Nasal-brain delivery preparation for treating biological rhythm disorder

Abstract

The invention provides an agomelatine nasal brain delivery system which is high in brain targeting, safe and non-invasive. According to the technical scheme, the agomelatine injection comprises the following components: agomelatine serving as an active ingredient, diethylene glycol monoethyl ether serving as a good solvent and isopropyl myristate serving as a diluent, and optionally, menthol serving as an aroma regulator. According to the nasal-brain delivery preparation, the agomelatine nasal-brain delivery preparation which is high in permeability coefficient, high in solubility, free of nasal cavity irritation and high in brain targeting is obtained through a simple preparation formula. The agomelatine nasal-brain delivery preparation is non-irritant to the nasal cavity, the active ingredient agomelatine is absorbed by the mucosa of the nasal cavity and directly enters the brain, the agomelatine can take effect quickly, and the effectiveness of the medicine is improved; meanwhile, the liver first-pass effect of agomelatine is avoided, the liver toxicity of agomelatine is reduced, and the safety of the medicine is improved; the nasal-brain delivery system provides a new treatment scheme for treating the biological rhythm disorder, and has a good industrial application prospect.

Description

Technical Field

[0001] The invention belongs to the field of medicine and relates to a nasal-cerebral delivery preparation, in particular to an agomelatine nasal-cerebral delivery preparation. Background Art

[0002] Agomelatine, molecular formula C 15 H 17 NO2, molecular weight 243.3, chemical name N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, structural formula is as follows:

[0003] Very slightly soluble or almost insoluble in water, soluble in ethanol.

[0004] Agomelatine is a melatonin MT1 and MT2 receptor agonist, and it is also a 5-HT2C receptor antagonist. The binding sites of agomelatine and 5-HT2C receptors are mainly concentrated in the amygdala, hippocampus and prefrontal cortex of the brain. Agomelatine is a drug used to treat major depression in adults. The oral dosage form (tablets) has been marketed in Europe under the trade name Valdoxan. Oral agomelatine has a high first-pass effect in the liver, and the absolute bioavailability is only about 5%, which can lead to elevated transaminases and cause liver toxicity. On October 30, 2012, the Medicines and Healthcare Products Regulatory Agency (MHRA) of the United Kingdom released safety information about agomelatine (Valdoxan). MHRA said that several reports of severe cases of liver toxicity were found in the use of agomelatine, including six cases of liver failure reported worldwide. The drug information for agomelatine already includes a recommendation that all patients undergo liver function tests at the start of treatment and during treatment, and this recommendation has now been extended to include liver function tests when the drug dose is increased. The MHRA recommends that agomelatine should be discontinued immediately if patients develop symptoms or signs of potential liver damage or if a liver function test shows an increase in serum aminotransferases exceeding 3 times the upper limit of normal (ULN).

[0005] As a systemic drug delivery route with fast absorption, high bioavailability, low damage to the body and convenient use, nasal administration has attracted more and more attention. Since Frey proposed in 1989 that drugs can be directly delivered to the brain parenchyma through nasal administration and exert therapeutic effects, targeted drug delivery into the brain through the nose has also made remarkable progress.

[0006] However, due to the existence of the human blood-brain barrier, most drugs cannot enter the brain. In order to make the drugs work, overcoming the blood-brain barrier and delivering drugs into the brain is the most critical issue. At present, the main research directions for transporting therapeutic drugs to the central nervous system are: ① Invasive drug delivery, including carotid artery injection of vasoactive substances, intrathecal injection and intraventricular injection. ② Use fat-soluble prodrugs, chemical delivery systems, carrier-mediated transport systems, adsorption-mediated and receptor-mediated endocytosis transport systems, immunoliposomes and nano-delivery systems to promote drug penetration through the BBB (blood-brain barrier). ③ Nasal administration bypasses the BBB and enters the brain. The first method above is effective but has poor safety and is prone to brain infection and surgical injury. The second method often requires injection, and patients with long-term medication have poor compliance. Nasal administration has been a research hotspot at home and abroad in the past decade, and has achieved many research results, with promising prospects, and is considered to be the most promising method. The olfactory neuroepithelium is the only tissue in direct contact between the CNS and the outside world. The axons of the olfactory sensory neurons covered by nasal cilia form bundles that can pass through the cribriform plate into the cranial cavity and form synaptic connections with the mitral cells and plexus cells of the olfactory bulb in the brain. This is the olfactory mucosal epithelial pathway for drugs to be absorbed from the nasal cavity into the brain. After nasal administration, drug molecules are retained in the olfactory mucosa and are easily absorbed into the cerebrospinal fluid, thus bypassing the BBB to enter the CNS and exert a therapeutic effect.

