WO2025140529A1 - Solution-type quetiapine composition for transnasal administration and use thereof - Google Patents

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

The invention belongs to the technical field of pharmaceutical preparations, in particular to the field of quetiapine pharmaceutical preparations, and specifically to a novel composition for nasal administration and application thereof.

Background Art

Quetiapine is a new atypical drug for the treatment of psychiatric disorders. The mechanism of action of quetiapine may be to exert its therapeutic effect by antagonizing central D2 receptors and 5-HT2A receptors. Around 1997, AstraZeneca promoted the first launch of quetiapine tablets in the United States. The current approved indications for tablets involve "schizophrenia, bipolar depression, bipolar I mania or mixed symptoms", and the listed specifications of tablets are 25mg, 50mg, 100mg, 200mg, 300mg, and 400mg. Around 2009, quetiapine sustained-release tablets were first launched in the United States. The current approved indications involve "schizophrenia, bipolar depression, bipolar I mania or mixed symptoms, and adjuvant treatment of major depressive disorder", and the listed specifications of sustained-release tablets are 50mg, 150mg, 200mg, 300mg, and 400mg.

The quetiapine tablets and sustained-release tablets that have been 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, absorption and onset of action, 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.

Therefore, there is still an unmet clinical demand for improved tablets and sustained-release tablets that have been marketed. Although there is such an obvious demand, even though the bioavailability of oral quetiapine is only about 10%, there is still no improved drug with good prospects on the market in the more than 20 years since quetiapine was first marketed. Moreover, in the past 20 years, most of the research literature on quetiapine in the industry has focused on the synthesis, tablets, sustained-release tablets or dispersible tablets of quetiapine, while there are few reports on the more substantial improvement research to solve the clinical defects of oral preparations.

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 dosage of the drug can be reduced, and the clinical safety risks of adverse drug reactions and high-dose medication can be reduced. Nevertheless, considering that the patients of quetiapine are patients with mental illnesses, their disease attacks are often accompanied by acute, manic and other characteristics, and the pain and other discomfort caused by injection at this time may aggravate the patient's tension and produce an emergency response. In addition, injection administration also requires higher medical skills, which is not convenient for patients to apply it by themselves, and the applicable scenarios are limited.

Indian patent applications represented by IN202211053155A provide a nanoemulsion that 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 of the liver and improve bioavailability. The "Bioavailability and biodistribution studies" section in the patent shows that compared with oral preparations, the C _max and AUC _0-480 of the provided nanoemulsion after nasal administration are significantly improved (Table.11).

However, even so, in the form of nanoemulsion preparation, since the drug quetiapine is dissolved in the oil phase, after administration, the drug still faces the crossing from the oil phase to the water phase during the absorption process. Since the saturated solubility concentration of quetiapine in the water phase is low, this leads to the extension of the peak and onset time of the nanoemulsion. For the same reason as oral preparations, this extension of the peak and onset time is not conducive to the rapid relief of some acute symptoms of mental illness. The characteristics of this nanoemulsion are also recorded in the "In-Vitro Drug Release Studies" section of the Indian patent, as shown in Table.10 and figure.6 and its analysis conclusions, "Diffusion from the oily core and interface is hindered by the aqueous medium. Since the saturated solubility concentration of quetiapine in water is very low, it has an obstructive effect on drug transport." Similarly, in Table 11 of the "Bioavailability and biodistribution studies" section of the Indian patent, the nasal nanoemulsion has the same peak blood drug concentration time T _max = 2h as the oral preparation (both are much shorter than 0.25h for injection), which is also mutually confirmed by the data and conclusions in the aforementioned in vitro studies.

From the above, we can see that in the field of quetiapine drug research: first, there are few studies on significant improvements to solve the clinical defects of oral preparations of marketed products. Secondly, the improvements provided in these rarely disclosed literature studies are still difficult to solve clinical defects similar to those of oral preparations. In this context, how to provide an improved form of quetiapine to solve the defects of marketed oral dosage forms and meet unmet urgent clinical needs is still a problem to be solved.

