Lamidipine composition as well as preparation method and application thereof

Abstract

The invention provides a pharmaceutical composition containing lamidetan. The pharmaceutical composition comprises lamidetan and / or pharmaceutically acceptable salt thereof, a filler, a disintegrating agent, a lubricant, an adhesive and a flow aid. The composition is good in auxiliary material compatibility, high in preparation stability, less in impurity degradation after being placed under the conditions of high temperature, high humidity and the like, stable in active ingredient crystal form, simple in preparation process, easy to operate and suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a lamiditan composition, a preparation method and uses thereof. Background Art

[0002] Lasmiditan (also known as COL-144, LY573144), chemical name is 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide, is a new type of selective 5-HT 1F Receptor agonists can be used to inhibit neuronal protein extravasation, treat or prevent migraine and other headaches related to 5-HT 1F Diseases or symptoms associated with receptor dysfunction. Lamiditan was approved for marketing by the U.S. FDA on October 11, 2019, under the trade name Reyvow. Its active ingredient is lamiditan hemisuccinate, with the chemical structure shown below:

[0003]

[0004] Chinese Patent CN100352817C discloses lamiditan and its hemisuccinate salt, and further discloses a method for treating migraine in a mammal, comprising administering an effective amount of lamiditan or a salt thereof to the mammal. U.S. Patent US8697876B2 discloses solid crystalline forms A, B, and C of lamiditan hemisuccinate. Chinese Patent CN110291079A discloses novel pseudopolymorphs D, E, and F of lamiditan hemisuccinate.

[0005] Chinese patent CN110291079A also mentions that starting from the crystalline form A or amorphous form of lamiditan hemisuccinate, the addition of water alone or a water / solvent mixture results in conversion from the crystalline form A or amorphous form to one of the novel pseudopolymorphs D, E or F, and that transcrystalization easily occurs.

[0006] In view of the shortcomings of the existing technology, it is necessary to develop a stable pharmaceutical composition preparation of lamivudine and a simple and easy preparation process thereof, so as to make it have stable crystal form and quality, low impurity content, good compatibility of excipients, and high preparation stability. Summary of the Invention

[0007] To solve the problems existing in the prior art, in a first aspect, the present invention provides a pharmaceutical composition comprising lamiditan and / or a pharmaceutically acceptable salt thereof, a filler, a disintegrant, a lubricant, a binder, and a glidant.

[0008] Furthermore, the filler is selected from at least one of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, lactose, glucose, sucrose, mannitol, sorbitol, starch and dextrin;

[0009] The disintegrant is selected from at least one of cross-linked povidone, sodium carboxymethyl starch, sodium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, carboxymethyl starch, modified starch, microcrystalline cellulose, sodium bicarbonate, silicon dioxide, sodium lauryl sulfate, magnesium lauryl sulfate, anhydrous sodium carbonate, methyl cellulose, and hydroxyethyl methyl cellulose;

[0010] The lubricant is selected from at least one of sodium stearyl fumarate, magnesium stearate, talc powder, zinc stearate, magnesium lauryl sulfate, silicon dioxide, and sodium behenyl sulfate;

[0011] The binder is selected from at least one of pregelatinized starch, hydroxypropyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl methyl cellulose, ethyl cellulose, poloxamer, modified starch, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, povidone, sucrose, monolaurate, and dextrin;

[0012] The glidant is selected from at least one of talc powder, silicon dioxide, colloidal silicon dioxide, magnesium stearate, magnesium trisilicate, and starch.

[0013] Furthermore, the filler is selected from at least one of microcrystalline cellulose, lactose, or cellulose lactose; the disintegrant is sodium carboxymethyl starch; the lubricant is at least one of magnesium stearate or sodium stearyl fumarate; the binder is pregelatinized starch; the glidant is silicon dioxide.

[0014] Furthermore, the lubricant includes an internal lubricant and an external lubricant.

[0015] Furthermore, the weight ratio of the internal lubricant to the external lubricant in the lubricant is 1:3 - 5, preferably 1:3 - 4; more preferably 1:3.

[0016] Furthermore, based on the total weight of the plain tablets,

[0017] The content of lamotrigine and / or its pharmaceutically acceptable salt is 30 - 70 wt%; the content of the filler is 10 - 90 wt%; the content of the disintegrant is 5 - 30 wt%; the content of the lubricant is 1.1 - 5 wt%; the content of the binder is 2 - 30 wt%; the content of the glidant is 1.1 - 5 wt%.