[0007] However, current research on nasal mucosal drug delivery systems has found that such preparations can cause irritation to the nasal mucosa, primarily due to ciliary toxicity, including the effects of drugs, additives, penetration enhancers and preservatives on ciliary activity, which results in certain limitations in the use of nasal mucosal drug delivery preparations (Zhou Liyu et al., Research Progress of Nasal Drug Delivery Systems, Chinese Modern Drug Applications, Vol. 3, No. 4, 2009).

[0008] Due to the influence of the special environment of the nasal cavity, it is difficult to develop drugs into nasal preparations. For agomelatine, various pharmaceutical companies focus on its research and development in the following aspects: In patent application CN202210639712.2, by adding DDM or vitamin E to the agomelatine preparation, the ethanol content is reduced and the irritation of ethanol is reduced, but the patent application does not reduce the irritation of other excipients in the preparation to the nasal cavity; in patent application CN202111598531.1, by adding absorption enhancers and metal ions to the agomelatine preparation to increase the blood concentration and AUC, but the increase in metal ions will lead to the accumulation of drugs in the brain, which is not conducive to clinical application implementation; in patent application 202111583617.7, by adding surfactants to the preparation and reducing the particle size of agomelatine, it is used to solve the problems of agomelatine due to poor water solubility and low bioavailability. It has been verified that the formulation scheme in this patent application still has strong nasal mucosal irritation and is not suitable for nasal brain delivery preparations. Patent application 202111269142.4 discloses a transdermal preparation of agomelatine. The combination of emulsifiers, co-emulsifiers, oil phases and water phases can improve the ability of agomelatine to penetrate the skin, thereby improving the bioavailability. However, the applicant found through Franz diffusion cell experiments that this type of preparation does not meet the requirements of nasal-cerebral delivery preparations due to its low permeability coefficient.

[0009] Therefore, whether it is possible to successfully develop a naso-cerebral delivery preparation of agomelatine that has a simple preparation process, is suitable for industrial production, has low production cost, is non-irritating, has good absorbability, takes effect quickly, and has no liver toxicity has become an urgent problem to be solved. Summary of the invention

[0010] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a novel naso-cerebral delivery preparation of agomelatine which has a simple preparation process, is suitable for industrial production, has low production cost, is non-irritating, and has good absorption. The preparation is convenient to administer, has rapid onset of action, can greatly improve bioavailability and efficacy, provides a new option for the treatment of patients, and fills the market gap.

[0011] The first aspect of the present patent application provides a naso-cerebral delivery preparation of agomelatine, comprising agomelatine, a good solvent and a diluent, and optionally, further comprising an aroma modulator, but excluding a surfactant and / or an absorption enhancer; the good solvent is a mixture of one or more selected from PEG400, ethanol, propylene glycol, benzyl alcohol, and diethylene glycol monoethyl ether, preferably diethylene glycol monoethyl ether; the aroma modulator is a mixture of one or more selected from grape flavor, borneol, cyclopentadecalactone, vanillin, 2-phenylethanol, menthol, strawberry flavor, orange flavor, lavender flavor, eucalyptus oil, and citric acid, preferably menthol.

[0012] The diluent is selected from a mixture of one or more of castor oil, monolinoleyl glyceryl, isopropyl myristate, medium chain triglycerides, vitamin E, and ethyl oleate, preferably isopropyl myristate.

