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

A solution-type quetiapine composition for nasal administration and its application Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, in particular to the field of quetiapine pharmaceutical preparations, and specifically relates to a novel composition for nasal administration and application thereof. Background Art

[0002] Quetiapine is a new atypical drug for the treatment of psychiatric disorders. Quetiapine's mechanism of action may be through antagonism of central D2 receptors and 5-HT2A receptors to exert its therapeutic effects. Around 1997, AstraZeneca launched the first quetiapine tablet formulation in the United States. The currently approved indications for the tablets include "schizophrenia, bipolar depression, bipolar I mania or mixed symptoms," and the tablet strengths are 25mg, 50mg, 100mg, 200mg, 300mg, and 400mg. Around 2009, quetiapine extended-release tablets were first launched in the United States. The currently approved indications include "schizophrenia, bipolar depression, bipolar I mania or mixed symptoms, and adjunctive treatment of major depressive disorder," and the extended-release tablet strengths are 50mg, 150mg, 200mg, 300mg, and 400mg.

[0003] The quetiapine tablets and sustained-release tablets on the market are both oral preparations, which have common clinical defects of oral preparations, such as poor compliance, the existence of first-pass effect leading to slow dissolution and absorption, and lower bioavailability. Especially for patients with mental illnesses, who are the target of their application, these defects often become unacceptable in the clinical application of the drug.

[0004] Therefore, there is still an unmet clinical need for improved tablet and sustained-release tablet formulations that are already on the market. Despite this clear need, even though the bioavailability of oral quetiapine is only about 10%, perhaps due to the inherent properties of quetiapine itself (such as difficulty in dissolving), no promising improved drug has been marketed in the more than 20 years since quetiapine was first marketed. Moreover, during these 20-plus years, most research literature on quetiapine in the industry has focused on the synthesis of quetiapine, the preparation of tablets, sustained-release tablets, or dispersible tablets, while there have been few reports on significant improvements to address the clinical deficiencies of oral formulations.

[0005] Chinese invention patents, represented by CN102552128B, provide an improved injection form. By making it into an injection form, the first-pass effect can be avoided, the drug dosage can be reduced, and the adverse drug reactions and clinical safety risks of high-dose medication can be reduced. However, considering that the patients of quetiapine are patients with mental illnesses, their disease attacks are often accompanied by acute and manic characteristics. At this time, the pain and other discomfort caused by injection may aggravate the patient's tension and produce an emergency reaction. In addition, injection administration requires high medical skills, is not convenient for patients to administer it themselves, and has limited application scenarios.

[0006] Indian patent application represented by IN202211053155A provides a nanoemulsion, which dissolves quetiapine in an oil phase and then prepares an oil-in-water nanoemulsion. The nanoemulsion is designed to be delivered to the brain through the nasal olfactory pathway to avoid metabolism caused by the first-pass effect in the liver and improve bioavailability. The "Bioavailability and biodistribution studies" section in the patent shows that compared with oral preparations, the C of the provided nanoemulsion after nasal administration is 2.34%. max , AUC 0-480 All of them have been significantly improved (Table 11).

[0007] However, even with this, the nanoemulsion formulation, since quetiapine is dissolved in the oil phase, still faces the challenge of transitioning from the oil phase to the aqueous phase during drug absorption after administration. Due to the low saturated concentration of quetiapine in the aqueous phase, this results in prolonged peak and onset times for the nanoemulsion. For the same reasons as for oral formulations, this prolonged peak and onset time is detrimental to the rapid relief of some acute symptoms of psychiatric disorders. The "In-Vitro Drug Release Studies" section of the Indian patent also describes the characteristics of this nanoemulsion, as shown in Table 10 and Figure 6, along with the analytical conclusions: "Diffusion from the oily core and interface is hindered by the aqueous medium. Due to the low saturated concentration of quetiapine in water, this hinders drug transport." Similarly, Table 11 in the "Bioavailability and biodistribution studies" section of the Indian patent shows that the nasal nanoemulsion has the same peak plasma concentration time, T, as the oral formulation. max =2h (much shorter than the 0.25h of injection), which is consistent with the data and conclusions of the aforementioned in vitro studies.

[0008] In summary, in the field of quetiapine drug research, there are: first, few studies addressing significant clinical deficiencies in the marketed oral formulation. Second, the improvements provided in these rarely published studies still struggle to address similar clinical deficiencies as the oral formulation. Against this backdrop, developing an improved form of quetiapine to address the deficiencies of the marketed oral formulation and meet urgent unmet clinical needs remains a pressing issue. Summary of the Invention

[0009] To address the aforementioned problems of the prior art, the primary objective of the present invention is to provide an improved form of quetiapine. Compared to marketed oral dosage forms, this novel improved form should have a rapid peak or onset of action, be easy to administer, and enhance patient compliance. Furthermore, this novel improved form should also have high bioavailability, avoiding the clinical safety risks associated with oral formulations requiring high doses due to low bioavailability.

[0010] For the primary purpose of the present invention, the present invention provides the following technical solutions after extensive attempts:

[0011] A composition for nasal administration of quetiapine, comprising quetiapine or a pharmaceutically acceptable salt thereof, is a solution. That is, the improved form provided by the present invention is a "solution-type nasal administration composition." After extensive research and exploration, it was surprisingly discovered that the present invention, by formulating quetiapine as a solution and administering it nasally, can significantly shorten the time to peak effect, for example, T max At the same time, formulating quetiapine into a solution and administering it through the nose can also achieve a significantly improved bioavailability, which is not achieved by conventional improvements.

[0012] For the solution-type quetiapine composition for nasal administration provided by the present invention:

[0013] In some embodiments, the weight percentage of quetiapine in the composition is 0.22-11.7% or 4.3-11.7% based on the free base. Alternatively, preferably, quetiapine is dissolved in the composition in the form of a fumarate salt, and the weight percentage of quetiapine fumarate in the composition is 0.25-13.4%, 0.25-5%, 0.25-1.7%, 5-13.4%, 5-9.7%, 5-7%, 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%.

