Nomeline nasal solution as well as preparation method and application thereof

Abstract

The invention provides a Nomeline nasal solution, which realizes rapid absorption through mucous membrane administration in a nose-smelling region through reasonable compatibility of the good solvent, the absorption enhancer and the diluent, and rapidly reaches the anterior cortex of a target region to play a drug effect. The Nomeline nasal solution can be used as a single preparation, and direct stimulation of gastrointestinal tracts caused by oral administration is avoided, so that the risk of drug absorption disorder or drug effect reduction caused by adverse reaction of digestive tracts is eliminated; the xenomeline nasal solution can be rapidly absorbed by crossing the nasal meatus olfactory mucosa and rapidly exert the drug effect, so that the acute surge state of a mental patient can be effectively controlled, the patient compliance is higher by adopting a cross-olfactory region mucosa administration mode, and the xenomeline nasal solution is more suitable for being applied to the mental patient.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a nasal solution, and particularly to a nasal solution of phenomeline. Background Technology

[0002] The treatment of central nervous system diseases has always been a major challenge in the medical field. Currently, the mainstream systemic drug delivery routes in clinical practice, such as oral administration, intravenous injection, sublingual administration, and transdermal patches, have inherent flaws in their drug delivery pathways to the brain: they must follow an indirect process of "first entering the bloodstream, then the brain." This pathway leads to two interconnected and serious problems: delayed onset of action and significant peripheral side effects, which together limit the clinical application of these drugs.

[0003] In recent years, nasal spray drug delivery has gradually gained attention. However, traditional nasal sprays are absorbed into the bloodstream and then cross the blood-brain barrier (BBB) ​​to reach the brain. While this can improve bioavailability and reduce the first-pass effect in the liver to some extent, the drugs must pass through the BBB in the peripheral circulation, and plasma protein binding rates are high. Therefore, to achieve a certain level of brain exposure, a relatively large dosage is required. Traditional nasal sprays have attracted attention due to their non-invasive nature and the potential for "direct brain access." However, their absorption route is still mainly through the nasal mucosa into the bloodstream, essentially remaining within the "bloodstream first" model. Therefore, their improvement in onset speed is limited, and they also cannot avoid the risk of side effects from systemic exposure.

[0004] Xanomeline, chemically known as 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine, is a partial agonist of muscarinic receptors and is used to treat schizophrenia, Alzheimer's disease, and other conditions. Currently, xanomeline is primarily administered via traditional routes such as oral, intramuscular, and subcutaneous injection. Xanomeline plays a major role in activating the M1 and M4 muscarinic receptors in the central nervous system. However, adverse reactions such as nausea, vomiting, and diarrhea limit its use; these adverse reactions are mainly caused by the activation of peripheral muscarinic receptors. To mitigate peripheral side effects, the FDA newly approved a combination oral capsule of zenomeprazole and troxetine in September 2024, which was approved for marketing in China on December 23, 2025. However, this combination formulation still does not solve the problems of poor central targeting and slow onset of action. The core shortcomings of zenomeprazole lie in "peripheral side effects" and "poor central targeting," both of which are closely related to the inability of traditional drug delivery methods to achieve precise central delivery. On another front, zenomeprazole faces a significant technical challenge in drug development and production: its poor chemical stability. Existing research indicates that zenomeprazole solutions are highly susceptible to degradation under high temperatures or during prolonged storage, leading to a rapid increase in the levels of related substances (impurities). This not only affects the content of the active ingredient but may also introduce unknown toxic impurities, posing a potential risk to drug safety. Against this backdrop, the development of a formulation of zenomeprazole that can rapidly distribute to the cerebral cortex to exert its effects, achieve efficient and direct brain targeting, significantly reduce peripheral side effects such as the risk of hypotension, and reduce gastrointestinal irritation, as well as innovative delivery strategies, has become an urgent clinical need. Summary of the Invention

[0005] In addressing the problems of large drug dosages, significant peripheral side effects, slow onset of action, and poor central targeting in the treatment of central nervous system diseases, especially schizophrenia, traditional drug administration routes require drugs to enter the brain via systemic circulation. This invention provides a nasal solution of phenomenal that can be delivered across the nasal mucosa, offering advantages such as convenient administration, rapid onset of action, avoidance of gastrointestinal side effects and the risk of abnormal blood pressure, improved brain targeting, lower dosage and less toxicity to the nasal mucosa, good drug formulation stability, and simple preparation method.

