Pharmaceutical composition for intranasal administration

Abstract

The invention provides a pharmaceutical composition administrated through a nasal cavity, and particularly relates to a nasal spray preparation of lumepirone and a preparation method of the nasal spray preparation. The pharmaceutical composition for intranasal administration, provided by the invention, comprises lemepirone in a free or pharmaceutically acceptable salt form and pharmaceutically acceptable auxiliary materials, the pharmaceutical composition is good in stability, not prone to precipitation and degradation, high in bioavailability and quick in effect taking, has brain targeting performance and is beneficial to improving medication convenience and compliance of patients. The preparation method of the pharmaceutical composition is simple, preparation conditions are controllable, and industrial production is facilitated.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical technology, specifically to a pharmaceutical composition for intranasal administration, particularly to a nasal spray formulation of lumepimeperone, and a method for its preparation. Background Technology

[0002] Lumepiride is a dopamine receptor phosphoprotein modulator (DPPM) that exerts its therapeutic effect by synergistically regulating the central 5-HT, DA, and glutamatergic systems. Its unique pharmacological mechanism results in a low incidence of EPS. It was approved by the FDA in December 2019 under the brand name CAPLYTA for the treatment of schizophrenia in adults. The dosage form is an oral capsule, and the active ingredient is lumepirobenzyl tosylate. The structure of lumepirobenzyl tosylate is as follows:

[0003]

[0004] Caplyta is the only FDA-approved medication for treating bipolar I or II-related depressive episodes in adults, both as monotherapy and as adjunctive therapy with lithium or valproate. Clinical data show that Caplyta has consistently good performance in terms of weight, cardiometabolic parameters, and extrapyramidal symptoms (movement disorders). CN112584838A discloses a drug capsule containing rumepiride; however, oral administration is known to have specific drawbacks, including first-pass metabolism of the active ingredient in the liver and enzymatic degradation in the gastrointestinal tract (and extra-gastrointestinal tract), which may affect drug efficacy. Furthermore, this product requires daily oral administration to maintain its blood concentration, leading to poor patient adherence due to the need for frequent dosing.

[0005] CN115554237A discloses a long-acting injectable form of rumepiride in situ gel, which can reduce the risk of sudden increases in blood drug concentration. However, injectable forms also have the problem of inconvenience in use. Administration by injection is usually limited to use by trained professional healthcare personnel in a strictly controlled clinical environment. In addition, administration by injection may be painful and may not be suitable for patients with needle phobia.

[0006] Therefore, there is still a need to develop new drug formulations for rumepiride that can reduce gastrointestinal irritation and degradation, while also exhibiting good brain targeting and high bioavailability, thereby maximizing patient adherence. Summary of the Invention

[0007] To address the aforementioned problems in the prior art, the present invention aims to provide a nasal intranasal drug composition, particularly a nasal intranasal drug composition containing lumepimeperone. The nasal intranasal drug composition provided by the present invention has one or more advantages, such as convenient administration, rapid onset of action, relatively high bioavailability, avoidance of gastrointestinal side effects, improved brain targeting, low toxicity to the nasal mucosa, good drug formulation stability, and simple preparation method.

[0008] First, the present invention provides a pharmaceutical composition for intranasal administration, the pharmaceutical composition comprising lumepone or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients; wherein the pharmaceutically acceptable excipients include one or more of absorption enhancers, solvents, antioxidants and pH adjusters.

[0009] In one embodiment of the invention, a nasal pharmaceutical composition is provided, the pharmaceutical composition comprising lumepimeperone or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients; wherein the pharmaceutically acceptable excipients include absorption enhancers and pH adjusters.

[0010] In a preferred embodiment, the pharmaceutical composition comprises: rumepiride or a pharmaceutically acceptable salt thereof, an absorption enhancer, and a pH adjuster, wherein the concentration of rumepiride, by total volume of the pharmaceutical composition, is 0.001–500 mg / ml, preferably 0.01–500 mg / ml, more preferably 0.2–300 mg / ml, or 0.2–10 mg / ml; the content of the absorption enhancer is 0.001%–10% (w / v), preferably 0.001%–5% (w / v); and the pH of the pharmaceutical composition is 4–8, preferably 5.5–7.5, more preferably 6.0–7.0.

[0011] In another embodiment of the invention, a nasal pharmaceutical composition is provided, the pharmaceutical composition comprising rumepiride or a pharmaceutically acceptable salt thereof, an absorption enhancer, a solvent, and an antioxidant; wherein, based on the total weight of the pharmaceutical composition, the rumepiride or a pharmaceutically acceptable salt thereof accounts for 0.1% to 90% (w / w), preferably 1% to 10% (w / w), more preferably 1% to 5% (w / w);

[0012] The absorption enhancer accounts for 0.01% to 0.5% (w / w), preferably 0.01% to 0.1% (w / w);

[0013] The antioxidant accounts for 0.01% to 0.5% (w / w), preferably 0.01% to 0.1% (w / w);

[0014] The solvent accounts for 50% to 99% (w / w), preferably 80% to 99% (w / w).

[0015] In a preferred embodiment, the pharmaceutical composition of the present invention wherein the absorption enhancer is one or more selected from cyclodextrins, bile salts, fatty acids, alcohols, surfactants, chelating agents, chitosans, and phospholipids.

[0016] Preferably, the cyclodextrins include one or more of methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin;

[0017] The bile salts include one or more of hepatobiliary salts, sodium deoxycholate, taurine cholate, and deoxycholate, such as sodium taurocholate, sodium deoxycholate, sodium glucochyl cholate, sodium deoxytaurine, and sodium glycocholate.

[0018] The fatty acids include one or more of lauric acid, oleic acid, palmitic acid, oleic acid, and monooleic glycerides;

[0019] The alcohols include one or more of ethanol, propanol, butanol, pentanol, benzyl alcohol, and propylene glycol;

[0020] The surfactants include sodium dodecyl sulfate, dodecyl-β-D maltodextrin, polysorbate 80, polysorbate 20, PEG400, and lithium polyethylene glycol dodecyl stearate. One or more of HS15 and poloxamer;

[0021] The chelating agent includes one or more of ethylenediaminetetraacetic acid (EDTA), disodium ethylenediaminetetraacetic acid (EDTA-2Na), ethylene glycol tetraacetic acid, salicylate, and citrate.

[0022] The chitosans include one or more of chitosan, carboxymethyl chitosan, deacetylated chitosan, and N-succinyl chitosan;

[0023] The phospholipids include dodecyl phosphate choline.

[0024] In a preferred embodiment of the present invention, the pharmaceutical composition wherein the absorption enhancer is selected from one or more of polysorbate 80, EDTA, disodium ethylenediaminetetraacetate, ethylene glycol tetraacetate, lithium polyethylene glycol dodecyl hydroxystearate, dodecyl phosphocholine, dodecyl-β-D-maltodextrin, chitosan, carboxymethyl chitosan, propylene glycol, hydroxypropyl-β-cyclodextrin, dimethyl-β-cyclodextrin, PEG400, sodium deoxycholate, and sodium taurocholate.

[0025] Further preferably, the absorption enhancer is selected from one or more of polysorbate 80, EDTA, disodium ethylenediaminetetraacetate, ethylene glycol tetraacetate, lithium polyethylene glycol dodecyl hydroxystearate, and choline dodecyl phosphate.

[0026] Particularly preferred is that the absorption enhancer includes at least one of polysorbate 80, disodium ethylenediaminetetraacetate (EDTA-2Na), or ethylenediaminetetraacetic acid (EDTA).

[0027] In a preferred embodiment, the pharmaceutical composition of the present invention wherein the pH adjuster is one or more selected from citrate buffer, phosphate buffer, PBS buffer, sodium hydroxide, potassium hydroxide, and hydrochloric acid.

[0028] In a preferred embodiment, the pharmaceutical composition of the present invention wherein the solvent is selected from at least one of water, anhydrous ethanol, and propylene glycol, preferably the solvent is selected from anhydrous ethanol and propylene glycol.

[0029] In one specific embodiment, a nasal-administered pharmaceutical composition is provided, wherein the pharmaceutically acceptable excipients include an absorption enhancer and a pH adjuster;

[0030] The concentration of rumepiride, based on the total volume of the pharmaceutical composition, is 0.001–500 mg / ml, preferably 0.01–500 mg / ml, and more preferably 0.2–300 mg / ml;

[0031] The concentration of the absorption enhancer is 0.001% to 10% (w / v), preferably 0.001% to 5% (w / v);

[0032] The pH of the pharmaceutical composition is 4-8, preferably 5.5-7.5;

[0033] Further, based on the total volume of the pharmaceutical composition, the content of the absorption enhancer is 0.001% to 10% (w / v), preferably 0.001% to 0.05% (w / v), for example 0.001% to 5% (w / v), 0.001% to 2% (w / v), 0.001% to 1% (w / v), 0.001% to 1.5% (w / v), 0.001% to 1% (w / v), 0.001% to 0.1% (w / v), 0.001% to 1.1% (w / v), 0.01% to 10% (w / v), 0.01% to 3% (w / v), 0.01% to 2%. (w / v), 0.01% to 1% (w / v), 0.05% to 3% (w / v), 0.05% to 10% (w / v), 0.05% to 2% (w / v), 0.05% to 1% (w / v), 0.05% to 0.5% (w / v), 1% to 10% (w / v), 1% to 5% (w / v), 2% to 10% (w / v), 2% to 4% (w / v), 3% to 5% (w / v), 4% to 8% (w / v), 0.1% to 0.5% (w / v) or 0.05% to 0.2% (w / v), etc., and any value between them, preferably 1% to 2% (w / v).

