Nimodipine nose-to-brain delivery preparation, preparation method therefor and use thereof

Abstract

Provided is a highly brain-targeted, safe and non-invasive nose-to-brain delivery preparation. The nose-to-brain 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 phospholipid. The nose-to-brain delivery preparation is prepared from a good solvent, a diluent, an absorption enhancer and other components in a specific proportion. By administrating the preparation by means of a specific superior nasal meatus administration technique, the active ingredient nimodipine is enriched in the cerebrospinal fluid and brain tissue, thus exerting a therapeutic effect; meanwhile, due to the fact that the proportion of nimodipine entering the bloodstream is reduced, cardiovascular toxicity and hepatotoxicity are reduced. In addition, the formula of the preparation does not irritate the local part of the nasal cavity, thereby improving the compliance of the patient.

Description

A nimodipine nasocephalic delivery preparation, its preparation method and use Technical Field

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

[0002] Nimodipine (NM) is a second-generation dihydropyridine calcium channel antagonist that inhibits calcium influx into cerebral vascular smooth muscle cells and neurons. It preferentially acts on arterioles, selectively dilating cerebral vessels and increasing cerebral blood flow. This protects ischemic neurons, improves memory, and promotes intellectual recovery, exhibiting both neurological and psychopharmacological effects. It has been clinically used to treat conditions such as cerebral ischemia, cerebral vasospasm caused by subarachnoid hemorrhage, and sudden deafness, with promising results. However, nimodipine has extremely poor water solubility, a strong oral first-pass effect, and low bioavailability. The injectable formulation used clinically uses a large amount of ethanol as a solvent, resulting in high irritation. Nimodipine also exhibits cardiovascular and hepatotoxicity. Furthermore, the blood-brain barrier is a major bottleneck for drugs to effectively cross the barrier, resulting in low brain penetration and limited potential for maximum therapeutic efficacy in treating brain diseases.

[0003] The nasal-brain delivery system, primarily for drug delivery through the upper nasal passages, has garnered widespread attention in recent years as a non-invasive drug delivery method. The olfactory mucosa of the upper nasal passages is rich in microvilli, significantly increasing the effective area for drug absorption. Nasal-brain delivery offers the following advantages: ① Convenient administration, allowing patients to self-administer medication; ② Rapid drug absorption and onset of action; ③ Avoiding first-pass hepatic effects; and ④ Enhanced drug delivery to the brain. Therefore, nasal delivery has the potential to increase drug concentrations in the brain, enhance therapeutic efficacy, and reduce toxic side effects.

[0004] In clinical practice, it has been found 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 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, resulting in the failure to achieve the purpose of drug nasal brain delivery. In particular, with the help of animal models, indirect research on human diseases is carried out. Small animals are the most commonly used and most common mammalian model carriers, but they are small in size. Many equipment and tools are not suitable for use on smaller animals, resulting in certain obstacles to the establishment of animal models. For drug delivery to the upper nasal cavity of small animals, the devices disclosed in the applicant's patent applications CN202021777601.0 and CN202010148279.3 can be used to deliver drugs to the upper nasal cavity of small animals such as mice and to achieve drug delivery at a constant rate under stable anesthesia, 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 cavity drug delivery technology is required.

[0005] Nimodipine naso-cerebral delivery preparations are delivered through the upper nasal cavity. Therefore, 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 cardiotoxicity and hepatotoxicity.

[0006] Due to its low solubility, nimodipine is generally solubilized in alcoholic preparations during clinical use. Currently, research on nimodipine formulations focuses on reducing the amount of ethanol used, but this has not reduced cardiotoxicity and hepatotoxicity.

