A capsule of lenvatinib mesylate and a method for preparing the same

Abstract

The present application relates to the technical field of pharmaceutical preparations, in particular to a kind of lenvatinib mesylate capsule and preparation method thereof.In order to overcome the dissolution problem of lenvatinib mesylate capsule, the present application is granulated by using aqueous solution of alkaline anticoagulant and the water addition amount in the granulation process is controlled, which can increase the particle size of the granules, thereby increasing the flowability of the granules, which is beneficial to industrial production, and on the other hand, it can improve the dissolution of lenvatinib mesylate capsule and thereby improve the bioavailability.The lenvatinib mesylate capsule prepared by the method of the present application has high dissolution rate, the product quality is more controllable, and the preparation process is simple and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations. Specifically, the present application relates to a lenvatinib mesylate capsule and a preparation method thereof. BACKGROUND

[0002] Lenvatinib, also known as Lenvatinib, has the chemical name of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, and the structure is as follows:

[0003] .

[0004] Lenvatinib mesylate is a multifunctional molecule itself, containing hydrophobic aromatic ring structures (such as quinoline ring, phenoxy) and hydrophilic groups (such as urea group, methanesulfonic acid ion). When water is encountered, the hydrophilic group is easy to combine with water molecules to form hydrogen bonds. Lenvatinib molecules contain multiple hydrogen bond donors and acceptors (such as urea group -NH-CO-NH-). After encountering water, the intermolecular hydrogen bonds are partially replaced by water molecules, and then the water molecules are connected to multiple lenvatinib molecules, resulting in gelation, which causes lenvatinib to be unable to be normally dissolved and released.

[0005] The original research patent CN101001629A provides a pharmaceutical composition using silicic acid or its salt or its solvate as an anti-gel agent. The pharmaceutical composition can reduce the gelation of the active pharmaceutical ingredient to a low level under wet, hot and other storage conditions, thereby ensuring the dissolution and release of the active ingredient.

[0006] In view of the dissolution problem of lenvatinib mesylate capsules, in recent years, other patents have also been disclosed in China.

[0007] CN202011228155.2 discloses a lenvatinib mesylate pharmaceutical composition and a preparation method thereof. Lactitol-aluminum silicate is used as a stabilizer, which significantly improves the problem of significant decrease in dissolution caused by surface gelation due to moisture absorption during storage of the pharmaceutical composition.

[0008] CN202011477137.8 relates to a lenvatinib mesylate pharmaceutical composition and a preparation method thereof. The pharmaceutical composition comprises lenvatinib mesylate, potassium bicarbonate or potassium carbonate, microcrystalline cellulose and other excipients. The selected preparation method is dry granulation. The composition and the preparation method can ensure that the preparation product has good stability and dissolution.

[0009] CN202111403157.5 provides a lenvatinib mesylate composition, which uses an acid regulator. On the one hand, it solves the problem that lenvatinib is easy to gelate in water. On the other hand, the acid regulator overcomes the problem of decreased solubility caused by the pH dependence of lenvatinib mesylate, ensuring rapid release and absorption of the drug.

[0010] Through analysis of the prior art, it is found that the solutions proposed for the dissolution problem of lenvatinib mesylate capsules all have certain defects. On the one hand, to overcome the problem that lenvatinib mesylate gels in water, which leads to low dissolution, adding an acidic anti-gelling agent can solve the gelling problem, but the acidic environment may increase the risk of degradation of the active ingredient. Adding an alkaline anti-gelling agent can also solve the gelling problem of lenvatinib, but due to the pH dependence of lenvatinib mesylate, the addition of alkaline anti-gelling agent will slow down the dissolution of the preparation. On the other hand, when using techniques such as micronization, solid dispersion, and self-emulsifying drug delivery system to solve this problem, the process will be complicated, leading to increased production costs.

[0011] The primary purpose of the present application is to overcome the shortcomings and deficiencies of the prior art and provide an improved preparation method for lenvatinib mesylate capsule formulation. During the development of lenvatinib mesylate capsule formulation using alkaline anti-gelling agent, the present inventors unexpectedly found that by using an aqueous solution of alkaline anti-gelling agent for granulation and controlling the amount of water added during the granulation process, the particle size of the granules can be increased, thereby increasing the flowability of the granules, which is beneficial for industrial production. On the other hand, it can improve the dissolution of lenvatinib mesylate capsules and thereby improve the bioavailability. SUMMARY

[0012] The present application aims to provide an improved preparation method for lenvatinib mesylate capsule formulation. Compared with the prior art, the method of the present application has the following advantages and effects:

[0013] The lenvatinib mesylate capsule formulation prepared by the method of the present application has high dissolution, the product quality is more controllable, and the preparation process is simple, suitable for industrial production.