[0013] In the agomelatine naso-cerebral delivery preparation of the present invention, the weight portion of agomelatine is 2 to 40 parts by weight, preferably, 5 to 15 parts by weight, for example, 5, 5.5, 10, 15 parts by weight or any value in between.

[0014] In the agomelatine naso-cerebral delivery preparation of the present invention, the weight portion of the good solvent is 20-500 weight portions, preferably, 50-300 weight portions, for example, 50, 80, 90, 100, 150, 200, 250, 280, 300 weight portions or any value therebetween.

[0015] In the agomelatine naso-cerebral delivery preparation of the present invention, the weight portion of the diluent is 500-950 weight portions, preferably 650-850 weight portions, for example, 650, 700, 750, 800, 850 weight portions or any value therebetween.

[0016] In the agomelatine naso-cerebral delivery preparation of the present invention, the weight portion of the aroma modulator is 0.2-20 weight portions, preferably 0.5-10 weight portions, for example, 0.5, 1, 3, 5, 7, 9, 10 weight portions or any value therebetween.

[0017] The agomelatine naso-cerebral delivery preparation of the present invention is in the form of a solution.

[0018] In certain embodiments of the present invention, the nasal-to-brain delivery preparation of agomelatine consists of the above-mentioned agomelatine, the above-mentioned good solvent, and the above-mentioned diluent; and / or, the nasal-to-brain delivery preparation of agomelatine consists of the above-mentioned agomelatine, the above-mentioned good solvent, the above-mentioned diluent, and the above-mentioned aroma regulator.

[0019] According to another particularly preferred embodiment of the present invention, the agomelatine nasal-cerebral 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.

[0020] The second aspect of the present patent application provides a method for preparing an agomelatine nasal-cerebral delivery preparation, comprising placing agomelatine and the above-mentioned good solvent in a container, and completely dissolving the agomelatine and the good solvent by ultrasonication, heating or stirring; optionally, adding an aroma regulator; and finally adding the above-mentioned diluent to the total mass of each prescription, and rotating and mixing to obtain the preparation.

[0021] The third aspect of the present patent application provides an agomelatine naso-cerebral delivery preparation prepared by the above-mentioned method for preparing the agomelatine naso-cerebral delivery preparation.

[0022] The fourth aspect of the present patent application provides a method for treating diseases caused by biological rhythm disorders by using an agomelatine naso-brain delivery preparation via a naso-brain delivery route; in particular, diseases caused by depression, anxiety, and sleep rhythm disorders, comprising administering a therapeutically effective amount of the agomelatine naso-brain delivery preparation to a patient in need thereof.

[0023] According to the fifth aspect of the present disclosure, the present disclosure also provides the use of the above-mentioned agomelatine nasal-brain delivery preparation in the preparation of a drug for treating a disease caused by biological rhythm disorders, especially the disease is caused by depression, anxiety, and sleep rhythm disorders. In particular, the present disclosure also provides the use of the above-mentioned agomelatine nasal-brain delivery preparation in the preparation of a drug for treating a disease caused by biological rhythm disorders, especially depression, anxiety, and sleep rhythm disorders, by delivering the drug into the brain through the nose.

[0024] According to the sixth aspect of the present disclosure, the present disclosure further provides a pharmaceutical composition comprising the above-mentioned nasal-cerebral delivery preparation of agomelatine and any suitable pharmaceutically acceptable excipients.

[0025] 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.

[0026] Compared with the prior art, the present invention has the following beneficial effects: In the agomelatine nasal-brain delivery preparation of the present invention, the solubility of agomelatine is increased from 0.3 mg / mL to 16.5 mg / mL by using fewer types of excipients; at the same time, the irritation of agomelatine to the nasal cavity is reduced; more importantly, the nasal mucosal penetration coefficient of agomelatine for nasal administration is increased, and good brain targeting is achieved.

