Nomeline nasal-brain delivery preparation

Abstract

The invention provides a nomeline nasal-brain delivery preparation for transnasal region mucosa administration, and an auxiliary material mixture of the nasal-brain delivery preparation comprises 1) phospholipid, and 2) any one of diluent ethyl oleate, isopropyl myristate, sesame oil or castor oil; optionally, the auxiliary material mixture can also comprise 3) a dissolving agent such as ethanol or diethylene glycol monoethyl ether, the auxiliary material mixture is a non-aqueous system, and a solution prepared from the mixture of the two or three auxiliary materials can be absorbed by the nasal meatus olfactory mucosa after being administrated through the nasal region mucosa, can be quickly conducted to the brain olfactory bulb region along olfactory nerves and cerebrospinal fluid, and can be used for treating the brain olfactory bulb. The problems that the peripheral side effect is high due to poor brain targeting of the medicine, the medicine takes effect slowly and the like are solved.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a naso-brain delivery formulation, and particularly to a naso-brain delivery formulation of zenomeprazole. 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, or 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] Specifically, under the aforementioned administration methods, the drug must first enter the systemic circulation and undergo complex absorption, distribution, and metabolism processes. Many drugs with central nervous system activity have extremely high plasma protein binding rates, meaning that most of the drug in the blood is bound to proteins and loses its ability to freely cross the blood-brain barrier. To overcome this barrier and ensure an effective therapeutic concentration in the brain, clinicians have to significantly increase the dosage. However, this "high-dose" strategy raises a therapeutic contradiction: 1. Slow onset of action: The drug enters the bloodstream from the administration site, then undergoes distribution and competitive dissociation into a free state before slowly crossing the blood-brain barrier. This entire process is lengthy. For acute or severe central nervous system diseases requiring rapid intervention (such as status epilepticus, cerebral edema, and acute severe pain), this delayed effect may lead to missed treatment opportunities and seriously affect the efficacy of treatment.

[0004] 2. Peripheral toxicity becomes prominent: High-dose administration leads to widespread and prolonged exposure of the drug in the systemic bloodstream. High concentrations of the drug accumulate in peripheral organs and tissues, easily triggering dose-limiting toxic side effects such as liver and kidney damage, cardiovascular abnormalities, and gastrointestinal reactions. This not only reduces patient tolerance and compliance but also forces treatment interruption, creating a vicious cycle of "insufficient doses result in no brain response, while excessive doses lead to systemic poisoning."

[0005] In recent years, transdermal, sublingual, and traditional nasal spray drug delivery routes all involve drugs being absorbed into the bloodstream and then crossing the blood-brain barrier (BBB) ​​to reach the brain. While these methods can improve bioavailability and reduce the first-pass effect in the liver to some extent, the drugs still require a relatively large dose to achieve adequate brain exposure because they must pass through the BBB in peripheral circulation and plasma protein binding rates are high. Traditional nasal administration (nasal sprays) has attracted attention due to its non-invasive nature and the potential for "direct brain access." However, its absorption route is still primarily through the nasal mucosa, essentially remaining within the "bloodstream first" model. Therefore, it offers limited improvement in onset speed and also cannot avoid the risk of side effects from systemic exposure.

[0006] 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 granted new approval to 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 its 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 drug delivery. Against this backdrop, developing an innovative delivery strategy that can bypass systemic circulation, achieve efficient direct brain targeting, rapid onset of action, and significantly reduce systemic exposure has become an urgent need to overcome the bottlenecks in the treatment of central nervous system diseases. Summary of the Invention

[0007] 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, under traditional drug delivery routes, drugs need to enter the brain through systemic circulation. This disclosure provides a naso-brain delivery formulation of zenomeprazole that can be delivered across the nasal olfactory mucosa. Through the rational combination of excipients and their proportions, the obtained naso-brain delivery formulation of zenomeprazole can be absorbed across the olfactory mucosa of the superior nasal passage, rapidly conducted along the olfactory nerve and / or cerebrospinal fluid to the olfactory bulb region of the brain, and then diffuse to other brain regions, thus rapidly exerting its effect.

