Lovatinib mesylate capsule and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a lenvatinib mesylate capsule and a preparation method thereof. In order to overcome the problem of dissolution of the lenvatinib mesylate capsule, an aqueous solution of an alkaline anti-gel agent is adopted for granulation, and the water adding amount in the granulation process is controlled, so that on one hand, the particle size can be increased, the particle fluidity is further improved, and industrial production is facilitated; on the other hand, the dissolution rate of the lenvatinib mesylate capsule can be improved, so that the bioavailability is improved. The lenvatinib mesylate capsule preparation prepared by the method disclosed by the invention is high in dissolution rate, more controllable in product quality, simple in preparation process and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology. Specifically, this invention relates to a lenvatinib mesylate capsule and its preparation method. Background Technology

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

[0003] Lenvatinib mesylate is a multifunctional molecule containing hydrophobic aromatic ring structures (such as quinoline rings and phenoxy groups) and hydrophilic groups (such as urea groups and mesylate ions). When it comes into contact with water, the hydrophilic groups readily combine with water molecules to form hydrogen bonds. Lenvatinib molecules contain multiple hydrogen bond donors and acceptors (such as urea groups -NH-CO-NH-). Upon contact with water, the intermolecular hydrogen bonds are partially replaced by water molecules, which then connect multiple lenvatinib molecules, ultimately leading to gelation and preventing the normal dissolution and release of lenvatinib.

[0004] The original patent CN101001629A provides a pharmaceutical composition using silicic acid or its salt or its solvate as an antigelling agent, which can reduce the gelation of the active pharmaceutical ingredient to a low level under storage conditions such as humidity and heat, thereby ensuring the dissolution and release of the active ingredient.

[0005] In response to the dissolution problem of lenvatinib mesylate capsules, other patents have been published in China in recent years.

[0006] CN202011228155.2 discloses a lenvatinib mesylate pharmaceutical composition and its preparation method, which uses lactamol-aluminum silicate as a stabilizer, significantly improving the problem of significant decrease in dissolution caused by surface gelation due to moisture absorption during storage.

[0007] CN202011477137.8 relates to a lenvatinib mesylate pharmaceutical composition and its preparation method. 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 preparation method described herein ensure that the formulation product has good stability and dissolution.

[0008] CN202111403157.5 provides a lenvatinib mesylate composition that uses an acid regulator. This composition solves the problem of lenvatinib easily gelling when it comes into contact with water. On the other hand, the acid regulator overcomes the problem of decreased solubility caused by the pH dependence of lenvatinib mesylate, thus ensuring rapid release and absorption of the drug.

[0009] Analysis of existing technologies revealed that solutions to the dissolution problem of lenvatinib mesylate capsules all have certain drawbacks. On one hand, while adding acidic antigel agents can solve the gelation problem caused by lenvatinib mesylate gelling upon contact with water, the acidic environment may increase the risk of degradation of the active ingredient. Adding alkaline antigel agents can also solve the gelation problem, but due to the pH dependence of lenvatinib mesylate, the added alkaline antigel agents will slow down the dissolution of the formulation. On the other hand, using technologies such as micronization, solid dispersions, and self-emulsifying drug delivery systems to solve this problem complicates the process and increases production costs.

[0010] The primary objective of this invention is to overcome the shortcomings and deficiencies of existing technologies and provide an improved method for preparing lenvatinib mesylate capsule formulations. During the development of lenvatinib mesylate capsule formulations using alkaline antigel agents, the inventors unexpectedly discovered that by using an aqueous solution of an alkaline antigel agent for granulation and controlling the amount of water added during the granulation process, the particle size can be increased, thereby increasing particle flowability and facilitating industrial production. Furthermore, the dissolution of lenvatinib mesylate capsules can be improved, thus enhancing bioavailability. Summary of the Invention

[0011] The purpose of this invention is to provide an improved method for preparing lenvatinib mesylate capsules. Compared with the prior art, the method of this invention has the following advantages and effects: The lenvatinib mesylate capsule formulation prepared by the method of the present invention has high dissolution rate, more controllable product quality, and a simple preparation process, making it suitable for industrial production.