[0027] The agomelatine nasal-cerebral delivery preparation of the present invention reduces the irritation of the preparation by adding the auxiliary material menthol, and more importantly, improves the efficiency of entering the brain through the nose by about 1.7 times.

[0028] In the agomelatine nasal-brain delivery preparation of the present invention, the efficacy of the agomelatine nasal-brain delivery preparation is improved by reasonable compatibility of excipients, and the preparation can quickly take effect after being administered through the upper nasal passages.

[0029] 4. In the agomelatine nasocerebral delivery preparation of the present invention, the efficiency of Cmax entering the brain is improved through the reasonable compatibility of the excipients, and the value entering the brain structure is higher than the value entering the systemic blood system. DETAILED DESCRIPTION

[0030] 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.

[0031] In this application: 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.

[0032] E80 refers to lecithin E80, which is a type of lecithin; CMC-Na refers to sodium carboxymethyl cellulose; PEG400 refers to polyethylene glycol 400; DDM refers to dodecyl-β-D-maltoside.

[0033] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0034] In this patent application, the permeability coefficient refers to the permeability coefficient of the porcine nasal mucosa, and the method for determining the permeability coefficient adopts the method known to those skilled in the art. In the present invention, the method for determining the permeability coefficient adopts the method known to those skilled in the art: using a Franz diffusion cell to simulate the process of drug absorption through the nasal mucosa. The drug solution diffuses from the supply pool through the porcine nasal mucosa to the receiving pool, and the drug solution in the receiving pool is collected at different time points, the concentration is measured, and the apparent permeability coefficient of drug absorption through the nasal mucosa is calculated.

[0035] In this patent application, the method for determining ciliary toxicity is: the in vivo toad palate ciliary method is used to investigate the toxicity of nasal preparations to nasal mucosal cilia. After the toad is fixed in a supine position, the mouth is opened with hemostatic forceps, and the nasal preparation and negative control saline are dripped on the palate mucosa, respectively. After 30 minutes, the mucosa is rinsed with 2 mL of saline, and the palate mucosa with an area of ​​about 3 mm × 3 mm is separated with ophthalmic surgical scissors. After washing with saline, it is spread flat on a glass slide with the mucosa facing upward, 0.2 mL of saline is dripped, and a coverslip is covered. The movement of cilia is observed under a 10×40 optical microscope, and then placed in a chromatography cylinder with a small amount of distilled water, sealed, so that the water vapor reaches a nearly saturated state, and the ambient temperature is maintained at 20-25°C. Every 8 minutes or so, the movement of cilia is observed, and the time required from the start of administration to the complete cessation of cilia movement, that is, the continuous movement time of cilia, is recorded. The duration of the palatal mucociliary movement of the toads in the drug group was divided by the duration of the palatal mucociliary movement of the toads in the negative control group to obtain the relative percentage of the duration of the cilia movement. The higher the percentage, the less toxic the preparation is to the cilia and the higher the safety of the preparation. The threshold of the safety of the preparation is a relative percentage of the duration of the cilia movement greater than 85%. (References: 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;) The following Examples 1 to 6 are the screening process of the applicant to obtain the optimal formulation. After screening different types and different contents of good solvents, absorption enhancers / surfactants, diluents and compounding of diluents, the nasal-brain delivery preparation of agomelatine was obtained. The applicant unexpectedly found that the nasal-brain delivery preparation of agomelatine, through the reasonable combination of good solvents and diluents in the present patent application, can improve the permeability coefficient of agomelatine without adding absorption enhancers and / or surfactants in the nasal-brain delivery preparation of agomelatine; adding an aromatic regulator can not only reduce irritation, but also further improve the permeability coefficient, and the brain penetration effect is improved by more than 1.7 times compared with the nasal-brain delivery preparation without adding an aromatic regulator, thereby completing the present invention.

