Lamidetan solid preparation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a lamidetan solid preparation and a preparation method thereof. The lamidetan solid preparation is prepared from the following raw materials: lamidetan, absolute ethyl alcohol, an absorbent, a filler, an adhesive, a disintegrating agent and a lubricant, the preparation method is anhydrous granulation. According to the lamidetan solid preparation, the lamidetan is uniformly dispersed in the absolute ethyl alcohol, moisture is not introduced, meanwhile, the wettability of API is improved, the problem of raw material adhesion is solved, the absorbent in the solid preparation can preferentially lock the moisture, and the influence of the moisture on a medicine crystal form is avoided; meanwhile, the lamidetan solid preparation disclosed by the invention also has the advantages of quick response, high bioavailability, simple preparation process and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a lamiditan solid preparation and a preparation method thereof. Background Art

[0002] Migraine is a common neurological disease, and according to the Lancet Global Burden of Disease Study, it was ranked as the second leading cause of disability among 328 diseases in 195 countries between 1990 and 2016, and is becoming a larger component of the global burden of disease. The important feature of migraine is moderate to severe, unilateral, throbbing headache attacks lasting 4 to 72 hours, accompanied by symptoms such as nausea, vomiting, phonophobia and / or photophobia.

[0003] Lasmiditan was launched in the United States in October 2019 under the trade name Reyvow. It is the first 5-HT 1F Receptor agonist. This drug targets and binds with high affinity to 5-HT in the trigeminal nerve pathway 1F It can penetrate the central nervous system to relieve migraine symptoms without vasoconstriction. Indications: It is suitable for the acute treatment of adult migraine patients with or without aura symptoms.

[0004] Patients with migraine who took lamiditan hemisuccinate tablets orally were rapidly absorbed and reached a peak plasma drug concentration (C max ) median time (t max ) is 1.8h. There is no difference in the absorption and pharmacokinetic parameters of lamivudine in patients with migraine during the attack and the interval between attacks. When taking the drug with a high-fat meal, the C max and AUC mean increased by 22% and 19%, respectively. max Delay 1h. After meal max A delay of 1 hour would affect the acute treatment of patients. The experiment found that there was a significant difference in the disintegration time of lamivudine tablets in simulated gastric fluid and simulated intestinal fluid, which may be the cause of the postprandial t max One of the reasons for the 1h delay.

[0005] Patent CN110291079A discloses a composition and method related to a pyridylpiperidine 5-HT1F agonist, which can be used, for example, in a pharmaceutical composition for treating and preventing migraine, as a novel pseudopolymorph of the hemisuccinate of 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide. The pharmaceutical composition comprises a mixture of polymorphs of compound I, wherein the mixture is selected from a mixture of crystalline forms A and D, a mixture of crystalline forms A and E, a mixture of crystalline forms D and E, and a mixture of crystalline forms A, D and E. Since the hemisuccinate lamiditan A crystalline form is affected by water, a crystal transformation phenomenon may occur in water of different proportions. The drug may have different bioavailability due to different crystalline forms, thereby affecting the efficacy of the drug.

[0006] In addition, through many tests and investigations, it was found that lamiditan has high viscosity and strong adsorption, and the content was obviously low during the content detection process; the EMA review report of lamiditan tablets (Reyvow) also mentioned that lamiditan has adhesion and adsorption problems.

[0007] In view of the above problems existing in the solid preparation of lamiditan, and considering the medication compliance of patients with dysphagia, it is of significant clinical value to research and develop a solid preparation of lamiditan that can improve patient compliance and has good stability and rapid onset of action. Summary of the invention

[0008] In view of the shortcomings of the prior art, the researchers of the present invention have discovered, through a large number of experimental investigations, a solid preparation of lamiditan that can maintain stable crystal form, stable content, and rapid onset of effect, and provide a method for preparing the solid preparation.

[0009] The specific technical solutions of the present invention are as follows:

[0010] In a first aspect, the present invention provides a lamiditan solid preparation, wherein the solid preparation is prepared from the following raw materials: lamiditan, anhydrous ethanol, an absorbent, a filler, a binder, a disintegrant, and a lubricant.

[0011] Preferably, the lamiditan is lamiditan hemisuccinate.

[0012] Preferably, the lamiditan is lamiditan hemisuccinate crystal form A.

[0013] Preferably, the weight ratio of lamiditan: anhydrous ethanol is 1:0.5-2; further preferably, the weight ratio of lamiditan: anhydrous ethanol is 1:0.75-1.5.

