Nilotinib sustained release tablet and preparation method thereof

Abstract

The invention discloses a nilotinib sustained release tablet and a preparation method thereof, the nilotinib sustained release tablet comprises a bleaching assisting layer and a drug-containing sustained release layer, the bleaching assisting layer is prepared from a hydrophilic polymer with the viscosity of 2000 mpa.s-6000 mpa.s, a hydrophobic bleaching assisting agent, an adhesive and a lubricant; the drug-containing sustained-release layer is prepared from the following raw materials: an amorphous solid dispersion containing nilotinib or salt thereof, a hydrophilic polymer with the viscosity of 40 mpa.s-2000 mpa.s, a water-soluble filler, a flow aid and a lubricant. The nilotinib sustained-release tablet can effectively prolong the retention time of nilotinib in the stomach, slowly release the medicine in the stomach, improve the solubility and bioavailability of the medicine and reduce the overall dosage, so that the adverse reaction of the medicine is reduced, and meanwhile, on the basis of ensuring that the nilotinib sustained-release tablet is not affected by food effects, the nilotinib sustained-release tablet only needs to be orally taken once every day, and the curative effect of the nilotinib sustained-release tablet is greatly improved. The medicine taking compliance of a patient is improved by reducing the medicine taking times.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, in particular, the present application relates to a kind of nilotinib sustained-release tablets and preparation method thereof. BACKGROUND

[0002] Nilotinib is the second generation of tyrosine kinase inhibitor, it is a high affinity ATP competitive inhibitor based on aminopyrimidine, effectively treat drug-resistant or intolerant chronic myeloid leukemia patients. Nilotinib targets the BCR-ABL fusion protein, inhibits its kinase activity, thereby blocking the proliferation and spread of cancer cells. BCR-ABL fusion protein is the hallmark of chronic myeloid leukemia (CML), which is formed by translocation of chromosome 9 and 22, leading to continuous activation of tyrosine kinase, and then driving the proliferation of cancer cells. Nilotinib effectively controls the progression of CML by blocking this signaling pathway.

[0003] Nilotinib is classified as BCS IV compound in the biopharmaceutics classification system (BCS), which has low / moderate water solubility and low permeability. The solubility of nilotinib in aqueous solution at 25℃ decreases sharply with increasing pH, and it is practically insoluble at pH 4.5 and above. The decrease in solubility of nilotinib in an environment with a pH greater than 1.0 leads to a decrease in the absorption of nilotinib.

[0004] Tasigna (nilotinib capsule) produced by Novartis uses hydrochloride form of nilotinib as raw material, which has slightly improved solubility but limited improvement. In addition, the prescription information of this drug stipulates that patients should fast within 2 hours before treatment and 1 hour after treatment. Nilotinib itself prolongs the QT interval (the time from the beginning of Q wave to the end of T wave on electrocardiogram, representing the total time from electrical activation to recovery of ventricular resting state), when taken with food, Tasigna can cause excessive absorption (compared with fasting state, when given 30 minutes after high-fat meal, the whole body exposure (AUC) increases by 82%), increasing the risk of QT interval prolongation on electrocardiogram, which is a potential cardiotoxicity that can cause serious cardiac events. Therefore, the specifications of Tasigna are 150 mg and 200 mg, taken twice a day, which is poor for patients who need long-term medication, and there are reports that about 1 / 4 of patients will miss the drug after taking it for a year due to food restriction and twice daily dosing, affecting the therapeutic effect.

[0005] The drug can be made into a sustained-release tablet to solve the compliance problem of the patient. However, the common sustained-release drug delivery system, although well controls the release of the drug from the system, cannot significantly improve the bioavailability of the drug because the residence time of some drugs in the gastrointestinal tract is too short, i.e. the drug has a narrow "absorption window", and the drug cannot be completely released when passing through the effective absorption site. The solubility of nilotinib in an aqueous solution at 25°C decreases sharply with the increase of pH, and it is practically insoluble at pH 4.5 and higher. Therefore, the nilotinib made into a common sustained-release tablet cannot achieve the purpose of long residence in the stomach to improve the solubility and bioavailability. SUMMARY

[0006] The purpose of the present application is to make the nilotinib stay in the stomach for a long time to improve the solubility and bioavailability, and to slowly release at a certain speed to reduce the frequency of taking medicine to improve the compliance of the patient.

[0007] The specific technical solutions for achieving the above-mentioned purposes of the present application include the following.

[0008] In a first aspect of the present application, a nilotinib sustained-release tablet is provided, which comprises a glidant layer and a drug-containing sustained-release layer, wherein the glidant layer is prepared from raw materials comprising 50% to 85% hydrophilic polymer, 10% to 20% hydrophobic glidant, 3% to 10% binder and 1% to 4% lubricant; the viscosity of the hydrophilic polymer is 2000 mpa·s to 6000 mpa·s; the drug-containing sustained-release layer is prepared from raw materials comprising 30% to 80% amorphous solid dispersion of nilotinib or its salt, 5% to 40% hydrophilic polymer, 5% to 20% water-soluble filler, 0.5% to 5% glidant and 1% to 4% lubricant; the viscosity of the hydrophilic polymer is 40 mpa·s to 2000 mpa·s.