[0018] Furthermore, based on the total weight of the plain tablets,

[0019] The content of the lamotrigine and / or its pharmaceutically acceptable salt is 45 - 55 wt%; the content of the filler is 20 - 40 wt%; the content of the disintegrant is 10 - 15 wt%; the content of the lubricant is 1.1 - 3 wt%; the content of the binder is 5 - 10 wt%; the content of the glidant is 1.1 - 3 wt%.

[0020] Further, based on the total weight of the core tablet,

[0021] The content of the lamotrigine and / or its pharmaceutically acceptable salt is 48 - 52 wt%; the content of the filler is 25 - 38 wt%; the content of the disintegrant is 11 - 13 wt%; the content of the lubricant is 1.1 - 2 wt%; the content of the binder is 6 - 8 wt%; the content of the glidant is 1.1 - 2 wt%.

[0022] Further, based on the total weight of the core tablet, the sum of the contents of the lamotrigine and / or its pharmaceutically acceptable salt, filler, disintegrant, lubricant, binder, and glidant is 100%.

[0023] According to an embodiment of the present invention, in the composition, the pharmaceutically acceptable salt of lamotrigine is selected from lamotrigine hemisuccinate.

[0024] In some embodiments, the ingredient is selected from lamotrigine hemisuccinate.

[0025] In some embodiments, the lamotrigine hemisuccinate includes solvates, clathrates, amorphous forms, and different crystal forms (polymorphs, pseudopolymorphs) of lamotrigine hemisuccinate.

[0026] The solvate refers to an association formed by one or more solvent molecules with the pharmaceutically active ingredient (2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate). The solvents forming the solvate include, but are not limited to, water, ethanol, methanol, etc. The solvate includes hydrates, which refer to the combination of stoichiometric or non-stoichiometric amounts of water through non-covalent intermolecular forces, such as hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, etc. The clathrate refers to a drug in the form of a crystal lattice containing a space (such as a channel) with a guest molecule (such as a solvent or water) trapped therein.

[0027] In some embodiments, the ramelteon hemisuccinate is selected from one crystal form or a mixture of two or more crystal forms, for example, selected from any one crystal form or a mixture of two or more crystal forms disclosed in US8697876B2 and CN110291079A. In some embodiments, the ramelteon hemisuccinate is selected from one or a mixture of two or more of crystal forms A, B, and C of ramelteon hemisuccinate disclosed in US8697876B2; in some embodiments, the ramelteon hemisuccinate is selected from one or a mixture of two or more of crystal forms D, E, and F of ramelteon hemisuccinate disclosed in CN110291079A.

[0028] In some embodiments, the pharmaceutical composition has the following component weight percentages (wt%):

[0029] (1) The pharmaceutical composition comprises:

[0030]

[0031] Or,

[0032] (2) The pharmaceutical composition comprises:

[0033]

[0034]

[0035] Or,

[0036] (3) The pharmaceutical composition comprises:

[0037]

[0038] In some embodiments, the pharmaceutical composition has the following component weight percentages (wt%): (1) The pharmaceutical composition comprises:

[0039]

[0040] Or,

[0041] (2) The pharmaceutical composition comprises:

[0042]

[0043] Or,

[0044] (3) The pharmaceutical composition comprises:

[0045]

[0046] According to an embodiment of the present invention, the pharmaceutical composition is a solid oral preparation, and the solid oral preparation is selected from the forms of a mixture directly obtained by mixing each component in the pharmaceutical composition, tablets, capsules, and granules, preferably tablets.

[0047] In some embodiments, the pharmaceutical composition of the present invention is a tablet, and the tablet includes a core tablet and a coating. The coating material is selected from at least one of film coating premix, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene glycol, and polyvinyl alcohol. The mass of the coating accounts for 1-5 wt%, preferably 1-4 wt%, more preferably 2-4 wt% of the total mass of the core tablet.

[0048] In the context of the present invention, the contents of ramelteon and / or its pharmaceutically acceptable salt, filler, disintegrant, lubricant, binder, and glidant are all weight percentages based on the total mass of the core tablet.