[0036] Embodiment 1: The following prescriptions are shown in Table 1, and the preparation method thereof adopts the preparation method known to those skilled in the art; for example, the prescribed amount of agomelatine and the corresponding good solvent such as diethylene glycol monoethyl ether are weighed into a glass bottle, and dissolved by ultrasound; then the corresponding amount of absorption enhancer such as lecithin is added, and the mixture is dissolved by shaking and ultrasound; finally, the prescribed amount of diluent is added until the total mass of each prescription reaches 1 g, and the mixture is rotated and mixed for 30 minutes to be evenly dispersed to obtain the following prescriptions, and the ciliary toxicity and permeability coefficient of each prescription are measured.

[0037] Table 1

[0038] Experimental conclusion: When diethylene glycol monoethyl ether is used as a good solvent, lecithin is used as an absorption enhancer, and castor oil is used as a diluent, although the ciliary toxicity meets the requirements, it becomes turbid on the second day when placed at room temperature, and cannot be used as a naso-cerebral delivery preparation; when isopropyl myristate is used as a diluent, its permeability coefficient can reach 14.5, and the solution remains clear at room temperature without becoming turbid, and the ciliary toxicity is passed.

[0039] Embodiment 2: The prescriptions shown in Table 2 were prepared by methods known to those skilled in the art, such as weighing the prescribed amount of agomelatine and the corresponding good solvent such as diethylene glycol monoethyl ether into a glass bottle, and dissolving them by ultrasonication; then adding the corresponding amount of absorption enhancer such as lecithin E80, shaking and ultrasonication to dissolve them; finally, adding the prescribed amount of diluent until the total mass of each prescription reaches 1g, rotating and mixing for 30 minutes to make the dispersion uniform, and then obtaining the following prescriptions, and measuring the ciliary toxicity and permeability coefficient of each prescription.

[0040] Table 2

[0041] Experimental conclusion: Each formulation had no effect on nasal cilia and no obvious irritation to mucosal cells; When the diluent was isopropyl myristate or ethyl oleate, the permeability coefficient was the highest; The lowest permeability coefficient was obtained when monolinoleylglycerol was used.

[0042] During the research and development, it was found that when water was used as a diluent, it had no effect on the nasal cilia, but was significantly irritating to the mucosal cells, causing some cells to fall out and only a few tissue boundaries to be clear.

[0043] Embodiment 3: The preparation method of the prescription shown in Table 3 can be prepared according to methods known to those skilled in the art, or can be prepared according to a method similar to Example 1.

[0044] Table 3

[0045] The samples were prepared using common good solvents for nasal preparations and isopropyl myristate, DDM as an absorption enhancer, polyoxyethylene hydrogenated castor oil, Tween 20 and Tween 80 as surfactants, and the absorption of pig nasal mucosa was investigated. The experimental results are shown in Table 4 below.

[0046] Table 4

[0047] Experimental conclusion: When 0.043% DDM was used, the permeability coefficient of the benzyl alcohol-free-0.5% Tween system was as high as 4.61±0.75; and when 0.21% DDM was used, the permeability coefficient was higher than 6. Although the permeability coefficient was improved, it still did not meet the permeability coefficient requirements of agomelatine naso-cerebral delivery preparations.

[0048] Example 4: Investigation of diluent compounding The formula of diethylene glycol monoethyl ether-lecithin PL-100M, as shown in Table 5, was prepared by compounding castor oil, ethyl oleate and isopropyl myristate. The appearance was examined under room temperature and refrigerated conditions, and the local absorption was further examined.

[0049]

[0050] The experimental results are shown in Table 6 below: Table 6

[0051] Experimental conclusion: 1. Without adding lecithin, the compound diluent samples were clear under cool and refrigerated conditions. (Formulation 23022703 and Formula 23022704).

[0052] 2. The samples to which lecithin PL-100M was added as an absorption enhancer became clear within 2 days under cool conditions (17°C), became turbid precipitate after being refrigerated overnight, and remained turbid after being further placed at 17°C overnight (prescriptions 23022701 and 23022702).

[0053] 3. The absorption of the compound diluent system is between the two diluents; and the addition of phospholipids does not improve local absorption.