[0009] In a second aspect of the present application, a preparation method of the above-mentioned nilotinib sustained-release tablet is provided, comprising the following steps: (1) granulate the hydrophilic polymer and the hydrophobic glidant under the action of the binder, integrate the granules, and then mix the lubricant to obtain the glidant layer raw materials; (2) mix the amorphous solid dispersion of nilotinib or its salt and the glidant, sieve, and then mix the hydrophilic polymer, the water-soluble filler and the lubricant to obtain the drug-containing sustained-release layer raw materials; (3) first pre-press the glidant layer raw materials of step (1) into tablets, and then pre-press the drug-containing sustained-release layer raw materials of step (2) into tablets, and the preparation is completed.

[0010] The nilotinib sustained-release tablet of the present application comprises a floating aid layer and a drug-containing sustained-release layer, wherein the floating aid layer can control the drug to float in the stomach for 24 hours, the drug in the drug-containing sustained-release layer is an amorphous nilotinib solid dispersion, and by using a low-viscosity hydrophilic polymer and a direct-pressing type water-soluble filler in combination, the nilotinib is allowed to be released slowly for 24 hours, and the release curve is approximately "first-order release", therefore, the nilotinib sustained-release tablet of the present application can effectively prolong the residence time of the nilotinib in the stomach, slowly release the drug in the stomach, improve the solubility of the drug, improve the bioavailability of the preparation, reduce the overall drug dosage, and thus reduce the adverse reactions of the drug.

[0011] Meanwhile, the nilotinib sustained-release tablet of the present application only needs to be taken orally once a day on the basis of ensuring that it is not affected by food effect, and the drug-taking compliance of the patient is improved by reducing the frequency of taking the drug.

[0012] In addition, the nilotinib sustained-release tablet of the present application can further comprise a retardation layer or a drug-containing immediate-release layer on the basis of the floating aid layer and the drug-containing sustained-release layer, and can further control the dissolution rate of the drug or adjust the drug release curve. BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1 Figure 1 is a structural schematic diagram of the multilayer sustained-release tablet of the present application; wherein 1 is a floating aid layer, 2 is a drug-containing sustained-release layer, and 3 is a retardation layer or a drug-containing immediate-release layer.

[0014] Figure 2 Figure 6 is a crystal pattern of the multilayer sustained-release tablet of Example 3 and Example 6 at 0 days and after accelerated storage for 1 month.

[0015] Figure 3 Figure 4 is a 24 h dissolution curve diagram of the single-layer sustained-release tablet of Example 1.

[0016] Figure 4 Figure 5 is a 24 h dissolution curve diagram of the single-layer sustained-release tablet of Example 2.

[0017] Figure 5 Figure 7 is a 24 h dissolution curve diagram of the double-layer sustained-release tablet of Example 3.

[0018] Figure 6 Figure 8 is a 24 h dissolution curve diagram of the three-layer sustained-release tablet of Example 4.

[0019] Figure 7 Figure 10 is a 24 h dissolution curve diagram of the three-layer sustained-release tablet of Example 6.

[0020] Figure 8 Figure 11 is a 24 h dissolution curve diagram of the three-layer sustained-release tablet of Example 7.

[0021] Figure 9 Figure 12 is a 60 min dissolution curve diagram of the nilotinib immediate-release capsule.

[0022] Figure 10 Figure 6 shows the XRPD patterns of nilotinib raw material, amorphous nilotinib solid dispersion, the blank sustained-release layer of the drug-containing sustained-release layer of Example 3, and the drug-containing sustained-release layer of Example 3 after immersion in simulated gastric fluid for different lengths of time. DETAILED DESCRIPTION

[0023] In order to facilitate the understanding of the present application, a more comprehensive description of the present application will be given below. The present application can be realized in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thorough and comprehensive.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in this application, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0025] The experimental methods in the following examples, unless otherwise specified, are generally carried out according to the conventional conditions, or according to the conditions recommended by the manufacturers. The various common chemical reagents used in the examples are commercially available products.

[0026] In some embodiments of the present application, a nilotinib sustained-release tablet is disclosed, which comprises a glidant layer and a drug-containing sustained-release layer, wherein the glidant layer is prepared from raw materials comprising the following mass percentages: 50% to 85% hydrophilic polymer, 10% to 20% hydrophobic glidant, 3% to 10% binder, and 1% to 4% lubricant; the viscosity of the hydrophilic polymer is 2000 mpa·s to 6000 mpa·s; the drug-containing sustained-release layer is prepared from raw materials comprising the following mass percentages: 30% to 80% amorphous solid dispersion of nilotinib or its salt, 5% to 40% hydrophilic polymer, 5% to 20% water-soluble filler, 0.5% to 5% glidant, and 1% to 4% lubricant; the viscosity of the hydrophilic polymer is 40 mpa·s to 2000 mpa·s.