[0012] The inventors made an unexpected discovery: in the preparation of lenvatinib mesylate capsules, lenvatinib mesylate and suitable excipients are first granulated together in an aqueous solution of an alkaline antigelling agent, and the amount of water added during the granulation process is controlled. On the one hand, this can increase the particle size, thereby increasing the flowability of the particles, which is beneficial for industrial production. On the other hand, it can improve the dissolution of lenvatinib mesylate capsules, thereby improving bioavailability.

[0013] Therefore, in a first aspect, the present invention provides a method for preparing lenvatinib mesylate capsule formulation, characterized in that the method comprises the following steps: i) Lenvatinib mesylate is premixed with excipients to obtain granulated material, wherein the excipients are a mixture of mannitol, microcrystalline cellulose and hydroxypropyl cellulose; ii) Granulate the granulated material obtained in step i) using an aqueous solution of an alkaline antigel agent, wherein the alkaline antigel agent is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate, and the amount of the alkaline antigel agent is 4%-10% relative to the total weight of the capsules, the weight ratio of lenvatinib mesylate to the alkaline antigel agent is 1.5:1 to 1:1.5; the percentage of water added during the granulation process relative to the amount of granulated material is 41%-55%. iii) The granules obtained in step ii) are dried, sized, optionally mixed with a lubricant, and then capsuled.

[0014] In one implementation, the ratio of mannitol, microcrystalline cellulose, and hydroxypropyl cellulose in step i) is mannitol:microcrystalline cellulose:hydroxypropyl cellulose = 3~4:10~12:1, for example, about 3.55:11.6:1.

[0015] In one embodiment, the alkaline antigel agent used in step ii) is sodium bicarbonate.

[0016] In one embodiment, the amount of alkaline antigel agent used in step ii) is 5%-8% relative to the total weight of the capsule, preferably 5%-6%, for example about 5.40%.

[0017] In one embodiment, the weight ratio of lenvatinib mesylate to the basic antigel agent is 1.2:1 to 1:1.2, preferably about 1.2:1.

[0018] In one embodiment, the percentage of water added during the granulation process relative to the amount of granulated material is 42%-54%, for example 45%-54%, for example about 46%, about 49%, about 52%, or about 54%.

[0019] In one embodiment, in step iii), the granules obtained in step 2 are dried and granulated, then mixed with a lubricant, and then capsuled; preferably, the lubricant is talc.

[0020] In a second aspect, the present invention provides a lenvatinib mesylate capsule formulation prepared by the method defined in the first aspect of the present invention.

[0021] In one embodiment, the capsule formulation comprises the following ingredients (by total weight of the capsules): 5%-10% lenvatinib mesylate; 4%-10% alkaline anti-gel agent: 15%-25% Mannitol: 55%-65% microcrystalline cellulose; 4%-8% hydroxypropyl cellulose; and 2%-5% talc, The sum of the components mentioned above is 100%.

[0022] In one embodiment, the capsule formulation comprises the following ingredients (by total weight of the capsules): 6%-8% lenvatinib mesylate; 5%-8% alkaline anti-gelling agent: 18%-20% Mannitol: 58%-62% microcrystalline cellulose; 5%-6% hydroxypropyl cellulose; and 3%-4% talc The sum of the components mentioned above is 100%.

[0023] In one embodiment, the capsule formulation comprises the following ingredients (by total weight of the capsules): Approximately 6.45% lenvatinib mesylate; Approximately 5.40% alkaline antigel agent: Approximately 18.68% mannitol: Approximately 61.05% microcrystalline cellulose; Approximately 5.26% hydroxypropyl cellulose; and Approximately 3.16% talc.

[0024] In one embodiment, the alkaline antigel agent is selected from alkali metal carbonates and bicarbonates, particularly sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate, preferably sodium bicarbonate and potassium bicarbonate, and more preferably sodium bicarbonate. Invention Details definition Unless otherwise stated, all percentages given in this application are weight percentages.

[0026] Those skilled in the art 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%).