[0014] In other embodiments, the solution-type quetiapine nasal administration composition further includes a solubilizer, a cosolvent, a viscosity enhancer, a stabilizer, a preservative, a pH adjuster, and a pH buffer. The solubilizer may optionally include a combination of one or more of benzyl alcohol, DMA, cyclodextrin, and a surfactant; the cyclodextrin may optionally include a combination of one or more of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin; and the surfactant may optionally include a combination of one or more of Tween, Span, carbomer, and polyethylene glycol-15 hydroxystearate. The cosolvent may optionally include a saturated alcohol; the saturated alcohol may optionally include a combination of one or more of propylene glycol, ethanol, and glycerol. The viscosity enhancer may optionally include a combination of one or more of polyethylene glycol, pectin, cellulose, polyethylene hydrocarbon, and polyacrylic acid. The stabilizer may optionally include edetate; and edetate may optionally include EDTA-2Na and / or EDTA-2K. Preservatives may optionally include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, potassium sorbate, methylparaben, ethylparaben, propylparaben, butylparaben, isopropylparaben, isobutylparaben, sodium propylparaben and / or sodium methylparaben. pH regulators may optionally include one or more combinations of citric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide and meglumine. pH buffers may optionally include one or more combinations of citrate buffer, phosphate buffer and acetate buffer.

[0015] In other embodiments, the solution-type quetiapine nasal composition further comprises a solubilizer, a cosolvent, a viscosity enhancer, and water, wherein the solubilizer is benzyl alcohol, and the mass percentage of benzyl alcohol in the composition can be selected from 1-10%, 1-9.3%, 5-9.3%, 1%, 3.2%, 5%, 7.5%, or 9.3%. The cosolvent is one or a combination of two or more of propylene glycol, ethanol and glycerol, preferably propylene glycol; wherein: the mass percentage of propylene glycol in the composition can be selected from 0-12%, 4.6-12%, 6-12%, 4.6%, 4.7%, 5%, 6%, 10%, 11% or 12%, the mass percentage of ethanol in the composition can be selected from 0-20%, 6-20%, 0-19.8%, 18.3-19.8%, 6%, 10%, 18.3%, 18.5% or 19.8%, and the mass percentage of glycerol in the composition can be selected from 0-5%, 0-3%, 0-2.5%, 0-2.2% or 2.2%. The viscosity enhancer is polyethylene glycol, preferably PEG3350 or PEG400; wherein: the mass percentage of PEG3350 in the composition can be selected as 0-20%, 2.5%-15%, 5-15%, 2.5%, 4.6%, 4.7%, 5%, 15% or 20%, and the mass percentage of PEG400 in the composition can be selected as 0-15%, 10% or 15%.

[0016] In other embodiments, the solution-type quetiapine nasal composition further comprises one or a combination of two or more of a stabilizer, a preservative, a pH adjuster, and a pH buffer. The stabilizer is EDTA-2Na, and the weight percentage of EDTA-2Na in the composition can be selected from 0-0.1% or 0.05%. The preservative is benzalkonium chloride, and the weight percentage of benzalkonium chloride in the composition can be selected from 0-0.02% or 0.02%. The pH adjuster is one or a combination of two or more of citric acid, hydrochloric acid, sodium hydroxide, and meglumine, and the pH adjuster adjusts the pH of the composition to 4.1-6.0, 4.5-6.0, 5.0-6.0, 4.1, 4.5, 4.9, 5.0, 5.1, 5.3, or 6.0. The pH buffer is a citrate buffer, a phosphate buffer, or an acetate buffer.

[0017] The second object of the present invention is to increase the saturated solubility concentration of quetiapine in the solution-type quetiapine composition for nasal administration based on the solution-type quetiapine composition for nasal administration provided by the primary object above.

[0018] Due to the limited area of ​​the nasal mucosa, the single dose volume for nasal administration cannot be too high. If the dose volume is too high, the excess liquid cannot be absorbed by the nasal mucosa and will flow out of the nasal cavity or even into the throat through the nasopharynx, failing to be absorbed and taking effect, while causing discomfort and unnecessary side effects. The single dose volume of nasal spray is usually no more than 200μL, and it is generally best to keep it no more than 100μL. When delivering in a "solution type" with such a small dose volume, the active ingredient of the drug needs to have a high solubility concentration to ensure the dosage. At the same time, the high concentration also avoids multiple doses and reduces nasal irritation. However, quetiapine has been tested to be a drug with a low saturated solubility concentration. The saturated solubility concentration of quetiapine fumarate in water is only 4.0mg / ml. Therefore, in order to ensure the dosage and reduce the number of sprays to reduce nasal irritation, it is very necessary to use methods to increase the saturated solubility concentration of quetiapine.

[0019] The second object of the present invention is achieved through the following technical solutions:

[0020] A composition for nasal administration for increasing the solubility concentration of quetiapine comprises quetiapine or a pharmaceutically acceptable salt thereof. The composition is a solution and further comprises a solubilizer. The solubilizer can optionally comprise one or a combination of two or more of benzyl alcohol, DMA, cyclodextrin and a surfactant, preferably benzyl alcohol or DMA.

[0021] Further research and exploration by the present invention revealed that for poorly soluble quetiapine, it is relatively easy to increase the saturated solubility concentration of quetiapine to around 20 mg / mL using common solubilization methods. However, further increasing the saturated solubility concentration of quetiapine has become increasingly difficult, especially to increase it to above 50 mg / mL. However, in order to deliver therapeutic doses of drugs in smaller dosage volumes, increasing the drug concentration to above 50 mg / mL is advantageous or even necessary. Extensive testing by the present invention surprisingly found that the use of the solubilizing agent benzyl alcohol, or DMA, is very beneficial for increasing the saturated solubility concentration of quetiapine to higher concentrations above 50 mg / mL.

[0022] In particular, the use of benzyl alcohol as a solubilizer has a particularly surprising beneficial effect. While significantly improving the saturated solubility concentration of quetiapine, it also takes into account a lower nasal mucosal irritation than other solubilizers represented by DMA (benzyl alcohol is also included in the "FDA Drug Inactive Ingredient Database" and is allowed to be used as an inactive ingredient excipient for nasal spray administration. The irritation and safety of the nasal route have been recognized by regulatory verification). It is very suitable as a solubilizer for the solution-type quetiapine nasal administration composition provided by the present invention. In addition, it is surprising that benzyl alcohol is widely used as a preservative and disinfectant in the industry. In the solution-type quetiapine nasal composition of the present invention, the addition of benzyl alcohol unexpectedly has a significant and beneficial effect on the improvement of the saturated solubility concentration of quetiapine. Therefore, benzyl alcohol is used as the most preferred solubilizer for the solution-type quetiapine nasal administration composition provided by the present invention. On this basis, in other embodiments, the solubilizer in the solution-type nasal administration composition for increasing the solubility concentration of quetiapine does not contain other types of solubilizers that are more irritating to the nasal cavity than benzyl alcohol; as several specific options: the solubilizer in the composition may be only benzyl alcohol, or the solubilizer in the composition may be only benzyl alcohol and cyclodextrin, or the solubilizer in the composition may be only benzyl alcohol and a surfactant, or the solubilizer in the composition may be only benzyl alcohol, cyclodextrin, and a surfactant.