[0027] The solubility of nilotinib is very low, it is difficult to release in the form of diffusion through the hydrophilic channel, and the drug selected in the present application is amorphous nilotinib solid dispersion, the release of nilotinib drug will also be affected by the high molecular polymer such as hydroxypropyl methyl cellulose acetate succinate and other excipients in the preparation process of the solid dispersion, therefore, when the nilotinib is prepared into sustained-release tablets, it is preferred to be slowly released by the way of gel matrix erosion, which requires to select a hydrophilic polymer material with lower viscosity to control the erosion speed; at the same time, since the solubility of nilotinib in aqueous solution at 25℃ decreases sharply with the increase of pH, and it is practically insoluble at pH 4.5 and higher pH, the drug stays in the gastrointestinal tract for too short a time, has a narrow "absorption window", in order to make the drug float in the stomach for a long time, a gel material with fast hydration expansion speed but slow erosion speed is required, which requires a hydrophilic polymer material with higher viscosity, which is contrary to the requirement of drug release control. The present application develops a multi-layer sustained-release tablet for amorphous nilotinib solid dispersion, which can slowly release at a certain speed to reduce the frequency of taking medicine, and can stay in the stomach for a long time to improve the solubility and bioavailability, and realizes the positioning and controlled release through the layered drug delivery system.

[0028] The nilotinib sustained-release tablet of the present application at least includes two layers: a drug-containing sustained-release layer and a floating aid layer. It can achieve the dual purpose of gastric floating and sustained release. First, amorphous nilotinib solid dispersion is selected as the raw drug in the drug-containing sustained-release layer, which is prepared by preparing hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and other cellulose-based high molecular polymers with nilotinib (the applicant's prior patent CN117100715B has a detailed description), which can greatly improve the bioavailability of nilotinib, reduce the dosage, and the bioavailability before and after meals is basically the same, reducing the influence of food effect, solving the problem of limited medication time for patients, improving the compliance of patients, and the amorphous nilotinib solid dispersion contacts fewer types of excipients, and the process of directly mixing with excipients and then tabletting is adopted when preparing the drug-containing sustained-release layer, reducing the risk of impurity degradation and crystallization caused by the process. Second, the sustained-release tablet of the present application adds a floating aid layer, which combines with the gastric floating technology to ensure the release of the drug in the stomach under low pH conditions, has high solubility, optimizes the "absorption window" of the ordinary controlled-release preparation of nilotinib, makes the drug slowly release in the stomach, and gradually reaches the absorption site as much as possible, and the long absorption window can further improve the bioavailability of the drug.

[0029] In the present application, the drug-containing sustained release layer adopts low viscosity hydrophilic polymer (viscosity range of 40-2000 mpa s), controls the slow release of the drug through swelling and dissolution, and selects appropriate viscosity, appropriate type and appropriate amount of hydrophilic polymer to achieve the purpose of 24 h slow release of the drug, which significantly prolongs the release time of nilotinib (nilotinib immediate-release capsules, 100% of which can be dissolved in 1 hour).

[0030] In one embodiment, the hydrophilic polymer in the drug-containing sustained release layer is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyoxyethylene, Kollidon® SR, sodium alginate and / or carbomer.

[0031] In one embodiment, the hydrophilic polymer in the drug-containing sustained release layer is hydroxypropyl methyl cellulose K100LV (adjusting the swelling and dissolution rate of the drug-containing sustained release layer, and the dissolution in water is not affected by pH, and the dissolution rate is not affected by eating or not).

[0032] In one embodiment, the hydrophilic polymer in the drug-containing sustained release layer is hydroxypropyl methyl cellulose K100LV (adjusting the swelling and dissolution rate of the drug-containing sustained release layer, and the dissolution in water is not affected by pH, and the dissolution rate is not affected by eating or not).

[0033] In one embodiment, the lubricant is magnesium stearate.

[0034] In one embodiment, the lubricant is magnesium stearate.

[0035] In one embodiment, the lubricant is magnesium stearate.

[0036] In one embodiment, the water-soluble filler is lactose, mannitol, sorbitol, xylitol and / or sucrose.

[0037] In one embodiment, the glidant is colloidal silicon dioxide.

[0038] In one embodiment, the glidant layer is prepared from raw materials comprising the following mass percentages: 75% to 85% hydroxypropyl methyl cellulose K4M, 13% to 15% glyceryl behenate or hydrogenated castor oil, 4% to 6% povidone K30, 1% to 3% magnesium stearate and a trace amount of bright blue.