[0014] The present inventors unexpectedly found that during the preparation of lenvatinib mesylate capsules, first granulate lenvatinib mesylate with suitable excipients using an aqueous solution of alkaline anti-gelling agent and control the amount of water added during the granulation process. On the one hand, this can increase the particle size of the granules, thereby increasing the flowability of the granules, which is beneficial for industrial production. On the other hand, it can improve the dissolution of lenvatinib mesylate capsules and thereby improve the bioavailability.

[0015] Therefore, in a first aspect, the present application provides a preparation method for lenvatinib mesylate capsule formulation, characterized in that the method comprises the following steps:

[0016] i) pre-mixing lenvatinib mesylate with excipients to obtain granulation material, wherein the excipients are a mixture of mannitol, microcrystalline cellulose and hydroxypropyl cellulose;

[0017] ii) granulating the granulation material obtained in step i) with an aqueous solution of an alkaline anti-gel agent, wherein the alkaline anti-gel agent is selected from sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate, and the amount of the alkaline anti-gel agent is 4-10% by weight of the total weight of the capsule, and the weight ratio of lenvatinib mesylate to the alkaline anti-gel agent is 1.5:1 to 1:1.5, and the amount of water added during the granulation is 41-55% by weight of the granulation material;

[0018] iii) drying and sizing the granules obtained in step ii), and optionally mixing with a lubricant, and then filling into capsules.

[0019] In one embodiment, the amount of mannitol, microcrystalline cellulose and hydroxypropyl cellulose used in step i) is in the ratio of mannitol: microcrystalline cellulose: hydroxypropyl cellulose = 3-4: 10-12: 1, for example about 3.55: 11.6: 1.

[0020] In one embodiment, the alkaline anti-gel agent used in step ii) is sodium bicarbonate.

[0021] In one embodiment, the amount of the alkaline anti-gel agent used in step ii) is 5-8% by weight of the total weight of the capsule, preferably 5-6%, for example about 5.40%.

[0022] In one embodiment, the weight ratio of lenvatinib mesylate to the alkaline anti-gel agent is 1.2:1 to 1:1.2, preferably about 1.2:1.

[0023] In one embodiment, the amount of water added during the granulation is 42-54% by weight of the granulation material, for example 45-54%, for example about 46%, about 49%, about 52%, about 54%.

[0024] In one embodiment, in step iii), after drying and sizing the granules obtained in step ii), the granules are mixed with a lubricant, and then filled into capsules; preferably, the lubricant is talc.

[0025] In a second aspect, the present application provides a lenvatinib mesylate capsule formulation prepared by the method defined in the first aspect of the present application.

[0026] In one embodiment, the capsule formulation comprises the following ingredients (by weight of the total weight of the capsule):

[0027] 5-10% lenvatinib mesylate;

[0028] 4-10% basic anticoagulating gel agent:

[0029] 15-25% mannitol:

[0030] 55-65% microcrystalline cellulose;

[0031] 4-8% hydroxypropyl cellulose; and

[0032] 2-5% talc,

[0033] wherein the sum of the components is 100%.

[0034] In one embodiment, the capsule formulation comprises the following ingredients (by total weight of the capsule):

[0035] 6-8% lenvatinib mesylate;

[0036] 5-8% basic anticoagulating gel agent:

[0037] 18-20% mannitol:

[0038] 58-62% microcrystalline cellulose;

[0039] 5-6% hydroxypropyl cellulose; and

[0040] 3-4% talc,

[0041] wherein the sum of the components is 100%.

[0042] In one embodiment, the capsule formulation comprises the following ingredients (by total weight of the capsule):

[0043] about 6.45% lenvatinib mesylate;

[0044] about 5.40% basic anticoagulating gel agent:

[0045] about 18.68% mannitol:

[0046] about 61.05% microcrystalline cellulose;

[0047] about 5.26% hydroxypropyl cellulose; and

[0048] about 3.16% talc.

[0049] In one embodiment, the basic anticoagulating gel agent is selected from the group consisting of carbonates and bicarbonates of alkali metals, in particular sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate, preferably sodium bicarbonate and potassium bicarbonate, more preferably sodium bicarbonate. DETAILED DESCRIPTION

[0051] DEFINITIONS

[0052] Unless explicitly stated otherwise, the percentages given in this application are percentages by weight.

[0053] The skilled person will understand that the sum of the weight percentages of the components in the capsule is < 100% (i.e. less than or equal to 100%).

