Cabozantinib malate tablet and preparation method thereof

Abstract

The present invention belongs to the technical field of pharmaceutical preparations and provides a cabozantinib malate tablet and a method for preparing the tablet. The tablet comprises the active ingredient cabozantinib malate, trehalose, lecithin, and other pharmaceutically acceptable binders, disintegrants, lubricants, and glidants. By controlling the dosage of trehalose and lecithin, the product achieves rapid dissolution, smooth preparation, stable quality, and safety and effectiveness.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a cabozantinib malate tablet and a preparation method thereof. Background Art

[0002] Cabozantinib is a tyrosine kinase inhibitor. In vitro biochemical and / or cell-based assays have shown that cabozantinib inhibits the tyrosine kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL and TIE-2 receptors.

[0003] In November 2012, the U.S. FDA approved cabozantinib malate capsules developed by Exelixis for the treatment of patients with advanced and metastatic medullary thyroid cancer (MTC). The product name is COMETRIQ TM COMETRIQ TM The active ingredient is the L-malate form of cabozantinib. In 2016, the US FDA approved Exelixis' cabozantinib malate tablets (trade name CABOMETYX, 20mg / 40mg / 60mg) for the treatment of patients with advanced renal cell carcinoma who have previously received anti-angiogenic therapy. Its chemical structure is shown below.

[0004]

[0005] CN108472242A and CN103221035A, CN106068255A, and CN106255499A disclose compositions of cabozantinib malate formulations. CN103221035A discloses premixing crushed Compound I cabozantinib malate with Avicel PH102, anhydrous lactose 60M, and croscarmellose sodium to form a binder solution; then performing high shear wet granulation to produce wet granules; performing wet screening to produce wet-screened granules; performing fluidized bed drying on the wet-screened granules to produce dry granules; dry milling the dry granules to produce dry ground granules; blending the dry ground granules with colloidal silicon dioxide and croscarmellose to produce an extragranular blend; lubricating the extragranular blend with magnesium stearate to produce a final blend; tableting the final blend to form uncoated core tablets; and film coating the uncoated core tablets. CN103459373A discloses a tablet composition and a capsule composition of cabozantinib and L-malate, and studies the stability of the pharmaceutical composition.

[0006] CN103751140A discloses a Cabozantinib dispersible tablet, its preparation method, and application. The Cabozantinib dispersible tablet comprises the following components, calculated by weight: 10-60% Cabozantinib, 10-40% filler, 10-50% disintegrant, 10-50% acidifier, 0.1-10% binder, and 0.1-20% lubricant and glidant. The Cabozantinib dispersible tablet prepared using this method exhibits high solubility, good bioavailability, rapid in vivo distribution, stable quality, and a pleasant taste. The preparation method is simple and easy to implement, making it suitable for industrial production.

[0007] CN103830203A provides a cabozantinib capsule composition and a preparation method thereof. The composition mainly includes cabozantinib, a carrier, an organic solvent, a surfactant, micropowder silica gel, starch, etc. The preparation method mainly comprises first adding a prescribed amount of the carrier to the organic solvent, heating to 60°C, then adding cabozantinib to dissolve it, vacuum drying at 40°C for 4 hours, air flow crushing, adding micropowder silica gel and starch, mixing evenly, and packaging the capsules.

[0008] CN107951850A discloses a method for preparing cabozantinib malate tablets. This method utilizes direct powder compression to produce tablets, overcoming the technical problem of poor flowability of the cabozantinib malate API after pulverization, making direct tableting unsuitable. The preparation process is simpler than wet granulation and tableting, and the resulting cabozantinib malate tablets meet acceptable hardness, friability, and content uniformity, while also improving the dissolution rate of the active drug. The cabozantinib malate API was pulverized to a particle size distribution D90 ≤ 25 μm. Dissolution was investigated under the following media conditions: 1) Standard medium (pH 2.0 hydrochloric acid medium). 2) Aqueous medium: 900 ml of water containing 0.5% Triton was used as the dissolution medium. 3) pH 4.5 acetate medium: 900 ml of a pH 4.5 acetic acid-sodium acetate solution containing 0.5% Triton was used as the dissolution medium. 4) pH 6.8 phosphate buffer medium: 0.5% Triton in pH 6.8 phosphate buffer was used as the dissolution medium.