[0039] In one embodiment, the drug-containing sustained-release layer is prepared from raw materials comprising the following mass percentages: 40% to 60% amorphous solid dispersion of nilotinib or a salt thereof, 15% to 25% hydroxypropyl methyl cellulose K100LV, 15% to 20% lactose or sorbitol, 2% to 4% colloidal silicon dioxide and 1% to 3% magnesium stearate.

[0040] In one embodiment, the amorphous solid dispersion of nilotinib or a salt thereof is made of amorphous nilotinib or a salt thereof and a high molecular polymer, which is hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and / or hydroxypropyl methyl cellulose phthalate (HPMCP).

[0041] In one embodiment, the mass ratio of the amorphous nilotinib or a salt thereof to the high molecular polymer is 1:1 to 1:15.

[0042] In one embodiment, the mass ratio of the amorphous nilotinib or a salt thereof to the high molecular polymer is 1:2 to 1:10.

[0043] In one embodiment, the nilotinib sustained-release tablet further comprises a retardant layer or a drug-containing immediate-release layer. On the basis of the glidant layer and the drug-containing sustained-release layer, a retardant layer is further added, and the glidant layer and the retardant layer sandwich the drug-containing sustained-release layer therebetween. Since the retardant layer has a faster dissolution rate, it slowly dissolves and decreases in volume over time, thereby controlling the dissolution rate by controlling the contact area of the drug-containing sustained-release layer with gastric juice. On the basis of the glidant layer and the drug-containing sustained-release layer, a drug-containing immediate-release layer is further added, and the drug-containing immediate-release layer and the glidant layer sandwich the drug-containing sustained-release layer therebetween. The drug-containing immediate-release layer preferentially releases the drug, and can reach a certain blood drug concentration in a short time after administration, so that the drug takes effect, and the drug-containing sustained-release layer continuously and slowly releases, thereby adjusting the drug release curve.

[0044] In one embodiment, the retardation layer is prepared from raw materials comprising the following mass percentages: 50-80% hydrophilic polymer, 10-30% hydrophobic skeleton material, 3-10% binder, and 1-4% lubricant; the viscosity of the hydrophilic polymer is 40 mpa-s to 2000 mpa-s.

[0045] In one embodiment, the hydrophilic polymer is hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyoxyethylene, Kollidon® SR, sodium alginate, and / or carbomer.

[0046] In one embodiment, the hydrophilic polymer is hypromellose K100LV. When the viscosity of the hydrophilic polymer used in the retardation layer is too large, it will affect the drug release.

[0047] In one embodiment, the hydrophobic skeleton material is one or more of glyceryl behenate, hydrogenated castor oil, cetyl alcohol, stearyl alcohol, beeswax, and glyceryl monostearate.

[0048] In one embodiment, the binder is povidone K30.

[0049] In one embodiment, the lubricant is magnesium stearate.

[0050] In one embodiment, the retardation layer further comprises a coloring agent, which is brilliant blue or iron oxide.

[0051] In one embodiment, the retardation layer is prepared from raw materials comprising the following mass percentages: 70-80% hypromellose K100LV, 20-25% hydrogenated castor oil, 3-5% povidone K30, 1-2% magnesium stearate, and trace amounts of iron oxide.

[0052] In one embodiment, the drug-containing immediate release layer is prepared from raw materials comprising the following mass percentages: 30-80% amorphous solid dispersion of nilotinib or a salt thereof, 5-40% filler, 5-20% disintegrant, and 1-4% lubricant.

[0053] In one embodiment, the filler is microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, or sucrose, and the disintegrant is crospovidone.

[0054] In one embodiment, the lubricant is magnesium stearate.

[0055] In one embodiment, the drug-containing immediate release layer is prepared from raw materials comprising the following mass percentages: 40-60% amorphous solid dispersion of nilotinib or a salt thereof, 30-40% microcrystalline cellulose 102 and / or sorbitol, 6-8% crospovidone, and 1-2% magnesium stearate.

[0056] In other embodiments of the present application, a preparation method of the above-mentioned nilotinib sustained release tablet is disclosed, comprising the following steps: (1) granulating the hydrophilic polymer and the hydrophobic glidant under the action of the binder, mixing the granules, and then adding the lubricant to obtain glidant layer raw materials; (2) mixing and sieving the amorphous solid dispersion of nilotinib or a salt thereof and the glidant, and then adding and mixing the hydrophilic polymer, the water-soluble filler, and the lubricant to obtain drug-containing sustained release layer raw materials; (3) first pre-pressing the glidant layer raw materials of step (1) into tablets, and then pre-pressing the drug-containing sustained release layer raw materials of step (2) into tablets.