[0049] The total mass of the core tablet refers to the sum of the masses of ramelteon and / or its pharmaceutically acceptable salt, filler, disintegrant, lubricant, binder, and glidant.

[0050] According to an embodiment of the present invention, the hardness of the pharmaceutical composition is 50 N to 130 N, for example, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130 N. Preferably, it is 70-110 N.

[0051] In a second aspect, the present invention provides a method for preparing the pharmaceutical composition, comprising the following steps:

[0052] (1) Crushing or sieving the ramelteon hemisuccinate raw material, and controlling the particle size (D90) to be 30-500 μm, preferably 30-350 μm;

[0053] (2) Sieving the ramelteon hemisuccinate raw material, filler, binder, disintegrant, and internal lubricant respectively, and mixing the sieved materials evenly;

[0054] (3) Granulating the above mixed materials;

[0055] (4) Sieving the glidant and external lubricant respectively, and mixing the sieved materials evenly with the granules prepared in step (3) to obtain an intermediate;

[0056] (5) Tableting the intermediate to obtain a core tablet; optionally, coating the obtained core tablet with a film coating premix.

[0057] According to an embodiment of the present invention, in the preparation method, in steps (2) and (4), the sieving is respectively carried out, and a sieve mesh between 30 and 60 meshes is independently selected for sieving, for example, 30, 40, 50, or 60 meshes.

[0058] According to an embodiment of the present invention, the preparation method further includes a coating step. The coating step is as follows: coating the core tablets with a coating material. Preferably, the obtained core tablets are coated with a film coating premix.

[0059] On the other hand, the present invention also provides the use of the pharmaceutical composition in the preparation of a drug for activating 5-HT1F receptors, inhibiting neuronal protein extravasation, treating and / or preventing migraine and / or anxiety in mammals.

[0060] On the other hand, the present invention also provides a method for treating and / or preventing migraine and / or anxiety in mammals, including administering the pharmaceutical composition of the present invention to a mammal in need of treatment.

[0061] On the other hand, the present invention also provides a method for treating 5-HT1F-mediated diseases, including administering the pharmaceutical composition of the present invention to a mammal in need of treatment.

[0062] In a preferred embodiment, the mammal in the present invention is a human.

[0063] Glossary of Terms

[0064] Unless otherwise specified, the relevant terms used in the present invention have the following meanings.

[0065] The term "two or more" herein means selected from two, three or more; "at least one" means selected from one, two, three or more.

[0066] The term "active ingredient" herein refers to the pharmacodynamic ingredient in the composition other than the excipients, which is equivalent to rimegepant and / or its pharmaceutically acceptable salts in the pharmaceutical composition.

[0067] The term wt% in the text refers to weight percentage.

[0068] The terms "internal lubricant" and "external lubricant" in the text are defined by the addition method of the lubricant during the preparation process, that is, the "internal lubricant" is added internally, and the "external lubricant" is added externally.

[0069] Beneficial Effects

[0070] Adopting the technical solution of the present invention, the advantages are as follows:

[0071] 1. The pharmaceutical composition containing rimegepant or its pharmaceutically acceptable salt provided by the present invention has a stable active ingredient quality, low impurity content, good excipient compatibility, the prepared tablets are complete and smooth, there is no sticking to the punch during the preparation process, and the prepared preparation has high stability.

[0072] 2. The preparation process of the pharmaceutical composition provided by the present invention can maintain the stable crystal form of the raw drug, is simple and easy to operate, and is suitable for large-scale industrial production. Detailed implementation manners

[0073] The technical solution of the present invention will be further described in detail below in combination with specific embodiments. It should be understood that the following embodiments are only for exemplarily illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technical solutions implemented based on the above content of the present invention are covered within the scope intended to be protected by the present invention.

[0074] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products, or can be prepared by known methods.

[0075] Instruments and testing and analysis methods

[0076] Dissolution detection: Take this product and, according to the dissolution and release determination method in the Chinese Pharmacopoeia (General Principles 0931, Method II) in 2020 edition, use 0.01 mol / L hydrochloric acid as the dissolution medium, the volume of the dissolution medium is 500 ml, the medium temperature is 37 ± 0.5 °C, and the rotation speed is 75 revolutions per minute.