[0009] CN115487157A provides a cabozantinib malate tablet and its preparation method. The tablet consists of the active ingredient cabozantinib malate, a filler, a binder, a disintegrant, a lubricant, a glidant, and a coating agent, wherein the lubricant is sodium stearyl fumarate. The present invention adjusts the cabozantinib malate tablet formulation by replacing the lubricant magnesium stearate with sodium stearyl fumarate, improving unknown single impurity growth, enhancing product stability, and ensuring rapid dissolution.

[0010] Cabozantinib malate is a white or off-white solid that is virtually insoluble in water, making it a poorly soluble drug. Tablets prepared from this product are prone to substandard dissolution, low bioavailability, and poor product stability. For example, during a stability study of a commercially available formulation in Japan, the moisture content increased from 1.13% to 5.34% over a two-week period, posing a serious threat to product stability. To address this issue, existing technologies include particle grinding, carrier dispersion technology, the addition of surfactants, and API pulverization or preparation of various crystalline forms. However, these methods currently offer suboptimal dissolution results, complex production processes, and poor product stability. The goal is to develop a cabozantinib malate tablet and its preparation method that exhibits advantages such as simple formulation, stable quality, high dissolution, high bioavailability, and ease of industrial production. Summary of the Invention

[0011] In view of the problems existing in the prior art, the present invention provides a cabozantinib malate tablet and a method for preparing the preparation. The present invention has the advantages of simple preparation process, stable quality, high dissolution rate, high bioavailability, and ease of industrial production.

[0012] Specifically, the purpose of the present invention is achieved through the following technical solutions:

[0013] A cabozantinib malate tablet comprises a tablet core and a coating, wherein the tablet core mainly consists of cabozantinib malate, trehalose, lecithin and other pharmaceutically acceptable binders, disintegrants, lubricants and glidants.

[0014] The mass ratio of cabozantinib malate to trehalose and lecithin is 1:5.0-6.0:0.2-0.6, preferably 1:5.5:0.4.

[0015] The binder is selected from one or more of gum arabic, dextrin, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, methyl cellulose, polymethacrylate, povidone, pregelatinized starch or sodium alginate. Preferably, the binder is hydroxypropyl cellulose.

[0016] The disintegrant is selected from one or more of hydroxymethylcellulose calcium, hydroxymethylcellulose sodium, cross-linked carboxymethylcellulose sodium, crospovidone, magnesium aluminum silicate or sodium alginate, preferably cross-linked carboxymethylcellulose sodium.

[0017] The glidant is selected from one or more of colloidal silicon dioxide, magnesium trisilicate, starch, talc, polyethylene glycol, glyceryl behenate, stearic acid or hydrogenated castor oil, preferably colloidal silicon dioxide.

[0018] The lubricant is selected from one or more of talc and magnesium stearate, preferably magnesium stearate.

[0019] The coating agent is selected from Opadry 03K92254.

[0020] In a preferred embodiment, the core of the cabozantinib malate tablet consists of the following ingredients:

[0021]

[0022] In a preferred embodiment, the core of the cabozantinib malate tablet consists of the following ingredients:

[0023]

[0024] Another object of the present invention is to provide a method for preparing the above-mentioned cabozantinib malate tablets, which mainly comprises the following steps:

[0025] 1) Place cabozantinib malate, lecithin, trehalose (internal addition), and disintegrant (internal addition) in a wet granulator, start the equipment, and premix for 20 minutes;

[0026] 2) Add appropriate amount of water to the adhesive to prepare an adhesive solution;

[0027] 3) adding the binder solution obtained in step 2 to the material in step 1 and starting a wet granulator to prepare wet granules, which are then granulated by a crushing and granulating machine;

[0028] 4) fluidizing the wet-screened granules to produce dry granules;

[0029] 5) blending the dried granules with a glidant, remaining trehalose, and remaining disintegrant to produce an extragranular blend;

[0030] 6) lubrication blending the extragranular blend and lubricant to produce a final blend;

[0031] 7) compressing the final blend to form uncoated core tablets;

[0032] 8) Film-coat the uncoated core tablets.