[0054] The term "about" as used herein before a numerical value means that the numerical value is extended by ± 10%, preferably by ± 5%. For example, "about 1.2%" means 1.15% to 1.25%, preferably 1.195% to 1.205%. DETAILED DESCRIPTION

[0055] In order to make the objects, technical solutions and advantages of the present application clearer, the present application will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and not used to limit the present application.

[0056] Example 1. Preparation of lenvatinib mesylate capsules

[0057] 1. Formulation prescription

[0058] The formulation prescription information of Formulations 1-5 and Comparative Example 1 is shown in Table 1, and the prescription information of the original formulation is shown in Table 2.

[0059] Table 1. Formulation prescription information of Formulations 1-5 and Comparative Example 1

[0060]

[0061] Note: The 4 mg and 10 mg specifications of lenvatinib mesylate capsules of the present composition are equi-proportional formulations.

[0062] The original formulation used in the present example is lenvatinib mesylate 4 mg capsules (trade name: Lenvima®, manufacturer: Eisai Co., Ltd. (1 Kawashimatakehaya-machi, Kakamigahara-shi, Gifu-ken, 501-6195, Japan)) and 10 mg capsules (trade name: LENVIMA® (Lenvima®), manufacturer: Eisai GmbH (Edmund-Rumpler-Straße 3, 60549 Frankfurt am Main. Deutschland)) of Nippon Shinyaku Pharmaceutical Co., Ltd. The specific information of the prescription is shown in Table 2.

[0063] Table 2. Prescription information of the original formulation

[0064]

[0065] The granulation water addition information of Formulations 1-5 and Comparative Example 1 is shown in Table 3.

[0066] Table 3. Granulation water addition of Formulations 1-5 and Comparative Example 1

[0067]

[0068] Note: *Water addition percentage = Water addition amount / Granulation material amount x 100%.

[0069] 2. Preparation process: Formulations 1-5 are prepared according to the following process.

[0070] 2.1 Mix lenvatinib mesylate, mannitol, microcrystalline cellulose, hydroxypropyl cellulose according to the prescription in Table 2;

[0071] 2.2 Preliminary premixing of the materials using a hopper mixer (mixing speed: 15 rpm, time: 5-15 min);

[0072] 2.3 Sieving using a mobile granulator (screen size 0.8-1.2 mm, speed: 200-600 rpm);

[0073] 2.4 After the premixing is completed, dry mixing of the materials into a high-speed shearing wet granulation kettle (Dongfulong, stirring paddle speed: 100-300 rpm, cutter speed: 2000-3000 rpm, time: 10-30 min);

[0074] 2.5 After the dry mixing is completed, prepare a sodium bicarbonate aqueous solution according to the water addition amount in Table 3 and granulate using the aqueous solution (stirring paddle speed: 100-300 rpm, cutter speed: 2000-3000 rpm, liquid addition time: 3-5 min);

[0075] 2.6 Continue granulation (stirring paddle speed: 100-300 rpm, cutter speed: 2000-3000 rpm, granulation time: 1-4 min);

[0076] 2.7 Dry using a fluidized bed until the granule LOD is below 1.0% (inlet air temperature 65 (60-70) °C);

[0077] 2.8 Sieving (screen aperture 0.8-1.2 mm, speed: 200-400 rpm);

[0078] 2.9 Final mixing, add talc to the dry granules and mix evenly (mixing speed: 15 rpm, time: 10-20 min);

[0079] 2.10 Capsule filling.

[0080] When the wet granulation was carried out according to the same process in Comparative Example 1, it was found that after the end of liquid addition, the material gathered into a mass and could not continue normal granulation, so the granulation was stopped.

[0081] Example 2. Powder property detection

[0082] The powder properties of the granules of Formulations 1-5 prepared in Example 1 were detected, and the results are shown in Table 4.

[0083] Table 4. Results of powder property detection of Formulations 1-5 prepared in Example 1 (particle size distribution (%))

[0084]

[0085] Conclusion: As can be seen from the particle size distribution results in Table 4, with the increase of the amount of water added during granulation, the proportion of coarse particles in the mixed granules also increases.

[0086] Example 3. Dissolution test

[0087] The dissolution test was performed on the lenvatinib mesylate capsules of Formulations 1-5 prepared in Example 1.

[0088] The dissolution was determined according to the dissolution and release test method (Chinese Pharmacopoeia 2020 edition four chapters 0931 second method).

[0089] Instrument: high performance liquid chromatograph and dissolution tester.

[0090] Dissolution medium: pH = 1.8.