[0034] Preferably, the absorption enhancer comprises polysorbate 80, and the concentration of polysorbate 80, based on the total volume of the pharmaceutical composition, is 0.1% to 5% (w / v), for example 0.1% to 4% (w / v), 0.1% to 3% (w / v), 0.1% to 2% (w / v), 0.1% to 1.5% (w / v), 0.1% to 1% (w / v), 0.5% to 5% (w / v), 0.5% to 4% (w / v), 0.5% to 3% (w / v). (v), 0.5%–2% (w / v), 0.5%–1.5% (w / v), 0.5%–1% (w / v), about 0.5% (w / v), about 0.6% (w / v), about 0.7% (w / v), about 0.8% (w / v), about 0.9% (w / v), about 1% (w / v), about 1.1% (w / v), about 1.2% (w / v), about 1.5% (w / v) or about 2% (w / v), etc., and the range between any two values;

[0035] Further preferably, the absorption enhancer further includes EDTA or EDTA-2Na, wherein the concentration of EDTA or EDTA-2Na, based on the total volume of the pharmaceutical composition, is independently 0.001% to 0.1% (w / v), for example 0.001% to 0.01% (w / v), 0.002% to 0.01% (w / v), 0.003% to 0.01% (w / v), 0. 004%~0.01%(w / v), 0.005%~0.01%(w / v), 0.006%~0.01%(w / v), 0.007%~0.01%(w / v) , 0.001% ~ 0.007% (w / v), 0.001% ~ 0.006% (w / v), 0.001% ~ 0.005% (w / v), 0.002% ~ 0.00 7% (w / v), 0.003%–0.007% (w / v), 0.004%–0.007% (w / v), 0.005%–0.007% (w / v), 0.006%–0.007% (w / v), approximately 0.002% (w / v), approximately 0.003% (w / v), approximately 0.004% (w / v), approximately 0.005% (w / v), approximately 0 The concentrations are approximately 0.006% (w / v), about 0.007% (w / v), about 0.008% (w / v), about 0.009% (w / v), or about 0.01% (w / v), and any two numbers thereof; more preferably, the concentration of the EDTA or EDTA-2Na is independently 0.005% to 0.1% (w / v), or 0.005% to 0.007% (w / v);

[0036] Further, based on the total volume of the pharmaceutical composition, the concentration of rumepiride is 0.001–500 mg / ml, preferably 0.01–500 mg / ml, for example 0.001–100 mg / ml, 0.002–100 mg / ml, 0.001–10 mg / ml, 0.002–10 mg / ml, 0.001–5 mg / ml, 0.001–4 mg / ml, 0.001–3.5 mg / ml, 0.05–500 mg / ml, 0.05–200 mg / ml, 0.05–150 mg / ml, 0.05–100 mg / ml, 0.1–400 mg / ml, 0.1–300 mg / ml, 0.1–200 mg / ml, 0.2–300 mg / ml, 1–400 mg / ml, 1–300 mg / ml. 1-200mg / ml, 1-100mg / ml, 5-200mg / ml, 5-100mg / ml, 10-200mg / ml, 20-200mg / ml, 1-50mg / ml, 2-50mg / ml, 0.2-5mg / ml, 0.3-5mg / ml, 0.05mg / ml, 0.1mg / ml, 0.15mg / ml, 0.5mg / ml, 1mg / ml, 2.5mg / ml, 3.0mg / ml, 3.5mg / ml, 5mg / ml, 10mg / ml, 20mg / ml, 25mg / ml, 50mg / ml, 100mg / ml, 150mg / ml, 200mg / ml, 300mg / ml, 400mg / ml or 500mg / ml, etc., and values ​​between any two numbers.

[0037] Further, the pH adjuster is one or more of citrate buffer, phosphate buffer, PBS buffer, sodium hydroxide, potassium hydroxide, or hydrochloric acid; more preferably, the citrate buffer includes one or more of citric acid, sodium citrate, and potassium citrate; the phosphate buffer includes one or more of phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate.

[0038] The pH of the pharmaceutical composition is 4 to 8, preferably 5 to 8, for example 5.5 to 7.5, or 6 to 8, or 6 to 7, or about 4, or about 5, or about 5.5, or about 6, or about 6.5, or about 7, or about 7.5, or about 8, etc., and any value between any two numbers.

[0039] In this invention, the pH adjuster is present in an amount sufficient to adjust the pH of the pharmaceutical composition to a target pH value, wherein the target pH of the pharmaceutical composition is 4 to 8, preferably 5 to 8, for example 5.5 to 7.5, or 6 to 8, or 6 to 7, or about 4, or about 5, or about 5.5, or about 6, or about 6.5, or about 7, or about 7.5, or about 8, etc., and any value between these values.

[0040] In a preferred embodiment, the pharmaceutical composition wherein the pH adjuster is one or more of PBS buffer, citrate buffer, phosphate buffer, sodium hydroxide, and hydrochloric acid, water is used as the suspension medium of the pharmaceutical composition, and the pH of the pharmaceutical composition is 4 to 8, for example, pH is about 4, or about 5, or about 5.5, or about 6, or about 6.5, or about 7, or about 7.5, or about 8, or any value between these values.

[0041] In a preferred embodiment, the present invention provides a nasal administration pharmaceutical composition comprising the following components:

[0042] Lumepiride p-toluenesulfonate, polysorbate 80, EDTA or EDTA-2Na, and pH adjuster;

[0043] Based on the total volume of the composition, the concentration of lumepirozoline (converted to lumepirozoline p-toluenesulfonate) is 0.001–500 mg / ml, preferably 0.01–500 mg / ml, for example 0.001–100 mg / ml, 0.002–100 mg / ml, 0.001–10 mg / ml, 0.002–10 mg / ml, 0.001–5 mg / ml, 0.001–4 mg / ml, 0.001–3.5 mg / ml, 0.1–400 mg / ml, 0.1–300 mg / ml, 0.1–200 mg / ml, 1–200 mg / ml, 1–100 mg / ml, 5–200 mg / ml, 5–100 mg / ml, 10–200 mg / ml, 2 0–200 mg / ml, 1–50 mg / ml, 2–50 mg / ml, 0.2–5 mg / ml, 0.3–5 mg / ml, 0.01 mg / ml, 0.05 mg / ml, 0.25 mg / ml, 0.35 mg / ml, 0.5 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 20 mg / ml, 25 mg / ml, 50 mg / ml, 100 mg / ml, 150 mg / ml, 200 mg / ml, 250 mg / ml, 300 mg / ml, 400 mg / ml or 500 mg / ml, etc., and values ​​between any two numbers;

[0044] The concentration of the polysorbate 80 is 0.1% to 10% (w / v), for example 0.1% to 9% (w / v), 0.1% to 8% (w / v), 0.1% to 7% (w / v), 0.1% to 6% (w / v), 0.1% to 5% (w / v), 0.1% to 4% (w / v), 0.1% to 3% (w / v), 0.1% to 2% (w / v), 0.1% to 1% (w / v), 0.5% to 3% (w / v), 0.5% to 2% (w / v). % (w / v), 0.5% to 1% (w / v), 0.5% to 1.5% (w / v), 1% to 1.5% (w / v), about 0.5% (w / v), about 0.6% (w / v), about 0.7% (w / v), about 0.8% (w / v), about 0.9% (w / v), about 1% (w / v)%, about 1.1% (w / v), about 1.2% (w / v), about 1.5% (w / v) or about 2% (w / v), etc., and values ​​between any two numbers;

[0045] The concentration of EDTA or EDTA-2Na is independently 0.001% to 0.1% (w / v), for example 0.001% to 0.01% (w / v), 0.002% to 0.01% (w / v), 0.003% to 0.01% (w / v), 0.004% to 0.01% (w / v), 0.005% to 0.01% (w / v), 0.006% to 0.01% (w / v), 0.0 07%~0.01% (w / v), 0.001%~0.007% (w / v), 0.001%~0.006% (w / v), 0.001%~0.005% (w / v), 0.00 2%~0.007% (w / v), 0.003%~0.007% (w / v), 0.004%~0.007% (w / v), 0.005%~0.007% (w / v), 0.00 6%–0.007% (w / v), approximately 0.1% (w / v), approximately 0.01% (w / v), approximately 0.001% (w / v), approximately 0.2% (w / v), approximately 0.02% (w / v), approximately 0.002% (w / v), approximately 0.3% (w / v), approximately 0.03% (w / v), approximately 0.003% (w / v), approximately 0.4% (w / v), approximately 0.04% (w / v), approximately 0.00 4% (w / v), about 0.5% (w / v), about 0.05% (w / v), about 0.005% (w / v), about 0.006% (w / v), about 0.007% (w / v), about 0.008% (w / v), or about 0.009% (w / v), and values ​​between any two numbers; preferably, the concentration of the EDTA or disodium ethylenediaminetetraacetate is independently 0.005% to 0.007% (w / v);

[0046] The pH adjuster is one or more of PBS buffer, citrate buffer, phosphate buffer, sodium hydroxide and hydrochloric acid, and water is used as the suspension medium of the drug composition. The pH of the drug composition is 4 to 8, preferably 5.5 to 7.5, for example, pH 4, or 5, or 5.5, or 6, or 6.5, or 7, or 7.5, or 8, etc.

[0047] More preferably, the pharmaceutical composition is an intranasal spray.

[0048] In a preferred embodiment, the present invention provides a nasal spray pharmaceutical composition comprising rumepiride or a pharmaceutically acceptable salt thereof, polysorbate 80 (also known as Tween 80), disodium EDTA, and a pH adjuster; wherein, based on the total volume of the composition, the concentration of rumepiride is 0.01–500 mg / ml; the concentration of polysorbate 80 is 0.1%–5% (w / v); the concentration of disodium EDTA is 0.001%–0.1% (w / v); the pH of the composition is 5–8, preferably 5.5–7.5; more preferably, the pH adjuster is PBS buffer, water is used as the suspension medium of the pharmaceutical composition, and the pharmaceutical composition is an intranasal spray.