[0027] As used herein, the term “about” implies a numerical value extended by ±10%, preferably ±5%. For example, “about 1.2%” means 1.15% to 1.25%, preferably 1.195% to 1.205%. Detailed Implementation

[0028] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0029] Example 1. Preparation of lenvatinib mesylate capsules 1. Pharmaceutical formulation The formulation information for formulations 1-5 and Comparative Example 1 is shown in Table 1, and the formulation information for the original formulation is shown in Table 2.

[0030] Table 1. Formulation information for formulations 1-5 and Comparative Example 1 Note: The 4mg and 10mg capsules of this composition are formulated in equal proportions.

[0031] The original formulations used in this embodiment were lenvatinib mesylate 4mg capsules (trade name Lenvima®, manufacturer: Eisai Co., Ltd. (1 Kawashimatakehaya-machi, Kakamigahara-shi, Gifu-ken, 501-6195, Japan)) and 10mg capsules (trade name LENVIMA®, manufacturer: Eisai GmbH (Edmund-Rumpler-Straße 3, 60549 Frankfurt amMain.Deutschland)) from Eisai Pharmaceutical Co., Ltd. Specific information about the formulation is shown in Table 2.

[0032] Table 2. Original Reagent Formulation Information The information on the amount of water added during granulation of the above formulations 1-5 and Comparative Example 1 is shown in Table 3.

[0033] Table 3. Water addition amount for granulation of formulations 1-5 and Comparative Example 1 Note: *Percentage of water added = Water added / Amount of granulated material × 100%.

[0034] 2. Preparation process: The above preparations 1-5 are all prepared according to the following process.

[0035] 2.1 Mix lenvatinib mesylate, mannitol, microcrystalline cellulose, and hydroxypropyl cellulose according to the formulation in Table 2; 2.2 Use a hopper mixer to premix the materials (mixing speed: 15 rpm, time: 5~15 min); 2.3 Use a mobile granulator for sieving (screen size 0.8~1.2mm, speed: 200~600rpm); 2.4 After premixing, add the material to a high-speed shear wet granulation pot for dry mixing (Dongfulong, stirring speed: 100~300rpm, cutting speed: 2000~3000rpm, time: 10~30min); 2.5 After dry mixing, prepare a sodium bicarbonate aqueous solution according to the water addition amount in Table 3 and use the aqueous solution for granulation (stirring speed: 100-300 rpm, cutter speed: 2000-3000 rpm, liquid addition time: 3-5 min); 2.6 Continue granulation (stirring speed: 100~300rpm, cutter speed: 2000~3000rpm, granulation time: 1~4min); 2.7 Use fluidized bed drying until the particle LOD is below 1.0% (inlet air temperature 65 (60~70) ℃); 2.8 Granulation (sieve aperture 0.8~1.2mm, speed: 200~400rpm); 2.9 Final mixing: Add talc to the dry granules and mix thoroughly (mixing speed: 15 rpm, time: 10~20 min); 2.10 Capsule filling.

[0036] In Comparative Example 1, when wet granulation was performed using the same process, it was found that after the liquid addition was completed, the material agglomerated into clumps and could not continue normal granulation, so granulation was stopped.

[0037] Example 2. Detection of powder properties The powder properties of the particles of formulations 1-5 prepared in Example 1 were tested, and the results are shown in Table 4.

[0038] Table 4. Results of powder properties analysis (particle size distribution (%)) of formulations 1-5 prepared in Example 1 Conclusion: As shown in Table 4, the proportion of coarse particles in the mixed granules increases with the increase of water content during granulation.

[0039] Example 3. Dissolution Test Dissolution tests were conducted on lenvatinib mesylate capsules prepared in Examples 1-5.

[0040] Dissolution was determined according to the Dissolution and Release Determination Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II).

[0041] Instruments: High performance liquid chromatograph and dissolution tester.

[0042] Dissolution medium: pH=1.8.

[0043] Dissolution medium volume: 900 mL.

[0044] Rotation speed: 50 rpm.

[0045] Sampling time: 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min.