[0057] Since the amorphous nilotinib solid dispersion has poor flowability and small density, and accounts for a large proportion, it brings great difficulty to the direct compression process. The colloidal silicon dioxide is a sub-micron-sized silica gel prepared by a gas phase method, which is light, loose, odorless, tasteless, and amorphous powder without grittiness. In step (2), the amorphous solid dispersion of nilotinib or a salt thereof and the glidant (colloidal silicon dioxide) are mixed and sieved for pretreatment, which can improve the flowability of the amorphous solid dispersion of nilotinib and solve the problem of poor flowability of the amorphous solid dispersion of nilotinib to meet the production requirements; at the same time, it can ensure that the density of the sustained release tablet is small, which is consistent with the density of the gastric floating tablet being less than the density of gastric juice (1.0 g / mL), which is beneficial to the floating of the tablet in the stomach without the need for additional swelling agents.

[0058] In one embodiment, step (2) further comprises the step of: granulating the hydrophilic polymer and the hydrophobic matrix material under the action of the binder, mixing the granules, and then adding the lubricant to obtain the retardation layer raw materials.

[0059] In one embodiment, step (3) further comprises the step of: after pre-pressing the drug-containing sustained release layer raw materials of step (2) into tablets, pre-pressing the retardation layer raw materials into tablets.

[0060] In one embodiment, step (2) further comprises the step of: mixing and sieving the amorphous solid dispersion of nilotinib or a salt thereof and the glidant, and then adding and mixing the filler, the disintegrant, and the lubricant to obtain the drug-containing immediate release layer raw materials.

[0061] In one embodiment, step (3) further comprises the step of: after pre-pressing the drug-containing sustained release layer raw materials of step (2) into tablets, pre-pressing the drug-containing immediate release layer raw materials into tablets.

[0062] The nilotinib in the following examples and comparative examples is all amorphous nilotinib solid dispersion (ASD, the preparation method is referred to the example 1 in the patent CN117100715B “A capsule containing amorphous nilotinib and a preparation method thereof” of the applicant), and the proportion of nilotinib in the solid dispersion is 30%. In the present application, the amorphous solid dispersion containing 30% of nilotinib is simply referred to as “30% ASD”.

[0063] The present application will be described in detail below in combination with specific examples.

[0064] Example 1~2 Single-layer sustained-release tablets Example 1 and example 2 prepared a single-layer sustained-release tablet containing amorphous nilotinib (drug-containing sustained-release layer), the prescription is shown in table 1.

[0065]

[0066] The preparation method of the single-layer sustained-release tablet containing amorphous nilotinib is as follows: 1. Ingredients Mix colloidal silicon dioxide with 30% ASD through a 40-mesh sieve, then add hydroxypropyl methylcellulose K100LV, lactose F100 (or polyoxyethylene N10, mannitol 100SD) mixture, and finally add magnesium stearate mixture.

[0067] 2. Tabletting Use 14.1 mm x 9 mm diamond punch to press into tablets with moderate hardness.

[0068] Example 3 Double-layer sustained-release tablets This example prepared a double-layer sustained-release tablet containing amorphous nilotinib (drug-containing sustained-release layer + auxiliary bleaching layer), including auxiliary bleaching layer and drug-containing sustained-release layer, the prescription is shown in table 2.

[0069]

[0070] The preparation method of the double-layer sustained-release tablet containing amorphous nilotinib is as follows: 1. Ingredients Auxiliary bleaching layer R: dissolve povidone K30 in 75% ethanol-water solution with a concentration of 10% as a binder, mix hydroxypropyl methylcellulose K4M, hydrogenated castor oil and bright blue uniformly, wet granulation, dry and granulate to obtain good flowability of the granules, and finally add magnesium stearate mixture.

[0071] Drug-containing sustained-release layer A: mix colloidal silicon dioxide with 30% ASD through a 40-mesh sieve, then add hydroxypropyl methylcellulose K100LV and lactose F100 mixture, and finally add magnesium stearate mixture.

[0072] 2. Tabletting Take the prescribed amount of drug-containing sustained-release layer A and pre-press it into a tablet, then add the glidant layer R and press them together into a double-layer sustained-release tablet using a 18 mm x 8 mm punch.

[0073] Example 4~6 Three-layer sustained-release tablets This example prepared a three-layer sustained-release tablet containing amorphous nilotinib, including a glidant layer, a drug-containing sustained-release layer, and a glidant or retardant layer. The prescription is shown in Table 3.

[0074]

[0075]

[0076] The preparation method of the three-layer sustained-release tablet of Example 4 (glidant layer R + drug-containing sustained-release layer A + glidant layer R) is as follows: 1. Ingredients Glidant layer R: Dissolve povidone K30 in a 75% ethanol-water solution at a concentration of 10% as a binder, mix bright blue and hydroxypropyl methylcellulose K4M through an 80-mesh sieve, then add glyceryl behenate and mix evenly; wet granulation, dry, and then size the granules to obtain good flowability, then add magnesium stearate and mix.

[0077] Drug-containing sustained-release layer A: Dissolve povidone K30 in a 75% ethanol-water solution at a concentration of 10% as a binder, mix lactose F100, hydroxypropyl methylcellulose K4M, and microcrystalline cellulose 102 evenly, wet granulate with the binder, dry, and then size the granules; mix colloidal silicon dioxide with 30% ASD through a 40-mesh sieve, then mix with the above granules, and finally add magnesium stearate.