[0014] Preferably, the weight ratio of lamiditan: absorbent is 1:0.25-2; further preferably, the weight ratio of lamiditan: absorbent is 1:0.375-1.5.

[0015] Preferably, the absorbent is one or more of silicon dioxide, calcium carbonate, calcium silicate, magnesium aluminum silicate, magnesium silicate, and aluminum metasilicate, preferably silicon dioxide and calcium carbonate.

[0016] Preferably, the filler is selected from one or more of lactose, mannitol, sorbitol, glucose, sucrose, xylitol and dextran.

[0017] Preferably, the disintegrant is one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone.

[0018] Preferably, the binder is one or more of povidone, hydroxypropyl cellulose, copovidone, and hydroxypropyl methylcellulose.

[0019] Preferably, the lubricant is one or more of magnesium stearate, calcium stearate, talc, and sodium stearyl fumarate.

[0020] Preferably, the solid preparation is a chewable tablet.

[0021] Preferably, the solid preparation is prepared from the following raw materials in parts by weight:

[0022]

[0023] In a preferred embodiment, the solid preparation is prepared from the following raw materials in parts by weight:

[0024]

[0025] The drug prescription may further include flavoring agents depending on drug compliance and patient palatability.

[0026] The flavoring agents include, but are not limited to, aspartame, mint, edible spices, orange peel syrup, citron syrup, cherry syrup, licorice syrup, cinnamon syrup, apple flavor, orange flavor, banana flavor, etc.

[0027] In a second aspect, the present invention also provides a method for preparing the above solid preparation, which is an anhydrous wet granulation method.

[0028] In one embodiment, the wet granulation comprises the following steps: adding lamiditan to anhydrous ethanol to form a suspension, adding the suspension to an absorbent, mixing, shearing, and drying to obtain granules, then adding a filler, a disintegrant, and a binder to mix evenly, and finally adding a lubricant to mix evenly, and tableting.

[0029] In one embodiment, the wet granulation comprises the following steps: adding lamiditan to anhydrous ethanol to form a suspension, adding the suspension to a mixture of an absorbent and a binder, mixing, shearing, and drying to obtain granules, then adding a filler and a disintegrant to mix evenly, and finally adding a lubricant to mix evenly, and tableting.

[0030] In one embodiment, the wet granulation steps are: adding lamiditan and a binder to anhydrous ethanol to form a suspension, adding the suspension to an absorbent, mixing, shearing, and drying to obtain granules, then adding a filler and a disintegrant to mix evenly, and finally adding a lubricant to mix evenly, and tableting.

[0031] Beneficial effects of the present invention:

[0032] The present invention provides a solid preparation of lamiditan. The inventors found in the research process that evenly dispersing lamiditan in anhydrous ethanol increases the wettability of API without introducing water, solves the problem of raw material adhesion, and in the preparation stability study, it is found that the absorbent in the solid preparation can preferentially lock water, further avoid the influence of water on the drug crystal form, and can keep the raw material in the preparation in a single crystal form. The preparation of the present invention is a chewable tablet, which is chewed in the mouth and swallowed when taken, avoiding the problem of different disintegration time limits of the preparation under different gastrointestinal conditions, and can make the preparation take effect quickly to achieve the effect of acute treatment. Compared with the prior art, the solid preparation of the present invention has stable content, stable crystal form, rapid onset, simple preparation process, good taste, suitable for patients with dysphagia or poor gastrointestinal function, easy to scale up, and suitable for industrial production. DETAILED DESCRIPTION

[0033] The beneficial effects of the present invention are further described below by way of examples. It should be understood that the following examples are only for illustrative purposes and are not intended to limit the scope of protection of the present invention. At the same time, obvious changes and modifications made by ordinary technicians in the art according to the present invention are also included in the scope of protection of the present invention. The active ingredients in each example are all in crystal form A, and the weight parts of the active ingredients in the example preparation prescriptions are all calculated as free base.

[0034] Example 1

[0035] prescription:

[0036]

[0037] Preparation process:

[0038] 1) homogenizing the prescribed amount of lamiditan hemisuccinate in anhydrous ethanol for 20 minutes to obtain a uniform suspension;

[0039] 2) adding the suspension to silicon dioxide, mixing, shearing, and drying at 50° C. to obtain particles;

[0040] 3) mixing the granules obtained in step 2, sorbitol, lactose, povidone and cross-linked sodium carboxymethyl cellulose uniformly;

[0041] 4) Add talcum powder and mix well;

[0042] 5) Tablet pressing.