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

[0008] Patent application CN201811046629.4 discloses a nimodipine nanoemulsion injection. This formulation eliminates the use of ethanol, reducing injection irritation and the risk of thrombophlebitis. However, its brain entry is low, blood levels are 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 gel is applied to the inferior nasal passages, and its improvement remains focused on increasing the amount of drug in the blood. When applied to the superior nasal passages, the formulation described in this patent application uses a Franz diffusion cell model, resulting in a very low permeability coefficient, making it difficult for nimodipine to enter the brain through the nose. Because nimodipine is only effective when it enters the brain or cerebrospinal fluid, this formulation does not improve efficacy. Furthermore, due to the high blood levels of the drug, the risk of cardiotoxicity and hepatotoxicity remains high.

[0010] In addition, current research on nasal mucosal drug delivery systems has found that such preparations can cause irritation to the nasal mucosa, primarily through ciliary toxicity, including the effects of drugs and excipients on ciliary activity. Literature reports 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 this preparation cannot be made into a drug due to its high ciliary toxicity, and the preparation concentration can only reach 7.5 mg / mL, limiting 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 and a high brain-blood ratio, is the key to whether nimodipine can be developed into a nasal cavity and upper nasal cavity delivery preparation. Summary of the Invention

[0012] In response to the technical problems in the prior art that nimodipine has a poor brain penetration rate and needs to pass through the blood-brain barrier to enter the brain after administration through the inferior nasal mucosa and intravenous injection, resulting in low drug concentration in the brain and nimodipine in the peripheral circulation system easily causing cardiovascular toxicity and hepatotoxic side effects, the present invention provides a reservoir-type nimodipine nasal-to-brain delivery preparation that has high cerebrospinal fluid / olfactory bulb / cortical brain tissue concentration, is non-nasal irritant, can exist stably for a long time, penetrates the olfactory mucosa of the upper nasal meatus directly into the brain tissue, can be smoothly absorbed, and has a high brain-to-blood ratio and a high cerebrospinal fluid-to-blood ratio.

[0013] According to the first aspect of the present invention, the present invention provides a nimodipine nasocephalic 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 phospholipids.

[0014] The diluent of the nimodipine nasocerebroventricular 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, propylene glycol laurate or propylene glycol dicaprylate, and the preferred diluent includes a combination of one or more of ethyl oleate, isopropyl myristate and propylene glycol dicaprylate.

[0015] In the nimodipine naso-cerebral delivery preparation of the present invention, the phospholipid can be lecithin or soybean lecithin; further, the model of the lecithin can be any model, for example, it can be lecithin E80 or lecithin PL100M, and the model of the soybean lecithin can be any model, for example, it can be 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, 5, 10, 15, 20, 30, 40 parts by weight, and most preferably 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, or 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, 725, 750, 785, 805, 825, 850 parts by weight, and most preferably 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 formulation 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 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.

[0023] In certain embodiments of the present invention, the nimodipine naso-cerebral delivery formulation contains 15 parts by weight of nimodipine, 100 parts by weight of diethylene glycol monoethyl ether, 100 parts by weight of phospholipid, and 785 parts by weight of isopropyl myristate. 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.

[0024] In certain embodiments of the present invention, the nimodipine naso-cerebral delivery formulation 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 dioctanoate. 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 formulation 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 formulation 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 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.

[0027] In certain specific embodiments of the present invention, the nimodipine naso-cerebral delivery formulation 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 formulation 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 formulation 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 phospholipid, and 785 parts by weight of ethyl oleate, wherein 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.

[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 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.

[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 phospholipid, and 765 parts by weight of ethyl oleate, wherein 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.

[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, and the above-mentioned absorption enhancer; optionally, further comprises an aroma, and the aroma is preferably grape flavor; preferably, the content of the grape flavor 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 nasocerebrospinal delivery formulation of the present invention with high concentrations in the olfactory area and brain can serve as a drug reservoir, maintaining a relatively stable concentration 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-brain delivery preparation of the present invention is delivered via the small animal intelligent integrated nasal delivery system (RA-IDDS) 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 it by shaking ultrasound; optionally, adding a fragrance, and finally using the above-mentioned diluent to the total mass of each formula, preferably rotating and mixing.

