Crizotinib capsule and preparation method thereof

Abstract

The invention discloses a crizotinib capsule and a preparation method thereof, the crizotinib capsule contains sustained-release particles, quick-release particles and optional particle additional auxiliary materials, the crizotinib in each particle is 50 parts by weight, the weight ratio of the sustained-release particles to the quick-release particles is (3: 7)-(7: 3), and the sustained-release particles contain hydrophilic gel type framework materials and organic acid. According to the crizotinib capsule disclosed by the invention, through sustained release and under the action of organic acid, higher bioavailability is obtained.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a crizotinib capsule and a preparation method thereof. Background Art

[0002] Crizotinib is a tyrosine kinase receptor inhibitor developed by Pfizer. It was approved by the US FDA in August 2011. It is in the form of capsules and its trade name is It was launched in Europe in October 2012 and was approved by CFDA for marketing in China in 2013. Its trade name is Xalcorin, and its specifications are 200mg and 250mg. Crizotinib is a highly selective tyrosine kinase receptor inhibitor that can block the activity of tyrosine kinase, inhibit the growth and proliferation of tumor cells by inhibiting cell signal transduction, and promote tumor cell apoptosis to achieve the purpose of anti-cancer. It is clinically used for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are positive for anaplastic lymphoma kinase (ALK), and also for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who are positive for ROS1.

[0003] Crizotinib is a BCS Class IV drug with pH-dependent solubility. When pH value increases from 1 to 8.4, the solubility decreases by more than 10 times. This product has low bioavailability. According to the import instructions of the original imported crizotinib capsule Xalkori, the average absolute bioavailability of crizotinib is 43%, ranging from 32% to 66%. This product has a large specification, with marketed specifications of 200 mg and 250 mg, which may be related to the solubility characteristics of the raw material and low bioavailability. The recommended clinical dose of this product is 250 mg orally, twice a day. On the other hand, the adverse reactions of this product will affect the use of this product, and the dose needs to be adjusted to 200 mg twice a day, or 250 mg once a day. If it cannot be tolerated, the drug should be permanently discontinued.

[0004] In order to solve the problem of low bioavailability of large-sized poorly soluble drugs, formulation methods are usually used to improve dissolution and thus improve their bioavailability. This is an important task for pharmaceutical formulation researchers and is also challenging. Formulation researchers have done a lot of research work for this purpose.

[0005] Chinese patent application 201410017288.3 discloses a crizotinib dispersible tablet, which adopts a wet granulation process, contains an acidifier, and uses the acidifier to wrap the main drug, which has the characteristics of fast disintegration speed. Although this dispersion technology claims to improve bioavailability, no corresponding experimental results are given, and its technical effect has not been verified.

[0006] Chinese patent application 201410154688.9 discloses a crizotinib capsule, which is granulated by a fluidized bed, mixed and filled. This technical solution requires the use of an 80% ethanol solution during granulation, which poses a safety hazard during commercial production.

[0007] Chinese patent application 201710275327.3 discloses a pharmaceutical composition containing crizotinib, in which the weight percentage of excipients in the pharmaceutical composition is 30%-35%, and the particle size distribution requirements of crizotinib are clarified. This technical solution adopts a dry granulation process with a low amount of excipients, which can improve patient compliance and reduce preparation costs, but does not improve dissolution.

[0008] Chinese patent application 202210956158.0 discloses a crizotinib liposome solid preparation, wherein the liposome is composed of crizotinib, phospholipids, and cholesterol, and then prepared into a capsule form. This scheme uses liposome technology, which has a certain effect on improving bioavailability, but the disadvantage is that the liposome preparation samples are mostly limited to laboratory research and are difficult to scale up and commercialize.

[0009] Chinese patent application CN202211669332.X discloses a method for preparing crizotinib capsules. The technical solution contains pregelatinized starch, sodium carboxymethyl starch, micro-powdered silica gel, and magnesium stearate in the prescription. The process is direct powder mixing, in which the pregelatinized starch needs to be micronized and the particle size needs to be controlled. Although the capsule improves dissolution, it does not improve bioavailability. In addition, the direct mixing filling process has poor material fluidity and commercial production is difficult.