Summary of the invention

In order to solve the above problems existing in the prior art, the primary purpose of the present invention is to provide an improved form of quetiapine, which should have a rapid peak or onset time compared to the marketed oral dosage form, and is easy to use and has strong patient compliance. At the same time, the novel improved form should also have a high bioavailability to avoid the problem of low bioavailability of oral preparations, which requires large doses and brings clinical safety risks.

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

A composition for nasal administration of quetiapine, comprising quetiapine or a pharmaceutically acceptable salt thereof, wherein the composition 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 is surprisingly found that the present invention formulates quetiapine into a solution type and simultaneously administers it via the nose, which can significantly shorten the peak onset time, such as a significant shortening of _Tmax . At the same time, formulating quetiapine into a solution type and simultaneously administering it via the nose can also take into account the achievement of significantly improved bioavailability, which is not available in conventional improvements.

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

In some embodiments, the mass 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, 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%.

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, or a combination of two or more thereof. Wherein: 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. Cosolvents may optionally include saturated alcohols, and saturated alcohols may optionally include a combination of one or more of propylene glycol, ethanol, and glycerol. Viscosifiers may optionally include a combination of one or more of polyethylene glycol, pectin, cellulose, polyethylene hydrocarbon, and polyacrylic acid. Stabilizers may optionally include edetate, and edetate may optionally include EDTA-2Na and/or EDTA-2K. Preservatives may include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, potassium sorbate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, isopropyl parahydroxybenzoate, isobutyl parahydroxybenzoate, sodium propyl parahydroxybenzoate and/or sodium methyl parahydroxybenzoate. pH regulators may include one or more combinations of citric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide and meglumine. pH buffers may include one or more combinations of citrate buffers, phosphate buffers and acetate buffers.

In other embodiments, the solution-type quetiapine nasal administration 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 to 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 of propylene glycol in the composition can be selected as 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 as 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 as 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%.

In other embodiments, the solution-type quetiapine nasal administration composition further comprises a stabilizer, a preservative, a pH regulator and a pH buffer, one or a combination of two or more thereof. Wherein: the stabilizer is EDTA-2Na, and the mass percentage of EDTA-2Na in the composition can be selected as 0-0.1% or 0.05%. The preservative is benzalkonium chloride, and the mass percentage of benzalkonium chloride in the composition can be selected as 0-0.02% or 0.02%. The pH regulator is a combination of one or more of citric acid, hydrochloric acid, sodium hydroxide and meglumine, and the pH value of the pH regulator adjusting the composition is 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.

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.

Limited by the area of the nasal mucosa, the single dosing volume during nasal administration cannot be too high. If the dosing volume is too high, the excess liquid medicine cannot be adsorbed by the nasal mucosa, and will flow out of the nasal cavity or even enter the throat through the nasopharynx. It cannot be absorbed and takes effect, and brings uncomfortable dosing feelings and unnecessary side effects. The single dosing volume of nasal spray is usually no more than 200μL, and it is generally best to keep it no more than 100μL. When delivered in a "solution type" with such a small dosing volume, the active ingredient of the drug needs to have a higher solubility concentration to ensure the dosage. At the same time, high concentration also avoids multiple dosing and reduces irritation to the nasal cavity. According to tests, quetiapine is 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 means to increase the saturated solubility concentration of quetiapine.

The second object of the present invention is achieved by the following technical solutions:

A composition for nasal administration with improved 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.

The present invention has found in further research and exploration that for the poorly soluble quetiapine, it is relatively easy to increase the saturated solubility concentration of quetiapine to about 20 mg/mL by using a common solubilization method. However, on this basis, it becomes increasingly difficult to further increase the saturated solubility concentration of quetiapine, especially to increase it to more than 50 mg/mL. In order to deliver therapeutic dose drugs under a smaller administration volume, it is advantageous or even necessary to increase the drug concentration to more than 50 mg/mL. In the extensive testing of the present invention, it is surprisingly found that the use of solubilizing agent benzyl alcohol or DMA is very beneficial for increasing the saturated solubility concentration of quetiapine to a higher concentration of more than 50 mg/mL.