[0054] Example 5 Diethylene glycol monoethyl ether-isopropyl myristate system Using diethylene glycol monoethyl ether as a good solvent and isopropyl myristate as a diluent, the amount of diethylene glycol monoethyl ether was adjusted to increase the API concentration, and the prescriptions were prepared to further investigate the local absorption. The prescriptions are shown in Table 7 below. The preparation method adopts a method known to those skilled in the art, for example, weighing the prescription amount of agomelatine and the corresponding good solvent such as diethylene glycol monoethyl ether into a glass bottle, dissolving them by ultrasound; finally, adding the prescription amount of diluent until the total mass of each prescription reaches 1g, rotating and mixing for 30 minutes to make the dispersion uniform, and then obtaining the following prescriptions, and measuring the ciliary toxicity and permeability coefficient of each prescription.

[0055] Table 7

[0056] The experimental results are shown in Table 8 below:

[0057] Experimental conclusion: 1) The applicant of this patent unexpectedly discovered that without using surfactants / absorption enhancers such as phospholipids, the permeability coefficient increased significantly; 2) When the dosage of diethylene glycol monoethyl ether reached 16% (23032206) and the API concentration was 16.5 mg / g (23032209), the ciliary toxicity was passed.

[0058] 3) As the dosage of diethylene glycol monoethyl ether increases, the absorption first decreases and then increases; when the dosage of diethylene glycol monoethyl ether is 10%, the absorption reaches the lowest value.

[0059] 4) API concentration does not affect the permeability coefficient of the solution.

[0060] 5) N / A, not tested. When the API concentration is the same, the dosage of diethylene glycol monoethyl ether is low, and the ciliary toxicity test is exempted, so no testing is required.

[0061] Example 6: Investigation of the irritation of the basic formula with the continued increase in the amount of diethylene glycol monoethyl ether The dosage of diethylene glycol monoethyl ether was increased and a double-concentration basic formulation was prepared to evaluate the irritation and permeability coefficient.

[0062] The experimental scheme is shown in Table 9 below:

[0063] The experimental results are shown in Table 10 below:

[0064] Experimental conclusion: 1. The dosage of diethylene glycol monoethyl ether was further increased, and the ciliary toxicity still passed; 2. 25% and 28% diethylene glycol monoethyl ether showed higher absorption, but the difference was not significant (prescription 23042602 and prescription 23042603); 3. Adding menthol slightly improved absorption (prescription 23042602 and prescription 23042604); 4. The dosage of menthol has little effect on absorption (prescription 23063001 and prescription 23042604); 5. N / A means not measured. Since the dosage of diethylene glycol monoethyl ether in the prescription is less than 300 mg / g, the ciliary toxicity test is exempted.

[0065] Effect embodiment 1: The following prescription is shown in Table 11. The solubility of the preparation is 5 mg / mL, the amount of diethylene glycol monoethyl ether is adjusted to 25%, i.e., 250 parts by weight, and the preparation is divided into two groups, one containing an aromatic modifier and one not containing an aromatic modifier. The preparation method is prepared by a conventional method of a person skilled in the art or by a preparation method similar to that of Example 5.

[0066] Adopt small animal intelligent integrated nasal drug delivery system (RA-IDDS ® ) administration, such as the administration system disclosed in CN202021777601.0 and CN202010148279.3, the pharmacological example was administered to rats, with 6 rats in each group in parallel, and the administration was continued for 7 days; the reaction of the animals was observed after each administration, and the average value was calculated. The experimental results are summarized in Table 12 below:

[0067] The experimental conclusions are as follows: The mucosal irritation reactions were all graded as non-irritating. Compared with the group without aroma modulators, the group with aroma modulators had significantly fewer sneezing reactions and a lower number of struggles during administration, proving that the nose-brain delivery preparation containing the aroma modulator menthol can further reduce the irritation to the nasal mucosa. There was no significant change in the frequency of drowsiness reactions in the rats in the group with aroma modulators after administration, and the aroma modulators that refresh the mind did not affect the efficacy of agomelatine in improving sleep. In addition, after observation, there were no abnormalities in the behavioral activities, mental state, respiratory condition, hair condition, body weight, and food intake of rats in each group.

