A high drug loading imatinib tablet

Abstract

The present application relates to a high drug loading imatinib tablet. Specifically, the present application belongs to the field of pharmaceutical preparations, and relates to a preparation method of imatinib mesylate tablet, and a high drug loading, high stability imatinib mesylate tablet obtained by the method. The present application solves the problems of low drug loading, large tablet weight, and the resulting difficulty in taking and safety of imatinib mesylate tablet by adjusting the formulation of excipients and the preparation process, and also solves the compressibility problem caused by high drug loading and meets the requirements of rapid disintegration and dissolution.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a method for preparing imatinib mesylate tablets, and imatinib mesylate tablets with high drug loading and high stability obtained by this method. Background Technology

[0002] Imatinib mesylate is a tyrosine kinase inhibitor developed by Novartis in Switzerland. It is used to treat patients with chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or chronic phase after failure of alpha-interferon therapy, as well as patients with unresectable or metastatic malignant gastrointestinal stromal tumors (GIST). Its chemical name is 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidinyl]amino]phenyl]-benzamide methanesulfonate, with the following structural formula:

[0003] .

[0004] The original brand-name imatinib mesylate tablets are available in 100mg and 400mg strengths (calculated as imatinib). Adults typically take 400mg or 600mg once daily, or a daily dose of 800mg, i.e., 400mg twice daily (morning and evening). Children and adolescents take the medication once daily or in two divided doses (morning and evening).

[0005] The original drug's formulation excipients include: microcrystalline cellulose (diluent), hydroxypropyl methylcellulose (binder), crospovidone (disintegrant), silica (flow aid), and magnesium stearate (lubricant), prepared using a wet granulation process. Imatinib mesylate raw material is a crystalline substance. Its disadvantages include poor compressibility and a tendency to form a gel upon contact with water, resulting in slow dissolution and slow onset of action. To address these issues, the original drug incorporated a significant amount of excipients, including diluents and crospovidone (disintegrant), to improve its compressibility and reduce slow dissolution. Due to the large tablet size of imatinib mesylate, the original drug has a large tablet weight and volume, especially the 400mg tablet, which weighs up to 750mg. As is well known, cancer patients are usually physically weak and have poor swallowing ability. Large pills are not easy to swallow and may even get stuck in the throat, resulting in poor patient safety and compliance. In addition, imatinib can easily react with peroxides to generate oxidative impurities, and the disintegrant crospovidone can easily degrade to generate peroxides. Therefore, the large-scale use of crospovidone in prescriptions can easily lead to an increase in oxidative degradation impurities, increasing safety risks.

[0006] To address the above issues, reducing the amount and types of excipients can solve the problems of low drug loading, heavy tablets, and instability. However, because imatinib mesylate has poor compressibility, reducing the excipients will result in poor compressibility and may cause tablet cracking during compression.

[0007] Using a binder for one-step granulation can encapsulate the imatinib mesylate active pharmaceutical ingredient (API), solving the compressibility problem, but it slows down tablet dissolution and disintegration. Mixing the API with a disintegrant before one-step granulation with a binder presents challenges: too much disintegrant results in large tablets; too little disintegrant leads to uneven mixing, causing significant differences in dissolution and disintegration between tablets. Even when the disintegrant is dispersed in a binder solution for one-step granulation, its lack of adhesiveness and insolubility in water prevents it from adhering well to the imatinib particles, resulting in large differences in disintegration and high relative standard deviations (RSDs) of dissolution even at low disintegrant concentrations.

[0008] The original drug patent CN101653424A (“High Drug Loading Tablets”) prepared a tablet containing 30-80% imatinib. The formulation contains diluents and disintegrants to improve compressibility and dissolution rate. The preferred example given is a 400mg tablet with a weight of about 750mg (Example 2). The tablet weight and volume are still very large. The active ingredient accounts for about 60% of the tablet weight. Furthermore, the peroxide impurities of the disintegrant cross-linked povidone were not considered in relation to the final impurities of the tablet.