In particular, the use of benzyl alcohol as a solubilizing agent has a particularly surprising beneficial effect. While significantly improving the saturated solubility concentration of quetiapine, it also takes into account the lower nasal mucosal irritation than other solubilizing agents represented by DMA (benzyl alcohol is also an inactive ingredient excipient included in the "FDA Drug Inactive Ingredient Database" and allowed to be applicable to the nasal spray administration route, and its irritation and safety of the nasal route have been recognized by regulatory verification), and is very suitable as a solubilizing agent 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, and in the solution-type quetiapine nasal composition of the present invention, the addition of benzyl alcohol unexpectedly has a significant and beneficial help to the improvement of the saturated solubility concentration of quetiapine. Therefore, benzyl alcohol is used as the most preferred solubilizing agent for the solution-type quetiapine nasal administration composition provided by the present invention. On this basis, in other schemes, 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 only contain benzyl alcohol, or the solubilizer in the composition may only contain benzyl alcohol and cyclodextrin, or the solubilizer in the composition may only contain benzyl alcohol and a surfactant, or the solubilizer in the composition may only contain benzyl alcohol, cyclodextrin and a surfactant.

In other embodiments, in the composition provided by the second object, the mass 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%. According to the amount of quetiapine added in the composition, the amount of benzyl alcohol added can fluctuate within ±20% of the amount of quetiapine added, that is, preferably, the mass ratio of benzyl alcohol to quetiapine in the composition is 1:0.8-1.2.

In other schemes, the solution-type nasal administration composition for improving the dissolution concentration of quetiapine of the present invention also includes a cosolvent, which can optionally include a saturated alcohol, and the saturated alcohol can optionally include one or more combinations of propylene glycol, ethanol and glycerol, and 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 dissolution 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 can be selected as 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 as 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%.

In other embodiments, the solution-type nasal administration composition for improving the solubility concentration of quetiapine of the present invention further includes a surfactant and/or polyethylene glycol, preferably also includes one or more combinations of Tween, PEG3350 and PEG400, and Tween includes Tween 80 or Tween 20. The addition of these additional substances can further stabilize the solution system, especially inhibit the accidental precipitation of quetiapine under high or low temperature conditions. Among them, from the specific embodiments provided by the present invention: 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%. The mass percentage of PEG400 in the composition can be selected as 0-15%, 10% or 15%. The mass percentage of Tween in the composition can be selected as 0-1.5%, 0.5%, 1%, 1.4% or 1.5%.

In other embodiments, the solution-type nasal administration composition for improving the dissolution concentration of quetiapine of the present invention further comprises cyclodextrin, which comprises one or a combination of two or more of β-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin, and the mass percentage of cyclodextrin in the composition can be selected as 0-10%, 1-5% or 5%. Cyclodextrin has a certain improvement on the saturated dissolution concentration of the quetiapine solution composition, but when used alone, it is not as effective as benzyl alcohol or DMA.

In other embodiments, in the solution-type nasal administration composition for improving the dissolution concentration of quetiapine of the present invention, the dissolution concentration of quetiapine in the composition is 4.3-11.7% by mass as a free base. In particular, the dissolution concentration of quetiapine free base is 5.6-11.7% by mass. As shown in the specific embodiments provided by the present invention, quetiapine is preferably dissolved in the composition in the form of fumarate, and the mass percentage 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%. The higher active ingredient concentration is particularly suitable for nasal spray administration, which can significantly reduce the number of nasal sprays during single treatment, thereby reducing frequent stimulation of the nasal cavity and alleviating clinical medication discomfort and side effects such as sneezing and tingling.

In other embodiments, the solution-type nasal administration composition for increasing the solubility concentration 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 object of the present invention of "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 primary object of the present invention.

