Nimodipine nasal-brain delivery preparation as well as preparation method and application thereof

Abstract

The present invention provides a high brain targeting, safe and noninvasive nasal-brain delivery preparation, which is characterized in that the nasal-brain delivery preparation comprises nimodipine, a good solvent, a diluent and an absorption enhancer, the good solvent is diethylene glycol monoethyl ether, and the absorption enhancer is phospholipid. The nasal-brain delivery preparation is prepared from a good solvent, a diluent, an absorption enhancer and the like according to a specific proportion. Nimodipine serving as an active ingredient is enriched in cerebrospinal fluid and brain tissues through a specific upper nasal meatus administration technology, so that the treatment effect of nimodipine is achieved; and meanwhile, the blood entering proportion is reduced, so that the cardiovascular toxicity and hepatotoxicity are reduced. In addition, the preparation formula has no irritation to local parts of the nasal cavity, and the compliance of a patient is improved.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and relates to a drug nasal-brain delivery preparation, in particular to a high-safety, high-brain-targeted nasal-brain delivery preparation, and especially to a high-safety, high-brain-targeted nasal-brain delivery preparation of nimodipine. Background Art

[0002] Nimodipine (NM) is a second-generation dihydropyridine calcium channel antagonist that can inhibit the influx of calcium ions in cerebral vascular smooth muscle cells and brain neurons. The drug preferentially acts on arterioles, selectively dilates cerebral blood vessels, increases cerebral blood flow, protects ischemic neurons, promotes memory and promotes intellectual recovery, and has both neurological and psychopharmacological effects. It is clinically used for the treatment of cerebral ischemic diseases, cerebral vasospasm caused by subarachnoid hemorrhage, sudden deafness and other diseases, and has achieved good therapeutic effects. However, nimodipine has extremely poor water solubility, strong oral first-pass effect, low bioavailability, and the injection used clinically uses a large amount of ethanol as a solvent, which makes it highly irritating. Nimodipine also has cardiovascular toxicity and hepatotoxicity. In addition, the blood-brain barrier is the main bottleneck for drugs to play a therapeutic role in central diseases. Nimodipine is not easy to effectively cross the blood-brain barrier, resulting in a low brain entry rate, and it is difficult to maximize the therapeutic effect of brain diseases.

[0003] The nose-brain delivery system mainly delivers drugs to the upper nasal passages. As a non-invasive drug delivery system, it has received extensive attention in recent years. The olfactory mucosa of the upper nasal passages has many fine villi, which can greatly increase the effective area for drug absorption. The nose-brain delivery system has the following advantages: ① convenient drug administration, and patients can take drugs on their own; ② rapid drug absorption and rapid onset of action; ③ avoiding the first-pass effect of the liver; ④ increasing the delivery of drugs to the brain. Therefore, nasal administration is expected to increase the brain drug concentration level, enhance the therapeutic effect of drugs, and reduce toxic side effects.

[0004] It has been found in clinical practice that although the olfactory nerve pathway in the olfactory area of ​​the upper nasal cavity is a non-invasive and convenient central drug delivery route, drug delivery in the olfactory area of ​​the upper nasal cavity is limited by many physiological factors. Traditional drug delivery devices cannot effectively deliver drugs to the olfactory area of ​​the nasal cavity, which makes it impossible to achieve the purpose of drug nasal brain delivery. In particular, with the help of animal models, indirect research on human diseases, small animals are the most commonly used and most common mammalian model carriers, but they are small in size, and many equipment and utensils are not suitable for use in animals of smaller size, resulting in certain obstacles to the establishment of animal models. For drug delivery to the upper nasal cavity of small animals, the equipment disclosed in the patent applications CN202021777601.0 and CN202010148279.3 of the applicant company can be used to deliver drugs to the upper nasal cavity of small animals such as mice and achieve drug delivery at a constant speed under a stable anesthesia state, ensuring the parallelism of preclinical research; the olfactory nerves in the nasal cavity of rodents are richly distributed, and are divided into olfactory and respiratory areas in primates. When applied to human clinical trials, more precise upper nasal delivery technology is required.

[0005] Nimodipine naso-cerebral delivery preparations are delivered through the upper nasal cavity, so the drug preparation needs to be formulated into a naso-cerebral delivery preparation with high concentration, no nasal toxicity and irritation, consistent with the nasal pH environment, and capable of being absorbed across the membrane into the brain, so as to reduce the content of nimodipine in the peripheral blood and reduce cardiac toxicity and hepatotoxicity.

[0006] Due to the low solubility of nimodipine, alcohol preparations are generally used for solubilization in clinical use. Currently, research on the preparation of nimodipine focuses on reducing the amount of ethanol, but does not reduce cardiac toxicity and hepatotoxicity.

[0007] The currently available Nimoton injection contains up to 20% ethanol, which can easily cause irritation and thrombophlebitis during injection.

[0008] Patent application CN201811046629.4 discloses nimodipine nanoemulsion injection. This preparation no longer uses ethanol, which reduces the irritation and the probability of thrombophlebitis under the injection route. However, its brain entry volume is low, the blood content is high, and the risk of cardiotoxicity and hepatotoxicity is high.

[0009] Patent application CN 200510023273.9 discloses a nimodipine gel for nasal administration. However, this type of gel is applied to the inferior nasal passages of the nasal cavity, and its improvement point is still to increase the amount of the drug in the blood. When the preparation of this patent application is applied to the superior nasal passages of the nasal cavity, it adopts the Franz diffusion cell model, and its permeability coefficient is very low and it is difficult to enter the brain through the nose. Because nimodipine works only when it enters the brain or cerebrospinal fluid, this type of preparation does not improve the efficacy of the drug, and because the content of the drug in the blood is still high, its risk of cardiotoxicity and hepatotoxicity is still very high.

[0010] In addition, current research on nasal mucosal drug delivery systems has found that such preparations can irritate the nasal mucosa, mainly through ciliary toxicity, including the effects of drugs and excipients on ciliary activity. It has been reported that nimodipine nasal preparations contain the surfactant Labrasol (Role of mucoadhesive polymers in enhancing delivery of nimodipine microemulsion to brain via intranasal route, Rudree Pathak et al., Acta Pharmaceutica Sinica B, 2014; 4(2): 151-160). However, the applicant has verified that the formulation of the preparation cannot be made into a drug due to its high ciliary toxicity, and the concentration of the preparation can only reach 7.5 mg / mL, which limits its application in medicine.