[0078] 2. Tabletting Use a 14.1 mm x 9 mm diamond punch to weigh the prescribed amount of glidant layer R and pre-press it into a tablet, then add the drug-containing sustained-release layer A pre-press tablet, and then add the glidant layer R together to press into a three-layer sustained-release tablet.

[0079] The preparation method of Example 5 (glidant layer R + drug-containing sustained-release layer A + retardant layer M) is as follows: 1. Ingredients Glidant layer R: Dissolve povidone K30 in a 75% ethanol-water solution at a concentration of 10% as a binder, mix bright blue and hydroxypropyl methylcellulose K4M through an 80-mesh sieve, then add stearic acid and mix evenly; wet granulation, dry, and then size the granules to obtain good flowability, then add magnesium stearate and mix.

[0080] Drug-containing sustained-release layer A: Mix colloidal silicon dioxide with 30% ASD through a 40-mesh sieve, then mix with hydroxypropyl methylcellulose K4M, lactose F100, and finally add magnesium stearate.

[0081] Retardant layer M: Povidone K30 was dissolved in 75% ethanol-water solution with a concentration of 10% as a binder. Hydroxypropyl methyl cellulose K100LV, hydrogenated castor oil, and iron oxide were mixed uniformly. The wet granulation was dried and then sized. Magnesium stearate was added for mixing.

[0082] 2. Tablet compression An 18 mm x 8 mm punch was used to compress the pre-pressed tablets of the buoyancy aid layer R and the pre-pressed tablets of the drug-containing sustained release layer A together into three-layer sustained release tablets.

[0083] As shown in Table 3, the use of a hydrophilic polymer with a high viscosity in the drug-containing sustained release layer A can affect drug release. The three-layer sustained release tablets of this example also failed to float.

[0084] Example 6 (Buoyancy aid layer R + Drug-containing sustained release layer A + Retardant layer M) was prepared as follows: 1. Ingredient preparation Buoyancy aid layer R: Povidone K30 was dissolved in 75% ethanol-water solution with a concentration of 10% as a binder. Bright blue and hydroxypropyl methyl cellulose K4M were mixed through an 80-mesh sieve, and glycerol monostearate was added for mixing.

[0085] Drug-containing sustained release layer A: Colloidal silicon dioxide was mixed with 30% ASD through a 40-mesh sieve, and hydroxypropyl methyl cellulose K100LV, lactose F100, and magnesium stearate were added for mixing.

[0086] Retardant layer M: Povidone K30 was dissolved in 75% ethanol-water solution with a concentration of 10% as a binder. Hydroxypropyl methyl cellulose K100LV, hydrogenated castor oil, and iron oxide were mixed uniformly. The wet granulation was dried and then sized. Magnesium stearate was added for mixing.

[0087] 2. Tablet compression An 18 mm x 8 mm punch was used to compress the pre-pressed tablets of the buoyancy aid layer R and the pre-pressed tablets of the drug-containing sustained release layer A together into three-layer sustained release tablets.

[0088] Example 7 Three-layer sustained release tablets This example prepared a three-layer sustained release tablet containing amorphous nilotinib, including a buoyancy aid layer R, a drug-containing sustained release layer A, and a drug-containing immediate release layer S. The prescription is shown in Table 4.

[0089]

[0090] Example 7 (Buoyancy aid layer R + Drug-containing sustained release layer A + Drug-containing immediate release layer S) was prepared as follows: 1. Ingredient preparation Raiding layer R: Povidone K30 was dissolved in 75% ethanol-water solution to a concentration of 10% as a binder. Bright blue and hydroxypropyl methyl cellulose K4M were mixed through an 80 mesh sieve, and glyceryl monostearate was added and mixed evenly. Wet granulation was performed, and the granules were dried and sized, to obtain granules with good flowability, and magnesium stearate was added and mixed.

[0091] Drug-containing sustained-release layer A: colloidal silicon dioxide was mixed with 30% ASD through a 40 mesh sieve, Kollidon® SR, sorbitol were added and mixed evenly, and finally magnesium stearate was added and mixed.

[0092] Drug-containing immediate-release layer S: colloidal silicon dioxide was mixed with 30% ASD through a 40 mesh sieve, microcrystalline cellulose 102, sorbitol, and cross-linked povidone were added and mixed evenly, and finally magnesium stearate was added and mixed.

[0093] 2. Tabletting An 18 mm x 8 mm punch was used to weigh the prescribed amount of raiding layer R and pre-press into tablets, then the drug-containing sustained-release layer A was pre-pressed into tablets, and then the drug-containing immediate-release layer S was added and pressed into a three-layer sustained-release tablet.