[0008] Therefore, in a first aspect, the present invention provides a naso-brain delivery formulation of zenomeprazole that can be delivered across the nasal olfactory mucosa: the naso-brain delivery formulation of zenomeprazole comprises: The active ingredient is nomerin or its pharmaceutically acceptable salts, isomers, solvates, and hydrates; 2) An excipient mixture, wherein the excipient mixture is a non-aqueous system, and the excipient mixture includes, i) Phospholipids; ii) Diluent: The diluent includes any one or more of ethyl oleate, isopropyl myristate, sesame oil, or castor oil; Optionally, it also includes iii) Solvent: The solvent is selected from diethylene glycol monoethyl ether or ethanol.

[0009] In some embodiments, the phospholipid can be lecithin or soybean lecithin; further, the lecithin can be of any type, such as lecithin E80 or lecithin PL100M, and the soybean lecithin can be of any type, such as soybean lecithin S75 or soybean lecithin S100.

[0010] In some embodiments, the phospholipid constitutes a mass percentage of 1% to 25% in the excipient mixture, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, or any value between any two of these values.

[0011] In some embodiments, the mass ratio of the solvent to the phospholipid is (0.8~3.0):1, for example 0.8:1, 0.9:1, 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 2:1, 2.5:1, 3.0:1 or any value between any two ratios.

[0012] In some implementations, the mass ratio of diethylene glycol monoethyl ether, phospholipid, and ethyl oleate is (0.8~1.5):1:(5~8), for example, 0.8:1:5, 0.9:1:5.5, 1.0:1:5.5, 1.1:1:6, 1.2:1:6, 1.2:1:7, 1.3:1:6.5, 1.4:1:6.5, 1.5:1:7, 1.2:1:7.5, 1.2:1:8, or any value between any two ratios.

[0013] In some implementations, the mass ratio of the ethanol, phospholipids, and castor oil is (1.0~3.0):1:(5~8), for example: 1:1:5, 1:1:6, 1:1:7, 1:1:8, 2:1:5, 2:1:6, 2:1:7, 2:1:8, 3:1:5, 3:1:6, 3:1:7, or 3:1:8, or any value between any two ratios.

[0014] In some embodiments, the mass ratio of the diethylene glycol monoethyl ether, phospholipid, and isopropyl myristate is (0.8~1.5):1:(5~8), for example, 0.8:1:5, 0.9:1:5.5, 1.0:1:5.5, 1.1:1:6, 1.2:1:6, 1.2:1:7, 1.3:1:6.5, 1.4:1:6.5, 1.5:1:7, 1.2:1:7.5, 1.2:1:8, or any value between any two ratios.

[0015] In some implementations, the mass ratio of diethylene glycol monoethyl ether, phospholipid, and sesame oil is (0.8~1.5):1:(5~8), for example, 0.8:1:5, 0.9:1:5.5, 1.0:1:5.5, 1.1:1:6, 1.2:1:6, 1.2:1:7, 1.3:1:6.5, 1.4:1:6.5, 1.5:1:7, 1.2:1:7.5, 1.2:1:8, or any value between any two ratios.

[0016] In some implementations, the mass ratio of the diethylene glycol monoethyl ether, phospholipid, and castor oil is (0.8~1.5):1:(5~8), for example, 0.8:1:5, 0.9:1:5.5, 1.0:1:5.5, 1.1:1:6, 1.2:1:6, 1.2:1:7, 1.3:1:6.5, 1.4:1:6.5, 1.5:1:7, 1.2:1:7.5, 1.2:1:8, or any value between any two ratios.

[0017] In some embodiments, the active ingredient in the naso-brain delivery formulation of zenomeline can be 0.1 to 20 mg / mL, for example 0.1 mg / mL, 0.3 mg / mL, 0.5 mg / mL, 1.0 mg / mL, 1.5 mg / mL, 2.0 mg / mL, 2.5 mg / mL, 3.0 mg / mL, 3.5 mg / mL, 4.0 mg / mL, 4.5 mg / mL, 5.0 mg / mL, 5.5 mg / mL, 6.0 mg / mL, 6.5 mg / mL, 7.0 mg / mL, 7.5 mg / mL, 8.0 mg / mL, 8.5 mg / mL, 9.0 mg / mL, 9.5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, or any value between two values.

[0018] In one specific embodiment, the zenomeprazole nasal-brain delivery formulation contains 12 parts by weight of diethylene glycol monoethyl ether, 10 parts by weight of lecithin, and 78 parts by weight of ethyl oleate; it also contains the active ingredient zenomeprazole, wherein the content of zenomeprazole is lower than the solubility saturation in the excipient mixture, and can be any amount, as long as it can satisfy the purpose of complete dissolution of the excipient mixture. Preferably, the lecithin is lecithin PL100M.