[0049] In a preferred embodiment, the present invention provides a nasal drug composition comprising lumepirozon p-toluenesulfonate, polysorbate 80, disodium EDTA, and a pH adjuster; wherein, based on the total volume of the composition, the concentration of lumepirozon (lumepirozon p-toluenesulfonate converted to lumepirozon) is 0.1–500 mg / ml, preferably 0.1–300 mg / ml; the concentration of polysorbate 80 is 0.1%–2% (w / v); the concentration of disodium EDTA is 0.005%–0.1% (w / v), preferably 0.005%–0.007% (w / v); the pH adjuster is PBS buffer, water is used as the suspension medium of the drug composition, and the pH of the drug composition is 5–8, preferably 6.0–7.0.

[0050] In a preferred embodiment, the present invention provides a pharmaceutical composition for intranasal administration, the composition comprising the following components:

[0051] The composition comprises: lumepirozoline p-toluenesulfonate, polysorbate 80, EDTA-2Na, and a pH adjuster; wherein, by total volume, the concentration of lumepirozoline (lumepirozoline p-toluenesulfonate converted to lumepirozoline) is 0.2–5 mg / ml; the concentration of polysorbate 80 is 0.1%–1.5% (w / v); the concentration of EDTA-2Na is 0.005%–0.1% (w / v), preferably 0.005%–0.007% (w / v); the pH of the pharmaceutical composition is 6–8, preferably 6.0–7.0; more preferably, the pH adjuster is PBS buffer, water is used as the suspension medium of the pharmaceutical composition, and the pharmaceutical composition is a nasal spray.

[0052] In another preferred embodiment, a pharmaceutical composition for intranasal administration is provided, the pharmaceutical composition comprising:

[0053] The composition comprises lumepimeperone p-toluenesulfonate, benzyl alcohol, dodecyl maltoside, and a pH adjuster; wherein, based on the total volume of the composition, the concentration of lumepimeperone is 0.2–5 mg / ml, the content of dodecyl maltoside is 0.1%–0.5% (w / v), and the content of benzyl alcohol is 1–5 (w / v); the pH of the pharmaceutical composition is 6–8, and the pH adjuster is one or more of PBS buffer, citrate buffer, phosphate buffer, sodium hydroxide, or hydrochloric acid, with water as the suspension medium; more preferably, the pharmaceutical composition is a nasal spray.

[0054] In another aspect of the present invention, a method for preparing the above-described pharmaceutical composition is provided, the method comprising the following steps:

[0055] Add the prescribed amount of rumepiride or its pharmaceutically acceptable salt, absorption enhancer, and optionally stabilizer to a certain amount of water, stir, then add a pH adjuster to adjust the pH of the system to the target value, mix well, and finally add water to make up the remaining amount and mix well to obtain the final product.

[0056] In one embodiment, a method for preparing the pharmaceutical composition is provided, the method comprising the steps of: adding a prescribed dose of an absorption enhancer, optionally further comprising a stabilizer, to a certain amount of PBS buffer at pH 6.8, stirring to obtain a solvent; then adding the solvent to lumepiroron in a free or pharmaceutically acceptable salt form, stirring to dissolve and obtain a clear and transparent solution.

[0057] In another embodiment of the invention, a nasal pharmaceutical composition is provided, the pharmaceutical composition comprising lumepimeperone or a pharmaceutically acceptable salt thereof, an absorption enhancer, a solvent, and an antioxidant.

[0058] The pharmaceutical composition contains, by weight, 0.1% to 90% (w / w) of rumepiride or its pharmaceutically acceptable salt, for example, 1% to 80% (w / w), 1% to 50% (w / w), 1% to 40% (w / w), 1% to 30% (w / w), 1% to 20% (w / w), 1% to 10% (w / w), 1% to 9% (w / w), 1% to 8% (w / w), 1% to 7% (w / w), 1% to 6% (w / w), 1% to 5% (w / w), 1% to 4% (w / w). The percentages are as follows: 1% to 3% (w / w), 1% to 2% (w / w), 1.5% (w / w), 1.4% (w / w), 1% (w / w), 0.9% (w / w), 0.8% (w / w), 0.7% (w / w), 0.6% (w / w), 0.5% (w / w), 0.4% (w / w), 0.3% (w / w), 0.2% (w / w), or 0.1% (w / w), and any value between these values; preferably 1% to 10% (w / w), more preferably 1% to 5% (w / w).

[0059] Preferably, the pharmaceutically acceptable salt of lumepirozon is p-toluenesulfonate of lumepirozon (also known as "lumepirozon p-toluenesulfonate"), and the structure of lumepirozon p-toluenesulfonate is as follows:

[0060]

[0061] Further, based on the total weight of the pharmaceutical composition, the absorption enhancer accounts for 0.01% to 0.5% (w / w), for example, 0.01% to 0.1% (w / w), 0.01% to 0.09% (w / w), 0.01% to 0.08% (w / w), 0.01% to 0.07% (w / w), 0.01% to 0.06% (w / w), 0.01% to 0.05% (w / w), 0.01% to 0.04% (w / w), 0.01% to 0.03% (w / w), or 0.01% to 0.02% (w / w), and any value between these values; preferably 0.01% to 0.1% (w / w), more preferably 0.01% to 0.02% (w / w).

[0062] The absorption promoter is selected from one or more of polysorbate 80, EDTA, disodium ethylenediaminetetraacetate, ethylene glycol tetraacetic acid, lithium polyethylene glycol dodecyl hydroxystearate, dodecyl choline phosphorophosphate, dodecyl-β-D-maltodextrin, chitosan, carboxymethyl chitosan, propylene glycol, hydroxypropyl-β-cyclodextrin, dimethyl-β-cyclodextrin, PEG400, sodium deoxycholate, and sodium taurocholate; preferably, the absorption promoter is selected from one or more of polysorbate 80, EDTA, disodium ethylenediaminetetraacetate, ethylene glycol tetraacetic acid, lithium polyethylene glycol dodecyl hydroxystearate, and dodecyl choline phosphorophosphate; particularly preferably, the absorption promoter is selected from at least one of disodium ethylenediaminetetraacetate (EDTA-2Na) or ethylenediaminetetraacetic acid (EDTA).

[0063] Further, based on the total weight of the pharmaceutical composition, the antioxidant accounts for 0.01% to 0.5% (w / w), for example 0.01% to 0.5% (w / w), 0.01% to 0.4% (w / w), 0.01% to 0.3% (w / w), 0.01% to 0.2% (w / w), 0.01% to 0.1% (w / w), 0.01% to 0.09% (w / w), 0.01% to 0.08% (w / w), 0.01% to 0.07% (w / w). The concentrations are 0.01% to 0.05% (w / w), 0.01% to 0.04% (w / w), 0.01% to 0.03% (w / w), 0.01% to 0.02% (w / w), 0.05% to 0.1% (w / w), 0.05% to 0.2% (w / w), or 0.05% to 0.5% (w / w), and any values ​​between these ranges; preferably 0.01% to 0.5% (w / w); more preferably 0.01% to 0.1% (w / w).

[0064] The antioxidant is selected from at least one of ascorbic acid, ascorbyl palmitate, sodium metabisulfite, vitamin E, butylated hydroxyanisole, butylated hydroxytoluene, di-tert-butylhydroquinone, butylated hydroxytoluene, gallic acid, propyl gallate, octyl gallate, hydroquinone, tocopheryl acetate, sodium sulfite, sodium thiosulfate, sodium dithionite, potassium metabisulfite, sodium ascorbate, isoascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, sodium isoascorbate, cysteine, L-cysteine ​​hydrochloride, glutathione, monothioglycerol, sodium formaldehyde sulfoxylate, thiourea, methionine, or thymol, preferably butylated hydroxyanisole.

[0065] Further, based on the total weight of the pharmaceutical composition, the solvent accounts for 50% to 99% (w / w), for example, 50% to 99% (w / w), 60% to 99% (w / w), 70% to 99% (w / w), 80% to 99% (w / w), 90% to 99% (w / w), 95% to 99% (w / w), and any value between these values; preferably 80% to 99% (w / w).

[0066] The solvent is selected from at least one of water, anhydrous ethanol, and propylene glycol, preferably selected from anhydrous ethanol and propylene glycol, wherein the weight ratio of anhydrous ethanol to propylene glycol is 2 to 6:1, for example 2:1, 3:1, 4:1, 5:1, or 6:1, and any two numbers in between.

[0067] In one specific embodiment, a nasal pharmaceutical composition is provided, the pharmaceutical composition comprising lumepeeron p-tosylate, EDTA-2Na, anhydrous ethanol, propylene glycol, and butylated hydroxyanisole, wherein, by weight of the total pharmaceutical composition, lumepeeron p-tosylate comprises 1% to 5% (w / w), preferably 1% to 2% (w / w); EDTA-2Na comprises 0.01% to 0.1% (w / w), preferably 0.01% to 0.05% (w / w); butylated hydroxyanisole comprises 0.01% to 0.1% (w / w); anhydrous ethanol comprises 70% to 90% (w / w), preferably 75% to 85% (w / w); and propylene glycol comprises 10% to 30% (w / w), preferably 15% to 25% (w / w).

[0068] The present invention also provides a method for preparing the pharmaceutical composition, comprising the following steps: weighing and mixing anhydrous ethanol, propylene glycol, EDTA-2Na, and butylated hydroxyanisole in the prescribed amounts; adding the prescribed amount of lumepone or its pharmaceutically acceptable salt to the above solution under a nitrogen-filled environment; and dissolving completely to obtain the pharmaceutical composition.

[0069] In another aspect of the invention, the use of the pharmaceutical composition in the preparation of a medicament for treating diseases that can be treated with rumepiride is also provided.