[0043] Supplementary Example 1:

[0044] Referring to the prescription and method of Example 1, the difference is that the amount of anhydrous ethanol is changed to 10 parts, 20 parts, 30 parts, 40 parts, 50 parts, 100 parts, 150 parts, 200 parts, 210 parts, and 220 parts, to obtain 10 tablets of different formulations, which are respectively recorded as A01, A02, A03, A04, A05, A06, A07, A08, A09, and A10. These 10 batches of tablets and Example 1 were tested by the content uniformity test method of Part IV 0941 of the 2020 edition of the Chinese Pharmacopoeia. The results showed that the A+1.80S value of Example 1 was 3.1, and the A+1.80S values ​​of A05 to A08 were in the range of 2.7 to 5.1; the A+1.80S values ​​of A09 and A10 were 6.0 and 7.3 respectively; the A+1.80S values ​​of A01 to A03 were all above 15.0, and the A+1.80S value of A04 was 13.7, which was close to the unqualified limit. It can be seen that too little anhydrous ethanol will lead to uneven content due to adhesion and other problems.

[0045] Supplementary Example 2:

[0046] Referring to the prescription and method of Example 1, the difference is that the amount of silicon dioxide therein is changed to 10 parts, 20 parts, 50 parts, 100 parts, 200 parts, and 250 parts, and 6 tablets of formulations are obtained, which are recorded as A11, A12, A13, A14, A15, and A16 respectively. These 6 batches of tablets were subjected to stability test according to the 9001 stability test guidelines of Part IV of the 2020 edition of the Chinese Pharmacopoeia, and were tested for 6 months at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%; as a result, the crystal forms of A11 and A12 showed obvious crystal transformation problems; the crystal forms of A13 to A15 were type A, and the active ingredient content was ≥ 99.7%; more absorbents did not bring better results.

[0047] Example 2

[0048] prescription:

[0049]

[0050] Preparation process:

[0051] 1) homogenizing the prescribed amount of lamiditan hemisuccinate in anhydrous ethanol for 20 minutes to obtain a uniform suspension;

[0052] 2) adding the suspension to the mixture of magnesium aluminum silicate and hydroxypropyl cellulose, mixing, shearing, and drying at 50° C. to obtain granules;

[0053] 3) mixing the granules obtained in step 2, glucose, mannitol and cross-linked polyvinylpyrrolidone uniformly;

[0054] 4) adding magnesium stearate and mixing evenly;

[0055] 5) Tablet pressing.

[0056] Example 3

[0057] prescription:

[0058]

[0059]

[0060] Preparation process:

[0061] 1) homogenizing the prescribed amount of lamiditan hemisuccinate and copovidone in anhydrous ethanol for 20 minutes to obtain a uniform suspension;

[0062] 2) adding the suspension to magnesium aluminum metasilicate, mixing, shearing, and drying at 50° C. to obtain granules;

[0063] 3) mixing the granules obtained in step 2, sucrose, mannitol and sodium carboxymethyl starch uniformly;

[0064] 4) Add sodium stearyl fumarate and mix well;

[0065] 5) Tablet pressing.

[0066] Example 4

[0067] prescription:

[0068]

[0069] Preparation process:

[0070] 1) homogenizing the prescribed amount of lamiditan hemisuccinate in anhydrous ethanol for 20 minutes to obtain a uniform suspension;

[0071] 2) adding the suspension to the mixture of light calcium carbonate and hydroxypropyl cellulose, mixing, shearing, and drying at 50° C. to obtain granules;

[0072] 3) mixing the granules obtained in step 2, glucose, mannitol and cross-linked polyvinylpyrrolidone uniformly;

[0073] 4) adding magnesium stearate and mixing evenly;

[0074] 5) Tablet pressing.

[0075] Example 5

[0076] prescription:

[0077]

[0078]

[0079] Preparation process:

[0080] 1) homogenizing the prescribed amount of lamiditan hemisuccinate and copovidone in anhydrous ethanol for 20 minutes to obtain a uniform suspension;

[0081] 2) adding the suspension to colloidal silicon dioxide, mixing, shearing, and drying at 50° C. to obtain particles;

[0082] 3) mixing the granules obtained in step 2, sucrose, sorbitol and sodium carboxymethyl starch uniformly;

[0083] 4) Add sodium stearyl fumarate and mix well;

[0084] 5) Tablet pressing.