[0006] Therefore, a first aspect of this disclosure provides a nasal solution of zenomeprazole that can be delivered across the nasal olfactory mucosa: the nasal solution of zenomeprazole comprises: 1) Active ingredient: Zanomeline or its pharmaceutically acceptable salts, isomers, solvates, and hydrates; 2) An excipient mixture, wherein the excipient mixture includes, 2-1) Good solvent: The good solvent is selected from one or more of propylene glycol, ethanol, benzyl alcohol, phenethyl alcohol, dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone (NMP); 2-2) Absorption enhancer: The absorption enhancer is not lecithin; 2-3) Diluent: The diluent is selected from one or more of the following: castor oil, sesame oil, vitamin E, DMA, propylene glycol monocaprylate, ethyl oleate, isopropyl myristate, and polyethylene glycol series; wherein the polyethylene glycol series is mPEG350 or PEG400. Optionally, it also includes 2-4) an antioxidant selected from EDTA or a pharmaceutically acceptable salt thereof and a mixture of BHT.

[0007] In one specific embodiment, the absorption enhancer is selected from one or more of DDM, menthol, cyclopentadecanol, dodecyl phosphate choline, and polyoxyethylene 40 hydrogenated castor oil, or a mixture thereof.

[0008] In one specific embodiment, the diluent is divided into diluent 1 and diluent 2. Diluent 1 is one of mPEG350, PEG400 or DMA. Diluent 2 includes one of castor oil, sesame oil, vitamin E, propylene glycol monocaprylate, ethyl oleate or isopropyl myristate.

[0009] In some embodiments, the concentration of the active ingredient in the nasal solution is 1 mg / mL to 50 mg / mL, preferably 5 mg / mL to 25 mg / mL, for example 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, or any value between any two values.

[0010] In some embodiments, the concentration of the good solvent in the nasal solution of phenomenal is 50-450 mg / mL, preferably 100-350 mg / mL, for example 100 mg / mL, 150 mg / mL, 200 mg / mL, 250 mg / mL, 300 mg / mL, 350 mg / mL or any value between any two values.

[0011] In some specific embodiments, the good solvent is a mixture of ethanol and propylene glycol, wherein the mass ratio of ethanol to propylene glycol is (1.0~3.5):1, for example, 1:1, 1.5:1, 2.0:1, 2.5:1, 3.0:1, 3.5:1 or any value between any two values.

[0012] In some embodiments, the concentration of the absorption enhancer in the nasal solution of zenomeline is 10-250 mg / mL, preferably 50-160 mg / mL, for example 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL or any value between any two values.

[0013] In some embodiments, the absorption enhancer is a mixture of DDM and menthol; the ratio of DDM to menthol is 1:(1~150), for example, 1:1, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, or any value between any two values.

[0014] In some embodiments, the concentration of the diluent in the nasal solution of phenomenal is 250-850 mg / mL, preferably 300-700 mg / mL, for example 300 mg / mL, 350 mg / mL, 400 mg / mL, 450 mg / mL, 500 mg / mL, 550 mg / mL, 600 mg / mL, 650 mg / mL, 700 mg / mL or any value between any two values.

[0015] In some embodiments, the concentration of the antioxidant in the nasal solution of zenomeline is 0.1 mg / mL to 1.0 mg / mL, for example, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, or any value between two values.

[0016] In one specific embodiment, the antioxidant is a mixture of BHT and EDTA, wherein the ratio of BHT to EDTA is (0.1~10):1, for example, 0.1:1, 0.5:1, 1.0:1, 1.5:1, 3:1, 3.5:1, 4.0:1, 4.5:1, 5.0:1, 6:1, 7:1, 8:1, 9:1, 10:1 or any value between any two values, most preferably, 1:1.

[0017] In one specific embodiment, the zenomeprazole nasal solution contains 1 mg / mL to 50 mg / mL of the active ingredient zenomeprazole or a pharmaceutically acceptable salt, 50 to 450 mg / mL of the good solvent, 10 to 250 mg / mL of the absorption enhancer, 250 to 850 mg / mL of the diluent, and optionally, 0.1 mg / mL to 1.0 mg / mL of the antioxidant.

[0018] In one specific embodiment, the zenomeline nasal solution comprises zenomeline tartrate at a concentration of 5 mg / mL to 25 mg / mL, a good solvent at a concentration of 100 mg / mL to 350 mg / mL, an absorption enhancer at a concentration of 50 to 160 mg / mL, and a diluent at a concentration of 300 to 700 mg / mL. Optionally, it further comprises an antioxidant at a concentration of 0.1 mg / mL to 0.5 mg / mL; wherein the good solvent is an ethanol-propylene glycol mixture, the antioxidant is a mixture of BHT and EDTA, the absorption enhancer is a mixture of DDM and menthol, and the diluent is castor oil.