[0038] According to a 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 disease, 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 nasocerebrospinal delivery preparation to a patient in need thereof.

[0040] According to a fifth aspect of the present invention, the present invention further provides the use of the above-mentioned nimodipine nasal-brain delivery formulation in the treatment of cerebral ischemic disease, cerebral vasospasm caused by subarachnoid hemorrhage, and sudden deafness via nasal administration. In particular, the present invention further provides the use of the above-mentioned nimodipine nasal-brain delivery formulation in the preparation of a medicament for the treatment of cerebral ischemic disease, cerebral vasospasm caused by subarachnoid hemorrhage, and sudden deafness via nasal administration.

[0041] On the basis of conforming to the common sense in this field, 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 nasocephalic delivery preparation of the present invention is prepared by selecting suitable diluents, good solvents, absorption enhancers and their reasonable proportions.

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

[0045] It has no nasal irritation and ciliary toxicity, will not damage the nasal mucosa, and is highly safe;

[0046] Avoids the phenomenon of abnormally high drug intake due to damage to the nasal mucosa caused by nasal irritation, which causes the drug to enter the brain directly;

[0047] Improves 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 and reach the olfactory bulb and brain;

[0048] The nimodipine naso-cerebral delivery preparation of the present invention facilitates the slow and steady release of nimodipine in the brain through reasonable compatibility, especially through reasonable selection of a diluent with a sustained-release effect, thereby forming a drug reservoir and exerting drug efficacy for a long time.

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

[0050] Therefore, the nimodipine naso-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) in the cerebrospinal fluid and olfactory bulb is close to 90%; and the high concentration of nimodipine in the olfactory area and the brain can serve as a reservoir for the drug, and can maintain a relatively stable concentration 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 combination, 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 naso-brain delivery preparation of the present invention is non-irritating to the nasal cavity and non-toxic to nasal cilia. While improving patient compliance, it also avoids the phenomenon of abnormally increased brain content caused by the drug directly entering the brain due to the damage of the preparation to the nasal mucosa, providing a new and effective way to treat neurological 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 following detailed description of non-limiting embodiments with reference to the accompanying drawings:

[0052] FIG1 is a graph comparing the drug concentrations in plasma of the naso-cerebral delivery formulation of Formula 5-8 in Example 5 of the present invention administered to the olfactory region of the upper nasal passages of mice and the commercially available Nimotop intravenously injected into mice in Pharmacological Experiment 1;

[0053] FIG2 is a comparison of drug concentrations in the cerebrospinal fluid of mice after administering the nasocephalic delivery formulation of Formula 5-8 in Example 5 of the present invention to the olfactory region of the upper nasal passages and intravenously injecting commercially available Nimotop into mice in Pharmacological Experiment Example 1;

[0054] FIG3 is a comparative graph showing the drug concentrations in the olfactory bulb of mice after administering the naso-cerebral delivery formulation of Formula 5-8 in Example 5 of the present invention to the olfactory region of the upper nasal passages and intravenously injecting commercially available Nimodon into the mice in Pharmacological Experiment Example 1;

[0055] FIG4 is a comparison of drug concentrations in the cortical brain tissue after administering the naso-cerebral delivery formulation of Formula 5-8 in Example 5 of the present invention to the olfactory region of the upper nasal passages of mice and intravenously injecting the commercially available Nimotop® into mice in Pharmacological Experiment Example 1.