[0019] In one specific embodiment, the zenomelin nasal-brain delivery formulation contains 4 mg of zenomelin tartrate, 0.24 g of diethylene glycol monoethyl ether, 0.20 g of lecithin, and 1.56 g of ethyl oleate; preferably, the lecithin is lecithin PL100M.

[0020] In one specific embodiment, the naso-brain delivery formulation of zenomeprazole contains 3 mg of zenomeprazole, 0.24 g of diethylene glycol monoethyl ether, 0.20 g of lecithin, and 1.56 g of ethyl oleate; preferably, the lecithin is lecithin PL100M.

[0021] In one specific implementation, the zenomeprazole nasal-brain delivery formulation contains 29 parts by weight of ethanol, 10 parts by weight of soybean lecithin, and 58 parts by weight of castor oil; it also contains the active ingredient zenomeprazole, the content of which can be any amount, as long as it can satisfy the purpose of complete dissolution of the excipient mixture.

[0022] In one specific implementation, the naso-brain delivery formulation of zenomeprazole contains 1.65 mg of zenomeprazole, 290 mg of ethanol, 95 mg of soybean lecithin, and 580 mg of castor oil.

[0023] In a second aspect, the present invention provides an excipient mixture comprising phospholipids, diethylene glycol monoethyl ether, and ethyl oleate.

[0024] In some embodiments, the phospholipid constitutes a mass percentage of 1% to 25% in the excipient mixture, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, or any value between any two of these values.

[0025] In some embodiments, the mass ratio of the diethylene glycol monoethyl ether to the phospholipid is (0.8~3.0):1, for example 0.8:1, 0.9:1, 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 2:1, 2.5:1, 3.0:1 or any value between any two ratios.

[0026] In some implementations, the mass ratio of diethylene glycol monoethyl ether, phospholipid, and ethyl oleate is (0.8~1.5):1:(5~8), for example, 0.8:1:5, 0.9:1:5.5, 1.0:1:5.5, 1.1:1:6, 1.2:1:6, 1.2:1:7, 1.3:1:6.5, 1.4:1:6.5, 1.5:1:7, 1.2:1:7.5, 1.2:1:8, or any value between any two ratios.

[0027] A third aspect of the present invention provides the use of the above-mentioned naso-brain delivery formulation of phenomenal in the preparation of a drug for treating schizophrenia.

[0028] A fourth aspect of the present invention provides a method for preventing or treating schizophrenia in patients, comprising the step of administering a therapeutically effective amount of the above-described phenomenonine naso-brain delivery formulation to a patient in need of it.

[0029] According to a fifth aspect of the invention, the invention also provides the use of the above-described naso-brain delivery formulation of zenomeprazole in the preparation of a medicament for the treatment or prevention of schizophrenia via nasal delivery to the brain. In particular, the invention also provides the use of the above-described naso-brain delivery formulation of zenomeprazole in the preparation of a medicament for the treatment or prevention of schizophrenia via nasal delivery to the brain.

[0030] 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.

[0031] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention uses a specific mixture of excipients to form a naso-brain delivery formulation of phenomenal. After administration through the nasal olfactory region, it can be absorbed across the olfactory mucosa of the upper nasal passage, rapidly conducted along the olfactory nerve / cerebrospinal fluid to the olfactory bulb region of the brain, and then diffuse to other brain regions to exert its therapeutic effect.

[0032] 2. The naso-brain delivery formulation of the present invention, after administration through the nasal olfactory region, exhibits a high brain-blood ratio, meaning that the drug concentration in the olfactory bulb is very high compared to the drug concentration in the plasma. This demonstrates that a small amount of the drug enters the capillaries and then circulates throughout the body, thus reducing the peripheral side effects of the drug.

[0033] 3. Compared with the oral control, the naso-brain delivery formulation of the present invention can take effect rapidly when administered across the olfactory mucosa, and the brain drug concentration can reach its peak in 15 minutes. When the dosage is 1 / 65 of the oral dosage, the brain drug concentration after transolfactory mucosa administration can reach 1 / 3 of the oral dosage. The drug efficiency is more than 20 times higher when administered across the olfactory mucosa than when administered orally. Attached Figure Description

[0034] 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 average concentration-time curve of the tartrate solution of 1-1 administered via the nasal olfactory region to the posterior anterior cortex of rats, including the striatum, contralateral hemisphere, and other brain regions. Figure 2 This is the average drug concentration-time curve of the tartrate solution of zenomeline in Example 1-1 after a single administration to the olfactory bulb on the administration side of the rat via the nasal olfactory region.