[0019] In one specific embodiment, the zenomeline nasal solution comprises zenomeline tartrate at a concentration of 5 mg / mL to 25 mg / mL, propylene glycol at a concentration of 80 mg / mL to 150 mg / mL, ethanol at a concentration of 200 mg / mL to 300 mg / mL, DDM at a concentration of 0.1 mg / mL to 10 mg / mL, menthol at a concentration of 5 mg / mL to 150 mg / mL, PEG400 at a concentration of 60 mg / mL to 160 mg / mL, and castor oil at a concentration of 300 mg / mL to 400 mg / mL.

[0020] In one specific embodiment, the zenomeline nasal solution comprises 20 mg / mL zenomeline tartrate, 350 mg / mL good solvent, 100 mg / mL absorption enhancer, and 500 mg / mL diluent. Optionally, it also comprises an antioxidant at a concentration of 0.2 mg / mL in the formulation. The good solvent is an ethanol-propylene glycol mixture, the antioxidant is a mixture of BHT and EDTA, the absorption enhancer is a mixture of DDM and menthol, and the diluent is a mixture of PEG400 and castor oil.

[0021] In one specific embodiment, the zenomeline nasal solution comprises 20 mg / mL zenomeline tartrate, 350 mg / mL good solvent, 100 mg / mL absorption enhancer, and 500 mg / mL diluent. Optionally, it further comprises an antioxidant at a concentration of 0.2 mg / mL in the formulation. The good solvent is an ethanol-propylene glycol mixture in a mass ratio of (1.0~3.5):1. The antioxidant is a mixture of BHT and EDTA in a ratio of (0.1~10):1. The absorption enhancer is a mixture of DDM and menthol in a ratio of 1:(1~150). The diluent is a mixture of PEG400 and castor oil in a mass ratio of PEG400 to castor oil of 1:(1.5~5).

[0022] In one specific embodiment, the zenomeline nasal solution comprises 20 mg / mL zenomeline tartrate, 350 mg / mL of a good solvent, 100 mg / mL of an absorption enhancer, and 350 mg / mL of a diluent. Optionally, it also comprises an antioxidant at a concentration of 0.2 mg / mL in the nasal solution. The good solvent is an ethanol-propylene glycol mixture in a mass ratio of 2.5:1. The antioxidant is a mixture of BHT and EDTA in a 1:1 ratio. The absorption enhancer is a mixture of DDM and menthol in a 1:100 ratio. The diluent is a mixture of PEG400 and castor oil in a 1:3 mass ratio.

[0023] In one specific embodiment, the zenomeline nasal solution comprises zenomeline tartrate 20 mg / mL, propylene glycol 100 mg / mL, ethanol 200 mg / mL, EDTA 0.1 mg / mL, BHT 0.1 mg / mL, PEG400 110 mg / mL, DDM 1 mg / mL, menthol 100 mg / mL, and castor oil 360 mg / mL as a diluent.

[0024] A second aspect of the present invention also provides a method for preparing a nasal solution for phenomenonol, specifically comprising the following steps: S1 Weigh the prescribed amounts of the above-mentioned antioxidant and absorption promoter into a container, then add the prescribed amounts of the above-mentioned good solvent, stir or sonicate to dissolve the above-mentioned antioxidant and absorption promoter; to obtain solution one; S2 weighs the prescribed amount of the above-mentioned active ingredient and the above-mentioned diluent 1, adds them to the solution one formed in S1, stirs or sonicates, and obtains solution two; S3 is added to the prescribed amount of the above-mentioned diluent 2, stirred or sonicated, and filtered through a PTFE microporous membrane with a pore size of 0.45μm to obtain the nasal solution of Zanomelin.

[0025] Preferably, the process of bubbling a good solvent and purging it with nitrogen gas is included before S1; More preferably, it also includes step S4, a step of bubbling and filling the nasal solution with nitrogen.

[0026] In one specific embodiment, a nasal solution for zenomeline prepared by the above preparation method is also provided.

[0027] A third aspect of the invention provides the use of the above-described zenomeline nasal solution in the preparation of a medicament for the prevention or treatment of diseases improved by activating muscarinic receptors.

[0028] Preferably, the disease is selected from schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, Lewy body dementia, movement disorder, drug addiction, pain, neurodegenerative diseases such as tau protein disease and conucleoprotein disease.

[0029] A fourth aspect of the present invention provides the use of the above-mentioned nasal solution of phenomenonol in the preparation of a medicament for the prevention or treatment of diseases improved by activating muscarinic receptors via nasal delivery to the brain, wherein the nasal delivery to the brain is a micro-delivery to a precise nasal olfactory region at a constant or pulsed rate, or wherein the nasal delivery to the brain is a targeted spray delivery to the nasal olfactory region.