[0010] Chinese patent application 202310749155.4 discloses a crizotinib composition in the form of a solid dispersion, which is prepared by a solvent method, in which the sample is prepared by dissolving the main drug and a cellulose derivative in an organic solvent such as dichloromethane. The sample prepared by this technical solution has a higher instantaneous solubility and dissolution rate, which is also a typical characteristic of solid dispersion technology. However, on the other hand, the use of a solvent method to prepare a solid dispersion will bring about environmental and occupational health problems due to the need to use organic solvents, and commercial production is also difficult.

[0011] In summary, with regard to the key technical difficulty of improving the bioavailability of crizotinib capsules, existing technical solutions mostly adopt rapid-release formulation design, and some also use special formulation methods such as liposomes and solid dispersions. Such technical solutions have problems such as complex production process, high production cost, poor process fluidity, and the need for organic solvents, which are not conducive to commercial production and environmental protection.

[0012] In order to solve the above problems, the inventors designed the crizotinib capsule to contain both sustained-release granules and immediate-release granules, and at the same time, according to the characteristics of the main drug, the prescription was improved through a large number of experiments, thereby obtaining a crizotinib capsule with high solubility and high bioavailability. The capsule is prepared by a conventional dry granulation process, which is convenient for commercial production and improves bioavailability, thereby completing the present invention. Summary of the invention

[0013] The object of the present invention is to provide a crizotinib capsule and a preparation method thereof. The crizotinib capsule of the present invention has higher bioavailability.

[0014] To solve the purpose of the present invention, the following technical solution is provided.

[0015] In one embodiment, a crizotinib capsule of the present invention comprises immediate-release granules and sustained-release granules, and optional granular additional excipients, wherein the weight ratio of the sustained-release granules to the immediate-release granules is 3:7 to 7:3, and preferably the weight ratio is 4:6 to 7:3.

[0016] In one embodiment, in a crizotinib capsule of the present invention, the granular excipients are selected from one or two of magnesium stearate and colloidal silicon dioxide.

[0017] In one embodiment, the weight portion of crizotinib in each part of the sustained-release granules and the immediate-release granules is 50 parts. Preferably, in a crizotinib capsule of the present invention, the sustained-release granules comprise 50 parts of crizotinib, 15 to 35 parts of a hydrophilic gel-type skeleton material, 12 to 32 parts of an organic acid, 0 to 7 parts of a filler, and 1 to 1.5 parts of a lubricant, all in parts by weight.

[0018] Preferably, in a crizotinib capsule of the present invention, the rapid-release granules contain: 50 parts of crizotinib, 40 parts to 44 parts of filler, 3 parts to 6 parts of disintegrant, and 1 part to 1.5 parts of lubricant, all measured in parts by weight.

[0019] Preferably, in the crizotinib capsules of the present invention, the hydrophilic gel-type skeleton material is selected from one or two of hydroxypropyl methylcellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium alginate, and xanthan gum, more preferably hydroxypropyl methylcellulose.

[0020] Preferably, in the crizotinib capsules of the present invention, the organic acid is selected from one or two of fumaric acid, adipic acid, citric acid and succinic acid, more preferably fumaric acid.

[0021] Preferably, in the crizotinib capsules of the present invention, the filler is selected from one or two of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, calcium sulfate and calcium carbonate.

[0022] Specifically, in the crizotinib capsules of the present invention, the filler in the sustained-release granules is preferably microcrystalline cellulose; the filler in the immediate-release granules is selected from one or two of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, calcium sulfate and calcium carbonate.

[0023] Preferably, in the crizotinib capsules of the present invention, the lubricant is magnesium stearate.

[0024] Preferably, in the crizotinib capsules of the present invention, the disintegrant is selected from one or more of sodium starch glycolate, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethylcellulose.

[0025] In some embodiments, in the crizotinib capsules of the present invention, the particle size of crizotinib d(0.9) is ≤230 μm.