[0033] The amount of trehalose (internal addition) is 60-80% by weight of the trehalose prescription, preferably 70%.

[0034] The amount of the disintegrant (added internally) is 20-30% by weight of the disintegrant formulation, preferably 25%.

[0035] In addition, the trehalose used in the present invention is trehalose dihydrate, CAS number being 6138-23-4.

[0036] Compared with the prior art, the cabozantinib malate tablets of the present invention contain trehalose that effectively reduces the hygroscopicity of the cabozantinib malate tablets, thereby significantly improving the tablet's stability. The addition of lecithin effectively improves the tablet's dissolution rate. By controlling the amounts of trehalose and lecithin, rapid dissolution of the product is ensured, resulting in smooth preparation, stable quality, and safety and effectiveness. DETAILED DESCRIPTION

[0037] The present invention is further illustrated by the following examples. It should be understood that the examples are provided for illustration only and are not intended to limit the present invention. Therefore, simple modifications to the present invention based on the method of the present invention fall within the scope of the present invention.

[0038] Example 1

[0039]

[0040] Production quantity: 5,000 films

[0041] Preparation process:

[0042] 1) Place the prescribed amount of cabozantinib malate, lecithin, 70% of the prescribed amount of trehalose (added internally), and 25% of the prescribed amount of disintegrant croscarmellose sodium (added internally) in a wet granulator, start the equipment, and premix for 20 minutes;

[0043] 2) Add appropriate amount of water to the adhesive hydroxypropyl cellulose to prepare an adhesive solution;

[0044] 3) adding the binder solution obtained in step 2 to the material in step 1 and starting a wet granulator to prepare wet granules, which are then granulated by a crushing and granulating machine;

[0045] 4) fluidizing the wet-screened granules to produce dry granules;

[0046] 5) blending the dried granules with a glidant, the remaining trehalose (external), and the remaining disintegrant (external) to produce an extragranular blend;

[0047] 6) lubrication blending the extragranular blend and lubricant to produce a final blend;

[0048] 7) compressing the final blend to form uncoated core tablets;

[0049] 8) Film-coat the uncoated core tablets with the film coating premix (Opadry 03K92254).

[0050] Example 2

[0051]

[0052] Production quantity: 5,000 films

[0053] Preparation process: same as Example 1.

[0054] Example 3

[0055]

[0056]

[0057] Preparation quantity: 5000 tablets. Preparation process: same as Example 1.

[0058] Example 4

[0059]

[0060] Preparation quantity: 5000 tablets. Preparation process: same as Example 1.

[0061] Example 5

[0062]

[0063]

[0064] Preparation quantity: 5000 tablets. Preparation process: same as Example 1.

[0065] Example 6

[0066]

[0067] Preparation quantity: 5000 tablets. Preparation process: same as Example 1.

[0068] Example 7

[0069]

[0070]

[0071] Preparation quantity: 5000 tablets. Preparation process: same as Example 1.

[0072] Example 8

[0073]

[0074] Preparation quantity: 5000 tablets. Preparation process: same as Example 1.

[0075] Example 9

[0076]

[0077]

[0078] Production quantity: 5,000 films

[0079] Preparation process: same as Example 1.