[0030] In a fifth aspect, the present invention provides a method for treating or preventing diseases caused by activation of muscarinic receptors, comprising administering the above-mentioned zenomeline solution to a subject, preferably, the administration method being a nasal-to-brain delivery method, wherein the nasal-to-brain delivery method is a micro-delivery to a precise nasal olfactory region at a constant rate or in a pulsed manner, or the nasal-to-brain delivery method is a targeted spray delivery to the nasal olfactory region; preferably, the disease is selected from schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, Lewy body dementia, movement disorders, drug addiction, pain, neurodegenerative diseases, such as tau protein diseases and conucleoprotein diseases.

[0031] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0032] Compared with the prior art, the present invention has the following beneficial effects: 1. The nasal solution of the present invention can be used as a single-ingredient preparation, avoiding direct gastrointestinal irritation caused by oral administration, thereby eliminating the risk of drug absorption impairment or reduced efficacy due to adverse reactions in the digestive tract.

[0033] 2. The nasal solution of the present invention can be rapidly absorbed across the olfactory mucosa of the upper nasal passage, exerting its therapeutic effect quickly, thereby effectively controlling the acute agitation state of patients with mental illness.

[0034] 3. The nasal solution of the present invention, when administered via the transnasal olfactory mucosa, achieves a drug concentration in the precortical layer of the target area that is 1.16 times that of the oral administration, with a dose that is only 1 / 23 of the oral dose, compared with the oral administration, thus realizing the therapeutic advantages of low dose, high efficiency and low systemic side effects.

[0035] 4. The nasal solution of this invention, administered via the nasal and olfactory mucosa, achieves a drug concentration ratio in the anterior cortex of the brain to that in plasma of 17.83–21.48, compared to 14.25 for oral administration. This brain-to-blood ratio is 1.25–1.5 times higher than that of oral administration, and exhibits good repeatability at both high and low doses. Therefore, the nasal solution of this invention reduces distribution in systemic circulation, thereby significantly reducing systemic adverse drug reactions (such as cardiovascular and gastrointestinal side effects) while providing patients with enhanced therapeutic efficacy, resulting in precise brain targeting and superior safety.

[0036] 5. The nasal solution of the present invention uses a transnasal olfactory mucosa administration method, which results in higher patient compliance and is convenient for patients with mental illness. Attached Figure Description

[0037] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings: Figure 1 The spectrum of the nasal solution of Zanomeprazole in Example 2 after being placed at 25°C for two days; Figure 2 This is the spectrum of the nasal solution of phenomenal from Example 2 after being placed at 25°C for seven days; Figure 3 The spectrum of the nasal solution of Zanomeprazole from Example 2 after being placed at 40°C for two days; Figure 4 This is the spectrum of the nasal solution of phenomenal from Example 2 after being placed at 40°C for seven days; Figure 5 This is the spectrum of the nasal solution in Control Example 1, which uses 0.2% BHT as an antioxidant, after being placed at 40°C for two days. Figure 6 The spectrum is that of the nasal solution in Control Example 1, which uses 0.2% citric acid as an antioxidant, after being placed at 40°C for two days; Figure 7 This is the spectrum of the nasal solution in Control Example 1, which uses 0.2% EDTA as an antioxidant, after being placed at 40°C for two days. Figure 8 This is the spectrum of pharmacological example 1; Figure 9 This is the spectrum of pharmacological example 2; Figure 10 This is the spectrum of pharmacological control example 1. Detailed Implementation

[0038] The measurement method of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0039] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods. Terminology Explanation

[0040] Brain-targeting parameters refer to the ratio of drugs that, after being administered via the olfactory region, cross the olfactory mucosa and directly enter brain tissue via the olfactory nerve or surrounding supporting cells to drugs that enter the blood system via capillaries. In this invention, the brain-targeting parameter, namely the brain-blood ratio, is the AUC ratio of drugs entering various brain tissues to drugs entering the blood plasma.

[0041] BHT stands for butylated hydroxytoluene. DDM stands for: dodecyl-β-D-maltodextrin; DMA stands for dimethylacetamide.

[0042] Good solvent: In this invention, it refers to a solvent with a solubility of more than 50 mg / g for phenomenal and pharmaceutically acceptable salts.