[0023] In other embodiments, in the composition provided by the second object, as shown in the specific embodiments provided by the present invention, the weight percentage of benzyl alcohol in the composition can be 1-10%, 3.2-10%, 5-10%, 5-9.3%, 5-7.5%, 1%, 3.2%, 5%, 7.5%, 9.3%, or 10%. Depending on the amount of quetiapine added to the composition, the amount of benzyl alcohol added can fluctuate within ±20% of the amount of quetiapine added. In other words, preferably, the weight ratio of benzyl alcohol to quetiapine in the composition is 1:0.8-1.2.

[0024] In other embodiments, the solution-type nasal administration composition for increasing the solubility concentration of quetiapine of the present invention further includes a cosolvent, which may optionally include a saturated alcohol, which may optionally include one or a combination of two or more of propylene glycol, ethanol, and glycerol. The saturated alcohol is preferably propylene glycol, or a combination of propylene glycol and ethanol. The additional addition of a cosolvent, such as propylene glycol, can promote the dissolution of poorly soluble drugs, which is helpful for further improving the saturated solubility concentration of quetiapine in the provided composition. Among them, from the specific embodiments provided by the present invention, the mass percentage of propylene glycol in the composition may be 0-12%, 4.6-12%, 6-12%, 4.6%, 4.7%, 5%, 6%, 10%, 11% or 12%. The mass percentage of ethanol in the composition may be 0-20%, 6-20%, 0-19.8%, 18.3-19.8%, 6%, 10%, 18.3%, 18.5% or 19.8%. The mass percentage of glycerol in the composition can be selected as 0-5%, 0-3%, 0-2.5%, 0-2.2% or 2.2%.

[0025] In other embodiments, the solution-type nasal administration composition for increasing the solubility of quetiapine of the present invention further comprises a surfactant and / or polyethylene glycol, preferably one or a combination of two or more of Tween, PEG3350, and PEG400, wherein Tween comprises Tween 80 or Tween 20. The addition of these additional substances can further stabilize the solution system, particularly inhibiting the unintended precipitation of quetiapine under high or low temperature conditions. Specifically, as shown in the specific embodiments provided herein, the weight percentage of PEG3350 in the composition can be 0-20%, 2.5%-15%, 5-15%, 2.5%, 4.6%, 4.7%, 5%, 15%, or 20%. The weight percentage of PEG400 in the composition can be 0-15%, 10%, or 15%. The weight percentage of Tween in the composition can be 0-1.5%, 0.5%, 1%, 1.4%, or 1.5%.

[0026] In other embodiments, the solution-type nasal administration composition for increasing the solubility concentration of quetiapine of the present invention further comprises cyclodextrin, including one or a combination of two or more of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin. The weight percentage of cyclodextrin in the composition can be selected to be 0-10%, 1-5%, or 5%. Cyclodextrin can improve the saturated solubility concentration of the quetiapine solution composition to a certain extent, but when used alone, it is not as effective as benzyl alcohol or DMA.

[0027] In other embodiments, the present invention provides a solution-type nasal composition with increased quetiapine solubility, wherein the quetiapine is dissolved in the composition at a concentration of 4.3-11.7% by weight, calculated as the free base. In particular, the quetiapine free base is dissolved in the composition at a concentration of 5.6-11.7% by weight. As shown in the specific embodiments provided herein, quetiapine is preferably dissolved in the composition as a fumarate salt, with the quetiapine fumarate content in the composition being 5-13.4%, 5-9.7%, 5-7%, 5%, 5.2%, 6%, 6.5%, 6.6%, 6.7%, 7%, 8.2%, 9.5%, 9.7%, 13%, 13.3%, or 13.4% by weight. This higher active ingredient concentration is particularly suitable for nasal spray administration, significantly reducing the number of nasal sprays required during a single treatment, thereby reducing frequent nasal irritation and alleviating clinical medication discomfort and side effects such as sneezing and stinging.

[0028] In other embodiments, the solution-type nasal composition for increasing the solubility of quetiapine of the present invention is an aqueous solution, which further includes water and one or a combination of two or more of a viscosity enhancer, a stabilizer, a preservative, a pH adjuster, and a pH buffer. It should be noted that the optional excipients described in the second aspect of the present invention regarding "viscosity enhancer, stabilizer, preservative, pH adjuster, and pH buffer" can be selected in any combination with reference to the corresponding excipient types and amounts mentioned anywhere in the first aspect of the present invention.

[0029] The third object of the present invention is to further provide a composition with good chemical stability based on the solution-type quetiapine composition for nasal administration provided by the first and second objects above.

[0030] The third object of the present invention is achieved through the following technical solutions:

[0031] A stable composition for nasal administration, which is a solution comprising water and the following components:

[0032] In some embodiments, the stable solution-type quetiapine composition for nasal administration has a mass percentage of quetiapine in the composition, calculated as free base, of 4.3-11.7%. As shown in the specific embodiments provided herein, quetiapine is preferably dissolved in the composition in the form of a fumarate salt, and the mass percentage of quetiapine fumarate in the composition is 0.25-13.4%, 0.25-5%, 0.25-1.7%, 5-13.4%, 5-9.7%, 5-7%, 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%.

[0033] In other embodiments, the solubilizer in the stable solution-type quetiapine nasal composition comprises one or a combination of two or more of benzyl alcohol, cyclodextrin, Tween, and polyethylene glycol-15 hydroxystearate, the cyclodextrin optionally comprising hydroxypropyl-β-cyclodextrin, and the Tween optionally comprising Tween 80 and / or Tween 20. As shown in the specific embodiments provided herein, the mass percentage of benzyl alcohol in the composition may be 1-10%, 1-9.3%, 5-9.3%, 1%, 3.2%, 5%, 7.5%, or 9.3%, the mass percentage of cyclodextrin in the composition may be 0-5% or 5%, the mass percentage of Tween in the composition may be 0-1.4%, 1% or 1.4%, and the mass percentage of polyethylene glycol-15 hydroxystearate in the composition may be 0-3%, 1.5%, or 3%.