[0009] Chinese patent document CN107625773A (“A pharmaceutical composition of imatinib mesylate and its formulation”) solves the stability problem of imatinib mesylate by preparing a composition of imatinib mesylate hydrate and amorphous powder, but still does not provide a scheme to reduce tablet weight, and its dosage is calculated based on imatinib mesylate, which does not match the actual dosage.

[0010] Chinese patent document CN102008734A (“An Inclusion Complex of α-Crystal Imatinib and Its Preparation Method”) addresses the instability of α-crystalline imatinib by using cyclodextrin or its derivatives to encapsulate it, resulting in a more stable formulation suitable for clinical use. This overcomes the sensitivity to light, temperature, and heat, improving the stability and ease of handling of the formulation. However, this document states that the weight percentage of imatinib is less than 3%, while the weight percentage of cyclodextrin is greater than 97%. This completely ignores the fact that a large dose of imatinib leads to a larger weight of the inclusion complex, and therefore, it does not provide an effective method to reduce tablet weight.

[0011] Therefore, none of the existing patent technology documents provide a method for preparing imatinib tablets that can both increase drug loading and reduce tablet weight while achieving rapid and uniform dissolution. Summary of the Invention

[0012] This invention provides a high-drug-load imatinib mesylate tablet and its preparation method, which solves the problems of low drug loading, resulting in large tablet weight and difficulty in administration and safety issues. At the same time, it also solves the compressibility problem caused by high drug loading and meets the requirements of rapid disintegration and dissolution.

[0013] In a first aspect, the present invention provides an imatinib mesylate tablet, characterized in that the tablet comprises imatinib mesylate in an amount of more than 90% by weight, as well as at least one binder, a disintegrant, and a lubricant.

[0014] In a preferred embodiment, the imatinib mesylate tablet is characterized in that the imatinib mesylate accounts for 95% of the weight of the tablet.

[0015] In a preferred embodiment, the weight ratio of the adhesive to the disintegrant is 1:4 to 4:1, preferably 1:3 to 3:1, such as 1:4, 1:3, 1:2, 1:1, 2:1, 3:1 or 4:1.

[0016] In a preferred embodiment, the imatinib mesylate tablet is characterized in that the binder is hydroxypropyl cellulose, and the binder accounts for less than 5% of the tablet weight, for example, 2%. Preferably, the hydroxypropyl cellulose is a low viscosity grade, preferably selected from Ashland's EF pharm, EXF pharm, ELF pharm or Nippon Soda's HPC-L, HPC-SL, etc.

[0017] In a preferred embodiment, the imatinib mesylate tablets are characterized in that the disintegrant is croscarmellose sodium, and the disintegrant accounts for less than 5% of the tablet weight, for example, 2%. Preferably, the croscarmellose sodium is selected from JRS or DuPont's equivalent product.

[0018] In a preferred embodiment, the imatinib mesylate tablets are characterized in that the lubricant is magnesium stearate, preferably, the lubricant accounts for less than 2% of the tablet weight, for example, 1%.

[0019] In a preferred embodiment, the imatinib mesylate tablets comprise the following components in the indicated weight ratios: imatinib mesylate 95.0%, hydroxypropyl cellulose 2.0%, croscarmellose sodium 2.0%, and magnesium stearate 1.0%.

[0020] In a preferred embodiment, the imatinib mesylate tablets optionally have a gastrointestinal coating.

[0021] In a preferred embodiment, the imatinib mesylate tablets are characterized in that the tablets are prepared by a one-step fluidized bed granulation process.

[0022] In a preferred embodiment, the imatinib mesylate tablets are characterized in that the preparation method includes the step of preparing a binder suspension by co-linking sodium carboxymethyl cellulose and hydroxypropyl cellulose.