[0043] In this invention, the local irritation test of the nasal cavity is determined using a ciliary toxicity model, which is a method known to those skilled in the art: the palatal cilia of toads are widely used as a commonly used model to simulate human nasal cilia [1]. After the test drug is dropped onto the mucosal surface for 60 minutes, the palatal mucosa is washed and separated. The continuous movement of the mucosal cilia is observed under an optical microscope, and its effect on the cilia is analyzed by comparing it with physiological saline as a control [2]. The movement of the cilia is observed, and the time required from the start of drug administration to the complete cessation of cilia movement is recorded, i.e., the continuous movement time of the cilia. The continuous movement time of the palatal mucosal cilia of the drug administration group is divided by the continuous movement time of the palatal mucosal cilia of the negative control group to obtain the relative percentage of the continuous movement time of the cilia. The higher this percentage, the lower the toxicity of the preparation to the cilia and the higher the safety of the preparation. The relative percentage of the continuous movement time of the cilia is greater than 85% as the threshold for the safety of the preparation. ([1] Jiang Xinguo, Cui Jingbin. Nasal mucociliary toxicity of drugs and evaluation methods[J]. Acta Pharmaceutica Sinica, 1995, 30: 848-53. [2] Li Xinfang, Li Xiangui, Ma Zhiqiang, et al. Preparation and safety study of menthol nasal in situ gel[J]. Journal of Pharmaceutical Practice, 2017, 3(4): 321-4.).

[0044] In the following examples, the content of drug molecules is exemplary and may be lower or higher than that in the listed examples, depending on the actual use, and is not particularly limited.

[0045] Example 1 Prepare the formulations shown in Table 1 below using methods known to those skilled in the art. Specifically, weigh the prescribed amount of absorption enhancer, add the prescribed amount of good solvent, and sonicate to dissolve the absorption enhancer to obtain solution one; then weigh the prescribed amount of active ingredient and diluent 1, add them to solution one, and stir or sonicate to obtain solution two; finally, add the prescribed amount of diluent 2, stir or sonicate, and filter through a PTFE microporous membrane with a pore size of 0.45 μm to obtain the nasal solution of Zanomeline.

[0046] The newly formulated formulations were placed in a nasal delivery device (the applicant's intelligent integrated nasal delivery system for small animals, as disclosed in CN202021777601.0 and CN202010148279.3) and administered to rats at a prescribed dose via the nose. In this embodiment, the single dose to rats was 0.15 mg / kg (calculated based on phenomenal), and the nasal delivery method was either a constant-rate administration over 2 minutes or a pulsatile administration. Pharmacokinetics and distribution of the nasally administered drug were evaluated in three parallel rats 2 minutes after administration. Plasma and precortical tissue samples were collected using methods commonly used by those skilled in the art. The drug concentration in each tissue at 2 minutes was determined, and the drug concentration ratio in the precortical tissue to the plasma at 2 minutes was calculated.

[0047] Table 1

[0048] Note: The dosage for prescriptions 1-7 is 0.375 mg / kg, based on data taken at 1 minute. Experimental conclusions: After careful selection and matching of excipients, the nasal irritation test was passed. Following nasal delivery, the drug concentration at 2 minutes was measured, and the concentration in the precortical brain target tissue was more than four times the plasma concentration. The formulation used had an appropriate viscosity, ensuring good compatibility with the nasal spray and excellent spray performance.

[0049] Example 2 Because the genomeline solution is unstable at high temperatures or during long-term storage and is prone to exceeding the impurity limit, this Example 2 has undergone a series of formulation optimizations to obtain a stable formulation 2.

[0050] Prepare the following prescription for nasal remedy using the formula in Table 2. The preparation method shall be the conventional method for those skilled in the art. For example, weigh the prescribed amounts of BHT, EDTA-2Na, DDM and menthol, add ethanol and propylene glycol, and sonicate for 5 min. Add API and PEG400, sonicate for 15 min; add castor oil, sonicate for 5 min; filter through a PTFE microporous membrane with a pore size of 0.45 μm to obtain the final product.

[0051] Table 2

[0052] The sample solution prepared in this embodiment was used for stability testing; the results are shown in Table 3 below. Figures 1-4 As shown: Table 3

[0053] Experimental Conclusions: Using a mixture of EDTA and BHT as an antioxidant results in good formulation stability, effectively controlling the content of oxidative degradation impurities in phenomenonine to below 0.1%, thus improving formulation stability and ensuring product quality. The appropriate viscosity of the formulation ensures good compatibility with the nasal spray and excellent spray performance. During development, it was found that impurity content control is independent of absorption enhancers. Even when using other absorption enhancers or surfactants such as dodecylphosphocholine, cyclopentadecanolactone, or altering the type and content of good solvents or diluents without adding absorption enhancers, as long as a mixture of EDTA and BHT is used as the antioxidant, the content of single impurities can be controlled below 0.1%.