[0080] Example 10

[0081]

[0082] Production quantity: 5,000 films

[0083] Preparation process:

[0084] 1) Place the prescribed amount of cabozantinib malate, lecithin, 80% of the prescribed amount of trehalose (added internally), and 30% of the prescribed amount of disintegrant croscarmellose sodium (added internally) in a wet granulator, start the equipment, and premix for 20 minutes;

[0085] 2) Add appropriate amount of water to the adhesive hydroxypropyl cellulose to prepare an adhesive solution;

[0086] 3) adding the binder solution obtained in step 2 to the material in step 1 and starting a wet granulator to prepare wet granules, which are then granulated by a crushing and granulating machine;

[0087] 4) fluidizing the wet-screened granules to produce dry granules;

[0088] 5) blending the dried granules with a glidant, the remaining trehalose (external), and the remaining disintegrant (external) to produce an extragranular blend;

[0089] 6) lubrication blending the extragranular blend and lubricant to produce a final blend;

[0090] 7) compressing the final blend to form uncoated core tablets;

[0091] 8) Film-coat the uncoated core tablets with the film coating premix (Opadry 03K92254).

[0092] Example 11

[0093]

[0094] Production quantity: 5,000 films

[0095] Preparation process:

[0096] 1) Place the prescribed amount of cabozantinib malate, lecithin, 60% of the prescribed amount of trehalose (added internally), and 20% of the prescribed amount of disintegrant croscarmellose sodium (added internally) in a wet granulator, start the equipment, and premix for 20 minutes;

[0097] 2) Add appropriate amount of water to the adhesive hydroxypropyl cellulose to prepare an adhesive solution;

[0098] 3) adding the binder solution obtained in step 2 to the material in step 1 and starting a wet granulator to prepare wet granules, which are then granulated by a crushing and granulating machine;

[0099] 4) fluidizing the wet-screened granules to produce dry granules;

[0100] 5) blending the dried granules with a glidant, the remaining trehalose (external), and the remaining disintegrant (external) to produce an extragranular blend;

[0101] 6) lubrication blending the extragranular blend and lubricant to produce a final blend;

[0102] 7) compressing the final blend to form uncoated core tablets;

[0103] 8) Film-coat the uncoated core tablets with the film coating premix (Opadry 03K92254).

[0104] Comparative Example 1

[0105]

[0106]

[0107] Production quantity: 5,000 films

[0108] Preparation process: same as Example 1.

[0109] Comparative Example 2

[0110]

[0111] Production quantity: 5,000 films

[0112] Preparation process:

[0113] 1) Place the prescribed amount of cabozantinib malate, 70% of the prescribed amount of trehalose (added internally), and 25% of the prescribed amount of disintegrant croscarmellose sodium (added internally) in a wet granulator, start the equipment, and premix for 20 minutes;

[0114] 2) Add appropriate amount of water to the adhesive hydroxypropyl cellulose to prepare an adhesive solution;

[0115] 3) adding the binder solution obtained in step 2 to the material in step 1 and starting a wet granulator to prepare wet granules, which are then granulated by a crushing and granulating machine;

[0116] 4) fluidizing the wet-screened granules to produce dry granules;

[0117] 5) blending the dried granules with a glidant, the remaining trehalose (external), and the remaining disintegrant (external) to produce an extragranular blend;

[0118] 6) lubrication blending the extragranular blend and lubricant to produce a final blend;

[0119] 7) compressing the final blend to form uncoated core tablets;

[0120] 8) Film-coat the uncoated core tablets with the film coating premix (Opadry 03K92254).