[0094] Test Example 1: Stability Investigation The multi-layer sustained-release tablets of Example 3 and Example 6 were placed in accelerated conditions (40°C, 75% RH) for one month, and the X-ray powder diffraction patterns are shown in Figure 2 .The results show that the crystal form of the drug in Example 3 and Example 6 did not change. Figure 2

[0095] On day 0 and after one month of acceleration, the maximum unknown single impurity and total impurities were detected, and the results are shown in Table 5.

[0096]

[0097] Table 5 shows that there was no significant increase in impurities, proving that the multi-layer sustained-release tablets of Example 3 and Example 6 of the present application have good stability.

[0098] Test Example 2: Dissolution of Sustained-Release Tablets under pH 1.0 Conditions The sustained-release tablets of Example 1, Example 2, Example 3, Example 4, Example 6, and Example 7 were placed in 0.1N hydrochloric acid medium, and the dissolution of nilotinib in each was detected every hour, and the 24 h dissolution curves were plotted, and the results are shown in Figures 3-8 .

[0099] From Figure 3 and Figure 4It can be seen that the single-layer sustained-release tablets of Example 1 can maintain stable release within 16 hours to reach a platform; the single-layer sustained-release tablets of Example 2 can have a longer duration within 24 hours and release more smoothly to reach a platform, close to zero-order release.

[0100] From Figure 5 It can be seen that the double-layer sustained-release tablets of Example 3 can maintain smooth drug release within 24 hours, and the 24-hour drug release reaches a platform, tending to zero-order release.

[0101] From Figure 6 It can be seen that when the two-layer sustained-release tablets (Example 4) are prepared by sandwiching the drug-containing sustained-release layer with two layers of bleaching aid, the drug-containing sustained-release layer will be greatly reduced in dissolution due to the slow swelling and dissolution rate of the two layers of bleaching aid, and only 34% of the drug is released within 24 hours.

[0102] From Figure 7 It can be seen that the three-layer sustained-release tablets (bleaching aid R + drug-containing sustained-release layer A + retardant layer M) prepared in Example 6 have a smooth and continuous drug release within 24 hours, close to zero-order release, and achieve the requirements of long-acting and controlled release of drugs.

[0103] From Figure 8 It can be seen that the three-layer sustained-release tablets (bleaching aid R + drug-containing sustained-release layer A + drug-containing immediate-release layer S) prepared in Example 7 have a more smooth and continuous drug dissolution within 24 hours, close to zero-order release.

[0104] The immediate-release capsules of nilotinib (original research Novartis, trade name Tasigna / Tasigna) were placed in 0.1N hydrochloric acid medium, and the dissolution of nilotinib therein was detected every 5 min, and the 60 min dissolution curve was drawn, as shown in Figure 9 From Figure 9 It can be seen that the cumulative dissolution of the immediate-release capsules of nilotinib reaches 93.8% at 30 min, and almost all of them are dissolved at 60 min.

[0105] Test Example 3 Change in crystal form under floating condition in simulated gastric juice for 24 h The double-layer sustained-release tablets of Example 3 were placed in simulated gastric juice (pH 1.2), and the change in crystal form of nilotinib in the drug-containing sustained-release layer was detected at 0 h, 3 h, 10 h, and 20 h, and the X-ray powder diffraction pattern is shown in Figure 10 From Figure 10 It can be seen that the nilotinib in the double-layer sustained-release tablets maintains an amorphous crystal form within 20 hours.

[0106] Any combination of the technical features in the above-described embodiments can be made, and for the sake of brevity, not all possible combinations are described, however, as long as the combination of the technical features does not exist in contradiction, it shall be considered within the scope of the present disclosure.

[0107] The above-described embodiments only express several implementation manners of the present application, and the description is relatively specific and detailed, but it shall not be understood as a limitation on the patent scope of the present application. It shall be pointed out that, for ordinary skilled persons in the art, several modifications and improvements can be made without departing from the concept of the present application, and these shall be within the protection scope of the present application. Therefore, the protection scope of the present application patent shall be subject to the appended claims.

Claims

1. A sustained release tablet of nilotinib, characterized in that, It comprises a bleaching-aid layer and a drug-containing sustained-release layer, wherein, the bleaching-aid layer is prepared from raw materials comprising the following mass percentages: 50%-85% hydrophilic polymer, 10%-20% hydrophobic bleaching aid, 3%-10% adhesive, and 1%-4% lubricant; the viscosity of the hydrophilic polymer is 2000 mpa·s-6000 mpa·s; the drug-containing sustained-release layer is prepared from raw materials comprising the following mass percentages: 30%-80% amorphous solid dispersion of nilotinib or a salt thereof, 5%-40% hydrophilic polymer, 5%-20% water-soluble filler, 0.5%-5% glidant, and 1%-4% lubricant; the viscosity of the hydrophilic polymer is 40 mpa·s-2000 mpa·s.