[0054] Example 3 The formulations for the preparations listed in Table 4 below shall be prepared in accordance with the conventional methods used by those skilled in the art; Table 4

[0055] Experimental conclusion: After the above formulation was placed at 40℃ and 75%RH for 7 days, the content of oxidative degradation impurities of phenomenal was controlled below 0.1%. Even after changing the proportion of raw materials and excipients in the formulation, the drug formulation still had good stability and the viscosity of the formulation was suitable, which not only ensured good compatibility with nasal sprayers, but also provided excellent spray performance.

[0056] Pharmacological Example 1 Pharmacokinetic data were assessed using the newly prepared zenomeprazole nasal solution formulation 2. The zenomeprazole nasal solution was placed in a nasal delivery device (the applicant's intelligent integrated nasal delivery system for small animals, as disclosed in CN202021777601.0 and CN202010148279.3) and administered to rats at a prescribed dose via nasal administration. In this embodiment, the single dose to rats was 0.75 mg / kg (calculated based on free zenomeprazole), and the nasal administration method was either a constant-rate or pulsatile administration over 2 minutes. Three rats were administered the drug in parallel at 1, 5, 15, 60, 240, and 360 minutes after administration to evaluate the pharmacokinetics and distribution of the nasal administration. The plasma precortical layer was sampled using methods commonly used by those skilled in the art. The pharmacokinetic parameters are shown in Table 5 below. Figure 8 As shown; Table 5

[0057] Pharmacological Example 2 Using a similar administration method to that in Pharmacological Example 1, the single dose for rats was 0.375 mg / kg (calculated based on the free fraction of nomerin). The pharmacokinetic parameters were measured as shown in Table 6 below. Figure 9 As shown; Table 6

[0058] Pharmacological control example 1: To prepare a solution of the marketed reference standard KarXT, specifically, weigh 10.17 mg of tromethorphan chloride, 35.12 mg of vitamin C, 70.05 mg of tartaric acid monamide, 35.19 mg of purified water, and 17.63 g of physiological saline, and sonicate for 3 mins to dissolve them.

[0059] The drug was administered to rats via gavage at a prescribed dose. In this embodiment, the single dose to rats was 13 mg / kg, which is equivalent to 8.5 mg / kg of free nomerin. Three rats were administered the drug in parallel at each time point (1, 5, 15, 60, 240 min, and 360 min) after administration to evaluate the pharmacokinetics and distribution of the intranasally administered drug. Plasma and precortical samples were collected using methods commonly used by those skilled in the art, and the data are shown in Table 7 below. Figure 10 As shown: Table 7

[0060] The oral dosage of 13 mg / kg is calculated based on the dosage of zenomeprazole tartrate, which translates to 8.5 mg / kg of free zenomeprazole. This dosage corresponds to the 100 mg dosage of the marketed control product KarXT in clinical use, converted to rat dosage based on body surface area. Comparison shows that the zenomeprazole nasal solution of this invention, administered across the nasal olfactory mucosa, can be rapidly delivered to the anterior cortex of the target area to exert its effect. At a dosage of 1 / 23 of the oral dose, the drug concentration in the anterior cortex of the target area can reach 1.16 times that of the oral dose, potentially achieving better efficacy with even lower dosages. Under cross-nasal olfactory mucosa administration, the AUC ratio (brain-blood ratio) of the drug in the anterior cortex of the target brain tissue to the plasma is 1.25 to 1.5 times that under oral administration, demonstrating good repeatability.

[0061] Compare with Example 1 Prepare the formulations shown in Table 8 below, using different types of antioxidants. Test the content of related substances after placing the solution at 40°C for 2 days. The preparation methods of each formulation are conventional methods for those skilled in the art and are not limited here, with the aim of obtaining a clear solution.

[0062] Table 8

[0064] Experimental conclusion: Based on the above experimental results and Figure 5 , Figure 6 , Figure 7 As shown, without the addition of antioxidants or using a single antioxidant, it is impossible to effectively control the oxidation of mono-oxidative substances to below 0.1%, which does not meet the quality standards of the formulation.

[0065] Compare with Example 2 The formulations shown in Table 9 below were prepared using methods conventional to those skilled in the art or methods similar to those in Example 1. Table 9

[0066] Experimental conclusion: When using the absorption enhancer phospholipid, the drug solution appears cloudy. It is not suitable for transnasal mucosal delivery.