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

[0057] The assay method of the present invention will be described in further detail below with reference to specific examples. It should be understood that the following examples are intended to illustrate and explain the present invention by way of example only and should not be construed as limiting the scope of protection of the present invention. All techniques implemented based on the above-mentioned content of the present invention are encompassed within the scope of protection that the present invention is intended to provide. definition:

[0058] In this application:

[0059] Transcutol P refers to diethylene glycol monoethyl ether;

[0060] Labrafil ® M1944CS refers to oleoyl macrogol glycerides;

[0061] HS15 refers to polyethylene glycol-12-hydroxystearate;

[0062] E80 refers to lecithin E80, a type of lecithin;

[0063] PL100M refers to lecithin PL-100M, a type of lecithin;

[0064] S75 refers to soybean lecithin S75, which is a type of soybean lecithin;

[0065] S100 refers to soybean lecithin S75, a type of soybean lecithin;

[0066] DDM refers to n-dodecyl-β-D-maltoside;

[0067] CMC-Na refers to sodium carboxymethylcellulose.

[0068] Nasal-brain delivery: Drugs are delivered directly or indirectly into the cerebrospinal fluid and brain tissue through a specific upper nasal route, and diffuse in the brain to exert their effects.

[0069] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0070] In the present invention, the permeability coefficient is determined using a method known to those skilled in the art: a Franz diffusion cell is used to simulate drug absorption through the nasal mucosa. A drug solution diffuses from a supply cell through the porcine nasal mucosa to a receiving cell. The drug solution in the receiving cell is collected at different time points, and the concentration is measured to calculate the apparent permeability coefficient of the drug absorbed through the nasal mucosa.

[0071] In the present invention, the local nasal irritation test is determined using a ciliary toxicity model, which is a method well known to those skilled in the art: the cilia of the palate of toads are 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. The effect on the cilia is analyzed by comparing it with physiological saline as a control [2]. The cilia movement is observed and the time required from the start of drug administration to the complete cessation of cilia movement is recorded, that is, the cilia continuous movement time. The cilia continuous movement time of the palate mucosa of the toads in the drug administration group is divided by the cilia continuous movement time of the palate mucosa of the toads in the negative control group to obtain the relative percentage of the cilia continuous movement time. The higher this percentage, the less toxic the preparation is to the cilia and the higher the safety of the preparation. The relative percentage of cilia continuous movement time greater than 85% is the threshold value of the preparation safety. ([1] Jiang Xinguo, Cui Jingbin. Nasal mucociliary toxicity of drugs and its evaluation method [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.)

[0072] Those skilled in the art should understand that in order to increase the subject's compliance with the naso-cerebral delivery preparation, flavoring agents such as grape flavoring can also be added to adjust the taste of the naso-cerebral delivery preparation. Accordingly, the amount of diluent used is reduced accordingly with the addition of flavoring agents. For example, if 2.5 parts by weight of grape flavoring is added, the amount of diluent is correspondingly reduced by 2.5 parts by weight. This does not constitute a limitation on the naso-cerebral delivery preparation of the present application.

[0073] Example 1:

[0074] The formulations of the formulations, as shown in Table 1, were prepared at room temperature in the following manner: the formulated amounts of nimodipine and the corresponding good solvent were weighed into a glass bottle and dissolved by ultrasonication; then, according to the specific components of each formulation, the corresponding amount of absorption enhancer was added and dissolved by shaking and ultrasonication; finally, the formulated 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 ensure uniform dispersion to obtain the following formulations; and the permeability coefficient was tested.

[0075]

[0076] Experimental conclusion: The permeability coefficient of nimodipine nasocerebrospinal delivery preparation can reach above 2 when using Transcutol P as a good solvent and castor oil as a diluent; the addition of DDM has little effect on the permeability coefficient.

[0077] Example 2:

[0078] The formulations of the formulations shown in Table 2 were prepared according to the preparation method of Example 1. Specifically, the formulated amounts of nimodipine and Transcutol P were weighed into a glass bottle and dissolved by ultrasonication. Then, the corresponding amount of absorption enhancer was added according to the specific components of each formulation, and the mixture was shaken and ultrasonicated to dissolve. Finally, the formulated amount of diluent was added until the total mass of each formulation reached 1 g. The mixture was mixed by rotation for 30 minutes to ensure uniform dispersion. The following formulations were obtained, and the permeability coefficient was measured.