[0011] Therefore, how to make nimodipine have both good nasal mucosal absorption performance and nasal safety, while having a high brain entry amount and a high brain-to-blood ratio, is the key to whether nimodipine can be developed into an upper nasal cavity delivery preparation. Summary of the invention

[0012] In view of the technical problems that the brain penetration rate of nimodipine in the prior art is poor, the drug needs to pass through the blood-brain barrier to enter the brain after administration through the inferior nasal mucosa and intravenous injection, thereby resulting in low drug concentration in the brain and nimodipine in the peripheral circulation system is prone to cause cardiovascular toxicity and hepatotoxic side effects, the present invention provides a reservoir-type nimodipine nose-to-brain delivery preparation with high cerebrospinal fluid / olfactory bulb / cortical brain tissue concentration, no local nasal irritation, long-term stable existence, direct entry into the brain tissue through the upper nasal mucosa of the olfactory area, stable absorption, and high brain-to-blood ratio and high cerebrospinal fluid-to-blood ratio.

[0013] According to the first aspect of the present invention, the present invention provides a nimodipine naso-cerebral delivery preparation, comprising nimodipine, a good solvent, a diluent and an absorption enhancer, wherein the good solvent is diethylene glycol monoethyl ether, and the absorption enhancer is one or more of phospholipids, n-dodecyl-β-D-maltoside (DDM), cyclopentadecalactone, polyethylene glycol-12-hydroxystearate and oleoyl macrogol glyceride; preferably, the absorption enhancer is one of phospholipids and cyclopentadecalactone, and most preferably, it is a phospholipid.

[0014] The diluent of the nimodipine nasocephalic delivery preparation of the present invention can be selected from one or more of isopropyl myristate, ethyl oleate, medium chain triglycerides, castor oil, soybean oil, sesame oil, oleic acid, vitamin E, monolinolein glyceryl, propylene glycol laurate or propylene glycol dicaprylate caprate. The preferred diluent includes a combination of one or more of ethyl oleate, isopropyl myristate and propylene glycol dicaprylate caprate.

[0015] In the nimodipine naso-cerebral delivery preparation of the present invention, the phospholipid can be lecithin or soybean lecithin; further, the type of lecithin can be any type, for example, lecithin E80 or lecithin PL100M, and the type of soybean lecithin can be any type, for example, soybean lecithin S75 or soybean lecithin S100.

[0016] In the nimodipine naso-cerebral delivery preparation of the present invention, the weight portion of nimodipine is 4-50 parts, preferably, 5-40 parts by weight, for example, it can be 5, 10, 15, 20, 30, 40 parts by weight, and most preferably, it is 15 parts by weight.

[0017] In the nimodipine naso-cerebral delivery preparation of the present invention, the weight portion of the good solvent is 5-300 parts, preferably, 40-200 parts by weight, for example, 40, 50, 80, 100, 120, 150, 160, 200 parts by weight.

[0018] In the nimodipine naso-cerebral delivery preparation of the present invention, the weight portion of the diluent is 500-900 parts, preferably, 700-850 parts by weight, for example, it can be 725, 750, 785, 805, 825, 850 parts by weight, most preferably, it is 785 parts by weight.

[0019] In the nimodipine naso-cerebral delivery preparation of the present invention, the weight portion of the absorption enhancer is 20-200 parts, preferably, 40-160 parts by weight, and can be 50 parts by weight, 60 parts by weight, 80 parts by weight, 100 parts by weight, 120 parts by weight, 150 parts by weight, 160 parts by weight, and most preferably, 100 parts by weight.

[0020] The nimodipine naso-cerebral delivery preparation of the present invention is in the form of a solution.

[0021] In certain embodiments of the present invention, the nimodipine naso-cerebral delivery preparation contains the above-mentioned nimodipine, the above-mentioned good solvent, the above-mentioned diluent, and the above-mentioned absorption enhancer.

[0022] In certain embodiments of the present invention, the nimodipine naso-cerebral delivery preparation contains 5-40 parts by weight of nimodipine, 40-200 parts by weight of diethylene glycol monoethyl ether, 40-160 parts by weight of phospholipids, and 700-850 parts by weight of isopropyl myristate. Preferably, the phospholipids are lecithin or soybean lecithin, wherein 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.

[0023] In certain embodiments of the present invention, the nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 100 parts by weight of diethylene glycol monoethyl ether, 100 parts by weight of phospholipids, and 785 parts by weight of isopropyl myristate. Preferably, the phospholipids are lecithin or soybean lecithin, wherein 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.

[0024] In certain embodiments of the present invention, the nimodipine naso-cerebral delivery preparation contains 5-40 parts by weight of nimodipine, 40-200 parts by weight of diethylene glycol monoethyl ether, 40-160 parts by weight of phospholipids, and 700-850 parts by weight of propylene glycol dicaprylate. Preferably, the phospholipid is lecithin or soybean lecithin, wherein the model of the lecithin can be any model, for example, lecithin E80 or lecithin PL100M, and the model of the soybean lecithin can be any model, for example, soybean lecithin S75 or soybean lecithin S100.

[0025] In certain specific embodiments of the present invention, the nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 100 parts by weight of diethylene glycol monoethyl ether, 100 parts by weight of lecithin, and 785 parts by weight of propylene glycol dicaprylate, wherein the lecithin can be of any type, for example, lecithin E80 or lecithin PL100M.

[0026] In certain specific embodiments of the present invention, the nimodipine naso-cerebral delivery preparation contains 5-40 parts by weight of nimodipine, 40-200 parts by weight of diethylene glycol monoethyl ether, 40-160 parts by weight of phospholipids, and 700-850 parts by weight of ethyl oleate. Preferably, the phospholipids are lecithin or soybean lecithin, wherein 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.

[0027] In certain specific embodiments of the present invention, the nimodipine naso-cerebral delivery preparation contains 5 parts by weight of nimodipine, 100 parts by weight of diethylene glycol monoethyl ether, 100 parts by weight of lecithin, and 795 parts by weight of ethyl oleate, wherein the lecithin can be any type, lecithin E80 or lecithin PL100M.

[0028] In certain specific embodiments of the present invention, the nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 60 parts by weight of diethylene glycol monoethyl ether, 100 parts by weight of lecithin, and 825 parts by weight of ethyl oleate, wherein the lecithin can be any type, lecithin E80 or lecithin PL100M.

[0029] In certain specific embodiments of the present invention, the nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 120 parts by weight of diethylene glycol monoethyl ether, 100 parts by weight of lecithin, and 765 parts by weight of ethyl oleate, wherein the lecithin can be any type, lecithin E80 or lecithin PL100M.