[0067] The embodiments described above are merely examples of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A nasal solution for nasal use, characterized in that, The nasal solution containing 100% nifedipine includes: 1) Active ingredient: Zanomeline or its pharmaceutically acceptable salts, isomers, solvates, and hydrates; 2) An excipient mixture, wherein the excipient mixture includes, 2-1) Good solvent: The good solvent is selected from one or more of propylene glycol, ethanol, benzyl alcohol, phenethyl alcohol, dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone (NMP); 2-2) Absorption promoter, wherein the absorption promoter is not lecithin; the absorption promoter is one or more of the following: DDM, menthol, cyclopentadecanol, dodecyl phosphate choline, and polyoxyethylene 40 hydrogenated castor oil; 2-3) Diluent: The diluent is selected from one or more of the following: castor oil, sesame oil, vitamin E, DMA, propylene glycol monocaprylate, ethyl oleate, isopropyl myristate, and polyethylene glycol series; wherein the polyethylene glycol series is mPEG350 or PEG400. The concentration of the active ingredient in the nasal solution is 1 mg / mL to 50 mg / mL; The concentration of the good solvent in the nasal solution of phenomeline is 50~450 mg / mL; The concentration of the absorption enhancer in the nasal solution of Zanomeline is 10~250 mg / mL; The concentration of the diluent in the nasal solution of phenomeline is 250-850 mg / mL.

2. The nasal solution for nifedipine according to claim 1, characterized in that, Optionally, it also includes 2-4) an antioxidant selected from EDTA or a pharmaceutically acceptable salt thereof mixed with BHT, wherein the concentration of the antioxidant in the nasal solution of phenomenin is 0.1 mg / mL to 1.0 mg / mL, or... The diluent is divided into diluent 1 and diluent 2. Diluent 1 is one of mPEG350, PEG400 or DMA. Diluent 2 includes one of castor oil, sesame oil, vitamin E, propylene glycol monocaprylate, ethyl oleate or isopropyl myristate.

3. The nasal solution for nifedipine according to claim 1 or 2, characterized in that, The concentration of the active ingredient in the nasal solution is 5 mg / mL to 25 mg / mL, for example, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, or any value between any two values; and / or, The concentration of the good solvent in the nasal solution of phenomenal is 100-350 mg / mL, for example 100 mg / mL, 150 mg / mL, 200 mg / mL, 250 mg / mL, 300 mg / mL, 350 mg / mL, or any value between any two values; and / or, The concentration of the absorption enhancer in the nasal solution of phenomeline is 50-160 mg / mL, for example, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, or any value between any two of these values; and / or, The concentration of the diluent in the nasal solution of phenomenal is 300-700 mg / mL, for example 300 mg / mL, 350 mg / mL, 400 mg / mL, 450 mg / mL, 500 mg / mL, 550 mg / mL, 600 mg / mL, 650 mg / mL, 700 mg / mL, or any value between any two of these values; and / or The concentration of the antioxidant in the nasal solution of zenomeline is 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, or any value between two values.

4. The nasal solution for nifedipine according to claim 1, characterized in that, The good solvent is a mixture of ethanol and propylene glycol, wherein the mass ratio of ethanol to propylene glycol is (1.0~3.5):1; and / or, The absorption enhancer is a mixture of DDM and menthol; the mass ratio of DDM to menthol is 1:(1~150); and / or, The antioxidant is a mixture of BHT and EDTA, wherein the mass ratio of BHT to EDTA is (0.1~10):

1.

5. The nasal solution for nifedipine according to claim 4, characterized in that, The mass ratio of ethanol to propylene glycol is 1:1, 1.5:1, 2.0:1, 2.5:1, 3.0:1, 3.5:1, or any value between any two of these values; and / or, The ratio of DDM to menthol is 1:1, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, or any value between any two values; and / or, The mass ratio of BHT to EDTA is 0.1:1, 0.5:1, 1.0:1, 1.5:1, 3:1, 3.5:1, 4.0:1, 4.5:1, 5.0:1, 6:1, 7:1, 8:1, 9:1, 10:1, or any value between any two values.