[0068] Effect embodiment 2: The following formulation in Table 13 is prepared by conventional preparation methods of those skilled in the art or by a preparation method similar to Example 6.

[0069]

[0070] The prepared agomelatine nasal brain delivery preparation (prescription number: 22082301) was placed in a nasal brain delivery device (RA-IDDS® small animal intelligent integrated nasal brain delivery system developed by the applicant company, as disclosed in CN202021777601.0 and CN202010148279.3), and the prescribed dose of the drug was administered to mice through the nose. The nasal brain delivery method was a 2-min constant speed administration under gas anesthesia. The pharmacokinetics and distribution of the nasal brain delivery of the formula were evaluated at 2, 5, 15, 30, 60, 120, and 180 min after administration. The collection and sampling methods of plasma, olfactory bulb, and cortical brain tissue were commonly used by those skilled in the art. For the collection of cerebrospinal fluid, the method of first evacuating blood and then collecting cerebrospinal fluid was adopted to avoid cerebrospinal fluid contamination by blood as much as possible, making the test results more accurate. The experimental results are shown in Table 14.

[0071] In this effect example, DP-0 refers to: 0.5% CMC-Na dissolved tablets of the original company (Videxin tablets of Servier Company, France), DP-0 is administered orally by gavage; the human clinical oral dose of 25 mg (60 kg) is converted to 5 mg / kg in mice by the body surface area method, and at this dose, the peak plasma and exposure of the original oral control DP-0 mice are 7.1 ng / mL and 66.3 min·ng / ml, respectively, which are comparable to the original human clinical oral data (peak 3 ng / mL, exposure 294 min·ng / ml).

[0072] The naso-cerebral delivery preparation of this patent application is significantly higher than the original oral control DP-0, and the content of the target brain tissue is greatly improved compared with the oral dosage form. Therefore, the preparation formula of this effect embodiment can be effective at a lower dose, which can reduce the amount of metabolism and avoid toxic reactions caused by liver metabolism.

[0073]

[0074] Effect embodiment 3: The formulations in Table 15 below are characterized in that they do not contain absorption enhancers / surfactants such as lecithin, and adopt a simplified formula. The preparation method thereof adopts a method known to those skilled in the art or a method similar to Example 6.

[0075]

[0076] The preparation prescription of Table 15 above is placed in a nasal administration device (RA-IDDS 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-min 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 min after administration. The sampling methods for plasma, olfactory bulb, and cortical brain tissue are commonly used by those skilled in the art; the experimental data are shown in Table 16 below.

[0077] in conclusion: The use of 25% (i.e. 250 parts by weight) of the good solvent diethylene glycol monoethyl ether and the agomelatine naso-cerebral delivery preparation (23041701) without the addition of lecithin increased the peak value of the target brain tissue in mice to 2.8 times (2457 ng / g VS 868.5 ng / g) compared with the prescription containing lecithin (22082301), which is beneficial for stimulating melatonin receptors and improving the effect of falling asleep.

[0078] The good solvent diethylene glycol monoethyl ether was used in an amount of 25%, i.e. 250 parts by weight, without adding lecithin, and 10% menthol, i.e. 10 parts by weight, was added to the agomelatine naso-cerebral delivery preparation (prescription 23050401). The exposure of the target brain tissue was increased to 2.1 times that of the prescription containing lecithin (22082301) (31999 min·ng / g VS 15582.0 min·ng / g), which is beneficial for antagonizing serotonin receptors to increase the release of norepinephrine and dopamine to enhance the antidepressant efficacy.

[0079] When the aroma modifier menthol is added to the naso-cerebral delivery preparation of agomelatine, the absorption and distribution efficiency of agomelatine can be improved, and the AUC value in brain tissue is significantly increased by about 1.7 times compared with the naso-cerebral delivery preparation without aroma modifier (31999 min·ng / g VS 18170.0 min·ng / g).