[0030] In certain specific embodiments of the present invention, the nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 100 parts by weight of diethylene glycol monoethyl ether, 100 parts by weight of phospholipids, and 785 parts by weight of ethyl oleate, wherein the phospholipids are lecithin or soybean lecithin, wherein 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.

[0031] In certain specific embodiments of the present invention, the nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 100 parts by weight of diethylene glycol monoethyl ether, 60 parts by weight of phospholipids, and 825 parts by weight of ethyl oleate, wherein the phospholipids are lecithin or soybean lecithin, wherein 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.

[0032] In certain specific embodiments of the present invention, the nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 100 parts by weight of diethylene glycol monoethyl ether, 120 parts by weight of phospholipids, and 765 parts by weight of ethyl oleate, wherein the phospholipids are lecithin or soybean lecithin, wherein 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.

[0033] In certain specific embodiments of the present invention, the nimodipine naso-cerebral delivery preparation comprises the above-mentioned nimodipine, the above-mentioned good solvent, the above-mentioned diluent, the above-mentioned absorption enhancer; optionally, further comprises an aroma agent, and the aroma agent is preferably grape flavor; preferably, the grape flavor content is 0-50 parts by weight; more preferably, it is 1-10 parts by weight, for example, 2.5 parts by weight.

[0034] In certain specific embodiments of the present invention, the nimodipine nose-brain delivery preparation of the present invention with high concentrations in the olfactory area and the brain can be used as a drug reservoir, and a relatively stable concentration can be maintained in the cerebrospinal fluid for a long time, thereby exerting a longer-term drug effect.

[0035] According to a particularly preferred embodiment, the nimodipine naso-cerebral delivery preparation of the present invention is composed of the above-mentioned nimodipine, the above-mentioned good solvent, the above-mentioned diluent and the above-mentioned absorption enhancer.

[0036] According to another particularly preferred embodiment, the nimodipine nasal-cerebral delivery preparation of the present invention is delivered via the small animal intelligent integrated nasal delivery system developed by the applicant company. Administration as disclosed in CN202021777601.0 and CN202010148279.3.

[0037] According to the second aspect of the present invention, the present invention provides a method for preparing a nimodipine naso-cerebral delivery preparation, which comprises: adding nimodipine and the above-mentioned good solvent into a glass bottle, preferably dissolving them by ultrasound; adding the above-mentioned absorption enhancer, preferably dissolving them by shaking ultrasound; optionally, adding a fragrance, and finally using the above-mentioned diluent to the total mass of each formula, preferably mixing by rotation.

[0038] According to the third aspect of the present invention, the present invention provides a nimodipine naso-cerebral delivery preparation prepared by the above-mentioned method for preparing the nimodipine naso-cerebral delivery preparation.

[0039] According to the fourth aspect of the present invention, the present invention provides a method for preventing or treating cerebral ischemic diseases, cerebral vasospasm caused by subarachnoid hemorrhage, and sudden deafness in patients, comprising the step of administering a therapeutically effective amount of the above-mentioned nimodipine nasocephalic delivery preparation to a patient in need thereof.

[0040] According to the fifth aspect of the present invention, the present invention also provides the use of the above-mentioned nimodipine nasal brain delivery preparation in the treatment of cerebral ischemic diseases, cerebral vasospasm caused by subarachnoid hemorrhage, and sudden deafness through the nasal brain. In particular, the present invention also provides the use of the above-mentioned nimodipine nasal brain delivery preparation in the preparation of a drug for the treatment of cerebral ischemic diseases, cerebral vasospasm caused by subarachnoid hemorrhage, and sudden deafness through the nasal brain.

[0041] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0042] The beneficial effects obtained by the present invention are as follows:

[0043] The nimodipine naso-cerebral delivery preparation of the present invention is prepared by selecting suitable diluents, good solvents, absorption enhancers and their reasonable proportions.

[0044] 1. The solubility of nimodipine was increased from 0.002 mg / mL to 13.5 mg / mL, an increase of more than 6,000 times;

[0045] 2. No nasal irritation and ciliary toxicity, no damage to nasal mucosa, high safety;

[0046] 3. It avoids the phenomenon of abnormal increase in the amount of drugs entering the brain due to damage to the nasal mucosa caused by nasal irritation;

[0047] 4. Improved the ability of nimodipine to be absorbed across the membrane, and the permeability coefficient can reach 2-10 (cm / s)10 -7 , the higher the permeability coefficient, the easier it is to pass through the nasal olfactory mucosa to reach the olfactory bulb and brain;

[0048] 5. The nimodipine naso-cerebral delivery preparation of the present invention, through reasonable compatibility, especially through reasonable selection of diluents with sustained-release effects, is conducive to the slow and stable release of nimodipine in the brain, can form a drug reservoir, and exert drug efficacy for a long time.

[0049] 6. The naso-cerebral delivery preparation of nimodipine of the present invention can directly bypass the blood-brain barrier and enter the brain to exert its efficacy, and the DTP (direct transport percentage) of cerebrospinal fluid and olfactory bulb is close to 90%.

[0050] Therefore, the nimodipine nose-brain delivery preparation of the present invention directly enters the cerebrospinal fluid and olfactory area without passing through the blood-brain barrier, and its DTP (direct transport percentage) of the cerebrospinal fluid and olfactory bulb is close to 90%; and the high concentration of nimodipine in the olfactory area and the brain can be used as a reservoir of the drug, and a relatively stable concentration can be maintained in the cerebrospinal fluid for a long time, thereby exerting a longer-term drug effect. At the same time, the preparation of the present invention improves the solubility of nimodipine through reasonable dosage and compatibility, and has a high permeability coefficient. The drug can reach the brain tissue at a higher concentration and can maintain a relatively stable concentration in the brain for a long time, thereby exerting a longer-term drug effect. The nose-brain delivery preparation of the present invention is non-irritating to the nasal cavity and non-toxic to the nasal cilia. While improving the patient's compliance, it also avoids the abnormal increase in brain content caused by the direct entry of the drug into the brain due to the damage of the preparation to the nasal mucosa, providing a new and effective way to treat nervous system diseases and has good industrial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Other features, objects and advantages of the present invention will become more apparent from the detailed description of non-limiting embodiments with reference to the following drawings:

[0052] Figure 1 This is a comparison chart of drug concentrations in plasma after administering the nose-brain delivery preparation of Formula 5-8 in Example 5 of the present invention to the olfactory area of ​​the upper nasal passage of mice and intravenously injecting the commercially available Nimodipine into mice in Pharmacological Experiment Example 1;