2. The sustained release tablet of nilotinib according to claim 1, characterized in that, the hydrophilic polymer in the bleaching-aid layer or the drug-containing sustained-release layer is hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyoxyethylene, Kollidon® SR, sodium alginate, and / or carbomer; preferably, the hydrophilic polymer in the bleaching-aid layer is hypromellose K4M, and the hydrophilic polymer in the drug-containing sustained-release layer is hypromellose K100LV.

3. The sustained release tablet of nilotinib according to claim 1, characterized in that, the hydrophobic bleaching aid is one or more of glyceryl behenate, hydrogenated castor oil, cetyl alcohol, stearyl alcohol, beeswax, and glycerol monostearate; and / or, the adhesive is povidone K30; and / or, the lubricant is magnesium stearate; and / or, the water-soluble filler is lactose, mannitol, sorbitol, xylitol, and / or sucrose; and / or, the glidant is colloidal silicon dioxide; and / or, the bleaching-aid layer further comprises a coloring agent, preferably, the coloring agent is brilliant blue or iron oxide.

4. The sustained release tablet of nilotinib according to claim 1, characterized in that, the bleaching-aid layer is prepared from raw materials comprising the following mass percentages: 75%-85% hypromellose K4M, 13%-15% glyceryl behenate or hydrogenated castor oil, 4%-6% povidone K30, 1%-3% magnesium stearate, and a trace amount of brilliant blue; and / or, the drug-containing sustained-release layer is prepared from raw materials comprising the following mass percentages: 40%-60% amorphous solid dispersion of nilotinib or a salt thereof, 15%-25% hypromellose K100LV, 15%-20% lactose or sorbitol, 2%-4% colloidal silicon dioxide, and 1%-3% magnesium stearate.

5. The sustained release tablet of nilotinib according to any one of claims 1 to 5, characterized in that, the amorphous solid dispersion of nilotinib or a salt thereof is made of amorphous nilotinib or a salt thereof and a high-molecular polymer, and the high-molecular polymer is hydroxypropyl methyl cellulose acetate succinate and / or hydroxypropyl methyl cellulose phthalate; preferably, the mass ratio of the amorphous nilotinib or a salt thereof to the high-molecular polymer is 1:1-1:15; more preferably, the mass ratio of the amorphous nilotinib or a salt thereof to the high-molecular polymer is 1:2-1:

10.

6. The sustained release tablet of nilotinib according to any one of claims 1 to 5, characterized in that, the nilotinib sustained-release tablet further comprises a retardant layer or a drug-containing immediate-release layer; The retardant layer is prepared from raw materials including 50-80% hydrophilic polymer, 10-30% hydrophobic skeleton material, 3-10% binder and 1-4% lubricant; the viscosity of the hydrophilic polymer is 40-2000 mpa·s; The drug-containing fast-release layer is prepared from raw materials including 30-80% amorphous solid dispersion of nilotinib or its salt, 5-40% filler, 5-20% disintegrant and 1-4% lubricant.

7. The sustained release nilotinib tablet according to claim 7, wherein The hydrophilic polymer is hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyoxyethylene, Kollidon SR, sodium alginate and / or carbomer, preferably hypromellose K100LV; The hydrophobic skeleton material is one or more of glyceryl behenate, hydrogenated castor oil, cetyl alcohol, stearyl alcohol, beeswax and glyceryl monostearate; The binder is povidone K30; The lubricant is magnesium stearate; The filler is microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol or sucrose, and the disintegrant is cross-linked povidone; The retardant layer further includes a coloring agent, preferably bright blue or iron oxide.

8. A process for the preparation of sustained release tablets of nilotinib according to any one of claims 1 to 6, characterized in that, The method comprises the following steps: (1) granulate the hydrophilic polymer and the hydrophobic skeleton material with the binder, mix the granules and add the lubricant to obtain the retardant layer raw materials; (2) mix the amorphous solid dispersion of nilotinib or its salt and the glidant, sieve and mix the hydrophilic polymer, water-soluble filler and lubricant to obtain the drug-containing slow-release layer raw materials; (3) pre-press the retardant layer raw materials of step (1) into tablets, and then add the drug-containing slow-release layer raw materials of step (2) to pre-press into tablets.

9. The method of claim 9, wherein the release of the nilotinib is sustained for at least 24 hours. After step (2), the method further comprises the step of granulating the hydrophilic polymer and the hydrophobic skeleton material with the binder, mixing the granules and adding the lubricant to obtain the retardant layer raw materials; in step (3), after the drug-containing slow-release layer raw materials of step (2) are pre-pressed into tablets, the method further comprises the step of adding the retardant layer raw materials to pre-press into tablets. After step (2), the method further comprises the step of mixing the amorphous solid dispersion of nilotinib or its salt and the glidant, sieving and mixing the filler, disintegrant and lubricant to obtain the drug-containing fast-release layer raw materials; in step (3), after the drug-containing slow-release layer raw materials of step (2) are pre-pressed into tablets, the method further comprises the step of adding the drug-containing fast-release layer raw materials to pre-press into tablets.

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