[0035] Figure 3 The average drug concentration-time curves in plasma and brain tissue of rats after oral administration of nomerin are shown in Control Example 1-1. Detailed Implementation

[0036] 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.

[0037] 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

[0038] Brain-targeting parameters refer to the ratio of drugs that, after being administered via the olfactory region, cross the olfactory mucosa and directly enter the brain tissue via the olfactory nerve or surrounding supporting cells to drugs that enter the blood system via capillaries. In this patent application, the brain-targeting parameter, i.e., the brain-blood ratio, is the AUC ratio of drugs entering the olfactory bulb to drugs entering the blood.

[0039] 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.

[0040] The preparation method of pH 4.5 100 mmol / L sodium citrate buffer solution adopts the conventional method of those skilled in the art. In this invention, the following method can be used: take 19 mL of 100 mmol / L sodium citrate solution and 35 mL of 100 mmol / L citric acid solution, mix them evenly, and then test the pH value to be 4.54.

[0041] Example 1-1 To prepare the naso-brain delivery formulation of zenomeprazole tartrate, first prepare a blank formulation by weighing 0.24 g of diethylene glycol monoethyl ether and 0.20 g of lecithin PL100M, and sonicating for 25 mins until completely dissolved. Then weigh 4 mg of zenomeprazole tartrate into the blank formulation and sonicate for 5 mins until dissolved. Finally, add 1.56 g of ethyl oleate to obtain the zenomeprazole naso-brain delivery formulation, designated RY25080601.

[0042] The naso-brain delivery formulation of zenomelin tartrate contains the following components: zenomelin tartrate 4 mg, diethylene glycol monoethyl ether 0.24 g, lecithin PL100M 0.20 g, and ethyl oleate 1.56 g.

[0043] Nasal and olfactory mucosal administration: Pharmacokinetic data were assessed using a freshly prepared naso-brain delivery formulation of zenomeprazole. The zenomeprazole 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 a prescribed dose of drug was administered nasally to rats. In this embodiment, the single dose to rats was 0.2 mg / kg, and the nasal delivery method was a constant-rate or pulsatile administration over 2 minutes. Three rats were administered in parallel at 2, 5, 15, 60, and 240 minutes after administration to evaluate the pharmacokinetics and distribution of the nasal delivery. Sampling of plasma, olfactory bulb (drug administration side), anterior cortex containing the striatum, other cerebral regions, deodorizing bulb (drug administration side), and contralateral hemisphere was performed using methods commonly used by those skilled in the art. The average drug concentrations in plasma and brain tissue after a single nasoencephalogenic administration of 0.2 mg / kg to rats (sample number RY25080601) of the nasoencephalogenic formulation are shown in Table 1 below. Figure 1 and Figure 2 As shown.

[0044] Table 1

[0045] Among them, BQL is below the lower limit of quantitation; The calculated brain-blood ratio AUC 0-t(组织) / AUC 0-t(血浆) As shown in Table 2 below; Table 2

[0046] Note: Plasma drug concentration is measured in ng / mL, and tissue drug concentration is measured in ng / g; since plasma AUC0-t only extends to 1 hour, the above brain-blood ratio uses AUC0. 0-inf The results of the calculations. The remaining brain regions refer to the remaining brain tissue on the side receiving the medication.

[0047] Experimental conclusion: The nasal-brain delivery formulation of zenomeprazole in this embodiment can be rapidly absorbed into various brain tissues after absorption across the nasal and olfactory mucosa, and its distribution in the brain reaches its peak within 15 minutes; the brain targeting parameter is 209.5.

[0048] Examples 1-2 To prepare a solution of zenomeline, first prepare a blank prescription by weighing 0.24 g of diethylene glycol monoethyl ether and 0.20 g of lecithin PL100M, and sonicating for 25 mins to dissolve them completely. Then weigh 3 mg of zenomeline into the blank prescription and sonicate for 5 mins to dissolve it. Finally, add 1.56 g of ethyl oleate to obtain the zenomeline solution, i.e., prescription 1-2.