[0079]

[0080] Experimental conclusion: The use of lecithin and pentadecanolide as absorption enhancers can help improve the permeability coefficient of nasal mucosa; among different diluents, isopropyl myristate sample has the best absorption; when 4% pentadecanolide is used as absorption enhancer and oleic acid is used as diluent, the permeability coefficient is at the critical value.

[0081] Example 3:

[0082] 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 disclosure.

[0083] The formulations of the formulations, as shown in Tables 3 and 4, were prepared at room temperature in the following manner: the formulated amount of nimodipine and the corresponding good solvent were weighed into a glass bottle and dissolved by ultrasonication; then, according to the specific components of each formulation, the corresponding amount of absorption enhancer was added and dissolved by shaking and ultrasonication; finally, the formulated 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 ensure uniform dispersion to obtain the following formulations, and the permeability coefficient was tested.

[0084]

[0085]

[0086] Experimental Conclusions: First, regarding the dosage of the absorption enhancer, it was found that the highest porcine nasal mucosal permeability coefficients were achieved when 10% lecithin or pentadecanolide was used (see Formulations 3-1 and 3-2, and Formulations 3-3 and 3-4, respectively, in Table 3). Second, regarding the type of absorption enhancer, it was found that the highest porcine nasal mucosal permeability coefficients were achieved when 10% lecithin was used (see Formulation 3-1, Table 3). However, it was found that the use of lecithin combined with pentadecanolide and HS15 as absorption enhancers decreased the permeability coefficients (see Formulations 3-5 to 3-8, Table 4, respectively). Furthermore, the permeability coefficients decreased with increasing dosages of pentadecanolide and HS15 (see Formulations 3-5 to 3-8, Table 4).

[0087] Therefore, using phospholipid alone as an absorption enhancer, the permeability coefficient of the nimodipine naso-cerebral delivery formulation of this embodiment is optimal. The amount of phospholipid can be selected to be 20-200 parts by weight, preferably 40-160 parts by weight.

[0088] Example 4:

[0089] This example compares the effects of using lecithin E80, lecithin PL100M, soy lecithin S75 and soy 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 of the nimodipine nasocephalic delivery formulation of the present invention.

[0090] The formulations shown in Tables 5 and 6 below were prepared using a method similar to that of Example 1. 15 mg of nimodipine and 100 mg of the good solvent Transcutol P were weighed into a glass bottle and sonicated for dissolution (approximately 7 minutes). The phospholipids corresponding to the formulations were then added and sonicated for dissolution (approximately 5 minutes). Finally, the diluents corresponding to the formulations were added to a total weight of 1 g, and the mixture was uniformly dispersed by rotation for 30 minutes. The following formulations were obtained.

[0091]

[0092]

[0093] Experimental Conclusions: First, among phospholipids used as absorption enhancers, egg lecithin PL-100M and soybean lecithin S75 exhibited the best transnasal absorption. Second, among diluents, ethyl oleate and isopropyl myristate exhibited the best transnasal absorption (see Formulation 4-4 in Table 6 and Formulation 4-2 in Table 5), followed by propylene glycol dicaprylate (see Formulation 4-6 in Table 6).

[0094] 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 as a diluent.

[0095] Example 5:

[0096] The nimodipine naso-cerebral delivery formulations of the present disclosure 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 ultrasonication; then, according to the specific components of each formulation, the corresponding amount of absorption enhancers (various phospholipids) were added and dissolved by shaking and ultrasonication; finally, the formulated amount of diluent ethyl oleate was added until the total weight of each formulation reached 1 g, and the mixture was mixed by rotation for 30 minutes to ensure uniform dispersion, thereby obtaining the following formulations.