[0053] Figure 2 This is a comparison chart of drug concentrations in the cerebrospinal fluid after administering the nasal-cerebral delivery preparation of Formula 5-8 in Example 5 of the present invention to the olfactory area of ​​the upper nasal passage of mice and intravenously injecting the commercially available Nimodipine into mice in Pharmacological Experiment Example 1;

[0054] Figure 3 This is a comparison chart of drug concentrations in the olfactory bulb after administering the nose-brain delivery preparation of Formula 5-8 in Example 5 of the present invention to the olfactory area of ​​the upper nasal cavity of mice and intravenously injecting the commercially available Nimodipine into mice in Pharmacological Experiment Example 1;

[0055] Figure 4 This is a comparison chart of drug concentrations in the cortical brain tissue after administering the nose-brain delivery preparation of Formula 5-8 in Example 5 of the present invention to the olfactory area of ​​the upper nasal cavity of mice and intravenously injecting the commercially available Nimodipine into mice in Pharmacology Experiment Example 1.

[0056] Figure 5 This is a comparison chart of drug concentrations in the brain after the nose-brain delivery preparations ST202-Y-1 and ST202-Y-3 of the present invention were administered to the olfactory area of ​​the upper nasal cavity of mice and the commercially available Nimodipine tablets were dissolved and then gavaged into mice in pharmacological experiment example 2. DETAILED DESCRIPTION

[0057] The following will be further described in detail with reference to specific examples. It should be understood that the following examples are only for exemplary description and explanation of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies realized based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0058] definition:

[0059] In this application:

[0060] TranscutolP refers to diethylene glycol monoethyl ether;

[0061] M1944CS refers to oleoyl macrogolglycerides;

[0062] HS15 refers to polyethylene glycol-12-hydroxystearate;

[0063] E80 refers to lecithin E80, which is a type of lecithin;

[0064] PL100M refers to lecithin PL-100M, a type of lecithin;

[0065] S75 refers to soybean lecithin S75, which is a type of soybean lecithin;

[0066] S100 refers to soybean lecithin S75, which is a type of soybean lecithin;

[0067] DDM refers to n-dodecyl-β-D-maltoside;

[0068] CMC-Na refers to sodium carboxymethyl cellulose.

[0069] Nasal-brain delivery: The drug is delivered directly or indirectly into the cerebrospinal fluid and brain tissue through a specific upper nasal passage, and diffuses in the brain to exert its effect.

[0070] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0071] In the present invention, the method for determining the permeability coefficient adopts a method known to those skilled in the art: a Franz diffusion cell is used to simulate the process of drug absorption through the nasal mucosa. The drug solution diffuses through the pig nasal mucosa from the supply cell to the receiving cell, and the drug solution in the receiving cell is collected at different time points, the concentration is measured, and the apparent permeability coefficient of drug absorption through the nasal mucosa is calculated.

[0072] In the present invention, the local nasal irritation test is determined by a model of ciliary toxicity, which is a method well known to those skilled in the art: the palate cilia of toads is widely used as a common model to simulate human nasal cilia [1]. After the test drug is dripped onto the mucosal surface for 60 minutes, the palate mucosa is washed and separated, and 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, that is, the continuous movement time of the cilia. The continuous movement time of the palate mucosa cilia of the toads in the drug administration group is divided by the continuous movement time of the palate mucosa cilia of the toads in the negative control group to obtain the relative percentage of the continuous movement time of the cilia. The higher this percentage is, the less toxic the preparation is to the cilia, and the higher the safety of the preparation is. The relative percentage of the continuous movement time of the cilia is greater than 85% as the threshold value of 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.)

[0073] Those skilled in the art should understand that in order to increase the subject's compliance with the naso-brain delivery preparation, a flavoring agent such as grape flavor can also be added to adjust the taste of the naso-brain delivery preparation. Accordingly, the amount of diluent is reduced with the addition of the flavoring agent. For example, if 2.5 parts by weight of grape flavor is added, the diluent is correspondingly reduced by 2.5 parts by weight. This does not constitute a limitation on the naso-brain delivery preparation of the present application.

[0074] Embodiment 1:

[0075] The formulations of the formulations, as shown in Table 1, were prepared at room temperature in the following manner, i.e., the formulation amounts of nimodipine and the corresponding good solvent were weighed into a glass bottle, and dissolved by ultrasound; then, according to the specific components of each formulation, the corresponding amount of absorption enhancer was added, and the mixture was dissolved by shaking and ultrasound; finally, the formulation amount of diluent was added until the total mass of each formulation reached 1 g, and the mixture was rotated and mixed for 30 minutes to make the dispersion uniform to obtain the following formulations; and the permeability coefficient was tested.

[0076] Table 1

[0077]

[0078] Experimental conclusion: The permeability coefficient of nimodipine nasocerebrospinal delivery preparation can reach above 2 when Transcutol P is used as a good solvent and castor oil is used as a diluent; the addition of DDM has little effect on the permeability coefficient.

[0079] Embodiment 2:

[0080] The formulations of the formulations, as shown in Table 2, were prepared according to the preparation method of Example 1; that is, the formulation amounts of nimodipine and Transcutol P were weighed into a glass bottle and dissolved by ultrasound; then, according to the specific components of each formulation, a corresponding amount of absorption enhancer was added, and the mixture was dissolved by shaking and ultrasound; finally, the formulation amount of diluent was added until the total mass of each formulation reached 1 g, and the mixture was rotated and mixed for 30 minutes to make it evenly dispersed to obtain the following formulations, and the permeability coefficient was tested.

[0081] Table 2

[0082]

[0083]

[0084] Experimental conclusion: The use of lecithin and cyclopentadecanolide as absorption enhancers can help improve the permeability coefficient of nasal mucosa; among the different diluents, the isopropyl myristate sample has the best absorption; when the absorption enhancer is 4% cyclopentadecanolide and the diluent is oleic acid, the permeability coefficient is at the critical value.

[0085] Embodiment 3:

[0086] This example compares the effects of using different weight portions of lecithin, cyclopentadecanolide, lecithin + cyclopentadecanolide, and lecithin + HS15 as absorption enhancers on the nasal mucosal permeability coefficient of the nimodipine naso-cerebral delivery formulation of the present invention.

[0087] The formulations of the formulations, as shown in Tables 3 and 4, were prepared at room temperature in the following manner, i.e., the formulation amounts of nimodipine and the corresponding good solvent were weighed into a glass bottle, and dissolved by ultrasound; then, according to the specific components of each formulation, the corresponding amount of absorption enhancer was added, and the mixture was dissolved by shaking and ultrasound; finally, the formulation amount of diluent was added until the total mass of each formulation reached 1 g, and the mixture was rotated and mixed for 30 minutes to make the dispersion uniform, and the following formulations were obtained, and the permeability coefficient was tested.