6. The nasal solution for nifedipine according to claim 1, characterized in that, The nasal solution for zanmomeline contains 1 mg / mL to 50 mg / mL of the active ingredient zanmomeline or a pharmaceutically acceptable salt, 50 to 450 mg / mL of a good solvent, 10 to 250 mg / mL of an absorption enhancer, and 250 to 850 mg / mL of a diluent. Optionally, it also includes 0.1 mg / mL to 1.0 mg / mL of the antioxidant; or... The nasal solution for jumperidone contains jumperidone tartrate at a concentration of 5 mg / mL to 25 mg / mL, a good solvent at a concentration of 100 mg / mL to 350 mg / mL, an absorption enhancer at a concentration of 50 to 160 mg / mL, and a diluent at a concentration of 300 to 700 mg / mL. Optionally, it also includes an antioxidant at a concentration of 0.1 mg / mL to 0.5 mg / mL; wherein the good solvent is an ethanol-propylene glycol mixture, the antioxidant is a mixture of BHT and EDTA, the absorption enhancer is a mixture of DDM and menthol, and the diluent is castor oil; or, The nasal solution for jumperidone contains jumperidone tartrate at a concentration of 5 mg / mL to 25 mg / mL, propylene glycol at a concentration of 80 mg / mL to 150 mg / mL (a good solvent), ethanol at a concentration of 200 mg / mL to 300 mg / mL (a good solvent), DDM at a concentration of 0.1 mg / mL to 10 mg / mL (an absorption enhancer), menthol at a concentration of 5 mg / mL to 150 mg / mL (an absorption enhancer), PEG400 at a concentration of 60 mg / mL to 160 mg / mL (a diluent 1), and castor oil at a concentration of 300 mg / mL to 400 mg / mL (a diluent 2); or, The zenomeprazole nasal solution comprises 20 mg / mL zenomeprazole tartrate, 350 mg / mL of a good solvent, 100 mg / mL of an absorption enhancer, and 500 mg / mL of a diluent. Optionally, it also includes an antioxidant at a concentration of 0.2 mg / mL in the formulation. The good solvent is an ethanol-propylene glycol mixture, the antioxidant is a mixture of BHT and EDTA, the absorption enhancer is a mixture of DDM and menthol, and the diluent is a mixture of PEG400 and castor oil; or... The zenomeline nasal solution contains 20 mg / mL zenomeline tartrate, 350 mg / mL of a good solvent, 100 mg / mL of an absorption enhancer, and 500 mg / mL of a diluent. Optionally, it also includes an antioxidant at a concentration of 0.2 mg / mL in the formulation. The good solvent is an ethanol-propylene glycol mixture in a mass ratio of (1.0~3.5):

1. The antioxidant is a mixture of BHT and EDTA in a ratio of (0.1~10):

1. The absorption enhancer is a mixture of DDM and menthol in a ratio of 1:(1~150). The diluent is a mixture of PEG400 and castor oil in a mass ratio of PEG400 to castor oil of 1:(1.5~5). The nasal solution of zenomeprazole contains 20 mg / mL zenomeprazole tartrate, 350 mg / mL of a good solvent, 100 mg / mL of an absorption enhancer, and 350 mg / mL of a diluent. Optionally, it also includes an antioxidant at a concentration of 0.2 mg / mL in the nasal solution. The good solvent is an ethanol-propylene glycol mixture at a mass ratio of 2.5:

1. The antioxidant is a mixture of BHT and EDTA at a ratio of 1:

1. The absorption enhancer is a mixture of DDM and menthol at a ratio of 1:

100. The diluent is a mixture of PEG400 and castor oil at a mass ratio of 1:

3. The nasal solution containing 20 mg / mL nasal tartaric acid, 100 mg / mL propylene glycol, 200 mg / mL ethanol, 0.1 mg / mL EDTA, 0.1 mg / mL BHT, 110 mg / mL PEG400, 1 mg / mL DDM, 100 mg / mL menthol, and 360 mg / mL castor oil as a diluent.

7. A method for preparing a nasal solution of phenomenonol, characterized in that, Includes the following steps: S1 Weigh the antioxidant and absorption promoter from the nasal solution of Zanomelide according to any one of claims 1 to 6 into a container, then add the good solvent according to any one of claims 1 to 6, stir or sonicate to dissolve the antioxidant and absorption promoter; to obtain solution one; S2 weighs the active ingredient and diluent 1 from the nasal solution of phenomeline according to any one of claims 1 to 6, adds them to the solution one formed in S1, and stirs or sonicates to obtain solution two; S3 Weigh out the diluent 2 to the solution formed by S2 in the nasal solution of phenomenal as described in any one of claims 1 to 6, stir or sonicate, and filter through a PTFE microporous membrane with a pore size of 0.45 μm to obtain the nasal solution of phenomenal. Preferably, the process of bubbling a good solvent and purging it with nitrogen gas is included before S1; More preferably, it also includes step S4, a step of bubbling and filling the nasal solution with nitrogen.

8. A nasal solution for zenomeline prepared by the preparation method of claim 7.

9. Use of the zenomeline nasal solution according to claims 1 to 6 or 8 in the preparation of a medicament for the prevention or treatment of diseases improved by activating muscarinic receptors.

10. The use according to claim 9, characterized in that, The diseases mentioned are selected from schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, Lewy body dementia, movement disorders, drug addiction, pain, and neurodegenerative diseases such as tau protein disease and conucleoprotein disease.

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