[0091] Dissolution medium volume: 900 mL.

[0092] Rotation speed: 50 revolutions per minute.

[0093] Sampling time: 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min.

[0094] Take lenvatinib mesylate capsules of Formulations 1-5, 4 mg and 10 mg specifications, according to the dissolution and release test method (Chinese Pharmacopoeia 2020 edition four chapters 0931 second method), take 900 mL pH = 1.8 buffer solution as the dissolution medium, paddle method 50 revolutions per minute, according to the operation, according to the sampling time, the dissolution data are shown in Table 5 and Table 6.

[0095] Table 5. Dissolution test results of Formulations 1-5 and original research Formulation 4 mg lenvatinib mesylate capsules (dissolution (%))

[0096]

[0097] Table 6. Dissolution test results of Formulations 1-5 and the reference formulation 10 mg lenvatinib mesylate capsules (dissolution rate (%))

[0098] .

[0099] From the dissolution data of Formulations 1-5 in Table 5 and Table 6, it can be seen that the lenvatinib mesylate capsules prepared by the method of the present application have good dissolution rate, and the dissolution results are comparable to or even better than the reference formulation. In particular, during the wet granulation process, when the amount of water reaches a certain amount, with the increase of the amount of water for granulation, the dissolution rate and dissolution degree of the 4 mg and 10 mg specifications of lenvatinib mesylate capsules are unexpectedly increased, and the dissolution rate is significantly better than the reference formulation. By increasing the amount of water for granulation and selecting optimization, on the one hand, granules with large particle size and high bulk density can be prepared, which increases the flowability of the granules, is conducive to the quality control of the intermediate product and industrialized production, on the other hand, the unexpected increase of the amount of water for granulation improves the dissolution rate and dissolution degree of lenvatinib mesylate capsule formulation, promotes the release of the drug, and improves the bioavailability.

Claims

1. A method of preparing a lenvatinib mesylate capsule formulation, characterized by, The method comprises the following steps: i) pre-mixing lenvatinib mesylate with excipients to obtain granulation material, wherein the excipients are a mixture of mannitol, microcrystalline cellulose and hydroxypropyl cellulose; ii) granulating the granulation material obtained in step i) with an aqueous solution of an alkaline anti-caking agent, wherein the alkaline anti-caking agent used is selected from sodium carbonate and sodium bicarbonate, the amount of the alkaline anti-caking agent used is 4%-10% relative to the total weight of the capsule, the weight ratio of lenvatinib mesylate to the alkaline anti-caking agent is 1.2:1 to 1:1.2, and the amount of water added during the granulation process is 41%-55% relative to the amount of the granulation material; iii) drying and sizing the granules obtained in step ii), optionally mixing with a lubricant, and then performing capsule filling.

2. The preparation method according to claim 1, wherein the alkaline anti-caking agent used in step ii) is sodium bicarbonate.

3. The preparation method according to claim 1 or 2, wherein the weight ratio of lenvatinib mesylate to the alkaline anti-caking agent is 1.2:

1.

4. The preparation method according to claim 1 or 2, wherein the amount of water added during the granulation process is 45%-54% relative to the amount of the granulation material.

5. The production method according to claim 1 or 2, wherein In step iii), after drying and sizing the granules obtained in step ii), the granules are mixed with a lubricant, and then capsule filling is performed.

6. The preparation method according to claim 5, wherein the lubricant is talc.

7. The production method according to claim 6, wherein The capsule preparation comprises the following ingredients by weight of the total weight of the capsule: 5%-10% lenvatinib mesylate; 4%-10% alkaline anti-caking agent selected from sodium carbonate and sodium bicarbonate; 15%-25% mannitol; 55%-65% microcrystalline cellulose; 4%-8% hydroxypropyl cellulose; and 2%-5% talc, wherein the sum of the components is 100%.

8. The production method according to claim 7, wherein The capsule preparation comprises the following ingredients by weight of the total weight of the capsule: 6%-8% lenvatinib mesylate; 5%-8% alkaline anti-caking agent selected from sodium carbonate and sodium bicarbonate; 18%-20% mannitol; 58%-62% microcrystalline cellulose; 5%-6% hydroxypropyl cellulose; and 3%-4% talc, wherein the sum of the components is 100%.

9. The production method according to claim 8, wherein The capsule preparation comprises the following ingredients by weight of the total weight of the capsule: 6.45% lenvatinib mesylate; 5.40% sodium bicarbonate; 18.68% mannitol; 61.05% microcrystalline cellulose; 5.26% hydroxypropyl cellulose; and 3.16% talc.

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