[0088] Table 3

[0089]

[0090] Table 4

[0091]

[0092] Experimental conclusion: First, regarding the dosage of the absorption enhancer, it was found that when 10% lecithin or cyclopentadecanolide was used, the corresponding highest value of the porcine nasal mucosal permeability coefficient was obtained (see Formula 3-1 and Formula 3-2; Formula 3-3 and Formula 3-4 in Table 3, respectively). Secondly, regarding the type of absorption enhancer, it was found that when 10% lecithin was used, the corresponding highest value of the porcine nasal mucosal permeability coefficient was obtained (see Formula 3-1 in Table 3). However, it was found that the use of lecithin combined with cyclopentadecanolide and HS15 as an absorption enhancer would reduce the permeability coefficient (see Formulas 3-5 to 3-8 in Table 4, respectively), and the permeability coefficient decreased as the dosage of cyclopentadecanolide and HS15 increased (see Formulas 3-5 to 3-8 in Table 4).

[0093] Therefore, the permeability coefficient of the nimodipine naso-cerebral delivery preparation of this embodiment is optimal by using a single phospholipid as an absorption enhancer. The amount of phospholipid can be selected to be 20-200 parts by weight, preferably 40-160 parts by weight.

[0094] Embodiment 4:

[0095] This example compares the effects of using lecithin E80, lecithin PL100M, soybean lecithin S75 and soybean lecithin S100 as absorption enhancers and using isopropyl myristate, propylene glycol dicaprylate, ethyl oleate and propylene glycol laurate as diluents on the appearance, local nasal irritation and nasal mucosal permeability coefficient of the nimodipine nasal-cerebral delivery formulation of the present invention.

[0096] The preparation methods of the formulations shown in Tables 5 and 6 below are similar to those in Example 1. 15 mg of nimodipine and 100 mg of the good solvent Transcutol P are weighed into a glass bottle and dissolved by ultrasound (about 7 minutes). The phospholipids corresponding to the different formulations are added and dissolved by shaking ultrasound (about 5 minutes). Finally, the diluents corresponding to the different formulations are added to a total mass of 1 g, and the mixture is rotated and mixed for 30 minutes to be evenly dispersed. The following formulations are obtained.

[0097] Table 5

[0098]

[0099] Table 6

[0100]

[0101] Experimental conclusion: First, for phospholipids used as absorption enhancers, egg lecithin PL-100M and soybean lecithin S75 have better absorption through the nasal mucosa. Secondly, for diluents, ethyl oleate and isopropyl myristate have the best absorption through the nasal mucosa (see Table 6 Formula 4-4 and Table 5 Formula 4-2), followed by propylene glycol dicaprylate caprate (see Table 6 Formula 4-6).

[0102] Taking into account the effects of the above-mentioned absorption enhancers and diluents on the appearance, local nasal irritation and nasal mucosal permeability coefficient of the nimodipine naso-cerebral delivery preparation of the present invention, the nimodipine naso-cerebral delivery preparation of the present invention preferably uses lecithin or soybean lecithin as an absorption enhancer; and preferably uses one or more of ethyl oleate, isopropyl myristate, and propylene glycol dicaprylate caprate as diluents.

[0103] Embodiment 5:

[0104] The nimodipine naso-cerebral delivery preparations of the present invention were prepared according to the formulations shown in Table 7. The specific preparation method was as follows: the formulated amount of nimodipine and the good solvent Transcutol P were weighed into a glass bottle and dissolved by ultrasound; then, according to the specific components of each formulation, the corresponding amount of absorption enhancers (various phospholipids) were added and dissolved by shaking and ultrasound; finally, the formulated amount of diluent ethyl oleate was added until the total mass of each formulation reached 1 g, and the mixture was rotated and mixed for 30 minutes to ensure uniform dispersion to obtain the following formulations.

[0105] Table 7

[0106]

[0107]

[0108] As can be seen from Table 7 above, firstly, the type of phospholipids has little effect on the permeability coefficient of the nimodipine nasal-brain delivery preparation disclosed in the present invention (see Table 7). Secondly, the weight ratio of Transcutol P and phospholipids is between 60-140, which can still meet the requirements of permeability coefficient and local nasal irritation for nasal-brain delivery preparations (see Table 7). Finally, as the API concentration decreases, local absorption decreases, and a high API concentration is conducive to local absorption (see Table 7 Formulations 5-8).

[0109] Comparative Example 1:

[0110] For the comparative example formulations shown in Table 8 and Table 9, weigh the formulated amount of nimodipine and the corresponding good solvent into a glass bottle, and dissolve them by ultrasonication; then, according to the specific components of each formulation, add the corresponding amount of absorption enhancer and / or surfactant, shake and ultrasonicate to dissolve; finally, add the formulated amount of diluent until the total mass of each formulation reaches 1g, and rotate and mix for 30 minutes to make it evenly dispersed.

[0111] Table 8

[0112]

[0113] Table 9

[0114]

[0115] The experimental results are shown in Table 10 and Table 11 below:

[0116] Table 10

[0117]

[0118] Table 11

[0119]

[0120] Experimental conclusion:

[0121] When alcohol is used as a good solvent in the naso-cerebral delivery preparation of nimodipine, even if a surfactant and / or an absorption enhancer is added, its permeability coefficient is still very low and cannot meet the requirements of naso-cerebral delivery preparations that enter the brain through the nasal olfactory mucosa.

[0122] Comparative Example 2:

[0123] The formulation shown in Table 12 below can be prepared according to the conventional method of those skilled in the art or according to the similar method of Comparative Example 1;

[0124] Table 12

[0125]

[0126] Experimental conclusion: For nimodipine nasocephalic delivery preparations, when polyoxyethylene castor oil ELP or Tween 80 is used as the absorption enhancer, the permeability coefficient is difficult to meet the requirements of nasocephalic delivery; when lecithin is used as the absorption enhancer, the type of diluent will affect the permeability coefficient. For example, when propylene glycol monocaprylate is used as the diluent, the permeability coefficient is only 1.6*10 -7 When using mono- and di-caprylic acid glyceryl or propylene glycol monolaurate, coagulation occurs, which does not meet the basic requirements of naso-cerebral delivery preparations.