[0070] The preferred use is to spray the pharmaceutical composition provided by the present invention into at least one nostril of a patient; more preferably, into both nostrils of a patient. In one embodiment, the amount of liquid sprayed is 100 μl, and the total amount of liquid sprayed into the nasal cavity each time is 25 to 150 μl.

[0071] In another preferred embodiment of the invention, the bioavailability achieved by the treatment with the pharmaceutical composition is about 80% to 130% of the bioavailability achieved by intramuscularly administering a similar amount of rumepiride or a pharmaceutically acceptable salt thereof, for example 80% to 110%, or 90% to 120%, or 100% to 125%, and any value between therewith, preferably 90% to 130%, more preferably 115% to 125%.

[0072] In another preferred embodiment of the invention, the bioavailability achieved by the treatment with the pharmaceutical composition is about 180% to 300% of the bioavailability achieved by a similar amount of rumepiride or a pharmaceutically acceptable salt thereof administered sublingually, for example 190% to 200%, or 200% to 250%, or 250% to 300%, preferably 190% to 300%, more preferably 200% to 250%.

[0073] In another preferred embodiment of the invention, the unit dosage volume of the pharmaceutical composition is about 1 μl to 1000 μl, for example, 1 μl, 5 μl, 10 μl, 20 μl, 30 μl, 40 μl, 50 μl, 100 μl, 120 μl, 150 μl, 180 μl, 200 μl, 220 μl, 220 μl, 250 μl, 300 μl, 400 μl, 500 μl, 600 μl, 700 μl, 800 μl, 900 μl, or 1000 μl, etc., and any value between these values, in a pharmaceutically acceptable spray formulation. Preferably, it is 1 μl to 500 μl, more preferably 10 μl to 200 μl.

[0074] In another embodiment, the pharmaceutical composition optionally further includes a stabilizer, said stabilizer being one or more of benzalkonium chloride, phenethyl alcohol, ascorbic acid, α-tocopherol, or sodium metabisulfite.

[0075] Further, the content of the stabilizer is 0.1% to 20% (w / v), 0.1% to 15% (w / v), 0.1% to 10% (w / v), 1% to 10% (w / v), 1% to 15% (w / v), 5% to 15% (w / v), 10% to 15% (w / v), 0.1% to 5% (w / v), for example, 0.1% to 3% (w / v), 0.1% to 2% (w / v), 0.1% to 1% (w / v), 0.5% to 3% (w / v), 0.5% to 2% (w / v), 0.5% to 1% (w / v), or 0.5% to 1.5% (w / v), etc., and any value between these values.

[0076] In another embodiment, the pharmaceutical composition optionally further includes an osmotic pressure regulator that works through any mechanism, including, for example, increasing membrane fluidity, forming transient hydrophilic pores in epithelial cells, reducing the viscosity of the mucus layer, or opening tight junctions. Preferably, the osmotic pressure regulator is selected to satisfy one or more, more preferably all of the following general requirements:

[0077] (a) It is effective in increasing the absorption rate of the active ingredient (preferably nasal absorption); (b) It is pharmacologically inert; (c) It is non-allergenic, non-toxic and / or non-irritating; (d) It is compatible with other components of the pharmaceutical composition; (e) It is odorless, colorless and / or tasteless; (f) It is acceptable to regulatory authorities; and (g) It is low-cost and can be used in high purity.

[0078] In a preferred embodiment, the osmotic pressure regulator is capable of increasing the absorption and / or bioavailability of lumepirozoline or its salts without causing nasal irritation. In one specific embodiment, the osmotic pressure regulator is glucose and / or sodium chloride.

[0079] In a preferred embodiment, the pharmaceutical composition of the present invention is an aqueous nasal oral medication; more preferably, the pharmaceutical composition is a drop, spray, or aerosol, and particularly preferably, the pharmaceutical composition is a nasal spray. Further preferably, the unit dosage volume of the pharmaceutical composition is 0.01–1 ml, for example, about 50 μl, about 100 μl, about 120 μl, about 150 μl, about 200 μl, about 250 μl, about 300 μl, about 400 μl, about 500 μl, or about 1000 μl, or any value between these values.

[0080] In another aspect of the invention, a nasal spray kit is also provided, the nasal spray kit comprising the pharmaceutical composition described in the invention and a device for delivering the pharmaceutical composition into the nasal cavity; in one embodiment, the device includes, for example, a pump, a nasal push button, a cover, and a bottle, etc.; in a more specific embodiment, the device includes an Aptar Classic pump, a screw 18 / 415, a nasal push button, a cover, and a bottle.

[0081] In one embodiment of the invention, the pharmaceutical composition, analyzed by a spray pattern and spray pattern analyzer, shows good morphology. More preferably, the intranasal pharmaceutical composition of the present invention, when tested for spray dosage uniformity using a delivery device, shows good uniformity; for example, in 20 consecutive sprays, sprays 3 to 18, preferably 5 to 15, have substantially the same volume of drug solution. The present invention, through a reasonable component ratio, formulates rumeperone or its pharmaceutically acceptable salts into a nasal-administered pharmaceutical composition. This composition exhibits good stability, minimal API precipitation and degradation, high bioavailability, rapid onset of action, brain targeting, and improved efficacy. It significantly reduces toxicity and vascular irritation during injection, avoids gastrointestinal reactions associated with oral administration, and is safer for clinical application, improving patient convenience and compliance. The preparation method is simple, and the preparation conditions are controllable, facilitating industrial production.

[0082] Furthermore, the pharmaceutical composition of lumepimeperone or a pharmaceutically acceptable salt thereof, which includes an antioxidant, a solvent, and an absorption enhancer, provided by the present invention, also has the advantages of increasing the drug loading of the nasal spray formulation and improving the stability of the formulation. Attached Figure Description

[0083] Figure 1 The diagram shows the blood drug concentration-time curves of the pharmaceutical composition provided by the present invention, as detected by the method of Test Example 1, through three different routes of administration; where PO refers to gavage administration, IV refers to injection, and Intranasal refers to intranasal administration; Intranasal refers to the nasal drop group, PO refers to the gavage group, and IV refers to the injection group.

[0084] Figure 2 This invention demonstrates the effect of the lumepirocin composition provided by the present invention on MK-801-induced hyperkinesis in mice via different administration routes; wherein Vehicle(iv)+MK-801 refers to the negative control group, Vehicle(in)+MK-801 refers to the model control group, 007-3.0mpk(po)+MK-801 refers to the gavage group, 007-0.3mpk(in) refers to the nasal drop group, and 007-0.1mpk(iv)+MK-801, 007-0.3mpk(iv)+MK-801, and 007-1.0mpk(iv)+MK-801 refer to the intravenous low, medium, and high dose groups, respectively.

[0085] Figure 3 The results show the total number of head-shaking events induced by DOI in mice within 20 minutes in different experimental groups. The vertical axis represents the number of head-shaking events induced by DOI in mice. The results show that the efficacy of the 0.01 mpk rubepiron intranasal administration group is better than that of the 0.01 mpk rubepiron injection group.

[0086] Figure 4 The results show the effects of different experimental groups on DOI-induced head-shaking behavior in mice at different time periods. The vertical axis represents the number of head-shaking events induced by DOI, and the horizontal axis represents time.

[0087] Figure 3 and Figure 4 Vehicle(iv) refers to the intravenous control group, Vehicle(in) refers to the nasal drop control group, 0.03mpk(po) refers to the gavage group, 0.01mpk(in) refers to the nasal drop group, and 0.01mpk(iv), 0.03mpk(iv), and 0.1mpk(iv) refer to the intravenous low, medium, and high dose groups, respectively.

[0088] Figure 5 The graph shows a comparison of blood drug concentration-time curves of the drug composition provided by the present invention administered via nasal cavity and the injection solution administered via intravenous cavity, as detected by the method of Test Example 6; where Intranasal (1mpk) group refers to the nasal drop group; IV (1mpk) group refers to the injection group. Specific Implementation

[0089] The technical solution and beneficial effects of the present invention will be described in detail below with reference to specific embodiments.

[0090] The present invention provides a pharmaceutical composition for intranasal administration, comprising lumepirozol in free or pharmaceutically acceptable salt form and pharmaceutically acceptable excipients;

[0091] The pharmaceutically acceptable excipients include absorption enhancers and pH adjusters.

[0092] The absorption enhancer is one or more of polysorbate 80, EDTA, disodium ethylenediaminetetraacetate, ethylene glycol tetraacetic acid, lithium polyethylene glycol dodecyl hydroxystearate, and dodecyl choline phosphate; preferably, the absorption enhancer includes at least one of polysorbate 80, disodium ethylenediaminetetraacetate (EDTA-2Na), or ethylenediaminetetraacetic acid (EDTA).