[0026] In another embodiment, the present invention also provides a method for preparing crizotinib capsules, the method comprising:

[0027] (1) Preparation of sustained-release granules

[0028] The prescribed amount of crizotinib, a hydrophilic gel-type matrix material, an organic acid and other optional pharmaceutically acceptable adjuvants are mixed and then dry granulated to prepare granules;

[0029] (2) Preparation of immediate-release granules

[0030] Mixing the prescribed amount of crizotinib, a filler, a disintegrant and any other pharmaceutically acceptable adjuvants and preparing granules by dry granulation;

[0031] (3) Total mixing of particles

[0032] The sustained-release granules obtained in step (1), the immediate-release granules obtained in step (2), and the additional excipients are mixed uniformly in a mixer;

[0033] (4) Filling capsules: putting the mixed granules prepared in step (3) into capsules.

[0034] Wherein, the added auxiliary materials are selected from one or two of magnesium stearate and colloidal silicon dioxide.

[0035] The research and development concept of the present invention is mainly that: crizotinib is a BCSIV class, and its solubility is obviously pH-dependent, with high solubility at low pH and low solubility at high pH. It was found during the in vitro dissolution study that during the pH increase, the main drug crizotinib will precipitate from the medium, and the in vitro and in vivo dissolution processes show a correlation. After oral administration of the capsule, the main drug first dissolves in the stomach, and as the pH of the subsequent parts of the gastrointestinal tract increases, crizotinib is precipitated again (solid), thereby affecting the absorption of the main drug, thereby reducing the bioavailability. In addition, the inventors found in the bioequivalence study of crizotinib capsules that as Cmax increases, the situation of AUC reduction occurs, which may be due to the increase in Cmax, causing more crizotinib to precipitate, resulting in reduced bioavailability. According to the above-mentioned properties of the main drug crizotinib, and the experimental results, the inventors were surprised to find that in the capsule research process, some crizotinib rapid-release granules were replaced with sustained-release granules to form a mixture of rapid-release granules and sustained-release granules. At the same time, organic acids were added to the sustained-release granules, which can make the main drug no longer precipitate or precipitate less at higher pH parts of the gastrointestinal tract. This design allows the drug to dissolve in stages, reducing the risk of main drug precipitation, thereby increasing bioavailability. After a large number of experimental studies, the complete formula of the sustained-release granules and the mass ratio of the sustained-release granules to the immediate-release granules were determined, achieving the purpose of the present invention.

[0036] Beneficial effects of the present invention: In vitro dissolution comparison studies show that the sustained-release granules of the present invention have a sustained-release effect, suggesting that the capsules of the present invention also have a sustained-release effect in vivo, which can reduce the risk of main drug precipitation. Simulated gastrointestinal main drug precipitation tests show that the capsules of the present invention can dissolve in higher pH intestinal areas, thereby reducing the risk of main drug precipitation in vivo. Furthermore, blood drug concentration determination shows that the capsules of the present invention have higher bioavailability.

[0037] Crizotinib is a BCSIV class drug with low solubility and low permeability, and has a half-life of about 42 hours. It has an accumulation property. It is well known in the art that drugs with these properties are not suitable for preparation into sustained-release preparations. Surprisingly, the present invention applies sustained-release particles to crizotinib capsules, which helps to improve its bioavailability. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The dissolution curves of the capsules of Comparative Example 1, Comparative Example 2 and Examples 1-5 in a pH 1.0 medium;

[0039] Figure 2 The dissolution curves of the capsules of Comparative Example 1, Comparative Example 2 and Examples 1-5 in a pH 4.5 medium;

[0040] Figure 3 The dissolution curves of the capsules of Comparative Example 1, Comparative Example 2 and Examples 1-5 in a pH 6.8 medium;

[0041] Figure 4 The dissolution curves of the capsules of Comparative Example 1, Comparative Example 2 and Examples 1-5 in a pH 6.8 medium (containing 1.5% Tween 80);

[0042] Figure 5 This is a graph showing the average blood drug concentration of the capsules of Comparative Example 1 and Example 1. DETAILED DESCRIPTION

[0043] The following examples are representative and are only used to illustrate and understand the spirit of the present invention, but are not intended to limit the scope of the present invention in any way.