[0127] Pharmacological Experiment Example 1: Comparison with intravenous control preparation

[0128] Formula 5-8 in Example 5 was used to test the pharmacokinetic data. The nimodipine nasal-cerebral delivery preparation of Formula 5-8 was placed in a nasal delivery device (developed by the applicant company). In the small animal intelligent integrated nasal drug delivery system, as disclosed in CN202021777601.0 and CN202010148279.3, a prescribed dose of drug is administered to mice via the nose, and the nasal administration method is a 2-minute constant speed administration under gas anesthesia. The pharmacokinetics and distribution of the formula administered via the nose are evaluated at 2, 5, 15, 30, 60, 120, and 180 minutes after administration. The collection and sampling methods of plasma, olfactory bulb, and cortical brain tissue adopt the methods commonly used by those skilled in the art; for the collection of cerebrospinal fluid, the method of first draining blood and then collecting cerebrospinal fluid is adopted to avoid cerebrospinal fluid contamination by blood as much as possible, making the test results more accurate.

[0129] In this experimental example, ST-0 refers to the Nimotong injection (specification 50 ml / 10 mg) produced by Bayer, and ST202-Y represents the formula of the nasal brain delivery preparation of the present application (formulation 5-8 prepared in Example 5); the DMPK comparison data of the nasal brain delivery preparation of the present application and the intravenous Nimotong injection for nasal administration are shown in Table 13 below:

[0130] Table 13

[0131]

[0132] When ST-0 was intravenously administered to mice, the administration was completed in 2 minutes. When ST202-Y, an improved formulation of the present invention, was administered to mice via the nasal cavity, the blood drug concentrations in plasma, cerebrospinal fluid, olfactory bulb, and cortical brain tissue were as follows: Figure 1 , Figure 2 , Figure 3 and Figure 4 shown.

[0133] Depend on Figure 1 It can be seen that the plasma drug exposure of nasal administration is only 1 / 4 of that of intravenous injection, which can reduce peripheral adverse reactions and is safer.

[0134] The clinical use of ST-0 Nimotop Injection is long-term intravenous administration, which is not convenient for direct comparison in animal experiments. Therefore, the cerebrospinal fluid-to-blood ratio, brain-to-blood ratio, and DTP% (direct drug transport percentage) in the PK data are most meaningful for reference; the cerebrospinal fluid-to-blood ratio and brain-to-blood ratio of nasal administration are about 10 times higher than those of intravenous control administration.

[0135] The main indication of nimodipine is subarachnoid hemorrhage, where the cerebrospinal fluid is located. Figure 2 and Figure 3As shown, within 3 hours, the exposure of the drug in the cerebrospinal fluid after nasal administration is more than twice that of intravenous injection, which is a significant advantage; the nasal brain delivery formulation disclosed in the present invention has a high drug concentration in the olfactory bulb after nasal administration, which can act as a drug reservoir, slowly releasing the drug into the cerebrospinal fluid for a long time; at 3 hours, the cerebrospinal fluid content of the intravenously injected ST-0 preparation has dropped to the lowest value, while the improved nasal brain delivery formulation ST202-Y of the present invention, which is administered nasally, is still at the second peak at 3 hours and is still exerting its drug effect. Figure 4 As shown, ST-0 easily enters the brain due to stimulating blood vessels and destroying the blood-brain barrier, resulting in a transient increase in brain content. However, the nose-brain delivery preparation disclosed in the present invention is safe and non-irritating, and has high targeting to both cerebrospinal fluid and cortical brain tissue.

[0136] After nasal administration, drugs can be absorbed into the brain through two pathways: systemic pathway and olfactory pathway. In order to more clearly illustrate the direct nose-to-brain transfer, i.e. brain targeting, of the nasal-brain delivery preparation of the present application, the DTP% value (direct nasal drug transport percentage) is used to represent it;

[0137] DTP%=(B in -B x ) / B in ×100%,

[0138]

[0139] B x It indicates the AUC value of the part of the drug that enters the brain through the BBB via systemic circulation after nasal administration;

[0140] P iv , B iv , P in , B in Respectively represent the AUC values ​​in blood and brain after intravenous or nasal administration,

[0141] After calculation: DTP% in cerebrospinal fluid = 83%; DTP% in olfactory bulb = 86%;

[0142] The nimodipine nasal-brain delivery preparation of the present application has a DTP% of 83% for cerebrospinal fluid and 86% for olfactory bulb. It directly enters the target part such as cerebrospinal fluid and brain tissue without passing through the blood-brain barrier, and has strong targeting. The main indication of nimodipine is subarachnoid hemorrhage, and the cerebrospinal fluid itself is in the subarachnoid space. Therefore, the nimodipine nasal-brain delivery preparation of the present application has obvious efficacy and significant advantages.

[0143] Pharmacological Experiment Example 2: Comparison with the Oral Control Preparation

[0144] ST-1 was dissolved in 0.5% CMC-Na to prepare a 1.5 mg / mL oral gavage solution, and an overall absorption and distribution test was performed. Plasma, cerebrospinal fluid, and brain tissue were collected at 5, 15, 30, 60, 120, 240, 360, and 480 mins, with 6 mice in parallel. The pharmacokinetics and distribution of oral administration were evaluated and compared with the naso-cerebral delivery formulation ST202-Y of this application.

[0145] In this pharmacological experiment example:

[0146] ST-1 refers to the Nimotong tablets produced by Bayer;

[0147] ST202-Y-1 refers to a 5 mg / g nasal-cerebral delivery preparation, using the formula 5-8 prepared in Example 5 of the present application, with a mouse dose of 1 mg / kg, using the Small animal intelligent integrated nasal drug delivery system;

[0148] ST202-Y-3 refers to a 15 mg / g nasal-cerebral delivery preparation, with a mouse dose of 3 mg / kg, developed by the applicant's company. Small animal intelligent integrated nasal drug delivery system; preparation method of ST202-Y-3 preparation: weigh 1.35g nimodipine, dissolve 10.08g Transcutol P, add 9g soybean lecithin, stir to dissolve, weigh 0.23g grape essence, add to the above solution, use ethyl oleate to make the total amount of the formula to 90g, stir to obtain 15mg / g nimodipine nasal brain delivery preparation.