[0034] In other embodiments, the cosolvent in the stable solution-type quetiapine nasal composition comprises one or a combination of two or more of propylene glycol, ethanol, and glycerol. As shown in the specific embodiments provided herein, the mass percentage of propylene glycol in the composition can be 0-12%, 4.6-12%, 6-12%, 4.6%, 4.7%, 6%, 11%, or 12%, the mass percentage of ethanol in the composition can be 0-20%, 0-19.8%, 18.3-19.8%, 18.3%, 18.5%, or 19.8%, and the mass percentage of glycerol in the composition can be 0-5%, 0-3%, 0-2.5%, 0-2.2%, or 2.2%.

[0035] In other embodiments, the viscosity-increasing agent in the stable solution-type quetiapine nasal composition comprises polyethylene glycol and / or pectin, and the polyethylene glycol may optionally comprise PEG3350 and / or PEG400. As shown in the specific embodiments provided herein, the mass percentage of PEG3350 in the composition may be 0-5%, 2.5%-5%, 2.5%, 4.6%, 4.7% or 5%, the mass percentage of PEG400 in the composition may be 0-15% or 15%, and the mass percentage of pectin in the composition may be 0-1% or 0.7%.

[0036] In other embodiments, the stable solution-type quetiapine nasal composition further comprises any one or a combination of two or more of the following components:

[0037] In other embodiments, the stabilizer in the stable solution-type quetiapine nasal composition comprises edetate, which comprises disodium edetate and / or dipotassium edetate, and the mass percentage of disodium edetate in the composition can be 0-0.1% or 0.05%. The preservative comprises benzalkonium chloride, and the mass percentage of benzalkonium chloride in the composition can be 0-0.02% or 0.02%.

[0038] In other embodiments, the pH adjuster in the stable solution-type quetiapine nasal composition comprises one or a combination of two or more of sodium hydroxide, potassium hydroxide, meglumine, citric acid and hydrochloric acid, and the amount of the pH adjuster added can be selected to adjust the pH of the composition to 4.1-6.0, 4.5-6.0, 5.0-6.0, 4.1, 4.5, 4.9, 5.0, 5.1, 5.3 or 6.0.

[0039] In other embodiments, the mass percentage of meglumine in the stable solution-type quetiapine nasal composition can be 0-0.5%, 0.02%, 0.25% or 0.5%, and the citric acid can be 1M citric acid solution.

[0040] In other embodiments, the stable solution-type quetiapine nasal composition may or may not be added with a pH buffer, which may include one or a combination of two or more of a citrate buffer, a phosphate buffer, and an acetate buffer.

[0041] In other embodiments, the stable solution-type quetiapine nasal composition does not contain sodium sulfite and sodium bisulfite. As shown in the specific examples provided by the present invention, the introduction of sodium sulfite and sodium bisulfite unexpectedly and significantly destroys the chemical stability of the formulation.

[0042] In other embodiments, the stable solution-type quetiapine nasal administration composition consists solely of quetiapine fumarate, a solubilizer, a cosolvent, a viscosity enhancer, and water, and except for pharmaceutically acceptable levels of impurities, contains no other unspecified components, and the solubilizer is benzyl alcohol, the cosolvent is one or a combination of two or more of propylene glycol, ethanol, and glycerol, particularly propylene glycol, and the viscosity enhancer is PEG 3350 and / or PEG 400. Optionally, the composition may further contain or not contain one or more of benzalkonium chloride, a pH adjuster, and a pH buffer.

[0043] Based on the above purposes, the present invention provides a solution-type quetiapine nasal administration composition. The present invention also provides a quetiapine nasal spray, which comprises any of the aforementioned solution-type quetiapine nasal administration compositions described in the present invention and a quantitative nasal spray device for delivering the composition into the nasal cavity. The volume of the composition delivered by each spray of the quantitative nasal spray device can be selected to be 25-200 μL, 50-150 μL, 25 μL, 50 μL, 75 μL, 100 μL, 125 μL, 150 μL, 175 μL or 200 μL.

[0044] Accordingly, based on the clinical value of quetiapine that has been discovered and verified by the animal experiments provided by the present invention, the present invention also provides the use of any of the aforementioned solution-type quetiapine nasal compositions of the present invention or the aforementioned quetiapine nasal spray of the present invention in the preparation of drugs for treating mental illnesses. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 shows the movement distance of the experimental rats every 5 minutes from minute 0 to minute 150 after the start of the test in Example A, Example 2. The data are expressed as Mean ± SEM and analyzed by two-way ANOVA (comparison of test substance A with test substance D, * indicates p < 0.05, ** indicates p < 0.01, *** indicates p < 0.001; comparison of test substance B with test substance D, # indicates p < 0.05);

[0046] Figure 2 shows the total movement distance of the experimental rats in Example A, Example 2, 60-150 minutes after the start of the test. The data are expressed as Mean ± SEM and analyzed by one-way ANOVA (comparison of test substance A and test substance D, * indicates p < 0.05). DETAILED DESCRIPTION

[0047] Unless otherwise specified, the percentages "%" appearing in various places in the present invention refer to percentages by mass.

[0048] In the present invention, in order to more conveniently estimate the saturated solubility concentration, the density of the solution composition is approximately converted to 1 g / mL.

[0049] In the present invention, the conversion coefficient between quetiapine fumarate and quetiapine free base is 1.15, that is, "the amount of quetiapine free base = the amount of quetiapine fumarate / 1.15".

[0050] In the present invention, the balance means adding the corresponding components to 100%.

[0051] The meanings of the abbreviations in the present invention are in accordance with the common understanding in the industry, and some terms are annotated as follows: IN: intranasal administration; PO: oral administration; IV: intravenous injection; IP: intraperitoneal injection; HS-15: polyethylene glycol-15 hydroxystearate; HP-β-CD: hydroxypropyl-β-cyclodextrin; PEG3350: polyethylene glycol 3350; PEG400: polyethylene glycol 400; EDTA: edetate; EDTA-2Na: disodium edetate, also known as disodium edetate; EDTA-2K: dipotassium edetate, also known as dipotassium edetate; DMA: N,N-dimethylacetamide.

[0052] The present invention will be further explained below with reference to the accompanying drawings and specific embodiments.

[0053] Example A: Animal study on the pharmacokinetic and pharmacodynamic properties of the solution-type nasal composition of the present invention

[0054] Example 1. Pharmacokinetic study in beagle dogs

[0055] 1. Purpose of the experiment

[0056] The purpose of this experimental study is to evaluate and compare the pharmacokinetic characteristics of the solution-type nasal administration composition of the present invention, oral tablets, and injection after administration to beagle dogs.