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.

The third object of the present invention is achieved by the following technical solutions:

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

In some embodiments, in the stable solution-type quetiapine composition for nasal administration, the mass percentage of quetiapine in the composition is 4.3-11.7% based on the free base. As shown in the specific embodiments provided by the present invention, quetiapine is preferably dissolved in the composition in the form of fumarate, 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%.

In other embodiments, the solubilizer in the stable solution-type quetiapine nasal administration composition includes one or a combination of two or more of benzyl alcohol, cyclodextrin, Tween and polyethylene glycol-15 hydroxystearate, cyclodextrin may include hydroxypropyl-β-cyclodextrin, and Tween may include Tween 80 and/or Tween 20. Derived from the specific embodiments provided by the present invention, wherein: 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%.

In other embodiments, the cosolvent in the stable solution-type quetiapine nasal administration composition includes one or a combination of two or more of propylene glycol, ethanol and glycerol. Derived from the specific embodiments provided by the present invention, the mass percentage of propylene glycol in the composition can be selected as 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 selected as 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 selected as 0-5%, 0-3%, 0-2.5%, 0-2.2% or 2.2%.

In other embodiments, the viscosity enhancer in the stable solution-type quetiapine nasal administration composition includes polyethylene glycol and/or pectin, and the polyethylene glycol may include PEG3350 and/or PEG400. Derived from the specific embodiments provided by the present invention, 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%.

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:

In other embodiments, the stabilizer in the stable solution-type quetiapine nasal administration composition includes edetate, which includes 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 includes benzalkonium chloride, and the mass percentage of benzalkonium chloride in the composition can be 0-0.02% or 0.02%.

In other embodiments, the pH adjuster in the stable solution-type quetiapine nasal composition includes 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.

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.

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

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.

In other embodiments, the stable solution-type quetiapine nasal administration composition consists only of quetiapine fumarate, a solubilizer, a cosolvent, a viscosity enhancer and water, and does not contain other unspecified components except for the pharmaceutically acceptable impurity content, and the solubilizer is benzyl alcohol, the cosolvent is one or a combination of two or more of propylene glycol, ethanol and glycerol, in particular propylene glycol, and the viscosity enhancer is PEG3350 and/or PEG400. Optionally, the composition may also be optionally added with or without one or a combination of two or more of benzalkonium chloride, a pH adjuster and a pH buffer.

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

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 administration 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

Fig. 1 is the movement distance of the experimental rats every 5 minutes from 0 to 150 minutes after the start of the test in Example A Example 2, and the data are expressed as Mean ± SEM, using 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);

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 one-way ANOVA was used (comparison of test substance A with test substance D, * indicates p<0.05).

DETAILED DESCRIPTION

The percentage "%" appearing in various places in the present invention refers to the mass percentage unless otherwise specified.

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.

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".

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

The meanings of the abbreviations in this invention are in accordance with the common understanding of the industry. Some of the terms are annotated as follows:
IN: intranasal administration;
PO: oral;
IV: intravenous;
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 ethylenediaminetetraacetic acid;
EDTA-2K: Edetic acid dipotassium, also known as ethylenediaminetetraacetic acid dipotassium;
DMA: N,N-dimethylacetamide.

The present invention will be further explained below in conjunction with the accompanying drawings and specific embodiments.

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

Example 1. In vivo pharmacokinetic study in beagle dogs

1. Purpose of the experiment

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 injections after administration to beagle dogs.

2. Test substances

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

The formulation compositions of test substances A and B are as follows:

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.

Group C quetiapine fumarate tablets were purchased from Hunan Dongting Pharmaceutical Co., Ltd. through ordinary commercial channels.

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

3. Test methods

3.1 Experimental animals

Healthy adult Beagle dogs, 8 males, weighing 6.5-9.5 kg.

3.2 Trial administration

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, with a 7-day washout period before changing the test substance in each cycle.