[0093] Preferably, the absorption enhancer comprises polysorbate 80, and the concentration of polysorbate 80, based on the total volume of the pharmaceutical composition, is 0.1% to 5% (w / v), for example 0.1% to 4% (w / v), 0.1% to 3% (w / v), 0.1% to 2% (w / v), 0.1% to 1.5% (w / v), 0.1% to 1% (w / v), 0.5% to 5% (w / v), 0.5% to 4% (w / v), 0.5% to 3% (w / v). (v), 0.5%–2% (w / v), 0.5%–1.5% (w / v), 0.5%–1% (w / v), about 0.5% (w / v), about 0.6% (w / v), about 0.7% (w / v), about 0.8% (w / v), about 0.9% (w / v), about 1% (w / v), about 1.1% (w / v), about 1.2% (w / v), about 1.5% (w / v) or about 2% (w / v), etc., and the range between any two values;

[0094] Further preferably, the absorption enhancer further includes EDTA or EDTA-2Na, wherein the concentration of EDTA or EDTA-2Na, based on the total volume of the pharmaceutical composition, is independently 0.001% to 0.1% (w / v), for example 0.001% to 0.01% (w / v), 0.002% to 0.01% (w / v), 0.003% to 0.01% (w / v), 0... .004%~0.01%(w / v), 0.005%~0.01%(w / v), 0.006%~0.01%(w / v), 0.007%~0.01%(w / v) ), 0.001% ~ 0.007% (w / v), 0.001% ~ 0.006% (w / v), 0.001% ~ 0.005% (w / v), 0.002% ~ 0.0 07% (w / v), 0.003% ~ 0.007% (w / v), 0.004% ~ 0.007% (w / v), 0.005% ~ 0.007% (w / v), 0. 006% ~ 0.007% (w / v), about 0.002% (w / v), about 0.003% (w / v), about 0.004% (w / v), about 0.005% (w / v), The concentrations are approximately 0.006% (w / v), approximately 0.007% (w / v), approximately 0.008% (w / v), approximately 0.009% (w / v), or approximately 0.01% (w / v), and any range between any two numbers; preferably, the concentration of the EDTA or EDTA-2Na is independently 0.005% to 0.1% (w / v) or 0.005% to 0.007% (w / v).

[0095] The pharmaceutical composition is an aqueous suspension, such as an intranasal spray in the form of an aqueous suspension; the pH of the pharmaceutical composition is 5 to 8, such as pH 5, 6, 7 or 8 and any value between them.

[0096] The pH adjuster is one or more of citrate buffer, phosphate buffer, PBS buffer, sodium hydroxide, potassium hydroxide, and hydrochloric acid; in some embodiments, the citrate buffer includes one or more of citric acid, sodium citrate, and potassium citrate; the phosphate buffer includes one or more of phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate.

[0097] Optionally, the drug combination further includes a stabilizer, said stabilizer being one or more of benzalkonium chloride, phenethyl alcohol, ascorbic acid, α-tocopherol, and sodium metabisulfite.

[0098] The stabilizer is present in the pharmaceutical composition at the following concentrations: 0.1%–20% (w / v), for example, 0.1%–15% (w / v), 0.1%–10% (w / v), 1%–10% (w / v), 1%–15% (w / v), 5%–15% (w / v), 10%–15% (w / v), 0.1%–5% (w / v), 0.1%–3% (w / v), 0.1%–2% (w / v), or 0.1%–1% (w / v). , 0.5% ~ 3% (w / v), 0.5% ~ 2% (w / v), 0.5% ~ 1% (w / v), 0.5% ~ 1.5% (w / v), 0.1% (w / v), 0.15% (w / v), 0.2% (w / v), 0.3% (w / v), 0.5% (w / v), 1% (w / v), 1.5% (w / v), 2% (w / v), 3% (w / v), 4% (w / v) or 5% (w / v) and any value therebetween.

[0099] The pharmaceutical composition optionally further includes an osmotic pressure regulator, which is glucose and / or sodium chloride. The osmotic pressure regulator is present in a concentration of 0–5% (w / v), for example, 0 (w / v), 0.1% (w / v), 0.5% (w / v), 0.8% (w / v), 1% (w / v), 1.5% (w / v), 2% (w / v), 2.5% (w / v), 3% (w / v), 4% (w / v), or 5% (w / v), and any value between these values.

[0100] The concentration of the rumepiride or its pharmaceutically acceptable salt, calculated as rumepiride, is 0.001–200 mg / ml, or 0.1–200 mg / ml, 1–200 mg / ml, or 1–100 mg / ml, or 5–200 mg / ml, or 5–100 mg / ml, or 10–200 mg / ml, or 20–200 mg / ml, preferably 1–50 mg / ml, or 2–50 mg / ml, or 0.001–10 mg / ml, or 0.2–5 mg / ml. The concentration may be g / ml, or 0.2–10 mg / ml, or 0.3–5 mg / ml, or 0.5 mg / ml, or 0.25 mg / ml, or 0.35 mg / ml, or 2.5 mg / ml, or 3.0 mg / ml, or 3.5 mg / ml, or 5 mg / ml, or 10 mg / ml, or 20 mg / ml, or 25 mg / ml, or 50 mg / ml, or 100 mg / ml, or 150 mg / ml, or 200 mg / ml, or any value between these values. More preferably, the pharmaceutically acceptable salt is lumepimeron p-toluenesulfonate.

[0101] Another embodiment of the present invention provides a nasal pharmaceutical composition comprising lumepimeperone p-toluenesulfonate, an absorption enhancer, a solvent, and an antioxidant, wherein the lumepimeperone or a pharmaceutically acceptable salt thereof comprises 0.1% to 90% (w / w), preferably 1% to 10% (w / w), and more preferably 1% to 5% (w / w), based on the total weight of the pharmaceutical composition.

[0102] The absorption promoter accounts for 0.01% to 0.5% (w / w), preferably 0.01% to 0.1% (w / w), more preferably 0.01% to 0.02% (w / w); the absorption promoter is selected from at least one of disodium ethylenediaminetetraacetate (EDTA-2Na) or ethylenediaminetetraacetic acid (EDTA).

[0103] The antioxidant accounts for 0.01% to 0.5% (w / w), preferably 0.01% to 0.1% (w / w); the antioxidant is selected from at least one of ascorbic acid, ascorbate palmitate, sodium metabisulfite, vitamin E or butylated hydroxyanisole, preferably butylated hydroxyanisole.

[0104] The solvent comprises 50% to 99% (w / w), preferably 80% to 99% (w / w); more preferably, the solvent is selected from anhydrous ethanol and propylene glycol, wherein the weight ratio of anhydrous ethanol to propylene glycol is 2 to 6:1, for example 2:1, 3:1, 4:1, 5:1, or 6:1, and any two numbers in between.

[0105] Terminology definition:

[0106] In the context of this invention, all figures disclosed herein are approximate, regardless of whether the words “about,” “approximately,” or “roughly” are used. Each figure may vary by less than 10% or by a difference that is considered reasonable by those skilled in the art, such as 1%, 2%, 3%, 4%, or 5%.

[0107] The term "w / v" as used herein refers to weight-volume ratio, expressed in mg / ml. For example, the statement "the content of the absorption enhancer in the pharmaceutical composition is 0.01% to 5% (w / v)" means the ratio of the weight (mg) of the absorption enhancer to the total volume (ml) of the pharmaceutical composition multiplied by 100%.

[0108] The term "w / w" refers to the weight ratio.

[0109] As used herein, the term "treatment" refers to a reduction in the intensity and / or duration of a symptom, or a similar effect. This term also encompasses the side effects of the treatment.

[0110] As used herein, the terms “optional,” “optionally,” or “optionally exist” mean that the event or situation described below may, but is not necessarily, occur, and that the description includes both the occurrence and non-occurrence of said event or situation.

[0111] As used herein, the terms “comprising” and “selected from” are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects. It should be understood that the terms “comprising” and “selected from” can also encompass a closed meaning, meaning “consisting of”.

[0112] As used herein, the terms “selected from…”, “preferred…” and “more preferred…” refer to one or more elements from the group listed below, selected independently, and may include combinations of two or more elements. In this invention, one element from the group listed below is preferred.

[0113] "Pharmaceutically acceptable salt" is intended to refer to salts of rumepiride that are non-toxic, biologically tolerable, or biologically suitable for administration to a subject. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for administration to a patient without undue toxicity, irritation, or allergic reactions. For example, pharmaceutically acceptable salts of rumepiride include toluenesulfonates, oxalates, 4-aminosalicylic acids, cyclamate salts, naphthalenesulfonates, dinaphthalenesulfonates, hydrochlorides, benzenesulfonic acids, dibenzenesulfonates, naphthalene-1,5-disulfonates, hydrobromide salts, phosphates, citrates, oxalates, and di-p-tolyl tartrates, etc.; the toluenesulfonates of rumepiride include one or more of the forms of monotoluenesulfonates, dibenzenesulfonates, and tribenzenesulfonates, wherein the toluenesulfonates include p-toluenesulfonates, o-toluenesulfonates, and meta-toluenesulfonates.

[0114] The term “composition” is intended to cover products containing specified amounts of specified ingredients, and any products obtained directly or indirectly by combining specified amounts of specified ingredients.

[0115] The term "unit formulation" as used in this invention has the conventional meaning in the art, referring to the smallest unit of administration, the smallest unit of payment, or the smallest unit of packaging that can be divided in a drug. For nasal sprays, a unit formulation is a dose of one vial.

[0116] Abbreviation: mpk refers to milligrams per kilogram (mg / kg);

[0117] C max Refers to: maximum plasma concentration;

[0118] The term "AUC" (inf) "" refers to the area under the plasma concentration-time curve from time zero to the time when the final measurable concentration is reached. In general, "time zero" refers to the starting point of the expected dose.

[0119] In some embodiments of the invention, the pharmaceutical composition is administered intranasally. In some embodiments of the invention, lumepimeperone is administered intranasally in the form of p-toluenesulfonate. When lumepimeperone is present in the pharmaceutical composition of the invention in the form of its pharmaceutically acceptable salt, such as p-toluenesulfonate, the content of lumepimeperone refers to the content after converting the pharmaceutically acceptable salt of lumepimeperone to an equimolar amount of lumepimeperone. For example, the conversion factor between lumepimeperone p-toluenesulfonate and lumepimeperone free base is 1.44, i.e., lumepimeperone p-toluenesulfonate mass / 1.44 = lumepimeperone mass.

[0120] In some embodiments of the present invention, the pharmaceutical composition contains rumepiride administered intranasally in an amount of 0.1–200 mg / ml, such as 0.1–100 mg / ml, or 0.1–50 mg / ml, or 0.1–5 mg / ml, or 0.1–10 mg / ml, or 0.25 mg / ml, or 0.35 mg / ml.