[0046] Take 4mg and 10mg lenvatinib mesylate capsules of formulations 1-5 and dissolve them according to the method of dissolution and release determination (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). Use 900mL of pH 1.8 buffer solution as the dissolution medium and paddle method at 50 revolutions per minute. Perform the operation according to the method and take the solution according to the sampling time. The dissolution data are shown in Tables 5 and 6, respectively.

[0047] Table 5. Dissolution test results of formulations 1-5 and the original formulation 4mg lenvatinib mesylate capsules (dissolution rate (%)) Table 6. Dissolution test results of formulations 1-5 and the original formulation 10mg lenvatinib mesylate capsules (dissolution rate (%)) .

[0048] As shown in Tables 5 and 6, the dissolution data of formulations 1-5 indicate that the lenvatinib mesylate capsules prepared by the method of this invention exhibit excellent dissolution, with results comparable to or even superior to the original formulation. In particular, during wet granulation, once a certain amount of water was added, the dissolution rate and degree of dissolution of the 4mg and 10mg lenvatinib mesylate capsules unexpectedly increased with further increases in water addition during granulation, demonstrating significantly better dissolution than the original formulation. By increasing the amount of water added during granulation and selectively optimizing the process, on the one hand, larger particle size and higher bulk density granules can be prepared, increasing particle flowability and facilitating quality control and industrial production of intermediate products. On the other hand, increasing the amount of water added during granulation unexpectedly improved the dissolution rate and degree of dissolution of the lenvatinib mesylate capsule formulation, promoting drug release and improving bioavailability.

Claims

1. A method for preparing a lenvatinib mesylate capsule formulation, characterized in that, The method includes the following steps: i) Lenvatinib mesylate is premixed with excipients to obtain granulated material, wherein the excipients are a mixture of mannitol, microcrystalline cellulose and hydroxypropyl cellulose; ii) Granulate the granulated material obtained in step i) using an aqueous solution of an alkaline antigel agent, wherein the alkaline antigel agent is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate, the amount of the alkaline antigel agent is 4%-10% relative to the total weight of the capsules, the weight ratio of lenvatinib mesylate to the alkaline antigel agent is 1.5:1 to 1:1.5, and the percentage of water added during the granulation process relative to the amount of granulated material is 41%-55%; iii) The granules obtained in step ii) are dried, sized, optionally mixed with a lubricant, and then capsuled.

2. The method of claim 1, wherein the alkaline antigel agent used in step ii) is sodium bicarbonate.

3. The method of claim 1 or 2, wherein the weight ratio of lenvatinib mesylate to the basic antigel agent is 1.2:1 to 1:1.

2.

4. The method of claim 1 or 2, wherein the weight ratio of lenvatinib mesylate to the basic antigel agent is 1.2:

1.

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

6. The method of claim 1 or 2, wherein, In step iii), the granules obtained in step ii) are dried and granulated, mixed with a lubricant, and then capsuled.

7. The method of claim 6, wherein the lubricant is talc.

8. A lenvatinib mesylate capsule formulation prepared by the method defined in any one of claims 1-7, wherein, Based on the total weight of the capsules, the capsule formulation comprises the following ingredients: 5%-10% lenvatinib mesylate; 4%-10% alkaline anti-gelling agent, wherein the alkaline anti-gelling agent is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate: 15%-25% mannitol: 55%-65% microcrystalline cellulose; 4%-8% hydroxypropyl cellulose; and 2%-5% talc, The sum of the components mentioned therein is 100%.

9. The lenvatinib mesylate capsule formulation of claim 8, wherein, Based on the total weight of the capsules, the capsule formulation comprises the following ingredients: 6%-8% lenvatinib mesylate; 5%-8% alkaline anti-gelling agent, wherein the alkaline anti-gelling agent is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate: 18%-20% Mannitol: 58%-62% microcrystalline cellulose; 5%-6% hydroxypropyl cellulose; and 3%-4% talc The sum of the components mentioned therein is 100%.

10. The lenvatinib mesylate capsule formulation of claim 9, wherein, Based on the total weight of the capsules, the capsule formulation comprises the following ingredients: 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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