Taking into account the specifications of the tablets and the saturated solubility concentration of the nasal spray, the dosage of the oral group and the intravenous injection group was set at 25 mg/piece, and the dosage of the nasal spray group was set at 27.75 mg/piece. The dosage was corrected to the same dosage for calculation of pharmacokinetic parameters.

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 min at 4°C within 2 hours to separate the plasma, and the plasma was stored at -80°C until testing.

Sampling time point:

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

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.

3.4 Analysis methods and results

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

The results showed that the solution-type nasal spray preparation of the present invention significantly shortened the peak time T _max compared with the marketed tablets, and significantly increased the maximum blood drug concentration C _max and bioavailability F to about 20 times and about 6 times, respectively.

Example 2. Drug efficacy study in the methamphetamine-induced rat hyperlocomotor activity model

1. Purpose of the experiment

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 rat high spontaneous activity model.

2. Test substances

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

The formulation compositions of each test substance are as follows:

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

3. Test methods

3.1 Experimental animals

Forty 7-week-old SD rats were randomly divided into four groups, 10 in each group, corresponding to each test substance. They were allowed to adapt to the experimental environment for one day before the test and enter the laboratory 1 hour in advance on the test day.

3.2 Trial administration

On the test day, different groups were given test substances A, B, C or D in different ways 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.

3.3 Phenomena, spontaneous activity testing and recording

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

Before the animals were dosed, they were placed in an observation box to monitor their spontaneous activity for 60 minutes.

According to the grouping, the animals were placed in an observation box after drug administration and observed and recorded for 90 minutes. The distance (meters) the animals moved in the observation box was counted every 5 minutes, and abnormal phenomena such as toxic reactions or deaths of animals during the experiment were recorded in a timely manner.

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 overly active or overly quiet animals, and whether there were any toxic reactions.

3.4 Data Collection

Prism software was used for statistical analysis of the data. The movement distance of each group of animals at different time points was compared using two-way analysis of variance with Bonferroni multiple comparison test data. The total movement distance of each group of animals was compared using one-way analysis of variance. p < 0.05 was considered to be a significant difference.

4. Experimental Results

As shown in Figure 1:

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

After 60 minutes of acclimatization, drug administration was started.

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 every 5 minutes compared with the blank group of test substance D.

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

As shown in Figure 2:

At 60-150 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 blank 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.

Observations at the cages during the experiment and the next day after the experiment showed that no weight loss, adverse mental state, or abnormal activity status of the animals was observed.

The results showed that the high-dose intranasal drop group significantly inhibited the high spontaneous activity behavior of rats induced by methamphetamine, including the 5-minute moving distance and the total distance, and had the significant inhibitory advantages of rapid onset of inhibition and long-term stability. The oral group was able to inhibit high spontaneous activity only at certain times, with a slower onset, weaker inhibition, and shorter duration, and there was no significant difference in total movement distance from the control. The intranasal drop group also showed good safety.

Example B: Quetiapine solubilization study test of the solution-type nasal administration composition of the present invention

1. Determination of saturated dissolved concentration

The present invention firstly tests the saturated solubility concentration of common solvents for quetiapine fumarate, as follows:

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.

The saturated solubility concentration is higher at a moderately lower pH, and the optimal pH for the solution type is 4.5-6.5. Even if the pH value is controlled at a lower level, the saturated solubility concentration of quetiapine fumarate is still at a low level, which cannot meet the needs of nasal delivery of solution-type preparations.

2. Add ethanol, propylene glycol, PEG400, Tween 20, and Span 20 to the saturated solution concentration

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

The above prescription solvent test experiments show that although the saturated solubility concentration of quetiapine fumarate is 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.

3. Solubilization basic formula design and buffer screening

The test process and results show that the above preparations have a certain improvement in the saturated solubility concentration of quetiapine fumarate, but the improvement is still limited and still difficult to meet the needs of nasal delivery solution preparations. It also shows that different types of buffer salts have no obvious effect on the saturated solubility concentration, but have a certain effect on the dissolution rate, and citric acid buffer is relatively better.