[0121] In some embodiments of the present invention, the pharmaceutical composition comprises 0.07 mg / mL to 3.5 mg / mL of lumepirocin p-toluenesulfonate, 0.005 to 0.1% (w / v) of disodium ethylenediaminetetraacetic acid (EDTA), 0.1 to 2% (w / v) of polysorbate 80 and PBS buffer, with water as the suspension medium, and the pharmaceutical composition having a pH of 4 to 7. The pharmaceutical composition is administered intranasally.

[0122] In some embodiments of the present invention, the pharmaceutical composition comprises 0.07 mg / mL to 10 mg / mL of lumepirozoline or equimolar amounts of lumepirozoline p-toluenesulfonate, 0.005 to 0.1% (w / v) of disodium ethylenediaminetetraacetic acid (EDTA), 0.1 to 2% (w / v) of polysorbate 80 and PBS buffer, with a pH of 6 to 7, and water as the suspension medium, and the pharmaceutical composition is administered intranasally.

[0123] In some embodiments, nasal spray pumps are used for intranasal delivery of lumepirozoline, wherein the pump delivers a 5 μL to 150 μL solution in water containing 0.07 mg / mL to 3.5 mg / mL of lumepirozoline or an equimolar amount of lumepirozoline p-toluenesulfonate, 0.005% to 0.1% (w / v), preferably 0.005% to 0.007% (w / v) of disodium EDTA, 0.5% to 2% (w / v) of polysorbate 80, and PBS buffer, at pH 4 to 7, preferably 5 to 7.

[0124] In some embodiments, a single pump from the nasal spray device may be configured to deliver about 50 μL to about 200 μL of a rumepiride pharmaceutical composition solution to the nostrils of a subject, preferably including about 60 μL, about 70 μL, about 80 μL, about 90 μL, about 100 μL, about 110 μL, about 120 μL, about 130 μL, about 140 μL, about 150 μL, about 160 μL, about 170 μL, about 180 μL, and about 200 μL of the rumepiride pharmaceutical composition solution. In some embodiments, two pumps are preferably used to deliver about 100 μL to about 400 μL of the rumepiride pharmaceutical composition solution to the subject.

[0125] In some embodiments, the pharmaceutical composition is a sterile solution wherein the bacterial count, calculated per milliliter, is not higher than 10. Furthermore, it is preferable that no pathogens are present. In some embodiments, the solution has self-protective, self-sterile, or both properties.

[0126] In some embodiments, the drug is lumepone or a pharmaceutically acceptable salt thereof in the form of microparticles and / or nanoparticles. Microparticles and nanoparticles of lumepone or a pharmaceutically acceptable salt thereof can be prepared by, for example, grinding, high-pressure homogenization, high-shear methods, etc.

[0127] Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions or as recommended by the manufacturer. Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available. "MK-801" in the following examples refers to dizocilpine.

[0128] Example 1: Pharmaceutical composition of lumepirocin

[0129] This embodiment provides a pharmaceutical composition of lumepirocin, comprising the following components by total volume: 1% (w / v) polysorbate 80, 0.1% (w / v) disodium EDTA, PBS buffer (pH = 6.8), lumepirocin p-toluenesulfonate at a concentration of 0.35 mg / ml (approximately 0.25 mg / ml based on lumepirocin content), and the balance being water. The w / v refers to the weight-to-volume ratio (unit: mg / ml).

[0130] Preparation method: Polysorbate 80 (final concentration 1% (w / v), unit mg / ml) and disodium EDTA (final concentration 0.1% (w / v), unit mg / ml) were added to PBS buffer at pH=6.8 to obtain a solvent. At room temperature, the prescribed amount of lumepirozoline p-toluenesulfonate was added to the corresponding volume of solvent and stirred until dissolved to obtain a clear and transparent solution.

[0131] Example 2: Pharmaceutical composition of lumepirocin

[0132] This embodiment provides a pharmaceutical composition of lumepirocin, comprising, by its total volume, the following components: 1% (w / v) polysorbate 80, 0.1% (w / v) disodium EDTA, PBS buffer (pH = 6.8), lumepirocin p-toluenesulfonate at a concentration of 3.5 mg / ml (approximately 2.5 mg / ml based on lumepirocin content), with the balance being water. The w / v refers to the weight-to-volume ratio (in mg / ml).

[0133] The preparation method is the same as in Example 1.

[0134] Example 3: Pharmaceutical composition of lumepirox

[0135] This embodiment provides a pharmaceutical composition of lumepirocin, comprising the following components by total volume: 1% (w / v) polysorbate 80, 0.1% (w / v) disodium EDTA, PBS buffer (pH = 6.8), lumepirocin p-toluenesulfonate at a concentration of 0.07 mg / ml (approximately 0.05 mg / ml based on lumepirocin content), with the balance being water. The w / v refers to the weight-to-volume ratio (unit: mg / ml).

[0136] The preparation method is the same as in Example 1.

[0137] Example 4: Pharmaceutical composition of lumepirox

[0138] This embodiment provides a lumepirocin pharmaceutical composition comprising polysorbate 80, disodium EDTA, PBS buffer, and lumepirocin p-toluenesulfonate (content based on lumepirocin), with the balance being water. The content of each component, based on the total volume of the pharmaceutical composition, is as follows:

[0139] Polysorbate 80 Disodium EDTA Lumepiride pH Example 4a 1% (w / v, mg / ml) 0.005% (w / v, mg / ml) 25mg / ml 5.5 Example 4b 1% (w / v, mg / ml) 0.007% (w / v, mg / ml) 25mg / ml 5.5 Example 4c 1% (w / v, mg / ml) 0.005% (w / v, mg / ml) 5mg / ml 7 Example 4d 1% (w / v, mg / ml) 0.1% (w / v, mg / ml) 0.3mg / ml 6.8 .

[0140] Example 5: Pharmaceutical composition of lumepirocin

[0141] Prescription composition:

[0142] Element Prescription dosage effect Lumepiride p-Toluenesulfonate 718.75mg raw materials Anhydrous ethanol 40g solvent Propylene glycol (for injection) 10g solvent Disodium EDTA (for injection) 6mg Absorption enhancer Butyl hydroxyanisole 5mg antioxidants

[0143] Preparation method:

[0144] Weigh the prescribed amounts of anhydrous ethanol, propylene glycol (for injection), disodium EDTA (for injection), and butylated hydroxyanisole into a 100ml volumetric flask. Under nitrogen purging, add the prescribed amount of active pharmaceutical ingredient into the above solution and dissolve it completely to obtain the final product.

[0145] Example 6: Pharmaceutical composition of lumepirox

[0146] Prescription composition:

[0147] Element Prescription dosage effect Lumepiride p-Toluenesulfonate 718.75mg raw materials Anhydrous ethanol 40g solvent Propylene glycol (for injection) 10g solvent Disodium EDTA (for injection) 6mg Absorption enhancer Butyl hydroxyanisole 50mg antioxidants

[0148] Preparation method:

[0149] Weigh the prescribed amounts of anhydrous ethanol, propylene glycol (for injection), disodium EDTA (for injection), and butylated hydroxyanisole into a 100ml volumetric flask. Under nitrogen purging, add the prescribed amount of active pharmaceutical ingredient into the above solution and dissolve completely to obtain the final product.

[0150] Example 7: Lumepiride nasal spray formulation

[0151] Prescription composition:

[0152]

[0153] Preparation method:

[0154] (1) Weigh 0.6805g potassium dihydrogen phosphate, 0.0896g sodium hydroxide, 1g Tween 80 and 0.1g disodium edetate (EDTA disodium salt) into a 100ml volumetric flask, add purified water, shake well and make up to volume to obtain a PBS (pH 6.8) solution containing 1% (w / v) Tween 80 and 0.1% (w / v) disodium edetate.

[0155] (2) Weigh the prescribed amount of p-toluenesulfonic acid lumepirozoline in a nitrogen-filled environment and place it in a round-bottom flask. Then add 50 ml of the solution prepared in step (1) to the round-bottom flask and stir magnetically to dissolve it, so as to obtain the lumepirozoline nasal spray preparation with a concentration of 10 mg / ml.

[0156] Test Example 1: Pharmacokinetic Study

[0157] Male rats were randomly divided into three groups (denoted as groups A, B, and C), with three rats in each group. The experimental drug was the rumeperone drug composition prepared in Examples 1-3 of this invention; wherein:

[0158] Group A was the nasal drop group, which was given the rumeperone drug composition prepared in Example 2. The administration method was as follows: after anesthesia with isoflurane, the drug was administered by dripping into the nasal cavity with a pipette. The drug concentration was 3.5 mg / ml (calculated as rumeperone p-tosylate) and the dose was 0.35 mg / kg.

[0159] Group B was the intravenous injection group, which was given the rumepiride drug composition prepared in Example 3. The administration method was: via tail vein injection, the drug concentration was 0.07 mg / ml (calculated as rumepiride p-tosylate), and the dose was 0.35 mg / kg.

[0160] Group C was the gavage group, which was given the rumepiride drug composition prepared in Example 1 by gavage at a concentration of 0.35 mg / ml (calculated as rumepiride p-tosylate) and a dose of 3.5 mg / kg.

[0161] After drug administration, blood samples were collected via the jugular vein at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h. Blood drug concentrations were measured by LC-MS / MS, and pharmacokinetic parameters were calculated. The experimental results are shown in Table 1.1 and... Figure 1 As shown.

[0162] Table 1.1: PK test results of three routes of administration for rumepiride drug compositions

[0163]

[0164]

[0165] From Table 1.1 above and Figure 1 The results show that the bioavailability of the rumepiride pharmaceutical composition provided by this invention, based on 100% bioavailability for intravenous injection, is approximately 156% for intranasal administration and 1.56% for gavage administration in rats. This indicates that the pharmaceutical composition provided by this invention has extremely high bioavailability when administered intranasally, approaching that of intravenous injection. The low bioavailability of gavage administration is consistent with previously published data, while the absorption characteristics of intranasal administration are similar to those of intravenous injection.