[0077] Powder science detection: Take this product and detect it according to the bulk density and tapped density determination method in the Chinese Pharmacopoeia (General Principles 0993) in 2020 edition.

[0078] The "rimegepant hemisuccinate" and "rimegepant hemisuccinate" mentioned in the context of the present invention refer to the same substance and can be replaced with each other. Its structure is as follows:

[0079]

[0080] The rimegepant hemisuccinate used in the following embodiments is all in Form A, that is, Form A mentioned in US Patent US********B2, and the X-ray diffraction pattern using Cu-K α radiation includes peaks at about 15.32 ± 0.10, 16.39 ± 0.10, 19.33 ± 0.10, 22.14 ± 0.10, 23.56 ± 0.10 and 25.91 ± 0.10 degrees 2θ.

[0081] Example 1 Preparation of rimegepant tablets

[0082] Table 1: Prescription composition of rimegepant tablets

[0083]

[0084]

[0085] Prepare the rimegepant tablets according to the prescription composition in Table 1. The tablets are prepared by the dry granulation process, and the steps are as follows:

[0086] 1) Crush or screen the rimegepant hemisuccinate raw material, and control the particle size (D90) between 30 - 350 μm;

[0087] 2) Screen the rimegepant hemisuccinate raw material, filler, binder, disintegrant, and internal lubricant respectively (30 - 60 mesh), and mix the screened materials evenly;

[0088] 3) Place the above - mentioned mixed materials in the barrel of a dry granulator for granulation;

[0089] 4) Screen the glidant and external lubricant respectively (30 - 60 mesh), and mix the screened materials evenly with the granules prepared in step (3) to obtain the intermediate;

[0090] 5) Press the intermediate to obtain the plain tablets;

[0091] 6) Coat the plain tablets with a film - coating premix.

[0092] Preparation of rimegepant tablets in Example 2

[0093] Table 2: Prescription composition of rimegepant tablets

[0094]

[0095] The preparation method is the same as that in Example 1.

[0096] Preparation of rimegepant tablets in Example 3

[0097] Table 3: Prescription composition of rimegepant tablets

[0098]

[0099] The preparation method is the same as that in Example 1.

[0100] Preparation of rimegepant tablets in Example 4

[0101] Table 4: Prescription composition of rimegepant tablets <9000223>

[0103] The preparation method is the same as that in Example 1.

[0104] Example 5

[0105] Table 5: Physicochemical properties of related samples and process parameters

[0106]

[0107] Note: Due to sticking during Example 3, physicochemical detection was not carried out.

[0108] Table 6: Dissolution curves of related samples in 0.01 mol / L hydrochloric acid solution

[0109]

[0110] Conclusion: The above results show that Formulation 1 and Formulation 4 meet the process requirements in terms of physicochemical properties, tableting, etc., while sticking occurred during tableting of Formulation 2 and Formulation 3; moreover, the dissolution curves of the samples prepared from Formulation 1 and Formulation 4 were both greater than 85% at 15 min, indicating good dissolution effect.

[0111] Stability data of Example 6

[0112] 4.1 Stress testing

[0113]

[0114]

[0115] Note: 92.5% high humidity was after aluminum-plastic packaging, and other conditions were for bare tablets.

[0116] Impurity I

[0117]

[0118] The above experimental results show that there were no obvious changes in related substances and crystal forms after the product was placed under light conditions for 10 days; there were no obvious changes in related substances and crystal forms after being placed at high temperature of 40 °C, 60 °C, high humidity of 75%, and 92.5% high humidity for 30 days.

[0119] Preparation of ramelteon tablets in Example 7

[0120] Table 7: Composition of ramelteon tablet formulation

[0121]

[0122]

[0123] The preparation method is the same as that in Example 1.

[0124] Preparation of ramelteon tablets in Example 8

[0125] Table 8: Composition of ramelteon tablet formulation

[0126]

[0127] The preparation method is the same as that of Example 1.

[0128] Preparation of ramelteon tablets in Example 9

[0129] Table 9: Prescription composition of ramelteon tablets

[0130]

[0131]

[0132] The preparation method is the same as that of Example 1.

[0133] Table 10: Micronization characteristics and process parameters of related samples

[0134]

[0135] Note: Since the tablet hardness of Example 9 did not meet the requirements, micronization detection was not carried out.