[0049] Following a method similar to that in Example 1-1, the drug was administered to rats via the nasal olfactory mucosa at a dose of 0.15 mg / kg. Pharmacokinetic data were collected and are shown in Table 3 below. Table 3

[0050] The calculated brain-blood ratio (AUC) 0-t(组织) / AUC 0-t(血浆) As shown in Table 4 below, Table 4

[0051] Experimental conclusion: The nasal-brain delivery formulation of zenomeprazole, formulated with phospholipid-containing excipients in its free form, can be absorbed across the nasal and olfactory mucosa and can be rapidly absorbed into various brain tissues, reaching peak distribution in the brain within 2 minutes; the brain targeting parameter is 456.14.

[0052] Examples 1-3 Formulas 1-3 for the nasal and brain-delivered preparations of zanmomeline are prepared using methods known to those skilled in the art; wherein, formulas 1-3 contain 1.65 mg of free zanmomeline, 290 mg of ethanol, 95 mg of soybean lecithin, and 580 mg of castor oil.

[0053] Following a similar method to Example 1-1, the drug was administered to rats via the nasal mucosa at a dose of 0.15 mg / kg. Pharmacokinetic data were collected, and the drug concentrations at various tissue sites were measured 2 minutes after administration, as shown in Table 5 below. Table 5

[0054] Wherein, the drug concentration is (ng / g or ng / mL), and the ratio of drug concentration in the olfactory bulb and plasma at 2 min on the administration side is calculated to be 147; Experimental conclusion: The naso-brain delivery formulation of the phenomenal used in this embodiment can be absorbed across the olfactory mucosa. The drug concentration in the brain, such as the olfactory bulb, that enters through the olfactory nerve / cerebrospinal fluid is much higher than that of the drug entering the blood system. Moreover, within 2 minutes, it has already diffused to other areas of the brain, such as the anterior cortex, and exerted its therapeutic effect.

[0055] Control Example 1-1 and Oral Control Add 80 mg of zenomeline tartrate, 375 μL of 320 mg / mL sodium chloride solution, and 39.62 mL of 100 mmol / L sodium citrate buffer solution (pH 4.5) to the sample at one time, and sonicate for 2 min to completely dissolve it to obtain the oral formulation of zenomeline YY25031201. The oral formulation YY25031201 was administered to rats via gavage. Plasma and brain tissue samples were collected at 5, 15, 30, 60, and 240 minutes after administration to measure drug concentration. Three rats were used in parallel at each time point. The average drug concentrations in plasma and brain tissue after a single oral administration of 13 mg / kg are shown in Table 6 below. Figure 3 As shown, Table 6

[0056] The calculated PK parameters in plasma and brain tissue are shown in Table 7 below. Table 7

[0057] Experimental conclusion: When administered orally at a dose of 13 mg / kg, the drug concentration in the brain reaches its peak after 60 minutes, and the proportion of drug entering the bloodstream is relatively high, resulting in a higher incidence of peripheral side effects.

[0058] The marketed reference drug KarXT compound was administered to rats by gavage at a dose of 13 mg / kg (calculated as tartaric acid equal to omeprazole). The time to peak concentration of the drug in the brain tissue was 30 minutes, while the AUC ratio of brain tissue to plasma was 12.81; the brain-blood ratio was still very low.

[0059] Comparative Examples 1-2: Nasal delivery of conventional solutions Add 10 mg of zenomeprazole tartrate, 50 μL of 320 mg / mL sodium chloride solution, and 4950 μL of pH 4.5 100 mmol / L sodium citrate buffer to the sampling bottle in sequence. Sonicate at room temperature for 2 mins and mix thoroughly. Filter through a 0.22 μm syringe filter to obtain the zenomeprazole solution, labeled YY25052001.

[0060] Using a nasoencephalogenic route similar to that in Example 2, rats were administered a prescribed dose of the nifedipine solution of this control example via nasal administration. In this example, the single dose for rats was 0.2 mg / kg, and the nasal administration method was either a constant-rate administration or a pulsatile administration over 2 mins. Pharmacokinetics and distribution of the nasally administered rats were assessed at 2, 5, 15, 60, and 240 mins after administration. Plasma, olfactory bulb (drug administration side), hypoolfactory bulb (drug administration side), and contralateral hemisphere were sampled using methods commonly used by those skilled in the art. The obtained pharmacokinetic data are shown in Table 8 below. Table 8

[0061] Note: The unit for drug concentration in plasma is ng / mL, and the unit for drug concentration in tissue is ng / g; Experimental conclusion: When zenomeprazole was administered via the nasal mucosa using an aqueous solution, the brain targeting parameter was 11.9, which is significantly lower than that of the zenomeprazole nasobrain delivery formulation containing excipient phospholipids. This demonstrates that the zenomeprazole nasobrain delivery formulation containing excipient phospholipids can be absorbed across the nasal mucosa, rapidly conducted along the olfactory nerve and cerebrospinal fluid to the olfactory bulb region of the brain, and then diffuse to other brain regions, with less drug selection in the blood system, thereby reducing peripheral side effects.