[0121] Comparative Example 3

[0122]

[0123] Production quantity: 5,000 films

[0124] Preparation process:

[0125] 1) Place the prescribed amount of cabozantinib malate, lecithin, the prescribed amount of trehalose, and 25% of the prescribed amount of disintegrant croscarmellose sodium (added internally) in a wet granulator, start the equipment, and premix for 20 minutes;

[0126] 2) Add appropriate amount of water to the adhesive hydroxypropyl cellulose to prepare an adhesive solution;

[0127] 3) adding the binder solution obtained in step 2 to the material in step 1 and starting a wet granulator to prepare wet granules, which are then granulated by a crushing and granulating machine;

[0128] 4) fluidizing the wet-screened granules to produce dry granules;

[0129] 5) blending the dried granules with a glidant and the remaining disintegrant (external) to produce an extragranular blend;

[0130] 6) lubrication blending the extragranular blend and lubricant to produce a final blend;

[0131] 7) compressing the final blend to form uncoated core tablets;

[0132] 8) Film-coat the uncoated core tablets with the film coating premix (Opadry 03K92254).

[0133] Comparative Example 4

[0134]

[0135]

[0136] Production quantity: 5,000 films

[0137] Preparation process:

[0138] 1) Place the prescribed amount of cabozantinib malate, lecithin, and 25% of the prescribed amount of disintegrant croscarmellose sodium (added internally) in a wet granulator, start the equipment, and premix for 20 minutes;

[0139] 2) Add appropriate amount of water to the adhesive hydroxypropyl cellulose to prepare an adhesive solution;

[0140] 3) adding the binder solution obtained in step 2 to the material in step 1 and starting a wet granulator to prepare wet granules, which are then granulated by a crushing and granulating machine;

[0141] 4) fluidizing the wet-screened granules to produce dry granules;

[0142] 5) blending the dried granules with a glidant, trehalose, and the remaining disintegrant (external) to produce an extragranular blend;

[0143] 6) lubrication blending the extragranular blend and lubricant to produce a final blend;

[0144] 7) compressing the final blend to form uncoated core tablets;

[0145] 8) Film-coat the uncoated core tablets with the film coating premix (Opadry 03K92254).

[0146] Verification example:

[0147] Test Example 1: Dissolution Test

[0148] Dissolution conditions: Determined according to the dissolution and release method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931, Method 2).

[0149] 1) Standard medium (pH 2.0 hydrochloric acid medium): 900 ml of a hydrochloric acid solution containing 0.5% Triton, adjusted to a pH of 2.00 ± 0.1 with hydrochloric acid, was used as the dissolution medium. The dissolution method was a paddle method at a rotation speed of 75 rpm. Sampling time points were 5 min, 10 min, 15 min, 20 min, 30 min, and 45 min.

[0150] Dissolution chromatography conditions: octadecylsilane bonded silica gel column; mobile phase: 0.02 mol / L ammonium acetate solution (pH adjusted to 5.2 with glacial acetic acid)-acetonitrile (48:52); flow rate: 1.0 ml / min; column temperature: 35°C; detection wavelength: 241 nm. Injection volume: 10 μl. The number of theoretical plates, calculated based on the cabozantinib peak, should be no less than 2000.

[0151] Table 1 Dissolution of tablets in various examples

[0152]

[0153] Test Example 2: Stability Test

[0154] (1) Investigation plan: The tablets of the examples and the comparative examples were placed naked in a constant temperature incubator, and samples were taken regularly to determine the moisture content and dissolution rate (cumulative dissolution rate at 20 min).

[0155] (2) Determine the content according to high performance liquid chromatography (General Chapter 0512 of the Chinese Pharmacopoeia 2020 Edition).

[0156] Chromatographic conditions: Column packed with octadecylsilane bonded silica gel; mobile phase A: 0.02 mol / L ammonium acetate solution (pH adjusted to 5.2 with glacial acetic acid); mobile phase B: acetonitrile; gradient elution. Flow rate: 1.0 ml / min; column temperature: 35°C; detection wavelength: 241 nm. Injection volume: 10 μl. The gradient is as follows:

[0157]

[0158]

[0159] Table 2 Stability test results

[0160] Stability test conditions: 30℃±2℃, 75%RH±5℃, accelerated 6 months.