[0097]

[0098] As shown in Table 7 above, first, the type of phospholipid has little effect on the permeability coefficient of the disclosed nimodipine naso-cerebral delivery formulation (see Table 7). Second, a ratio of Transcutol P to phospholipids between 60 and 140 parts by weight still meets the permeability coefficient and local nasal irritation requirements for naso-cerebral delivery formulations (see Table 7). Finally, decreasing API concentration reduces local absorption, while higher API concentrations favor local absorption (see Formulations 5-8 in Table 7).

[0099] Comparative Example 1:

[0100] For the comparative example formulations shown in Tables 8 and 9, the formulated amount of nimodipine and the corresponding good solvent were weighed into a glass bottle and dissolved by ultrasonication. Then, according to the specific components of each formulation, the corresponding amount of absorption enhancer and / or surfactant was added, and the mixture was dissolved by shaking and ultrasonication. Finally, the formulated 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 ensure uniform dispersion.

[0101]

[0102]

[0103] The experimental results are shown in Table 10 and Table 11 below:

[0104]

[0105]

[0106] Experimental conclusion:

[0107] For nimodipine naso-cerebral delivery preparations, when alcohols are used as good solvents, even if surfactants and / or absorption enhancers are added, the 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.

[0108] Comparative Example 2:

[0109] The formulation shown in Table 12 below can be prepared according to conventional methods of those skilled in the art or by a similar method to Comparative Example 1;

[0110]

[0111] Experimental conclusion: When polyoxyethylene castor oil ELP or Tween 80 is used as the absorption enhancer for nimodipine naso-cerebral delivery, the permeability coefficient is difficult to meet the requirements of naso-cerebral 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 mono- and di-caprylic acid capric glyceride or propylene glycol monolaurate is used, coagulation occurs, which does not meet the basic requirements of naso-cerebral delivery preparations.

[0112] Pharmacological Experiment Example 1: Comparison with intravenous control preparation

[0113] Pharmacokinetic data were tested using Formulations 5-8 in Example 5. The naso-cerebral delivery formulation of nimodipine in Formulations 5-8 was placed in a nasal drug delivery device (the RA-IDDS® Small Animal Intelligent Integrated Nasal Drug Delivery System, developed by the applicant, as disclosed in CN202021777601.0 and CN202010148279.3). A prescribed dose of the drug was administered nasally to mice using a 2-minute constant-rate administration under air anesthesia. The pharmacokinetics and distribution of the nasal formulations were evaluated 2, 5, 15, 30, 60, 120, and 180 minutes after administration. Plasma, olfactory bulb, and cortical brain tissue were sampled using methods commonly used by those skilled in the art. For cerebrospinal fluid collection, a blood draw was performed prior to cerebrospinal fluid collection to minimize contamination of the cerebrospinal fluid and enhance test accuracy.

[0114] In this experimental example, ST-0 refers to the Nimotop injection (50 ml / 10 mg) produced by Bayer, and ST202-Y represents the naso-cerebral delivery formulation of the present application (Formulation 5-8 prepared in Example 5). The DMPK comparison data of the naso-cerebral delivery formulation of the present application for nasal administration and intravenous Nimotop injection are shown in Table 13 below:

[0115]

[0116] When ST-0 was intravenously administered to mice within 2 minutes, and the improved formulation ST202-Y 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 shown in Figures 1, 2, 3, and 4, respectively.

[0117] As shown in Figure 1, 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.

[0118] 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.

[0119] The main indication for nimodipine is subarachnoid hemorrhage, and the cerebrospinal fluid itself is located in the subarachnoid space. As shown in Figures 2 and 3, within 3 hours, the exposure to the cerebrospinal fluid of the drug after nasal administration is more than twice that of intravenous injection, which is a significant advantage. The nose-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 and exerting its effect 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 nose-brain delivery formulation ST202-Y of the present invention, which is administered nasally, still reaches the second peak at 3 hours and is still exerting its drug effect. As shown in Figure 4, ST-0 is very easy to enter the brain due to irritation of blood vessels and destruction of the blood-brain barrier, resulting in a transient increase in brain content. However, the nose-brain delivery formulation disclosed in the present invention is safe and non-irritating, and has high targeting to both cerebrospinal fluid and cortical brain tissue.