[0023] In a preferred embodiment, the imatinib mesylate tablets are characterized in that the preparation method of the binder suspension includes: first dispersing sodium cross-linked carboxymethyl cellulose in water and homogenizing it at high temperature and high speed; after the homogenized solution is cooled to room temperature, adding hydroxypropyl cellulose and stirring to mix evenly to obtain a mixed binder solution.

[0024] In a more preferred embodiment, the imatinib mesylate tablets are characterized in that the crosslinking temperature of the mixed binder during preparation is not lower than 80°C and the homogenization speed is not lower than 8000 rpm; preferably, the homogenization temperature is 90°C and the homogenization speed is 10000 rpm.

[0025] In one embodiment, the aforementioned imatinib mesylate tablets are prepared by the method described in the second aspect.

[0026] Secondly, the present invention provides a method for preparing imatinib mesylate tablets, comprising the following steps:

[0027] Step 1: Place imatinib mesylate in a fluidized bed;

[0028] Step 2: Disperse sodium cross-linked carboxymethyl cellulose in water and homogenize it at high temperature and high speed. After cooling the suspension, add hydroxypropyl cellulose to prepare a mixed adhesive solution.

[0029] Step 3: The mixed binder solution is granulated in one step by spraying it from the top of a fluidized bed;

[0030] Step 4: After granulation, magnesium stearate is added for total mixing, and then compressed into tablets.

[0031] In a preferred embodiment, the homogenization temperature of the crosslinked sodium carboxymethyl cellulose during the preparation of the mixed adhesive is not lower than 80°C and the homogenization speed is not lower than 8000 rpm; preferably, the homogenization temperature is 90°C and the homogenization speed is 10000 rpm. Attached Figure Description

[0032] Figure 1 The length, thickness, and width of the self-developed tablet (the tablet of Example 1) are compared with those of the original formulation product (reference tablet). Detailed Implementation

[0033] The present invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention.

[0034] Comparative Example 1

[0035] The tablet weight and size are the same as those of the original drug, Gleevec, according to Example 2 of the original patent CN101653424A.

[0036]

[0037] Note: 478mg imatinib mesylate is equivalent to 400mg imatinib free base.

[0038] The specific steps are as follows:

[0039] Step 1: Mixing: Take imatinib mesylate, microcrystalline cellulose and crospovidone and mix them evenly to obtain a mixture;

[0040] Step 2: Granulation: Dissolve hydroxypropyl methylcellulose in an appropriate amount of purified water, add it to the mixture and stir thoroughly to obtain a soft mass;

[0041] Step 3: Drying: The soft material is granulated by sieving and then dried in a fluidized bed;

[0042] Step 4: Granulation, total mixing and tableting: Sieve and granulate, add silica and magnesium stearate, mix evenly, and then compress into tablets.

[0043] Comparative Example 2

[0044] wet granulation

[0045]

[0046] The specific steps are as follows:

[0047] Step 1: Mixing: Weigh 478g of imatinib mesylate, 10g of hydroxypropyl cellulose and 10g of croscarmellose sodium, mix them evenly to obtain a mixture;

[0048] Step 2: Granulation: Add an appropriate amount of purified water, stir thoroughly, and obtain a soft mass;

[0049] Step 3: Drying: The soft material is granulated by sieving and then dried in a fluidized bed;

[0050] Step 4: Granulation, total mixing and tableting: Sieve and granulate, add 5g of magnesium stearate, mix evenly, and compress into tablets.

[0051] Comparative Example 3

[0052] Fluidized bed one-step granulation (stirring preparation of 1:1 binder mixture)

[0053]

[0054] The specific steps are as follows:

[0055] Step 1: Adhesive preparation: Disperse 10g of croscarmellose sodium and 10g of hydroxypropyl cellulose in purified water, stir thoroughly to prepare a 5% mixed adhesive solution;

[0056] Step 2: One-step granulation: Place 478g of imatinib mesylate in a fluidized bed. After preheating, atomize and add the mixed binder for one-step granulation. After granulation, dry the product.