[0166] Test Example 2: Pharmacokinetic Study

[0167] Male rats were randomly divided into three groups (A, B, and C, respectively), with three rats in each group. Each group was given the drug composition of rumepiride prepared in Example 2 (concentration 3.5 mg / ml, calculated as rumepiride p-tosylate), with a dosage of 0.35 mg / kg. In Group A, the drug composition was administered sublingually by pulling the rat's tongue and using a pipette for 30 seconds. In Group B, the drug was administered via nasal instillation after anesthesia with isoflurane. In Group C, the drug was administered via intramuscular injection in the left thigh.

[0168] After drug administration, blood samples were collected via the jugular vein at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h. Blood drug concentrations were measured by LC-MS / MS, and pharmacokinetic parameters were calculated. The experimental results are shown in Table 1.2.

[0169] Table 1.2: PK test results of rumepiride drug compositions via three routes of administration

[0170] route of administration inside the nose Sublingual Intramuscular injection <![CDATA[t 1 / 2 (h)]]> 1.58±0.12 1.67±0.18 1.57±0.28 <![CDATA[C max (ng / mL)]]> 159.67±43.78 61.47±5.03 35.97±16.20 <![CDATA[T max (h)]]> 0.08±0.00 0.25±0.00 0.39±0.53 <![CDATA[AUC (inf) (ng·h / mL)]]> 98.59±18.19 47.52±23.11 80.96±8.64 <![CDATA[AUC (0-t) (ng·h / mL)]]> 97.42±18.38 46.75±23.05 78.59±9.55 <![CDATA[AUC inf / AUC t ]]> 101.26±0.56 101.86±1.06 103.15±2.15 Bioavailability* (%) 100 48.20 82.11

[0171] *: Based on the results of test example 2, intranasal administration was used as 100% bioavailability for calculation.

[0172] The results above show that, based on the bioavailability of nasal drops as 100%, the bioavailability of the rubepirolone drug composition provided by the present invention is approximately 82% and 48% when administered intramuscularly and sublingually in rats, respectively. This indicates that the bioavailability of the drug composition provided by the present invention is higher when administered intranasally than when administered sublingually and intramuscularly.

[0173] Test Example 3: Effects of different routes of administration of rumepiride on brain distribution

[0174] Test substance: pharmaceutical compositions of lumepirozoline p-tosylate prepared in Examples 2 and 3 (dosage and concentration are in lumepirozoline, the same below);

[0175] Experimental Methods: Male SD rats (weighing 180-220g) were randomly divided into three groups: nasal drop group and gavage group (n=18 per group), and intravenous group (n=6 per group). The nasal drop group and gavage group each included six subgroups (10 min, 30 min, 60 min, 120 min, 240 min, 480 min), while the intravenous group included two subgroups (10 min, 120 min), with three rats in each subgroup. The gavage group received 25 mg / kg lumepirozoline via gavage, the intravenous group received 0.25 mg / kg lumepirozoline via intravenous injection, and the nasal drop group received 0.25 mg / kg lumepirozoline via nasal drop under sevoflurane anesthesia. Animals were sacrificed at the corresponding time points according to subgroup classification. Plasma and brain homogenates were collected and prepared (brain homogenate prepared at a 1:4 ratio). The concentration of lumepirozoline in plasma and brain tissue was analyzed, and pharmacokinetic parameters and the brain-blood exposure ratio were calculated. Dosage and volume are shown in Table 3.1.

[0176] Table 3.1: Dosage and Volume

[0177]

[0178] The experimental results are shown in Table 3.2. Although the gavage group (PO) reached peak concentration in the brain and plasma faster (10-60 min), the peak concentration in clinical oral administration takes about 3-4 hours. It is expected that brain exposure time is highly correlated with clinical drug absorption. The intranasal administration group reached peak drug concentration in the brain faster and had a higher brain-blood ratio, indicating that intranasal administration can accelerate drug entry into the brain and increase brain exposure. Furthermore, the intranasal administration group (IN) had a dosage that was only 1 / 100 of that in the gavage group, but its brain exposure was much higher than that in the gavage group (PO). This indicates that the intranasal drug composition provided by this invention has significant advantages over oral formulations in terms of brain targeting, improved bioavailability, reduced dosage, and reduced side effects.

[0179] Table 3.2: Experimental Results

[0180]

[0181] Test Example 4: Effect of intranasal administration of lumepimeperone on MK-801-induced hyperkinesis in mice

[0182] Test substance:

[0183] Negative control group and model control group: The test substance was an intravenous injection solvent, which was a PBS (pH 6.8) solvent containing 1% (w / v, mg / ml) polysorbate 80 and 0.1% (w / v, mg / ml) EDTA-2Na; the preparation method was the same as step (1) in Example 7.

[0184] Gavage group, nasal drop group, low-dose intravenous group, medium-dose intravenous group, and high-dose intravenous group: The test substance was a rumepiride pharmaceutical composition; the preparation method was to dilute the rumepiride nasal spray preparation (10 mg / ml) prepared in Example 7 with intravenous injection solvent to rumepiride concentrations of 0.3 mg / ml, 1.5 mg / ml, 0.02 mg / ml, 0.06 mg / ml, and 0.2 mg / ml, respectively, for later use.

[0185] Experimental methods:

[0186] Male C57BL6 mice were randomly divided into 7 groups (n=12 per group) according to their body weight (22-30g): negative control group (no MK-801), model control group, gavage group, nasal drop group, and intravenous low, medium, and high dose groups. Except for the negative control group (no MK-801), all other groups were intraperitoneally injected with 0.3mg / kg MK-801 5 min later (the gavage group was administered MK-801 by gavage 45 min before injection). The negative control group and model control group were intravenously injected with the solvent. The nasal drop group and the intravenous low, medium, and high dose groups were administered the corresponding dose of rumepiride via the corresponding route according to their group.

[0187] Open field testing was conducted 15 minutes after MK-801 injection (10 minutes after intravenous / nasal administration). The total distance and speed of movement of the mice within the test chamber were recorded. Each mouse was observed for 2 hours (15-135 minutes after administration). The movement of the mice at each time point was statistically analyzed. The administration routes and dosages for each group are shown in Table 4.1.

[0188] Table 4.1: Groups, routes of administration, and dosages

[0189]

[0190] Experimental results are as follows Figure 2As shown, MK-801 induces hallucinations, delusions, and bizarre behaviors similar to those in schizophrenia by antagonizing NMDA receptors. In the experiment, the nasal drop group (0.3 mg / kg) showed a significant therapeutic effect on MK-801-induced hyperkinesis, with an EC50 < 0.1 mg / kg. In the experiment, the nasal drop group (0.3 mg / kg) and the intravenous injection group (0.1-1 mg / kg) were administered 15 minutes before MK-801 injection, while the gavage group (3 mg / kg) was administered 60 minutes before MK-801 injection, and all achieved similar therapeutic effects, suggesting that nasal drops / intravenous injection have an advantage in onset speed compared to oral administration.

[0191] Test Example 5: Effect of Lumepiride Nasal Spray on DOI-Induced Head-Shaking Behavior in Mice

[0192] Test substance: A pharmaceutical composition of rumepiride, prepared as a similar method to Example 7, comprising 1% (w / v, mg / ml) polysorbate 80 and 0.1% (w / v, mg / ml) EDTA-2Na and rumepiride p-toluenesulfonate, at pH 6.8, wherein the concentration of rumepiride is 0.3 mg / ml. It was then diluted with solvent to rumepiride concentrations of 0.003 mg / ml, 0.05 mg / ml, 0.002 mg / ml, 0.006 mg / ml, and 0.02 mg / ml, respectively, for later use.

[0193] Solvent: A solution of PBS (pH 6.8) containing 1% (w / v, mg / ml) polysorbate 80 and 0.1% (w / v, mg / ml) EDTA-2Na.

[0194] Experimental Methods: Male C57BL6 mice were randomly divided into 7 groups (n=12 per group) according to their body weight (22-30g): intravenous control group, nasal drop control group, gavage group (po), nasal drop group (in), and intravenous (iv) low, medium, and high dose groups. 1 mg / kg of 2,5-dimethoxy-4-iodoamphetamine (DOI) was administered intraperitoneally 15 minutes before the injection (30 minutes before DOI injection for the gavage group). The intravenous and nasal drop control groups received the solvent via intravenous injection or nasal drop, respectively. The gavage, nasal drop, and intravenous low, medium, and high dose groups received the corresponding dose of lumepimeperone according to their respective routes of administration.

[0195] Immediately after DOI injection, the mice were placed in a head-shaking test chamber, and the number of head-shaking events in ICR mice was recorded within 20 minutes. The administration routes and dosages for each group are shown in Table 5.1.

[0196] Table 5.1: Groups, routes of administration, and dosages

[0197]

[0198] Experimental results are as follows Figure 3 and 4 As shown, DOI induces head-twitching behavior in mice by activating 5-HT2A receptors. Lumepiride has strong inhibitory activity against 5-HT2A receptors. In the experiment, nasal administration of 0.01 mg / kg of lumepimepiride significantly treated DOI-induced head-twitching behavior, with EC50 < 0.01 mg / kg. In the experiment, nasal or intravenous administration of 0.01 mg / kg of lumepimepiride had similar therapeutic effects, and the effect was stronger than that of 0.03 mg / kg of lumepimepiride administered by gavage. This indicates that the drug composition provided by the present invention has an advantage in effective dose when administered via nasal drops compared to oral administration.