[0057] 2. Test substance

[0058] The codes for the types of test substances are as follows:

[0059] The formulations of test substances A and B are as follows:

[0060] Preparation method of test substances A and B: weigh each component, mix evenly and dissolve until clear, fill into a medium borosilicate glass bottle, and assemble with a nasal spray metering pump.

[0061] Group C quetiapine fumarate tablets were purchased from Hunan Dongting Pharmaceutical Co., Ltd. through common commercial channels.

[0062] The injection in group D was prepared by dissolving quetiapine fumarate in normal saline.

[0063] 3. Test methods

[0064] 3.1 Experimental animals

[0065] Eight healthy adult Beagle dogs, male, weighing 6.5-9.5 kg.

[0066] 3.2 Trial administration

[0067] Two mice in each group were randomly divided into 4 groups. Except for one group that was randomly given intravenous injection of test substance D, the other three groups were given test substances A, B, and C in rotation in each cycle for cross-administration. The administration was given for three cycles in total, and the washout period was 7 days before changing the test substance in each cycle.

[0068] Taking into account the tablet specifications and the saturated solubility concentration of the nasal spray, the oral and intravenous doses in this trial were set at 25 mg / animal, and the nasal spray dose was set at 27.75 mg / animal. Pharmacokinetic parameters were calculated using the same dose correction.

[0069] 3.3 Blood sample collection and processing

[0070] One 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). The plasma was separated by centrifugation at 3200 g for 10 min at 4°C within 2 hours and stored at -80°C until testing.

[0071] Sampling time point:

[0072] C oral group: before administration (0h), 25min, 45min, 1h, 1.5h, 2h, 4h, 6h, 8h, and 12h after administration.

[0073] A, B nasal spray groups and D intravenous injection group: before administration (0h), 5min, 10min, 15min, 30min, 45min, 1h, 4h, 8h, and 12h after administration.

[0074] 3.4 Analysis methods and results

[0075] The drug concentrations in the plasma of Beagle dogs at different time points after administration were measured, and the plasma concentration-time curves were drawn. The main pharmacokinetic parameters were calculated using WinNonlin 8.3 software as follows:

[0076] The results showed that the solution-type nasal spray preparation of the present invention reached peak time T max Significantly shortened, and the maximum blood concentration C max , and bioavailability F were significantly increased to about 20 times and about 6 times, respectively.

[0077] Example 2. Drug efficacy study in a methamphetamine-induced rat hyperlocomotor activity model

[0078] 1. Purpose of the experiment

[0079] The purpose of this experimental study is to evaluate and compare the efficacy of the solution-type nasal administration composition of the present invention and the oral preparation of quetiapine in the methamphetamine-induced high spontaneous activity model of rats.

[0080] 2. Test substance

[0081] The codes for the types of test substances are as follows:

[0082] The formulation compositions of each test substance are as follows:

[0083] Preparation method of each test substance: weigh each component, mix evenly and dissolve until clear.

[0084] 3. Test methods

[0085] 3.1 Experimental animals

[0086] Forty 7-week-old SD rats were randomly divided into four groups of 10 rats each, corresponding to each test substance. They were allowed to acclimate to the experimental environment for one day before testing and to enter the laboratory 1 hour before testing.

[0087] 3.2 Trial administration

[0088] On the day of the test, different groups were given test substances A, B, C, or D according to different administration methods while the animals were awake. Immediately after administration, methamphetamine modeling was performed (intraperitoneal injection). The methamphetamine dosage was 3 mg / kg to induce hyperactivity in the animals.

[0089] 3.3 Phenomenon, spontaneous activity testing and recording

[0090] Any-maze software recorded the distance the animals moved every five minutes to assess spontaneous activity.

[0091] Before administration, the animals were placed in an observation box to detect their spontaneous activity for 60 minutes.

[0092] According to the grouping, after the animals are given the drug, they are placed in an observation box and observed and recorded for 90 minutes. The distance (meters) the animals move in the observation box is counted every 5 minutes, and abnormal phenomena such as toxic reactions or deaths of animals during the experiment are recorded in a timely manner.

[0093] On the second day after the experiment, a cage-side observation was conducted to record the status of each group of experimental animals, to observe whether the activity level returned to normal, whether there were overactive or overly quiet animals, and whether there were any toxic reactions.

[0094] 3.4 Data Collection

[0095] Prism software was used for statistical analysis of data. The movement distances of the animals in each group at different time points were compared using two-way analysis of variance with Bonferroni's multiple comparison test. The total movement distances of the animals in each group were compared using one-way analysis of variance. A significant difference was considered to be present at p < 0.05.

[0096] 4. Experimental Results

[0097] As shown in Figure 1:

[0098] There was no statistical difference in the total distance moved by the animals in the four groups from 0 to 60 minutes after the start of the test.

[0099] After 60 minutes of acclimatization, drug administration was started.

[0100] At 65-110 minutes after the start of the test, the high-dose intranasal drops group of test substance A significantly reduced the distance the animals moved within 5 minutes compared with the blank group of test substance D.

[0101] At 85 and 105-110 minutes after the start of the test, the oral administration of test substance C significantly reduced the distance the animals moved every 5 minutes compared with the blank group of test substance D.

[0102] As shown in Figure 2:

[0103] From 60 to 150 minutes after the start of the test, the total distance traveled by animals in the high-dose intranasal administration group of Test A was significantly reduced compared to the blank group of Test D. However, there was no significant difference in the total distance traveled by animals in the oral administration group of Test C compared to the blank group of Test D.

[0104] Observations at the cages during the experiment and the day after the experiment showed no weight loss, poor mental state, or abnormal activity status of the animals.

[0105] Results showed that the high-dose intranasal administration significantly inhibited methamphetamine-induced hyperlocomotor activity in rats, including both 5-minute distance traveled and total distance traveled. The inhibitory effect was rapid and stable over time. The oral administration only suppressed hyperlocomotor activity at certain times, with a slower onset, weaker inhibition, and shorter duration. Total distance traveled was not significantly different from the control group. The intranasal administration also demonstrated a favorable safety profile.

[0106] Example B: Quetiapine solubilization study of the solution-type nasal composition of the present invention

[0107] 1. Determination of saturated solubility concentration

[0108] The present invention first tested the saturated solubility concentration of common solvents for quetiapine fumarate, as follows:

[0109] The above tests show that the saturated solubility concentration of quetiapine fumarate in water is very low (4.0 mg / mL), and the saturated solubility concentration in some other common solvents such as ethanol is also low.

[0110] The saturated solubility concentration is higher at a moderately lower pH, and the optimal pH for solution is 4.5-6.5. Even with a lower pH, the saturated solubility concentration of quetiapine fumarate remains low, failing to meet the requirements of nasal solution-type formulations.