[0085] Example 6

[0086] prescription:

[0087]

[0088] Preparation process:

[0089] 1) homogenizing the prescribed amount of lamiditan hemisuccinate in anhydrous ethanol for 20 minutes to obtain a uniform suspension;

[0090] 2) adding the suspension to silicon dioxide and povidone, mixing, shearing, and drying at 50° C. to obtain granules;

[0091] 3) mixing the granules obtained in step 2, sorbitol, lactose and cross-linked sodium carboxymethyl cellulose uniformly;

[0092] 4) Add talcum powder and mix well;

[0093] 5) Tablet pressing.

[0094] Example 7

[0095] square:

[0096]

[0097]

[0098] Preparation process:

[0099] 1) homogenizing the prescribed amount of lamiditan hemisuccinate in anhydrous ethanol for 20 minutes to obtain a uniform suspension;

[0100] 2) adding the suspension to magnesium aluminum metasilicate and copolyvidone, mixing, shearing, and drying at 50° C. to obtain granules;

[0101] 3) mixing the granules obtained in step 2, sucrose, mannitol and sodium carboxymethyl starch uniformly;

[0102] 4) Add sodium stearyl fumarate and mix well;

[0103] 5) Tablet pressing.

[0104] Verification Example

[0105] 1. Taste evaluation

[0106] The swallowability, palatability and chewing difficulty of chewable tablets were evaluated.

[0107] Swallowing, palatability, and ease of chewing were tested in the presence of a qualified physician. An 11-question taste questionnaire was given to 20 subjects aged 18 to 65 years to evaluate the swallowing, palatability, and ease of chewing of the chewable tablets.

[0108] Table 1 Evaluation results of swallowability, palatability and chewing difficulty of chewable tablets

[0109] sample Taste evaluation Example 1 good Example 2 good Example 3 good Example 4 good Example 5 good Example 6 good Example 7 good

[0110] Lamidetan chewable tablets have a good taste and are suitable for patients with dysphagia and poor gastrointestinal function.

[0111] 2. Stability test

[0112] According to the general rules 9001 and 9015 of the fourth volume of the Chinese Pharmacopoeia 2020 edition, the samples prepared in Examples 1-7 were stored at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months, and the content and related substances were measured at 0, 3, and 6 months, respectively. The crystal stability after 6 months was determined by X-ray powder diffraction. The specific results are shown in Table 2.

[0113] Table 2 Stability test results of Examples 1-5

[0114]

[0115] As shown in Table 2, the crystal form of the lamiditan chewable tablets in Examples 1 to 7 did not change after being stored under accelerated conditions for 6 months, and the content remained stable, which shows that the lamiditan chewable tablets in the present invention have good crystal form and formulation stability.

Claims

1. A lamiditan solid preparation, characterized in that: The solid preparation is prepared from the following raw materials: lamiditan, anhydrous ethanol, an absorbent, a filler, a binder, a disintegrant and a lubricant.

2. The solid preparation according to claim 1, characterized in that The lamiditan is lamiditan hemisuccinate, more preferably lamiditan hemisuccinate crystal form A.

3. The solid preparation according to claim 1, characterized in that The weight ratio of lamiditan to anhydrous ethanol is 1:0.5-2; the weight ratio of lamiditan to absorbent is 1:0.25-2.

4. The solid preparation according to claim 1, characterized in that The absorbent is one or more of silicon dioxide, calcium carbonate, calcium silicate, magnesium aluminum silicate, magnesium silicate, and aluminum metasilicate.

5. The solid preparation according to claim 1, characterized in that The filler is selected from one or more of lactose, mannitol, sorbitol, glucose, sucrose, xylitol, and dextran; the disintegrant is one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone.

6. The solid preparation according to claim 1, characterized in that The lubricant is one or more of magnesium stearate, calcium stearate, talc, and sodium stearyl fumarate; the binder is one or more of povidone, copovidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

7. The solid preparation according to any one of claims 1 to 6, characterized in that: Made from the following raw materials in parts by weight:

8. The solid preparation according to any one of claims 1 to 6, characterized in that: Made from the following raw materials in parts by weight:

9. The solid preparation according to any one of claims 1 to 6, characterized in that: The solid preparation is a chewable tablet.

10. A method for preparing the solid preparation according to any one of claims 1 to 6, characterized in that: The preparation method is anhydrous wet granulation.

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