[0149] The experimental results are shown in Tables 14 and 15 below;

[0150] Table 14

[0151]

[0152] Table 15

[0153]

[0154] Experimental conclusion: Compared with the oral control group ST-1, the nose-brain delivery preparation disclosed in the present invention has obvious advantages and reaches the peak quickly; the dosage only needs 1 / 10 of the oral dosage, the plasma and brain drug exposure are 1.75 and 3.61 times that of the oral control ST-1, respectively, and the peak drug concentrations in plasma and brain are 1.37 and 3.22 times that of the oral control ST-1, respectively, and the drug efficacy is obvious;

[0155] When the dose is 1 / 3 of the oral dose, the exposure in the brain can be as high as 10 times that of the oral dose (such as Figure 5 shown);

[0156] Compared with the oral control ST-1, the naso-cerebral delivery preparation of the present invention has a longer half-life in mouse plasma and brain, which can reduce the number of dosing times and improve compliance.

[0157] Pharmacological Experiment Example 3: Rat Tissue Distribution

[0158] The oral control ST-1 adopts the same formulation as in Pharmacological Example 2. The concentration of the nasocephalic delivery preparation ST202-Y-4 in this pharmacological example is 15 mg / g. The preparation method is as follows: 0.405 kg of nimodipine and 3.20 kg of Transcutol P are added to a reactor, stirred until dissolved, and then 2.70 kg of egg yolk lecithin PL-100M is added, stirred until dissolved, and then 67.50 g of grape essence and 20.59 kg of ethyl oleate are added, stirred until dissolved, and the mixture is obtained; the same dosing device as in Pharmacological Example 2 is used to administer to rats;

[0159] The experimental results are shown in Table 16 below:

[0160] Table 16

[0161]

[0162]

[0163] Experimental conclusion:

[0164] The rat dosage of ST202-Y-4, a naso-cerebral delivery system of nimodipine, was 1 / 10 of that of the oral control ST-1. The drug exposure in plasma, cerebrospinal fluid and brain was 5.11, 4.89 and 9.78 times that of the oral control ST-1, respectively. The peak concentrations in plasma, cerebrospinal fluid and brain were 5.34, 2.35 and 11.54 times that of the oral control ST-1, respectively.

[0165] In rat tissue distribution, brain>plasma>cerebrospinal fluid. The brain / plasma exposure ratio of ST202-Y-4, a naso-cerebral delivery of nimodipine, was higher than that of the oral control ST-1 (2.47 VS1.29), and the peak ratio was also higher than that of the oral control ST-1 (2.30 VS1.07).

[0166] At the final time point of 120 minutes, the distribution concentration of ST202-Y-4, the naso-cerebral release of nimodipine, in tissues was 20.83% to 100.00% of the peak value, while the oral control ST-1 had been largely eliminated to 7.33% to 14.33% of the peak value.

[0167] Pharmacological Experiment Example 4: 14-day toxicological pre-experiment in rats

[0168] Physiological saline, full excipients, high-dose and low-dose nasal-cerebral delivery preparations were administered nasally, with four male and female rats in each group. The test was performed 14 days after administration. For example, in this pharmacological experiment:

[0169] All excipients and ST-202-Y-high are prepared in the proportions shown in Table 17 below, which can be prepared by the method disclosed in Example 1 of the present application, or by methods known to those skilled in the art;

[0170] Table 17

[0171]

[0172]

[0173] NA* represents 0, i.e., no nimodipine.

[0174] ST202-Y-Low: The concentration of this formulation is 5 mg / g. The preparation method of this formulation is to weigh 120 g of all excipients and 60 g of ST202-Y-High formulation and mix them.

[0175] The experimental groups are shown in Table 18 below:

[0176] Table 18

[0177]

[0178] The experimental monitoring items and their results are as follows:

[0179] 1. Observation beside the cage:

[0180] During the experiment, there were no abnormalities in the rats' appearance, behavioral activities, mental state, respiratory state, hair condition and other general conditions.

[0181] 2. Weight gain is shown in Table 19 below:

[0182] Table 19

[0183]

[0184] Conclusion on weight gain: There was no abnormality in the weight gain of rats in each dosage group.

[0185] 3. Changes in organ weights are shown in Table 20 below:

[0186] Table 20

[0187]

[0188]

[0189] Conclusion on changes in organ weights: There were no abnormalities in organ weights of rats in each dose group.

[0190] 4. Observation of nasal irritation:

[0191] Two people observed the appearance of the nose 30 minutes before and after administration and recorded it with photos or videos, and expressed it in points according to the "Grading Standard for Local Mucosal Irritation Reaction". The average score of 0.00-0.40 is non-irritating; the average score of 0.41-1.50 is mild irritating; the average score of 1.51-2.50 is moderate irritating; the average score>2.51 is severe irritating.

[0192] Evaluation of mucosal irritation: The mucosal irritation response of rats in each dose group was graded as no irritation; the details are shown in Table 21 below.

[0193] Table 21

[0194]

[0195] 5. Pathological results:

[0196] Pathological sections of the rats were taken 14 days after administration, and the experimental results showed that there was no difference in drug exposure between male and female animals in this experiment, and there was no difference in case morphology between males and females; no pathological changes were found in the olfactory bulb and other brain areas of each group; no pathological changes were found in the nasal concha mucosa and olfactory mucosa of each group; in summary: all excipients and preparation formulas were not toxic to rats.

[0197] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of this application.

Claims

1. A nimodipine nasal-cerebral delivery preparation, characterized in that: The nasocephalic delivery preparation comprises nimodipine, a good solvent, a diluent and an absorption enhancer, wherein the good solvent is diethylene glycol monoethyl ether, and the absorption enhancer is one or more of phospholipids, n-dodecyl-β-D-maltoside, cyclopentadecalactone, polyethylene glycol-12-hydroxystearate and oleoyl macrogol glyceride; preferably, the absorption enhancer is one of phospholipids and cyclopentadecalactone, and most preferably, it is a phospholipid.

2. The nimodipine naso-cerebral delivery preparation according to claim 1, characterized in that: The diluent is selected from one or more of isopropyl myristate, ethyl oleate, medium chain triglycerides, castor oil, soybean oil, sesame oil, oleic acid, vitamin E, glyceryl monolinoleate, propylene glycol laurate or propylene glycol dicaprylate caprate, preferably, it is a combination of one or more of ethyl oleate, isopropyl myristate and propylene glycol dicaprylate caprate.

3. The nimodipine naso-cerebral delivery preparation according to claim 1 or 2, characterized in that: The content of nimodipine is 4-50 parts by weight; and / or The content of the good solvent is 5-300 parts by weight; and / or The content of the diluent is 500-900 parts by weight; and / or The content of the absorption enhancer is 20-200 parts by weight.