[0062] Comparative Examples 1-3; Nasal Delivery of Nomercaprol Oil Solution Weigh 10 mg of zenomeline, 250 mg of ethyl oleate, 2 g of polyoxyethylene hydrogenated castor oil RH40, and 2 g of propylene glycol into a sample bottle. Sonicate at room temperature for 20 mins to dissolve and mix thoroughly to obtain the zenomeline solution, number: YY25092301.

[0063] The freshly prepared zanmectin solution was administered to rats via the nasal olfactory region using a method similar to that in Example 1. The dose was 0.2 mg / kg. Samples were taken at 2, 5, 15, 60, and 240 min after administration to assess the pharmacokinetics and distribution of the nasally administered solution. The pharmacokinetic data obtained are shown in Table 9 below. Table 9

[0064] Note: The unit for drug concentration in plasma is ng / mL, and the unit for drug concentration in tissue is ng / g; Experimental conclusion: The naso-brain delivery formulation of zenomeprazole, formulated with ethyl oleate, polyoxyethylene hydrogenated castor oil RH40, and propylene glycol, showed a brain targeting parameter of 15.1 after administration across the nasal olfactory mucosa. This is significantly lower than that of the naso-brain delivery formulation of zenomeprazole containing phospholipids as an excipient. This demonstrates that the naso-brain delivery formulation of zenomeprazole containing phospholipids can be absorbed across the olfactory mucosa of the superior nasal passage and rapidly conducted to the olfactory bulb region of the brain along the olfactory nerve / cerebrospinal fluid, with less drug entering the bloodstream, thereby reducing peripheral side effects.

[0065] Compare with Examples 1-4 0.7 mL of the zenomeprazole solution prepared in Examples 1-3 was weighed and diluted with 1.4 mL of physiological saline to obtain a zenomeprazole emulsion, designated YY25092601. This naso-brain delivery solution was administered to rats via the nasal olfactory region using a method similar to that in Examples 1-1, at a dose of 0.067 mg / kg. Samples were taken at 2, 5, 15, 60, and 240 min after administration to assess the pharmacokinetics and distribution of the nasally administered drug. The pharmacokinetic data obtained are shown in Table 10 below.

[0066] Table 10

[0067] Note: The unit for drug concentration in plasma is ng / mL, and the unit for drug concentration in tissue is ng / g.

[0068] Experimental conclusion: Even when using the emulsion form of zenomeprazole, the brain targeting parameter was only 5.2 after administration across the nasal olfactory mucosa, which is far lower than that of the zenomeprazole nasobrain delivery formulation containing excipient phospholipids. This proves that the zenomeprazole nasobrain delivery formulation containing excipient phospholipids can be absorbed across the olfactory mucosa of the superior nasal passage and rapidly conducted to the olfactory bulb region of the brain along the olfactory nerve / cerebrospinal fluid, while less drug enters the bloodstream, thereby reducing peripheral side effects.

[0069] 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-brain delivery formulation of phenomenal, characterized in that, The nasobrain delivery formulation of the aforementioned nifedipine includes: 1) The active ingredient is phenomenal or its pharmaceutically acceptable salt, isomer, solvate, or hydrate; 2) An excipient mixture, wherein the excipient mixture is a non-aqueous system, and the excipient mixture includes, i) Phospholipids, wherein the phospholipids are selected from either lecithin or soybean phospholipids, and the phospholipids constitute 1% to 25% of the mass percentage of the excipient mixture; ii) Diluent: The diluent contains any one or more of ethyl oleate, isopropyl myristate, sesame oil, or castor oil; Optionally, it also includes iii) Solvent: The solvent is diethylene glycol monoethyl ether or ethanol.

2. The naso-brain delivery formulation of phenomenal according to claim 1, characterized in that, The lecithin is of type E80 or PL100M; and / or, The soybean lecithin is soybean lecithin S75 or soybean lecithin S100.