[0161]

[0162] As can be seen from Table 1 and Table 2, the dissolution effects of Comparative Examples 1 and 2 are relatively poor. In Comparative Example 1, the trehalose in the prescription is replaced with lactose, which loses the trehalose dispersibility, thereby slowing dissolution. Comparative Example 2 does not add lecithin, which loses the effect of the lecithin surfactant cosolvent, and dissolves slowly. By analyzing the data of Implementations 1-11, the lecithin dosage is too little and does not play the role of cosolvent. Too much dosage can cause the serious gel-like viscosity of emulsification to increase, which is unfavorable for dissolution. It can also cause the tablet hygroscopicity to be difficult to control, and can stick in the preparation process. Excessive moisture content in the storage process is unfavorable for the stability of the preparation. Too little trehalose dosage is unfavorable for the control of the preparation hygroscopicity. Too much trehalose has poor hygroscopicity and affects the water absorption and disintegration effect of the disintegrant, which is unfavorable for dissolution. If you want to ensure dissolution, you need to further increase the dosage of the disintegrant, which will increase the tablet weight. Patients take a large amount of disintegrants and trehalose, which is unfavorable for drug safety. The present invention controls the content of trehalose and lecithin on the basis of existing formulations, while ensuring the water absorption and dissolution performance of the formulation, so that the formulation product meets the quality requirements and satisfies consumer needs. In addition, the inventors have also verified the types and dosages of other adhesives, disintegrants, lubricants, and glidants, and similarly achieved good results. The adhesives, disintegrants, lubricants, and glidants listed in the above embodiments are not limitations of the present invention.

Claims

1. A cabozantinib malate tablet, characterized in that: Comprising a tablet core and a coating, the cabozantinib malate tablet core is composed of the following ingredients: 76.03 parts of cabozantinib malate 380.15-456.18 parts of trehalose 15.2-45.6 parts of lecithin 6-8 parts of hydroxypropyl cellulose 12-16 parts of croscarmellose sodium 0.6-1 part of colloidal silicon dioxide 1-2 parts of magnesium stearate; The mass ratio of cabozantinib malate to trehalose and lecithin is 1:5.0-6.0:0.2-0.6; the coating agent is selected from Opadry 03K92254; The preparation of the cabozantinib malate tablets mainly comprises the following steps: 1) Place cabozantinib malate, lecithin, trehalose, and croscarmellose sodium in a wet granulator, start the machine, and premix for 20 minutes; 2) Add appropriate amount of water to hydroxypropyl cellulose to prepare hydroxypropyl cellulose solution; 3) adding the hydroxypropyl cellulose solution obtained in step 2 to the material in step 1 and starting a wet granulator to prepare wet granules, which are then granulated by a pulverizer; 4) fluidizing the wet-screened granules to produce dry granules; 5) blending the dried granules with colloidal silicon dioxide, remaining trehalose, and remaining croscarmellose sodium to produce an extragranular blend; 6) lubrication blending the extragranular blend and magnesium stearate to produce a final blend; 7) compressing the final blend to form uncoated core tablets; 8) Film coating of uncoated core tablets; The amount of trehalose added internally accounts for 60-80% of the weight of the trehalose prescription; The amount of cross-linked carboxymethyl cellulose sodium added accounts for 20-30% of the weight of the cross-linked carboxymethyl cellulose sodium prescription.

2. The cabozantinib malate tablet according to claim 1, wherein The core of the cabozantinib malate tablet is composed of the following ingredients: 76.03 parts of cabozantinib malate 418.2 parts of trehalose 30.4 parts of lecithin 7.2 parts of hydroxypropyl cellulose 15 parts of cross-linked carboxymethyl cellulose sodium 1 part colloidal silicon dioxide 1.5 parts of magnesium stearate.

3. The cabozantinib malate tablet according to claim 1, wherein The amount of trehalose added internally accounts for 70% of the weight of the trehalose prescription; the amount of cross-linked carboxymethyl cellulose sodium added internally accounts for 25% of the weight of the cross-linked carboxymethyl cellulose sodium prescription.

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