[0120] After nasal administration, drugs can be absorbed into the brain through two pathways: the systemic pathway and the olfactory pathway. To more clearly illustrate the direct nose-to-brain transfer, i.e., brain targeting, of the nasal-brain delivery formulation of the present application, the DTP% value (direct nasal drug transport percentage) is used;

[0121] DTP% = (B in -B x ) / B in ×100%,

[0122] B x It indicates the AUC value of the drug that enters the brain through the BBB via systemic circulation after nasal administration;

[0123] P iv， B iv , P in , B in Respectively represent the AUC values ​​in blood and brain after intravenous or nasal administration,

[0124] After calculation: DTP% in cerebrospinal fluid = 83%; DTP% in olfactory bulb = 86%;

[0125] The naso-cerebral delivery formulation of nimodipine in this application has a DTP% of 83% in the cerebrospinal fluid and 86% in the olfactory bulb. It directly enters the targeted areas, such as the cerebrospinal fluid and brain tissue, without crossing the blood-brain barrier, demonstrating strong targeting. Nimodipine's primary indication is subarachnoid hemorrhage, and cerebrospinal fluid itself is located in the subarachnoid space. Therefore, the naso-cerebral delivery formulation of nimodipine in this application has significant efficacy and advantages.

[0126] Pharmacological Experiment Example 2: Comparison with Oral Administration Control Preparation

[0127] ST-1 was dissolved in 0.5% CMC-Na to prepare a 1.5 mg / mL oral gavage solution, and a holistic absorption and distribution study was conducted. Plasma, cerebrospinal fluid, and brain tissue were collected at 5, 15, 30, 60, 120, 240, 360, and 480 mins, with six 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.

[0128] In this pharmacological experiment:

[0129] ST-1 refers to Nimotop tablets produced by Bayer;

[0130] ST202-Y-1 refers to a 5 mg / g nasal-cerebral delivery formulation, using formulation 5-8 prepared in Example 5 of the present application, with a mouse dose of 1 mg / kg, administered using the RA-IDDS® Small Animal Intelligent Integrated Nasal Drug Delivery System developed by the applicant company;

[0131] ST202-Y-3 refers to a 15 mg / g naso-cerebral delivery formulation, with a mouse dose of 3 mg / kg, administered using the RA-IDDS® Small Animal Intelligent Integrated Nasal Drug Delivery System developed by the applicant. The ST202-Y-3 formulation is prepared by weighing 1.35 g of nimodipine and dissolving 10.08 g of Transcutol P. Then, 9 g of soy lecithin is added and stirred to dissolve. 0.23 g of grape essence is weighed and added to the above solution. Ethyl oleate is used to increase the total amount of the formulation to 90 g. Stirring yields a 15 mg / g nimodipine naso-cerebral delivery formulation.

[0132] The experimental results are shown in Tables 14 and 15 below.

[0133]

[0134]

[0135] Experimental conclusion: Compared with the oral control group ST-1, the disclosed naso-cerebral delivery formulation has obvious advantages and reaches peak effect quickly; the dosage is only 1 / 10 of the oral dose, the plasma and brain drug exposure are 1.75 and 3.61 times that of the oral control ST-1, respectively, and the peak plasma and brain drug concentrations are 1.37 and 3.22 times that of the oral control ST-1, respectively, indicating significant drug efficacy;

[0136] 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 (as shown in Figure 5);

[0137] 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 administrations and improve compliance.

[0138] Pharmacological Experiment Example 3: Tissue Distribution in Rat

[0139] A method similar to that used in Pharmacological Example 2 was used for the oral control ST-1, which had the same formulation as in Pharmacological Example 2. The concentration of the naso-cerebral delivery formulation ST202-Y-4 in this pharmacological example was 15 mg / g. The preparation method was as follows: 0.405 kg of nimodipine and 3.20 kg of Transcutol P were added to a reactor, stirred until dissolved, and then 2.70 kg of egg yolk lecithin PL-100M was added and stirred until dissolved. 67.50 g of grape essence and 20.59 kg of ethyl oleate were added and stirred until dissolved. The product was administered to rats using the same dosing device as in Pharmacological Example 2.