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

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

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

The test process and results show that the addition of cyclodextrin (HP-β-CD) has a certain improvement on the saturated solubility concentration of quetiapine fumarate, but the improvement is still limited. Surfactants have limited improvement on the saturated solubility concentration of quetiapine fumarate. Further tests also show that the addition of PEG400 and surfactants can stabilize the prescription and prevent precipitation.

6. Study on the effect of adding DMA on solubilization effect

The test process and results show that the addition of DMA significantly increases the saturated solubility concentration of quetiapine fumarate, making it suitable for nasal spray administration. An active ingredient concentration greater than 50 mg/mL for nasal spray administration can significantly reduce the frequency of administration and thus reduce the corresponding nasal irritation.

7. Study on the effect of adding benzyl alcohol on solubilization effect

The test process and results show that the addition of benzyl alcohol significantly increases the saturated solubility concentration of quetiapine fumarate, exceeding 50 mg/ml, which is suitable for nasal spray administration. The saturated solubility concentration is positively correlated with the amount of benzyl alcohol used. Compared with DMA, the addition of benzyl alcohol to benzyl alcohol achieves a higher saturated solubility concentration while avoiding the defect of DMA's strong nasal irritation.

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

The test process and results show that the addition of benzyl alcohol can significantly enhance the saturated solubility concentration of quetiapine. The addition of different amounts of pectin can also maintain a high saturated solubility concentration. When the PEG3350 is reduced from 15% to 5% of the prescription, the saturated solubility concentration increases significantly, which may be because the excessive PEG3350 occupies the prescription solubility. The possible reason for the increase in the solubility of the above prescription is that benzyl alcohol, propylene glycol and ethanol form a mixed system with stronger solubilization ability. Tween 20 and PEG3350 mainly play a stabilizing role in the prescription preparation, inhibiting the precipitation of quetiapine under high and low temperature conditions.

9. Further preparation and verification of other examples of prescription preparations with good solubilization effects

On the basis of the above solubilization exploration research summary, the amount of organic solvent used was reduced, and the following nasal spray preparations of quetiapine solution-type nasal administration compositions were further prepared, all of which had good high active ingredient concentrations. (The concentrations in the table are estimated based on the complete dissolution of quetiapine fumarate, and the estimated concentrations are based on free base).

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

1. Basic prescription preparation design and stability study

The chemical stability of the above preparations was investigated at 40°C and 75% RH (impurity G: Impurity H: ), the test and analysis data are as follows:

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

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

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.

The above prescription was tested in long-term (25°C, 75% RH) and accelerated (40°C, 75% RH) tests. The test and analysis data are as follows:

The results showed that the stability of the formulation with the addition of surfactants HS-15 and Tween 80 was controllable and did not lead to a significant increase in related substances. However, the introduction of the antioxidant sodium sulfite not only failed to improve the stability, but also unexpectedly caused the stability of the formulation to drop sharply.

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.

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

Increasing the pH of the formulation can inhibit the growth of impurity G. Try replacing the introduction of organic base meglumine to increase the pH of the formulation to enhance stability.

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

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.

4. Further expand the stability study of the prescription

Firstly, the stability study was conducted with or without nitrogen filling, changing or adding the dosage of solubilizer cyclodextrin HP-β-CD, surfactant HS-15, and stabilizer disodium edetate. The formulation was designed as follows:

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

The results showed that by changing or adding the dosage of solubilizer cyclodextrin HP-β-CD, surfactant HS-15, and stabilizer disodium edetate, the stability of the prescription was controllable and did not lead to a significant increase in related substances. However, the introduction of the antioxidant sodium bisulfite surprisingly did not improve the antioxidant properties of quetiapine, but instead caused the stability of the prescription to drop rapidly.

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 with or without nitrogen filling.

Based on the above research, the following prescription preparations were further prepared, which were stable under long-term and accelerated test observations. The solution-type nasal administration composition preparation used in animal test research was also stable.