[0057] Step 3: Sieve and granulate, add 5g of magnesium stearate, mix well, and compress into tablets.

[0058] Example 1

[0059] One-step fluidized bed granulation (homogenization for preparing a 1:1 binder mixture)

[0060]

[0061] The specific steps are as follows:

[0062] Step 1: Adhesive preparation: Disperse 10g of croscarmellose sodium in an appropriate amount of purified water, homogenize at 90℃ and 10000rpm, and cool to room temperature after thorough homogenization to obtain suspension 1. Dissolve 10g of hydroxypropyl cellulose in purified water to obtain solution 2; mix suspension 1 and solution 2 evenly to prepare a 5% mixed adhesive;

[0063] Step 2: One-step granulation: Place 478g of imatinib mesylate in a fluidized bed. After preheating, atomize and add the mixed binder for one-step granulation. After granulation, dry the product.

[0064] Step 3: Sieve and granulate, add 5g of magnesium stearate, mix well, and compress into tablets.

[0065] Example 2

[0066] One-step fluidized bed granulation (homogenization for preparing a 1:4 binder mixture)

[0067]

[0068] The specific steps are as follows:

[0069] Step 1: Adhesive preparation: Disperse 16g of croscarmellose sodium in an appropriate amount of purified water, homogenize at 90℃ and 10000rpm, and cool to room temperature after thorough homogenization to obtain suspension 1. Dissolve 4g of hydroxypropyl cellulose in purified water to obtain solution 2; mix suspension 1 and solution 2 evenly to prepare a 5% mixed adhesive;

[0070] Step 2: One-step granulation: Place 478g of imatinib mesylate in a fluidized bed. After preheating, atomize and add the mixed binder for one-step granulation. After granulation, dry the product.

[0071] Step 3: Sieve and granulate, add 5g of magnesium stearate, mix well, and compress into tablets.

[0072] Example 3

[0073] Fluidized bed one-step granulation (homogenization preparation of a 4:1 binder mixture)

[0074]

[0075] Step 1: Adhesive preparation: Disperse 4g of croscarmellose sodium in an appropriate amount of purified water, homogenize at 90℃ and 10000rpm, and cool to room temperature after thorough homogenization to obtain suspension 1. Dissolve 16g of hydroxypropyl cellulose in purified water to obtain solution 2; mix suspension 1 and solution 2 evenly to prepare a 5% mixed adhesive;

[0076] Step 2: One-step granulation: Place 478g of imatinib mesylate in a fluidized bed. After preheating, atomize and add the mixed binder for one-step granulation. After granulation, dry the product.

[0077] Step 3: Sieve and granulate, add 5g of magnesium stearate, mix well, and compress into tablets.

[0078] Example 4

[0079] Fluidized bed one-step granulation (homogenization preparation of a 3:1 binder mixture, API content 91%)

[0080]

[0081] Step 1: Adhesive preparation: Disperse 11.25g of croscarmellose sodium in an appropriate amount of purified water, homogenize at 90℃ and 10000rpm, and cool to room temperature after thorough homogenization to obtain suspension 1. Dissolve 33.75g of hydroxypropyl cellulose in purified water to obtain solution 2; mix suspension 1 and solution 2 evenly to prepare a 5% mixed adhesive.

[0082] Step 2: One-step granulation: Place 478g of imatinib mesylate in a fluidized bed. After preheating, atomize and add the mixed binder for one-step granulation. After granulation, dry the product.

[0083] Step 3: Sift and granulate, add 5g of magnesium stearate, mix well, and compress into tablets;

[0084] Step 4: Coat the tablets with a 12% gastric-soluble coating powder (Opadry 03A565002) aqueous dispersion.