[0136] Table 11: Dissolution curves of related samples in 0.01 mol / L hydrochloric acid solution

[0137]

[0138] Conclusion: The above results show that the prescriptions of Examples 7 and 8 meet the process requirements in terms of granulation, micronization characteristics, tableting, etc., and the dissolution curves of the prepared samples are all greater than 85% at 15 minutes, with good dissolution effect. The tablet hardness of the prescription in Example 9 did not meet the requirements during tableting.

[0139] Preparation of ramelteon tablets in Example 10

[0140] Table 12: Prescription composition of ramelteon tablets

[0141]

[0142] The preparation method is the same as that of Example 1.

[0143] Preparation of ramelteon tablets in Example 11

[0144] Table 13: Prescription composition of ramelteon tablets

[0145]

[0146] The preparation method is the same as that of Example 1.

[0147] Preparation of ramelteon tablets in Example 12

[0148] Table 14: Prescription composition of ramelteon tablets

[0149]

[0150] The preparation method was the same as that of Example 1.

[0151] Table 15: Physicochemical properties and process parameters of related samples

[0152]

[0153] Table 16: Dissolution curves of related samples in 0.01 mol / L hydrochloric acid solution

[0154]

[0155] Conclusion: The above results show that the formulations of Example 10, Example 11 and Example 12 meet the process requirements in terms of granulation, physicochemical properties, tableting, etc., and the dissolution curves of the samples prepared from the formulations are all greater than 85% at 15 min, with good dissolution effect.

[0156] Preparation of ramelteon tablets in Example 13

[0157] Table 17: Composition of ramelteon tablet formulation

[0158]

[0159] The preparation method was the same as that of Example 1.

[0160] Preparation of ramelteon tablets in Example 14

[0161] Table 18: Composition of ramelteon tablet formulation

[0162]

[0163] The preparation method was the same as that of Example 1.

[0164] Preparation of ramelteon tablets in Example 15

[0165] Table 19: Composition of ramelteon tablet formulation

[0166]

[0167] The preparation method was the same as that of Example 1.

[0168] Table 20: Physicochemical properties and process parameters of related samples

[0169]

[0170] Note: Since granulation was difficult in Example 13, physicochemical detection and tableting were not carried out.

[0171] Table 21: Dissolution curves of related samples in 0.01 mol / L hydrochloric acid solution

[0172]

[0173] Conclusion: The above results indicate that the formulations of Example 13 and Example 14 affect the granulation process. The formulation of Example 15 meets the process requirements in terms of granulation, powder properties, tableting, etc., and the dissolution curves of the prepared samples at 15 minutes are all greater than 85%, showing good dissolution effect.

[0174] Preparation of Ramelteon Tablets in Example 16

[0175] Table 22: Composition of Ramelteon Tablet Formulation

[0176]

[0177] The preparation method is the same as that of Example 1.

[0178] Table 23: Powder Properties and Process Parameters of Related Samples

[0179]

[0180] Table 24: Dissolution Curves of Related Samples in 0.01 mol / L Hydrochloric Acid Solution

[0181]

[0182]

[0183] Conclusion: The above results indicate that the formulation of Example 16 meets the process requirements in terms of granulation, powder properties, tableting, etc., and the dissolution curves of the prepared samples at 15 minutes are all greater than 85%, showing good dissolution effect.

[0184] Stability data:

[0185] Tablets obtained by the dry granulation process step using the formulations of different examples were subjected to stress testing, and the results are as follows:

[0186] Table 25: Summary of Related Substances Results under Light (5000 lux, 90 uW / cm 2 ) Conditions

[0187]

[0188] Table 26: Summary of Related Substances Results under High Temperature (60 °C) Conditions

[0189]

[0190] Table 27: Summary of Related Substances Results under High Humidity (RH 75% ± 5%) Conditions

[0191]

[0192] Table 28: Summary of related substance results under high humidity (RH 92.5% ± 5%) conditions

[0193]

[0194] Conclusion: The related substances of the samples prepared in Examples 7 - 8, Examples 10 - 12, and Examples 15 - 16 showed no significant changes after being placed under light conditions for 10 days; and no significant changes after being placed under high temperature of 60°C, high humidity of 75%, and high humidity of 92.5% for 30 days.