The present invention is not limited to the above optional implementations, and anyone can derive other various forms of products under the enlightenment of the present invention. The above specific implementations should not be understood as limiting the scope of protection of the present invention. The scope of protection of the present invention should be based on the definition in the claims, and the description can be used to interpret the claims.

Claims (28)

A composition for nasal administration of quetiapine, characterized in that it comprises quetiapine or a pharmaceutically acceptable salt thereof, and the composition is a solution. The composition according to claim 1, characterized in that: the mass 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 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%. The composition according to claim 1, characterized in that it also includes one or a combination of two or more of a solubilizer, a co-solvent, a viscosity enhancer, a stabilizer, a preservative, a pH adjuster and a pH buffer. The composition according to claim 3, characterized in that: The solubilizer may include one or more of benzyl alcohol, DMA, cyclodextrin and surfactant, the cyclodextrin may include one or more of β-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin, and the surfactant may include one or more of Tween, Span, carbomer and polyethylene glycol-15 hydroxystearate; The cosolvent may optionally include saturated alcohol, and the saturated alcohol may optionally include one or a combination of two or more of propylene glycol, ethanol and glycerol; The viscosity enhancer may include one or a combination of two or more of polyethylene glycol, pectin, cellulose, polyethylene hydrocarbon and polyacrylic acid; The stabilizer may optionally include edetate, and the edetate may optionally include EDTA-2Na and/or EDTA-2K; Preservatives may include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, potassium sorbate, methylparaben, ethylparaben, propylparaben, butylparaben, isopropylparaben, isobutylparaben, sodium propylparaben and/or sodium methylparaben; The pH adjuster may include one or a combination of two or more of citric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide and meglumine; The pH buffer may include one or a combination of two or more of a citrate buffer, a phosphate buffer and an acetate buffer. The composition according to claim 1, characterized in that it also includes a solubilizer, a co-solvent, a viscosity enhancer and water; The solubilizer is benzyl alcohol, and the mass percentage of benzyl alcohol in the composition can be selected to 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 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%. The composition according to claim 5, characterized in that it 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 mass percentage of EDTA-2Na in the composition can be selected to be 0-0.1% or 0.05%; The preservative is benzalkonium chloride, and the mass percentage of benzalkonium chloride in the composition can be selected to be 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 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. A composition for nasal administration with improved dissolution concentration of quetiapine, characterized in that it comprises quetiapine or a pharmaceutically acceptable salt thereof, the composition is a solution, and further comprises a solubilizing agent. The composition according to claim 7, characterized in that the solubilizer comprises one or a combination of two or more of benzyl alcohol, DMA, cyclodextrin and a surfactant. The composition according to claim 7, characterized in that the solubilizer comprises benzyl alcohol and/or DMA. The composition according to claim 7, characterized in that: the solubilizer comprises benzyl alcohol, and the mass percentage of benzyl alcohol in the composition can be selected as 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 1:0.8-1.2. The composition according to claim 10, characterized in that: The solubilizer in the composition may be only benzyl alcohol, Alternatively, the solubilizer in the composition may be only benzyl alcohol and cyclodextrin, Alternatively, the solubilizer in the composition may be only benzyl alcohol and a surfactant, Alternatively, the solubilizer in the composition may be only benzyl alcohol, cyclodextrin and surfactant. The composition according to claim 10, characterized in that: it also includes a co-solvent, the co-solvent may optionally include a saturated alcohol, the saturated alcohol may 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; Wherein: the mass percentage of propylene glycol in the composition can be selected as 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 as 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%. The composition according to claim 10, characterized in that: it further comprises a surfactant and/or polyethylene glycol, preferably further comprises one or a combination of two or more of Tween, PEG3350 and PEG400, and Tween comprises Tween 80 or Tween 20; 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%; The mass percentage of PEG400 in the composition can be selected as 0-15%, 10% or 15%; The mass percentage of Tween in the composition can be selected as 0-1.5%, 0.5%, 1%, 1.4% or 1.5%. The composition according to claim 8 is characterized in that the cyclodextrin includes one or a combination of two or more of β-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin, and the mass percentage of cyclodextrin in the composition can be selected as 0-10%, 1-5% or 5%. The composition according to claim 7, characterized in that: the dissolved concentration of quetiapine in the composition is 4.3-11.7% or 5.6-11.7% by mass based on the free base; Alternatively, preferably, quetiapine is dissolved in the composition in the form of a fumarate salt, and the mass percentage 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%. The composition according to any one of claims 7 to 15, characterized in that it further comprises 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. A stable composition for nasal administration, characterized in that the composition is a solution, comprising water and the following components:
The composition according to claim 17, characterized in that: the mass percentage of quetiapine in the composition is 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 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%. The composition according to claim 17, characterized in that: The solubilizer includes one or a combination of two or more of benzyl alcohol, cyclodextrin, Tween and polyethylene glycol-15 hydroxystearate, the cyclodextrin may include hydroxypropyl-β-cyclodextrin, and the Tween may include Tween 80 and/or Tween 20; Wherein: the mass percentage of benzyl alcohol in the composition can be selected as 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 can be selected as 0-5% or 5%, the mass percentage of Tween in the composition can be selected as 0-1.4%, 1% or 1.4%, and the mass percentage of polyethylene glycol-15 hydroxystearate in the composition can be selected as 0-3%, 1.5% or 3%. The composition according to claim 17, characterized in that: The cosolvent includes one or a combination of two or more of propylene glycol, ethanol and glycerol; Wherein: the mass percentage of propylene glycol in the composition can be selected as 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 selected as 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 selected as 0-5%, 0-3%, 0-2.5%, 0-2.2% or 2.2%. The composition according to claim 17, characterized in that: The viscosity enhancer includes polyethylene glycol and/or pectin, and the polyethylene glycol may optionally include PEG3350 and/or PEG400; Wherein: the mass percentage of PEG3350 in the composition can be selected as 0-5%, 2.5%-5%, 2.5%, 4.6%, 4.7% or 5%, the mass percentage of PEG400 in the composition can be selected as 0-15% or 15%, and the mass percentage of pectin in the composition can be selected as 0-1% or 0.7%. The composition according to claim 17, characterized in that it further comprises any one or a combination of two or more of the following components:

The composition according to claim 22, characterized in that: The stabilizer includes edetate, and the edetate includes disodium edetate and/or dipotassium edetate, and the mass percentage of disodium edetate in the composition can be selected to be 0-0.1% or 0.05%; The preservative includes benzalkonium chloride, and the mass percentage of benzalkonium chloride in the composition can be selected to be 0-0.02% or 0.02%; The pH adjuster includes one or a combination of two or more of sodium hydroxide, potassium hydroxide, meglumine, citric acid and hydrochloric acid. 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, wherein the mass percentage of meglumine in the composition can be selected to be 0-0.5%, 0.02%, 0.25% or 0.5%, and the citric acid can be selected to be 1M citric acid solution. According to the composition of claim 23, the composition is optionally added with or without a pH buffer, and the pH buffer may optionally include one or a combination of two or more of a citrate buffer, a phosphate buffer and an acetate buffer. The composition according to claim 17, characterized in that: The composition is free of sodium sulfite and sodium bisulfite. The composition according to claim 17, characterized in that: The composition consists of quetiapine fumarate, a solubilizer, a co-solvent, a viscosity increasing agent 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 viscosity enhancer is PEG3350 and/or PEG400; The composition may optionally contain one or a combination of two or more of benzalkonium chloride, a pH adjuster and a pH buffer. A quetiapine nasal spray, comprising the composition of any one of claims 1 to 26 and a quantitative nasal spray device for delivering the composition into the nasal cavity, wherein 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. Use of the composition according to any one of claims 1 to 26 or the quetiapine nasal spray according to claim 27 in the preparation of a medicament for treating mental illness.