[0111] 2. Add ethanol, propylene glycol, PEG400, Tween 20, and Span 20 to the saturated solubility concentration

[0112] The present invention further tested the following prescription solvents, and the saturated solubility concentration of quetiapine fumarate was as follows:

[0113] The above prescription solvent test experiments show that although the saturated solubility concentration of quetiapine fumarate can be improved to a certain extent after adding ethanol, propylene glycol, PEG400, Tween 20 and Span 20 to the aqueous solution, the improvement is still limited and it is still difficult to meet the needs of nasal delivery of solution-type preparations.

[0114] 3. Solubilization basic formula design and buffer screening

[0115] The experimental process and results showed that the above formulations improved the saturated solubility concentration of quetiapine fumarate to a certain extent, but the improvement was still limited and still could not meet the requirements of solution-type formulations for nasal delivery. It also showed that different buffer salt types had no significant effect on the saturated solubility concentration, but did have a certain impact on the dissolution rate, with citric acid buffer being relatively superior.

[0116] 4. Study on the effect of adding Tween 20 and PEG3350 on stabilization and preventing precipitation

[0117] The test process and results showed that Tween 20 and PEG3350 both had a good stabilizing effect on the prescription solution and prevented precipitation.

[0118] 5. Study on the effect of adding surfactants and cyclodextrin on solubilization effect

[0119] The experimental process and results showed that the addition of cyclodextrin (HP-β-CD) improved the saturated solubility concentration of quetiapine fumarate to a certain extent, but the improvement was still limited. Surfactants also had a limited effect on the saturated solubility concentration of quetiapine fumarate. Further experiments also showed that the addition of PEG400 and surfactants could stabilize the formulation and prevent precipitation.

[0120] 6. Study on the effect of adding DMA on solubilization effect

[0121] The experimental process and results showed that the addition of DMA significantly increased the saturated solubility concentration of quetiapine fumarate, making it suitable for nasal spray administration. Nasal spray administration with an active ingredient concentration greater than 50 mg / mL can significantly reduce dosing frequency and associated nasal irritation.

[0122] 7. Study on the effect of adding benzyl alcohol on solubilization effect

[0123] The experimental process and results showed that the addition of benzyl alcohol significantly increased the saturated solubility concentration of quetiapine fumarate, exceeding 50 mg / ml, making it suitable for nasal spray administration. The saturated solubility concentration was positively correlated with the amount of benzyl alcohol used. Compared to DMA, the addition of benzyl alcohol to quetiapine fumarate achieved a higher saturated solubility concentration while avoiding the severe nasal irritation associated with DMA.

[0124] 8. Extended study on the solubilization effect of adding benzyl alcohol

[0125] The experimental process and results showed that the addition of benzyl alcohol significantly enhanced the saturated solubility concentration of quetiapine. The addition of various amounts of pectin also maintained a high saturated solubility concentration. When the PEG3350 content was reduced from 15% to 5% of the formulation, the saturated solubility concentration increased significantly, likely due to the excessive PEG3350 occupying the formulation solubility. This increased solubility may be due to the formation of a mixed system with enhanced solubilization capabilities by benzyl alcohol, propylene glycol, and ethanol. Tween 20 and PEG3350 primarily play a stabilizing role in the formulation, inhibiting the precipitation of quetiapine at both high and low temperatures.

[0126] 9. Further preparation and verification of other examples of good solubilization effect of the prescription preparation

[0127] Based on the above solubilization research, the amount of organic solvent used was reduced, and the following quetiapine solution-based nasal spray compositions were further prepared, all of which exhibited high concentrations of the active ingredient. (The concentrations in the table are estimated based on complete dissolution of quetiapine fumarate, and are calculated based on the free base.)

[0128] Example C: Chemical stability study of the solution-type nasal composition of the present invention

[0129] 1. Basic prescription preparation design and stability study

[0130] The chemical stability of the above preparation was investigated at 40°C and 75% RH (Impurity G: Impurity H: ), the detection and analysis data are as follows:

[0131] The results showed that the solution-type nasal administration composition with increased saturated solubility concentration prepared above had good chemical stability.

[0132] 2. Study on the stability of formulations with added surfactants and antioxidants

[0133] Based on the aforementioned C4 formulation, surfactants polyethylene glycol-15-hydroxystearate (HS-15) and Tween 80 were introduced, and the pH of the solution was adjusted with NaOH to investigate its effect on the chemical stability of the formulation.

[0134] The above formulation was tested under long-term (25°C, 75% RH) and accelerated (40°C, 75% RH) conditions. The test results are as follows:

[0135] The results showed that the addition of surfactants HS-15 and Tween 80 maintained controllable formulation stability and did not significantly increase the levels of related substances. However, the introduction of the antioxidant sodium sulfite not only failed to improve stability but also unexpectedly caused a sharp decrease in formulation stability.

[0136] The use of NaOH to adjust the pH does not destroy the chemical stability. When the pH is appropriately increased, the formation of hydrolysis impurity G is inhibited and the chemical stability is improved.

[0137] 3. Study on the stability of the formulation after the introduction of organic base

[0138] Increasing the pH of the formulation can inhibit the growth of impurity G. An attempt was made to replace and introduce the organic base meglumine to increase the pH of the formulation to enhance stability.

[0139] The above formulation was tested for 30 days at long-term (25°C, 75% RH) and accelerated (40°C, 75% RH) conditions. The test and analysis data are as follows:

[0140] The results showed that using the organic base meglumine to increase pH was beneficial to inhibiting the formation of hydrolysis impurity G and improving chemical stability.

[0141] 4. Further expand the stability study of the prescription

[0142] First, stability studies were conducted with or without nitrogen filling, and with changes or additions in the dosage of solubilizer cyclodextrin HP-β-CD, surfactant HS-15, and stabilizer disodium edetate. The formulation was designed as follows:

[0143] The above formulation was tested for 24 days at long-term (25°C, 75% RH) and accelerated (40°C, 75% RH) conditions. The test and analysis data are as follows:

[0144] Results showed that changing or adding the dosage of the solubilizer cyclodextrin HP-β-CD, surfactant HS-15, and stabilizer disodium edetate controlled the formulation stability without significantly increasing the levels of related substances. However, the introduction of the antioxidant sodium bisulfite surprisingly failed to improve quetiapine's antioxidant properties and actually caused a rapid decrease in formulation stability.