[0140] The experimental results are shown in Table 16 below:

[0141]

[0142] Experimental conclusion:

[0143] The dose of ST202-Y-4, a naso-cerebral delivery drug of nimodipine, to rats 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.

[0144] Ø In rat tissue distribution, brain>plasma>cerebrospinal fluid. The brain / plasma exposure ratio of ST202-Y-4, a naso-cerebral delivery drug of nimodipine, was higher than that of the oral control ST-1 (2.47 VS 1.29), and the peak ratio was also higher than that of the oral control ST-1 (2.30 VS 1.07).

[0145] Ø At the terminal time point of 120 minutes, the distribution concentration of ST202-Y-4, the nose-brain release of nimodipine, in tissues was 20.83%~100.00% of the peak value, while the oral control ST-1 had been largely eliminated to 7.33%~14.33% of the peak value.

[0146] Pharmacological Experiment Example 4: 14-day toxicological pre-experiment in rats

[0147] Physiological saline, complete excipients, high-dose and low-dose nasal-brain delivery preparations were administered nasally, with four rats of both sexes in each group. The results were verified 14 days after administration. For example, in this pharmacological experiment:

[0148] All excipients and ST-202-Y-high are prepared in the proportions shown in Table 17 below. They can be prepared by the method disclosed in Example 1 of this application or by methods known to those skilled in the art.

[0149]

[0150] NA* represents 0, i.e., no nimodipine.

[0151] 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.

[0152] The experimental groups are shown in Table 18 below:

[0153]

[0154] The experimental monitoring items and their results are as follows:

[0155] 1. Observation beside the cage:

[0156] During the experiment, no abnormalities were found in the rats' appearance, behavioral activities, mental state, respiratory state, hair condition, and other general conditions.

[0157] 2. Weight gain is shown in Table 19 below:

[0158]

[0159] Conclusion on weight gain: There was no abnormality in the weight gain of rats in each dosage group.

[0160] 3. Changes in organ weights are shown in Table 20 below:

[0161]

[0162] Conclusion on changes in organ weights: There were no abnormalities in organ weights of rats in each dose group.

[0163] 4. Observation of nasal irritation:

[0164] The appearance of the nose was observed by two people 30 minutes before and after administration, recorded with photos or videos, and expressed as a score according to the "Grading Standard for Local Mucosal Irritation Reaction." An average score of 0.00-0.40 indicates no irritation; an average score of 0.41-1.50 indicates mild irritation; an average score of 1.51-2.50 indicates moderate irritation; and an average score >2.51 indicates severe irritation.

[0165] Mucosal irritation evaluation: The mucosal irritation response of rats in each dose group was graded as no irritation; the details are shown in Table 21 below.

[0166]

[0167] 5. Pathological results:

[0168] Pathological sections were taken from the rats 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 morphological difference between males and females; no pathological changes were found in the olfactory bulb and other brain regions of each group; no pathological changes were found in the nasal concha mucosa and olfactory mucosa of each group; in summary, all excipients and formulations were not toxic to rats.

[0169] Obviously, the above embodiments are merely examples for clarity of explanation and are not intended to limit the implementation methods. Those skilled in the art will readily appreciate that other variations or modifications based on the above descriptions are possible. It is not necessary and impossible to enumerate all implementation methods here. Obvious variations or modifications arising therefrom remain 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 nasal-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 a nimodipine nasal-cerebral delivery preparation in the preparation of a drug for treating cerebral ischemic diseases, cerebral vasospasm caused by subarachnoid hemorrhage, and sudden deafness.

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