4. The nimodipine naso-cerebral delivery preparation according to claim 3, characterized in that: The content of nimodipine is 5-40 parts by weight, for example, 5, 10, 15, 20, 30, 40 parts by weight, and most preferably, 15 parts by weight; and / or The content of the good solvent is 40-200 parts by weight, for example, 40, 50, 80, 100, 120, 150, 160, 200 parts by weight, and most preferably, 100 parts by weight; and / or The content of the diluent is 700-850 parts by weight, for example, 725, 750, 785, 805, 825, 850 parts by weight, and most preferably, 785 parts by weight; and / or The content of the absorption enhancer is 40-160 parts by weight, for example, 50, 60, 80, 100, 120, 150, 160 parts by weight, and most preferably, 100 parts by weight.

5. The nimodipine naso-cerebral delivery preparation according to claim 1, 2 or 4, characterized in that: The phospholipid is one of lecithin and soybean lecithin; and / or The lecithin is any type of lecithin, such as lecithin E80 or lecithin PL100M; the soybean lecithin is any type of soybean lecithin, such as soybean lecithin S75 or soybean lecithin S100.

6. The nimodipine naso-cerebral delivery preparation according to claim 1, 2 or 4, characterized in that: The nimodipine naso-cerebral delivery preparation further comprises an aromatic agent, and the aromatic agent is preferably grape flavor. The content of the grape flavor is preferably 0-50 parts by weight, more preferably 1-10 parts by weight; for example, 2.5 parts by weight.

7. The nimodipine naso-cerebral delivery preparation according to claim 1, 2 or 4, characterized in that: The nimodipine naso-cerebral delivery preparation contains 5-40 parts by weight of nimodipine, 40-200 parts by weight of diethylene glycol monoethyl ether, 40-160 parts by weight of phospholipids; 700-850 parts by weight of isopropyl myristate, preferably, the phospholipids are lecithin or soybean lecithin, wherein the lecithin is any type of lecithin, such as lecithin E80 or lecithin PL100M, and the soybean lecithin is any type of soybean lecithin, such as soybean lecithin S75 or soybean lecithin S100; or The nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 100 parts by weight of diethylene glycol monoethyl ether, 100 parts by weight of phospholipids, and 785 parts by weight of isopropyl myristate. Preferably, the phospholipids are lecithin or soybean lecithin, wherein the lecithin is any type of lecithin, such as lecithin E80 or lecithin PL100M, and the soybean lecithin is any type of soybean lecithin, such as soybean lecithin S75 or soybean lecithin S100; or The nimodipine naso-cerebral delivery preparation contains 5-40 parts by weight of nimodipine, 40-200 parts by weight of diethylene glycol monoethyl ether, 40-160 parts by weight of phospholipids, and 700-850 parts by weight of propylene glycol dicaprylate caprylate. Preferably, the phospholipids are lecithin or soybean lecithin, wherein the lecithin is any type of lecithin, such as lecithin E80 or lecithin PL100M, and the soybean lecithin is any type of soybean lecithin, such as soybean lecithin S75 or soybean lecithin S100; or The nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 100 parts by weight of diethylene glycol monoethyl ether, 100 parts by weight of lecithin, and 785 parts by weight of propylene glycol dicaprylate, wherein the lecithin can be any type of lecithin, such as lecithin E80 or lecithin PL100M; or The nimodipine naso-cerebral delivery preparation contains 5-40 parts by weight of nimodipine, 40-200 parts by weight of diethylene glycol monoethyl ether, 40-160 parts by weight of phospholipids, and 700-850 parts by weight of ethyl oleate. Preferably, the phospholipids are lecithin or soybean lecithin, wherein the lecithin is any type of lecithin, such as lecithin E80 or lecithin PL100M, and the soybean lecithin is any type of soybean lecithin, such as soybean lecithin S75 or soybean lecithin S100; or The nimodipine naso-cerebral delivery preparation contains 5 parts by weight of nimodipine, 100 parts by weight of diethylene glycol monoethyl ether, 100 parts by weight of lecithin, and 795 parts by weight of ethyl oleate, wherein the lecithin is of any type, such as lecithin E80 or lecithin PL100M; or The nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 60 parts by weight of diethylene glycol monoethyl ether, 100 parts by weight of lecithin, and 825 parts by weight of ethyl oleate, wherein the lecithin is of any type, such as lecithin E80 or lecithin PL100M; or The nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 120 parts by weight of diethylene glycol monoethyl ether, 100 parts by weight of lecithin, and 765 parts by weight of ethyl oleate, wherein the lecithin is any type, such as lecithin E80 or lecithin PL100M; or The nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 100 parts by weight of diethylene glycol monoethyl ether, 100 parts by weight of phospholipids, and 785 parts by weight of ethyl oleate. Preferably, the phospholipids are lecithin or soybean lecithin, wherein the lecithin is any type of lecithin, such as lecithin E80 or lecithin PL100M, and the soybean lecithin is any type of soybean lecithin, such as soybean lecithin S75 or soybean lecithin S100; or The nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 100 parts by weight of diethylene glycol monoethyl ether, 60 parts by weight of phospholipids, and 825 parts by weight of ethyl oleate. Preferably, the phospholipids are lecithin or soybean lecithin, wherein the lecithin is any type of lecithin, such as lecithin E80 or lecithin PL100M, and the soybean lecithin is any type of soybean lecithin, such as soybean lecithin S75 or soybean lecithin S100; or The nimodipine naso-cerebral delivery preparation contains 15 parts by weight of nimodipine, 100 parts by weight of diethylene glycol monoethyl ether, 120 parts by weight of phospholipids, and 765 parts by weight of ethyl oleate. Preferably, the phospholipids are lecithin or soybean lecithin, wherein the lecithin is any type of lecithin, such as lecithin E80 or lecithin PL100M, and the soybean lecithin is any type of soybean lecithin, such as soybean lecithin S75 or soybean lecithin S100.

8. The nimodipine naso-cerebral delivery preparation according to claim 1, 2 or 4, characterized in that: The nimodipine naso-cerebral delivery preparation functions as a drug reservoir.

9. A method for preparing a nimodipine naso-cerebral delivery preparation, characterized in that: include: Adding nimodipine and the good solvent according to any one of claims 1 to 8 into a container to dissolve them; Add the absorption enhancer according to any one of claims 1 to 8 and dissolve it; optionally, add the fragrance according to claim 6, and finally add the diluent according to any one of claims 1 to 8 to the total mass, and mix to obtain.

10. Use of nimodipine nasal-cerebral delivery preparation in the preparation of drugs for treating cerebral ischemic diseases, cerebral vasospasm caused by subarachnoid hemorrhage, and sudden deafness.

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