[0145] The results also showed that there was no significant difference in the impurity growth rate and content of the two preparations with or without nitrogen filling, which means that stable prescription preparations can be obtained regardless of whether nitrogen filling is used or not.

[0146] Based on the above research, the following formulations were further prepared, which were stable under long-term and accelerated tests. The solution-type nasal composition formulation used in animal studies was also stable.

[0147] The present invention is not limited to the above optional embodiments. Anyone can derive various other forms of products based on the teachings of the present invention. The above specific embodiments should not be construed as limiting the scope of protection of the present invention. The scope of protection of the present invention shall be based on the scope defined in the claims, and the description can be used to interpret the claims.

Claims

1. A composition for intranasal administration of quetiapine, characterized in that: Comprising quetiapine or a pharmaceutically acceptable salt thereof, and the composition is a solution.

2. The composition according to claim 1, wherein: Calculated as the free base, the mass percentage content of quetiapine in the composition is 0.22 - 11.7% or 4.3 - 11.7%. Alternatively, preferably, quetiapine is dissolved in the composition in the form of fumarate, and the mass percentage content of quetiapine fumarate in the composition is 0.25 - 13.4%, 0.25 - 5%, 0.25 - 1.7%, 5 - 13.4%, 5 - 9.7%, 5 - 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: It also includes one or a combination of two or more of solubilizers, cosolvents, thickeners, stabilizers, preservatives, pH regulators and pH buffers.

4. The composition according to claim 3, characterized in that: The solubilizer may optionally include one or a combination of two or more of benzyl alcohol, DMA, cyclodextrin and surfactants. The cyclodextrin may optionally include one or a combination of two or more of β - cyclodextrin, hydroxypropyl - β - cyclodextrin and sulfobutyl - β - cyclodextrin. The surfactant may optionally include one or a combination of two or more of Tween, Span, carbomer and polyethylene glycol - 15 hydroxystearate. The cosolvent may optionally include saturated alcohols, and the saturated alcohols may optionally include one or a combination of two or more of propylene glycol, ethanol and glycerol. The thickener may optionally include one or a combination of two or more of polyethylene glycol, pectin, cellulose, polyethylene hydrocarbons and polyacrylic acid. The stabilizer may optionally include edetates, and the edetates may optionally include EDTA - 2Na and / or EDTA - 2K. The preservative may optionally include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, potassium sorbate, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isopropyl paraben, isobutyl paraben, sodium propyl paraben and / or sodium methyl paraben. The pH regulator may optionally include one or a combination of two or more of citric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide and meglumine. The pH buffer may optionally include one or a combination of two or more of citrate buffer, phosphate buffer and acetate buffer.

5. The composition according to claim 1, wherein: It also includes a solubilizer, a cosolvent, a thickener and water. The solubilizer is benzyl alcohol, and the mass percentage content of benzyl alcohol in the composition may optionally be 1 - 10%, 1 - 9.3%, 5 - 9.3%, 1%, 3.2%, 5%, 7.5% or 9.3%. The cosolvent is one or a combination of two or more of propylene glycol, ethanol, and glycerol, preferably propylene glycol; wherein: the mass percentage content of propylene glycol in the composition can be optionally 0-12%, 4.6-12%, 6-12%, 4.6%, 4.7%, 5%, 6%, 10%, 11%, or 12%, the mass percentage content of ethanol in the composition can be optionally 0-20%, 6-20%, 0-19.8%, 18.3-19.8%, 6%, 10%, 18.3%, 18.5%, or 19.8%, and the mass percentage content of glycerol in the composition can be optionally 0-5%, 0-3%, 0-2.5%, 0-2.2%, or 2.2%; The thickener is polyethylene glycol, preferably PEG3350 or PEG400; wherein: the mass percentage content of PEG3350 in the composition can be optionally 0-20%, 2.5%-15%, 5-15%, 2.5%, 4.6%, 4.7%, 5%, 15%, or 20%, and the mass percentage content of PEG400 in the composition can be optionally 0-15%, 10%, or 15%.

6. The composition according to claim 5, characterized in that: It also includes one or a combination of two or more of a stabilizer, a preservative, a pH regulator, and a pH buffer; The stabilizer is EDTA-2Na, and the mass percentage content of EDTA-2Na in the composition can be optionally 0-0.1% or 0.05%; The preservative is benzalkonium chloride, and the mass percentage content of benzalkonium chloride in the composition can be optionally 0-0.02% or 0.02%; The pH regulator is one or a combination of two or more of citric acid, hydrochloric acid, sodium hydroxide, and meglumine, and the pH regulator adjusts the pH value of the composition to 4.1-6.0, 4.5-6.0, 5.0-6.0, 4.1, 4.5, 4.9, 5.0, 5.1, 5.3, or 6.0; The pH buffer is a citrate buffer, a phosphate buffer, or an acetate buffer.

7. A nasal administration composition for increasing the dissolution concentration of quetiapine, characterized in that: It includes quetiapine or a pharmaceutically acceptable salt thereof, the composition is a solution, and it also includes a solubilizer.

8. The composition according to claim 7, characterized in that: The solubilizer includes one or a combination of two or more of benzyl alcohol, DMA, cyclodextrin, and a surfactant.

9. The composition according to claim 7, wherein: The solubilizer includes benzyl alcohol and / or DMA.

10. The composition according to claim 7, characterized in that: The solubilizer includes benzyl alcohol, and the mass percentage content of benzyl alcohol in the composition can be optionally 1-10%, 3.2-10%, 5-10%, 5-9.3%, 5-7.5%, 1%, 3.2%, 5%, 7.5%, 9.3%, or 10%; optionally, the mass ratio of benzyl alcohol to quetiapine in the composition is 1:0.8 to 1.

2.

11. The composition according to claim 10, wherein: The solubilizer in the composition can be only benzyl alcohol, or the solubilizer in the composition can be only benzyl alcohol and cyclodextrin, or the solubilizer in the composition can be only benzyl alcohol and a surfactant, or the solubilizer in the composition can be only benzyl alcohol, cyclodextrin, and a surfactant.

12. The composition according to claim 10, wherein: It also includes a cosolvent, and the cosolvent can optionally include a saturated alcohol, and the saturated alcohol can optionally include one or a combination of two or more of propylene glycol, ethanol, and glycerol, and the saturated alcohol is preferably propylene glycol, or a combination of propylene glycol and ethanol; Among them: the mass percentage content of propylene glycol in the composition can be optionally 0-12%, 4.6-12%, 6-12%, 4.6%, 4.7%, 5%, 6%, 10%, 11% or 12%; The mass percentage content of ethanol in the composition can be optionally 0-20%, 6-20%, 0-19.8%, 18.3-19.8%, 6%, 10%, 18.3%, 18.5% or 19.8%; The mass percentage content of glycerol in the composition can be optionally 0-5%, 0-3%, 0-2.5%, 0-2.2% or 2.2%.