[0080] The naso-cerebral delivery preparation of the present patent application is significantly higher than the preparation formula of Example 2, and the Cmax and AUC values ​​of the target brain tissue are greatly improved compared with the preparation formula of Example 2. Therefore, the preparation formula of this example can be effective at a very low dose, further reducing liver toxicity caused by liver metabolism.

[0081] In summary, the agomelatine nasal-cerebral delivery preparation of the present invention can effectively penetrate the blood-brain barrier, enrich the drug in the brain, and has a good targeting effect on CNS diseases. At the same time, the preparation of the present invention avoids the adverse reactions of agomelatine and excipients to the human body through reasonable dosage and compatibility, has no nasal toxicity, and improves the patient's compliance. It provides a new and effective way for the successful preparation of agomelatine into nasal preparations, and has good industrial application prospects.

[0082] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A nasal-cerebral delivery preparation of agomelatine, comprising agomelatine as an active ingredient, characterized in that: The invention also comprises a good solvent diethylene glycol monoethyl ether and a diluent isopropyl myristate, and optionally, contains an aroma modulator menthol, and does not contain an absorption enhancer and / or a surfactant, wherein the absorption enhancer and / or the surfactant is lecithin, polyoxyethylene hydrogenated castor oil RH40, Tween 20 or Tween 80.

2. The naso-cerebral delivery preparation according to claim 1, characterized in that: The nasal-cerebral delivery preparation is composed of agomelatine, diethylene glycol monoethyl ether and isopropyl myristate; or, The nasal and cerebral delivery preparation consists of agomelatine, diethylene glycol monoethyl ether, isopropyl myristate and menthol.

3. The naso-cerebral delivery preparation according to claim 1 or 2, characterized in that: The content of the active ingredient agomelatine is 2 to 40 parts by weight; and / or, The content of diethylene glycol monoethyl ether is 20 to 500 parts by weight; and / or, The content of isopropyl myristate is 500-950 parts by weight; and / or, The content of the aroma regulator is 0.2 to 20 parts by weight.

4. The naso-cerebral delivery preparation according to claim 3, characterized in that: The content of the active ingredient agomelatine is 5 to 15 parts by weight; and / or, The content of diethylene glycol monoethyl ether is 50 to 300 parts by weight; and / or, The content of isopropyl myristate is 650-850 parts by weight; and / or, The content of the aroma regulator is 0.5 to 10 parts by weight.

5. The naso-cerebral delivery preparation according to claim 3, characterized in that: The content of the active ingredient agomelatine is 5, 5.5, 10, 15 parts by weight or any value between the two values; and / or, The content of diethylene glycol monoethyl ether is 50, 80, 90, 100, 150, 200, 250, 280, 300 parts by weight or any value between the two values; and / or, The content of isopropyl myristate is 650, 700, 750, 800, 850 parts by weight or any value between the two values; and / or, The content of the fragrance regulator is 0.5, 1, 3, 5, 7, 9, 10 parts by weight or any value therebetween.

6. A method for preparing an agomelatine nasal-cerebral delivery preparation, comprising placing the agomelatine described in any one of claims 1 to 5 and the good solvent described in any one of claims 1 to 5 in a container, and completely dissolving the agomelatine and the good solvent by ultrasonication, heating or stirring; optionally, adding the aroma regulator described in any one of claims 1 to 5; and finally adding the diluent described in any one of claims 1 to 5 to the total weight of each prescription, and rotating and mixing to obtain the preparation.

7. An agomelatine nasal-brain delivery preparation prepared by the method for preparing the agomelatine nasal-brain delivery preparation according to claim 6.

8. Use of the agomelatine naso-cerebral delivery preparation according to any one of claims 1 to 5 or 7 in the preparation of a drug for treating a disease caused by biological rhythm disorders; wherein: The condition is caused by depression, anxiety or sleep rhythm disorders.

9. A pharmaceutical composition comprising the naso-cerebral delivery preparation of agomelatine according to any one of claims 1 to 5 or 7 and any suitable pharmaceutically acceptable excipient.

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