3. The naso-brain delivery formulation of zenomeprazole according to claim 1, characterized in that, The mass ratio of the solvent to the phospholipid is (0.8~3.0):

1.

4. The naso-brain delivery formulation of zenomeprazole according to claim 3, characterized in that, The mass ratio of the solvent to the phospholipid is 0.8:1, 0.9:1, 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 2:1, 2.5:1, 3.0:1, or any value between any two ratios.

5. The naso-brain delivery formulation of zenomeprazole according to claim 1, characterized in that, The mass ratio of the diethylene glycol monoethyl ether, the phospholipid, and the diluent is (0.8~1.5):1:(5~8).

6. The naso-brain delivery formulation of zenomeprazole according to claim 5, characterized in that, The mass ratio of the diethylene glycol monoethyl ether, the phospholipid, and the diluent is 0.8:1:5, 0.9:1:5.5, 1.0:1:5.5, 1.1:1:6, 1.2:1:6, 1.2:1:7, 1.3:1:6.5, 1.4:1:6.5, 1.5:1:7, 1.2:1:7.5, 1.2:1:8, or any value between any two ratios.

7. The naso-brain delivery formulation of phenomenal according to claim 1, characterized in that, The mass ratio of ethanol, phospholipids, and castor oil is (1.0~3.0):1:(5~8), for example: 1:1:5, 1:1:6, 1:1:7, 1:1:8, 2:1:5, 2:1:6, 2:1:7, 2:1:8, 3:1:5, 3:1:6, 3:1:7, or 3:1:8, or any value between any two ratios.

8. The naso-brain delivery formulation of zenomeprazole according to claim 1, characterized in that, The naso-brain delivery formulation of the aforementioned vinorelbine may have an active ingredient content of 0.1 to 20 mg / mL, for example, 0.1 mg / mL, 0.3 mg / mL, 0.5 mg / mL, 1.0 mg / mL, 1.5 mg / mL, 2.0 mg / mL, 2.5 mg / mL, 3.0 mg / mL, 3.5 mg / mL, 4.0 mg / mL, 4.5 mg / mL, 5.0 mg / mL, 5.5 mg / mL, 6.0 mg / mL, 6.5 mg / mL, 7.0 mg / mL, 7.5 mg / mL, 8.0 mg / mL, 8.5 mg / mL, 9.0 mg / mL, 9.5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, or any value between two of these values.

9. The naso-brain delivery formulation of zenomeprazole according to claim 1, characterized in that, The nasocerebrospinal delivery formulation of zanmomeline contains 12 parts by weight of diethylene glycol monoethyl ether, 10 parts by weight of lecithin, and 78 parts by weight of ethyl oleate, and also contains the active ingredient zanmomeline or its pharmaceutically acceptable salts, isomers, solvates, and hydrates, wherein the content of zanmomeline or its pharmaceutically acceptable salts, isomers, solvates, and hydrates is less than the solubility saturation in the excipient mixture; and / or, The nasocerebrospinal delivery formulation of zenomeprazole contains 4 mg of zenomeprazole tartrate, 0.24 g of diethylene glycol monoethyl ether, 0.20 g of lecithin, and 1.56 g of ethyl oleate; preferably, the lecithin is lecithin PL100M, and / or... The nasocerebrospinal delivery formulation of zanmomelin contains 3 mg of zanmomelin, 0.24 g of diethylene glycol monoethyl ether, 0.20 g of lecithin, and 1.56 g of ethyl oleate; preferably, the lecithin is lecithin PL100M, and / or... The nasocerebrospinal delivery formulation of zenomeline contains 29 parts by weight of ethanol, 10 parts by weight of soybean lecithin, and 58 parts by weight of castor oil; it also contains the active ingredient zenomeline or its pharmaceutically acceptable salts, isomers, solvates, and hydrates, wherein the content of the active ingredient zenomeline or its pharmaceutically acceptable salts, isomers, solvates, and hydrates is less than the solubility saturation in the excipient mixture; and / or, The naso-brain delivery formulation of the aforementioned zenomeline contains 1.65 mg of zenomeline, 290 mg of ethanol, 95 mg of soybean lecithin, and 580 mg of castor oil.

10. The use of the naso-brain delivery formulation of zenomeline according to any one of claims 1 to 9 in the preparation of a drug for treating schizophrenia.

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