[0085] Experimental results

[0086] The tablet data for Comparative Examples 1, 2, and 3, and Examples 1, 2, 3, and 4 are summarized in the table below:

[0087]

[0088] The results above show that conventional wet granulation (Comparative Example 2) cannot solve the compressibility problem caused by high drug loading (high tablet breakage and friability; according to the Chinese Pharmacopoeia, friability should be <1%). One-step granulation using a mixed binder can solve the compressibility (friability) problem; however, the tablets prepared without homogenization (Comparative Example 3) have low dissolution and large differences in dissolution between tablets, with an RSD > 6%, which does not meet the requirements. The mixed binder prepared by homogenization (Example 1) is significantly better than the method without homogenization (Comparative Example 3), meeting the expected requirements in all aspects. For homogenized mixed binder preparation, as the amount of hydroxypropyl cellulose increases, the tablet hardness increases and the dissolution decreases. Therefore, it can be concluded that using a mixed binder for fluidized bed one-step granulation, with the mixed binder prepared by homogenization, and controlling the ratio of hydroxypropyl cellulose to croscarmellose sodium at 1:4 to 4:1, can yield qualified samples.

[0089] Dissolution test method: Determined according to the method for determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II).

[0090] Dissolution conditions: Use 1000 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium, rotate at 50 rpm, operate according to the procedure, and take a sample after 15 minutes.

[0091] Test solution: Filter the dissolution solution and collect the filtrate.

[0092] Reference solution: Accurately weigh an appropriate amount of imatinib mesylate reference standard, add an appropriate amount of acetonitrile, sonicate to dissolve, and then quantitatively dilute with dissolution medium to prepare a solution containing approximately 100 μg of imatinib per ml. Chromatographic conditions: Use an octadecylsilane-bonded silica gel column (C18, 100 × 4.6 mm, 3.5 µm or equivalent column); use 0.1% phosphoric acid solution-acetonitrile (85:15) as the mobile phase; detection wavelength is 268 nm; injection volume is 5 µl; flow rate is 1.0 ml per minute; column temperature is 25 °C.

[0093] Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the dissolution amount per tablet.

[0094] Comparison of related substances

[0095] The tablets of Example 1 were packaged in aluminum-plastic blister packs and subjected to accelerated stability tests. The results were compared with the original formulation of commercially available Gleevec. The results showed that the impurity stability of the formulation of the present invention was superior to that of the original formulation.

[0096]

[0097] The results show that the tablets of Example 1 have better stability than the original formulation, with virtually no change in degradation impurities, while the content of degradation impurities J and total impurities in the original formulation more than doubled during the experiment.

[0098] The relevant substances were determined according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0512).

[0099] Diluent: Phosphate buffer (3.4 g potassium dihydrogen phosphate dissolved in 1000 ml of water, pH adjusted to 2.5 ± 0.05 with phosphate) - acetonitrile (95:5).

[0100] Test solution: Take 10 tablets of this product, add an appropriate amount of acetonitrile to disintegrate, then add diluent, sonicate to dissolve, cool to room temperature, and quantitatively dilute with diluent to prepare a solution containing approximately 10 mg of imatinib per ml. Take an appropriate amount of supernatant, quantitatively dilute with diluent to prepare a solution containing approximately 200 μg of imatinib per ml, centrifuge, and collect the supernatant.

[0101] Reference solution: Weigh an appropriate amount of imatinib mesylate reference standard accurately, dissolve it in diluent and dilute quantitatively to prepare a solution containing approximately 1 μg of imatinib per ml.

[0102] Sensitivity solution: Transfer 1 ml of the reference solution to a 10 ml volumetric flask, dilute to the mark with diluent, and shake well.

[0103] System suitability solution: Take appropriate amounts of imatinib mesylate reference standard and impurity IMP-10, dissolve them in diluent and dilute quantitatively to prepare a solution containing approximately 200 μg of imatinib and 0.4 μg of impurity IMP-10 per ml.