[0195] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the limitations of the above embodiments, and the above embodiments and the descriptions in the specification are only for explaining the principles of the present invention.

[0196] Without departing from the concept of the present invention, those skilled in the art will also make various non - substantial changes and improvements to the present invention, and all of these fall within the scope of protection required by the present invention.

Claims

1. A pharmaceutical composition comprising rimegepant and / or its pharmaceutically acceptable salt, a filler, a disintegrant, a lubricant, a binder, and a glidant.

2. The pharmaceutical composition according to claim 1, wherein The filler is selected from at least one of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, lactose, glucose, cellulose lactose, sucrose, mannitol, sorbitol, starch, and dextrin, preferably at least one of microcrystalline cellulose, lactose, or cellulose lactose; The disintegrant is selected from at least one of crospovidone, sodium croscarmellose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, carboxymethyl starch, modified starch, microcrystalline cellulose, sodium bicarbonate, silica, sodium lauryl sulfate, magnesium lauryl sulfate, anhydrous sodium carbonate, methyl cellulose, and hydroxyethyl methyl cellulose, preferably sodium croscarmellose; The lubricant is selected from at least one of sodium stearyl fumarate, magnesium stearate, talc, zinc stearate, magnesium lauryl sulfate, silica, and sodium behenyl sulfate, preferably at least one of magnesium stearate or sodium stearyl fumarate; The binder is selected from at least one of pregelatinized starch, hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, ethyl methyl cellulose, ethyl cellulose, poloxamer, modified starch, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, povidone, sucrose, monolaurate, and dextrin, preferably pregelatinized starch; The glidant is selected from at least one of talc, silica, colloidal silica, magnesium stearate, magnesium trisilicate, and starch, preferably silica.

3. The pharmaceutical composition according to claim 1 or 2, wherein Based on the total weight of the plain tablets, the content of rimegepant and / or its pharmaceutically acceptable salt is 30 - 70 wt%; the content of the filler is 10 - 90 wt%; the content of the disintegrant is 5 - 30 wt%; the content of the lubricant is 1.1 - 5 wt%; the content of the binder is 2 - 30 wt%; the content of the glidant is 1.1 - 5 wt%.

4. The pharmaceutical composition according to any one of claims 1-3, characterized in that, The pharmaceutically acceptable salt of rimegepant is rimegepant hemisuccinate.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The pharmaceutical composition has the following component weight percentages (wt%): (1) The pharmaceutical composition comprises: Or, (2) The pharmaceutical composition comprises: Or, (3) The pharmaceutical composition comprises:

6. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The pharmaceutical composition has the following component weight percentages (wt%): (1) The pharmaceutical composition comprises: Or, (2) The pharmaceutical composition comprises: Or, (3) The pharmaceutical composition comprises:

7. The pharmaceutical composition according to any one of claims 1-6, characterized in that, The pharmaceutical composition is a solid oral preparation, and the solid oral preparation is selected from the form of a mixture directly obtained by mixing each component in the pharmaceutical composition, tablets, capsules, or granules, preferably tablets.

8. The pharmaceutical composition according to any one of claims 1-7, characterized in that, The pharmaceutical composition is a tablet, and the tablet comprises a plain tablet and a coating; Preferably, the coating material is selected from at least one of film coating premix, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, polyethylene glycol, and polyvinyl alcohol.

9. A method for preparing the pharmaceutical composition according to any one of claims 1 - 8, comprising the following steps: (1) Crush or screen the raw material of ramelteon hemisuccinate, and control the particle size (D90) within 30 - 500 μm, preferably 30 - 350 μm; (2) Screen the raw material of ramelteon hemisuccinate, filler, binder, disintegrant, and internal lubricant respectively, and mix the screened materials evenly; (3) Granulate the above - mixed materials; (4) Screen the glidant and external lubricant respectively, and mix the screened materials evenly with the prepared granules to obtain the intermediate; (5) Press the intermediate to obtain the plain tablets; Optionally, it further includes coating the plain tablets with a coating material, and the coating material is preferably a film - coating premix.

10. Use of the pharmaceutical composition according to any one of claims 1-8 for preparing a medicament for activating 5-HT 1F receptors, inhibiting neuronal protein extravasation, treating and / or preventing migraine and / or treating anxiety in mammals, particularly humans.

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