13. The composition according to claim 10, characterized in that: It also includes a surfactant and / or polyethylene glycol, preferably it also includes one or a combination of more than two of Tween, PEG3350 and PEG400, and Tween includes Tween 80 or Tween 20; Among them: the mass percentage content of PEG3350 in the composition can be optionally 0-20%, 2.5%-15%, 5-15%, 2.5%, 4.6%, 4.7%, 5%, 15% or 20%; The mass percentage content of PEG400 in the composition can be optionally 0-15%, 10% or 15%; The mass percentage content of Tween in the composition can be optionally 0-1.5%, 0.5%, 1%, 1.4% or 1.5%.

14. The composition according to claim 8, characterized in that: Cyclodextrin includes one or a combination of more than two of β-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin, and the mass percentage content of cyclodextrin in the composition can be optionally 0-10%, 1-5% or 5%.

15. The composition according to claim 7, wherein: Calculated as the free base, the dissolution concentration of quetiapine in the composition is 4.3-11.7% or 5.6-11.7% by mass percentage; Or, preferably, quetiapine is dissolved in the composition in the form of fumarate, and the mass percentage content of quetiapine fumarate in the composition is 5-13.4%, 5-9.7%, 5-7%, 5%, 5.2%, 6%, 6.5%, 6.6%, 6.7%, 7%, 8.2%, 9.5%, 9.7%, 13%, 13.3% or 13.4%.

16. The composition according to any one of claims 7-15, characterized in that: It also includes water, and one or a combination of more than two of a thickening agent, a stabilizer, a preservative, a pH regulator and a pH buffer.

17. A stable composition for nasal administration, characterized in that, The composition is a solution, comprising water and the following components:

18. The composition according to claim 17, wherein: Calculated as the free base, the mass percentage content of quetiapine in the composition is 4.3-11.7%; Or, preferably, quetiapine is dissolved in the composition in the form of fumarate, and the mass percentage content of quetiapine fumarate in the composition is 0.25-13.4%, 0.25-5%, 0.25-1.7%, 5-13.4%, 5-9.7%, 5-7%, 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%.

19. The composition according to claim 17, wherein: The solubilizer includes one or a combination of more than two of benzyl alcohol, cyclodextrin, Tween and polyethylene glycol-15 hydroxystearate, cyclodextrin can optionally include hydroxypropyl-β-cyclodextrin, and Tween can optionally include Tween 80 and / or Tween 20; Among them: the mass percentage content of benzyl alcohol in the composition can be optionally 1-10%, 1-9.3%, 5-9.3%, 1%, 3.2%, 5%, 7.5% or 9.3%; the mass percentage content of cyclodextrin in the composition can be optionally 0-5% or 5%; the mass percentage content of Tween in the composition can be optionally 0-1.4%, 1% or 1.4%; the mass percentage content of polyethylene glycol-15 hydroxystearate in the composition can be optionally 0-3%, 1.5% or 3%.

20. The composition according to claim 17, wherein: The co-solvent includes one or a combination of two or more of propylene glycol, ethanol and glycerol; Among them: the mass percentage content of propylene glycol in the composition can be optionally 0-12%, 4.6-12%, 6-12%, 4.6%, 4.7%, 6%, 11% or 12%; the mass percentage content of ethanol in the composition can be optionally 0-20%, 0-19.8%, 18.3-19.8%, 18.3%, 18.5% or 19.8%; the mass percentage content of glycerol in the composition can be optionally 0-5%, 0-3%, 0-2.5%, 0-2.2% or 2.2%.

21. The composition according to claim 17, wherein: The thickener includes polyethylene glycol and / or pectin, and the polyethylene glycol can optionally include PEG3350 and / or PEG400; Among them: the mass percentage content of PEG3350 in the composition can be optionally 0-5%, 2.5%-5%, 2.5%, 4.6%, 4.7% or 5%; the mass percentage content of PEG400 in the composition can be optionally 0-15% or 15%; the mass percentage content of pectin in the composition can be optionally 0-1% or 0.7%.

22. The composition according to claim 17, wherein It also includes any one of the following components or a combination of two or more:

23. The composition according to claim 22, wherein: The stabilizer includes edetate, and the edetate includes disodium edetate and / or dipotassium edetate. The mass percentage content of disodium edetate in the composition can be optionally 0-0.1% or 0.05%; The preservative includes benzalkonium chloride, and the mass percentage content of benzalkonium chloride in the composition can be optionally 0-0.02% or 0.02%; The pH regulator includes one or a combination of two or more of sodium hydroxide, potassium hydroxide, meglumine, citric acid and hydrochloric acid. The addition amount of the pH regulator can be optionally an amount that adjusts the pH of the composition to 4.1-6.0, 4.5-6.0, 5.0-6.0, 4.1, 4.5, 4.9, 5.0, 5.1, 5.3 or 6.

0. Among them, the mass percentage content of meglumine in the composition can be optionally 0-0.5%, 0.02%, 0.25% or 0.5%, and the citric acid can be 1M citric acid solution.

24. The composition according to claim 23, wherein the composition further optionally adds or does not add a pH buffer, and the pH buffer can optionally include one or a combination of two or more of citrate buffer, phosphate buffer and acetate buffer.

25. The composition according to claim 17, wherein: The composition does not contain sodium sulfite and sodium bisulfite.

26. The composition according to claim 17, wherein: the composition consists of quetiapine fumarate, solubilizer, cosolvent, thickener and water, the solubilizer is benzyl alcohol, the cosolvent is one or a combination of two or more of propylene glycol, ethanol and glycerol, preferably propylene glycol, the thickener is PEG3350 and / or PEG400; the composition further optionally contains or does not contain one or a combination of two or more of benzalkonium chloride, pH regulator and pH buffer.

27. A quetiapine nasal spray, comprising the composition according to any one of claims 1-26 and a metered nasal spray device for delivering the composition into the nasal cavity, and the volume of the composition delivered per spray by the metered nasal spray device can be selected from 25-200 μL, 50-150 μL, 25 μL, 50 μL, 75 μL, 100 μL, 125 μL, 150 μL, 175 μL or 200 μL.

28. Use of the composition according to any one of claims 1-26 or the quetiapine nasal spray according to claim 27 in the preparation of a drug for treating mental diseases.

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