of the composition according to any one of claims 1 to 17 or using the quetiapine nasal spray according to claim 18 to a subject in need thereof.

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