[0199] Test Example 6: Pharmacokinetic Study

[0200] Test substance: Intranasal administration group was given the rumeperone pharmaceutical composition prepared in Example 6 at a volume of 0.1 ml / kg and a dose of 1 mg / kg;

[0201] The preparation process for the injection administration group (IV) was as follows: An appropriate amount of lumepirozol p-tosylate was added to physiological saline solution, vortexed, and sonicated to prepare a solution with a concentration of 0.5 mg / ml. The administration volume was 2 ml / kg, and the dosage was 1 mg / kg.

[0202] Experimental Methods: Male rats were randomly divided into two groups (injection group and intranasal administration group), with 3 rats in each group. Each group was administered rumeperone at a dose of 1.0 mg / kg. In the intranasal administration group, the drug was administered via pipette after isoflurane anesthesia, while the injection group received the drug via tail vein injection. After administration, blood samples were collected via jugular vein at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, and 8 h. Blood drug concentrations were measured by LC-MS / MS, and pharmacokinetic parameters were calculated. Results are as follows: Figure 5 As shown, the pharmaceutical composition of rumepiride provided by the present invention can achieve similar pharmacokinetic characteristics to rumepiride injection when administered intranasally.

[0203] Test Example 7: Spray Pattern Detection

[0204] 2 ml of the lumepone drug composition solution prepared in Examples 1-6 of this invention (hereinafter referred to as "lumepone p-toluenesulfonate nasal spray") was packaged in packaging material (Aptar Classic pump, 100ul, screw cap 18 / 415 + nasal push button + outer cover + 10ml bottle). The spray mode, spray morphology and particle size distribution of the lumepone p-toluenesulfonate nasal spray (multi-spray) were detected using a Spray VIEW spray mode and spray pattern analyzer and an STP5315 spray particle size analyzer.

[0205] Spray pattern testing was performed using an automatic trigger, while spray mode testing was performed using an automatic actuator.

[0206] Experimental results show that, through the investigation of the spray pattern, spray morphology and droplet size of Lumepiride p-toluenesulfonate nasal spray, the greater the amount of Lumepiride p-toluenesulfonate, the greater the ellipticity value of the spray pattern, the smaller the spray angle and width, and the larger the droplet size Dv(50)(μm) and Dv(90)(μm).

[0207] An automatic press-triggered device was used to test the uniformity of the spray dosage. Using this packaging material (Aptar Classic pump, 100μl, screw cap 18 / 415 + nasal push button + outer cover + 10ml bottle), 2ml of lumepirolimus p-toluenesulfonate solution had essentially the same drug content in the 5th to 15th sprays, indicating that the lumepirolimus p-toluenesulfonate drug composition prepared by this invention for intranasal administration has good uniformity.

[0208] Test Example 8: Stability Study

[0209] Appropriate amounts of the rumepiride drug compositions prepared in Examples 5 and 6 were placed at room temperature and 2–8°C for 16–20 days to investigate the changes in related substances. The test results are shown in Table 8.1 below.

[0210] Table 8.1: Stability Test Results

[0211]

[0212] As shown in Table 8.1, the nasal spray drug composition prepared in this invention showed no significant changes in related substances after being stored at 2–8°C for 16 days compared to before storage (3 days at room temperature). After being stored at room temperature for 20 days, the drug composition prepared in Example 6 was more stable than the sample in Example 5.

Claims

1. A pharmaceutical composition for intranasal administration, characterized by comprising, a pharmaceutical composition comprising lumefanlum or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; the pharmaceutically acceptable excipient comprising one or more of an absorption enhancer, a solvent, an antioxidant, and a pH adjuster.

2. The pharmaceutical composition of claim 1, wherein, the pharmaceutically acceptable excipient comprising an absorption enhancer and a pH adjuster; the concentration of lumefanlum is 0.001 to 500 mg / ml, preferably 0.01 to 500 mg / ml, more preferably 0.2 to 300 mg / ml, based on the total volume of the pharmaceutical composition; the concentration of the absorption enhancer is 0.001% to 10% (w / v), preferably 0.001% to 5% (w / v); the pH of the pharmaceutical composition is 4 to 8, preferably 5.5 to 7.

5.

3. The pharmaceutical composition of claim 1, wherein, the pharmaceutical composition comprises lumefanlum or a pharmaceutically acceptable salt thereof, an absorption enhancer, a solvent, and an antioxidant, wherein the lumefanlum or a pharmaceutically acceptable salt thereof is 0.1 to 90% (w / w), preferably 1 to 20% (w / w), more preferably 1 to 10% (w / w), based on the total weight of the pharmaceutical composition; the absorption enhancer is 0.01 to 0.5% (w / w), preferably 0.01 to 0.1% (w / w); the antioxidant is 0.01 to 0.5% (w / w), preferably 0.01 to 0.1% (w / w); the solvent is 50 to 99% (w / w), preferably 80 to 99% (w / w).

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, the absorption enhancer is selected from one or more of cyclodextrins, cholate salts, fatty acids, alcohols, surfactants, chelating agents, chitosans, and phospholipids; preferably, the absorption enhancer is one or more of polysorbate 80, EDTA, disodium ethylenediaminetetraacetate, ethylene glycol tetraacetic acid, lithium polyethylene glycol dodecylhydroxystearate, dodecylphosphocholine, dodecyl-β-D-maltoside, chitosan, carboxymethyl chitosan, propylene glycol, hydroxypropyl-β-cyclodextrin, dimethyl-β-cyclodextrin, PEG 400, sodium deoxycholate, and sodium taurocholate; more preferably, the absorption enhancer is one or more of polysorbate 80, EDTA, disodium ethylenediaminetetraacetate, ethylene glycol tetraacetic acid, lithium polyethylene glycol dodecylhydroxystearate, dodecylphosphocholine; particularly preferably, the absorption enhancer is one or more of polysorbate 80 and disodium ethylenediaminetetraacetate.

5. The pharmaceutical composition according to any one of claims 1 to 2, characterized in that, the pH adjuster is one or more of citrate buffer, phosphate buffer, PBS buffer, sodium hydroxide, potassium hydroxide, and hydrochloric acid.

6. The pharmaceutical composition according to any one of claims 1 or 3 to 4, characterized in that, The antioxidant is selected from at least one of ascorbic acid, ascorbyl palmitate, sodium metabisulfite, vitamin E, butylated hydroxyanisole, butylated hydroxytoluene, di-tert-butylhydroquinone, butylated hydroxytoluene, gallic acid, propyl gallate, octyl gallate, hydroquinone, tocopheryl acetate, β-cyclodextrin, sodium sulfite, sodium thiosulfate, sodium dithionite, potassium metabisulfite, sodium ascorbate, isoascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, sodium isoascorbate, cysteine, L-cysteine ​​hydrochloride, glutathione, monothioglycerol, sodium formaldehyde sulfoxylate, thiourea, methionine, or thymol, preferably butylated hydroxyanisole; The solvent is selected from at least one of water, anhydrous ethanol, and propylene glycol, preferably selected from anhydrous ethanol and propylene glycol.

7. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises rumepiride or a pharmaceutically acceptable salt thereof, polysorbate 80, disodium EDTA, and a pH adjuster; The composition contains, by total volume, 0.01–500 mg / ml of lumepirozoline, 0.1–5% (w / v) of polysorbate 80, 0.001–0.1% (w / v) of disodium ethylenediaminetetraacetate, and has a pH of 5–8, with water as the medium. More preferably, the pharmaceutical composition comprises the following components: Lumepiride p-toluenesulfonate, polysorbate 80, disodium EDTA and pH adjuster; Based on the total volume of the composition, the concentration of lumepirozoline p-toluenesulfonate converted to lumepirozoline is 0.2–200 mg / ml; The concentration of polysorbate 80 is 0.1-2% (w / v); the concentration of disodium ethylenediaminetetraacetate is 0.001-0.1% (w / v), preferably 0.005-0.01% (w / v); The pH adjuster is PBS buffer, and water is used as the suspension medium for the drug composition. The pH of the drug composition is 5-8.

8. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition comprises rumepiride or a pharmaceutically acceptable salt thereof, disodium ethylenediaminetetraacetate, butylated hydroxyanisole, anhydrous ethanol, and propylene glycol; by total weight of the pharmaceutical composition, rumepiride or a pharmaceutically acceptable salt thereof comprises 1-10% (w / w), disodium ethylenediaminetetraacetate comprises 0.01%-0.1% (w / w), butylated hydroxyanisole comprises 0.01%-0.1% (w / w), anhydrous ethanol comprises 70-90% (w / w), and propylene glycol comprises 10-30% (w / w). Further preferably, the lumepone or a pharmaceutically acceptable salt thereof is selected from lumepone p-toluenesulfonate.

9. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that, The pharmaceutical composition is a drop, spray, or aerosol, preferably a spray; More preferably, the unit dosage volume of the pharmaceutical composition is 1 μl to 1000 μl.

10. Use of the pharmaceutical composition according to any one of claims 1 to 9 in the preparation of a medicament for treating patients with a disease that can be treated with rumepiride; Preferably, the bioavailability achieved by the pharmaceutical composition is about 80% to 130% of the bioavailability achieved by a similar amount of lurasidone or a pharmaceutically acceptable salt thereof administered by intramuscular injection; and / or, the bioavailability achieved by the pharmaceutical composition is 180% to 300% of the bioavailability achieved by a similar amount of lurasidone or a pharmaceutically acceptable salt thereof administered sublingually. Preferably, the bioavailability achieved by the pharmaceutical composition is about 80% to 130% of the bioavailability achieved by a similar amount of lurasidone or a pharmaceutically acceptable salt thereof administered by intramuscular injection; and / or, the bioavailability achieved by the pharmaceutical composition is 180% to 300% of the bioavailability achieved by a similar amount of lurasidone or a pharmaceutically acceptable salt thereof administered sublingually.

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