[0104] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Phenomenex Luna C18, 4.6 × 200 mm, 5 μm or equivalent column); mobile phase A was buffer solution (3.4 g potassium dihydrogen phosphate dissolved in 1000 ml of water, pH adjusted to 2.5 ± 0.05 with phosphoric acid); mobile phase B was acetonitrile; gradient elution was performed according to the table below; detection wavelength was 235 nm; injection volume was 30 µl; flow rate was 1.0 ml per minute; column temperature was 40 °C.

[0105]

[0106] System suitability requirements: In the sensitivity solution chromatogram, the signal-to-noise ratio of the imatinib peak should be greater than 10; in the system suitability solution chromatogram, the resolution between the imatinib peak and the impurity IMP-10 peak should be no less than 1.5; for six consecutive injections of the reference solution, the relative standard deviation of the imatinib peak area should be no greater than 5.0%.

[0107] Assay: Accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms.

[0108] Limits: If impurity peaks are present in the chromatogram of the test solution, the impurity J, impurity IMP-11, and impurity IMP-12 shall not exceed 0.2% respectively, calculated using the external standard method with correction factor added, based on the average peak area of ​​imatinib in the chromatograms of the reference solution from 6 consecutive injections; other unknown impurities shall not exceed 0.1%; and the total impurity shall not exceed 0.5%.

[0109] Degradation impurities J: .

[0110] Comparison of sheet sizes

[0111] from Figure 1 The results show that the self-developed tablets (the tablets in Example 1) have significantly reduced length, thickness and width compared to the original formulation product (reference tablets), thereby greatly improving patient compliance and safety.

Claims

1. A tablet of imatinib mesylate characterized in that The tablet is composed of imatinib mesylate accounting for more than 90% by weight, hydroxypropyl cellulose, croscarmellose sodium and magnesium stearate, and the weight ratio of the hydroxypropyl cellulose and the croscarmellose sodium is 1:4 to 4:1; The imatinib mesylate tablet is prepared by a method comprising the following steps: Step 1: placing imatinib mesylate in a fluidized bed; Step 2: dispersing croscarmellose sodium in water for homogenization, and adding hydroxypropyl cellulose to the suspension after cooling to prepare a mixed binder solution, wherein the homogenization of the croscarmellose sodium is performed at a homogenization temperature not lower than 80°C and a homogenization speed not lower than 8000 rpm; Step 3: performing one-step granulation by spraying the mixed binder solution through the top of the fluidized bed; Step 4: after granulation, adding magnesium stearate for general mixing, and then compressing into tablets.

2. The imatinib mesylate tablet according to claim 1, characterized by The imatinib mesylate accounts for 95% by weight in the tablet.

3. The imatinib mesylate tablet according to claim 1, characterized by The hydroxypropyl cellulose accounts for less than 5% by weight of the tablet.

4. The imatinib mesylate tablet according to claim 1, characterized by The croscarmellose sodium accounts for less than 5% by weight of the tablet.

5. The imatinib mesylate tablet of claim 1, comprising the following components by weight: imatinib mesylate 95.0%, hydroxypropyl cellulose 2.0%, croscarmellose sodium 2.0%, and magnesium stearate 1.0%.

6. The imatinib mesylate tablet of any one of claims 1-5, which is optionally provided with a gastric-soluble coating.

7. A method for preparing the imatinib mesylate tablet of any one of claims 1-6, comprising the following steps: Step 1: placing imatinib mesylate in a fluidized bed; Step 2: dispersing croscarmellose sodium in water for homogenization, and adding hydroxypropyl cellulose to the suspension after cooling to prepare a mixed binder solution, wherein the homogenization of the croscarmellose sodium is performed at a homogenization temperature not lower than 80°C and a homogenization speed not lower than 8000 rpm; Step 3: performing one-step granulation by spraying the mixed binder solution through the top of the fluidized bed; Step 4: after granulation, adding magnesium stearate for general mixing, and then compressing into tablets.

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