[0044] The crizotinib capsules of the following examples contain a sustained-release granule part, a rapid-release granule part, and a granule-added excipient part, wherein the sustained-release granules contain a hydrophilic gel-type skeleton material, an organic acid, and a raw material. The particle size of crizotinib satisfies d(0.9)≤230 μm.

[0045] Example 1 Crizotinib Capsules

[0046] The prescription is shown in Table 1. The total designed weight of the capsule content is 500 mg, the ratio of slow-release granules to quick-release granules is 1:1, and the weight ratio of granules to external excipients is 98:2. Among them, the composition of slow-release granules and quick-release granules is calculated by weight.

[0047] Table 1. Crizotinib capsule prescription of Example 1

[0048]

[0049] Capsule preparation process:

[0050] The following steps are involved:

[0051] 1. Preparation of sustained-release particles

[0052] A) Material weighing

[0053] Weigh all raw and auxiliary materials according to the prescription and set aside.

[0054] B) Mixed

[0055] Add the weighed raw and auxiliary materials into the three-dimensional mixer, rotate at 10 rpm, and mix for 10 minutes.

[0056] C) Granulation

[0057] The mixed material is granulated by dry granulation process, and the process conditions are: pressing speed 8rpm~25rpm, pressure 15bar~50bar, material gap 1.0mm~2.5mm, granulation speed 100rpm~200rpm, screen aperture 1.2mm.

[0058] 2. Preparation of Immediate Release Granules

[0059] A) Material weighing

[0060] Weigh all raw and auxiliary materials according to the prescription and set aside.

[0061] B) Mixed

[0062] Add the weighed raw and auxiliary materials into the three-dimensional mixer, rotate at 10 rpm, and mix for 10 minutes.

[0063] C) Granulation

[0064] The mixed material is granulated by dry granulation process, and the process conditions are: pressing speed 8rpm~25rpm, pressure 15bar~50bar, material gap 1.0mm~2.5mm, granulation speed 100rpm~200rpm, screen aperture 1.2mm.

[0065] 3. Particle mixing

[0066] The sustained-release granules, immediate-release granules, additional magnesium stearate and colloidal silicon dioxide were added into a three-dimensional mixer according to the prescription ratio, the speed was 10 rpm, and the mixing was carried out for 10 minutes.

[0067] 4. Filling capsules

[0068] The granules after total mixing are used to fill capsules with a 0# capsule filling machine. The theoretical content weight is 500 mg, and the crizotinib content in each capsule is 250 mg.

[0069] Alternatively, when filling capsules, 1# capsules can be used, the weight of the filling content can also be 400 mg, and the crizotinib content in each capsule is 200 mg.

[0070] Example 2 Crizotinib Capsules

[0071] The prescription is shown in Table 2. The total designed weight of the capsule contents is 500 mg, the ratio of slow-release granules to quick-release granules is 3:7, and the weight ratio of granules to external additives is 98:2. Among them, the components of slow-release granules and quick-release granules are calculated by weight respectively.

[0072] Table 2. Crizotinib capsule prescription of Example 2

[0073]

[0074]

[0075] Capsule preparation process:

[0076] The following steps are involved:

[0077] 1. Preparation of sustained-release particles

[0078] A) Material weighing

[0079] Weigh all raw and auxiliary materials according to the prescription and set aside.

[0080] B) Mixed

[0081] Add the weighed raw and auxiliary materials into the three-dimensional mixer, rotate at 10 rpm, and mix for 10 minutes.

[0082] C) Granulation

[0083] The mixed material is granulated by dry granulation process, and the process conditions are: pressing speed 8rpm~25rpm, pressure 15bar~50bar, material gap 1.0mm~2.5mm, granulation speed 100rpm~200rpm, screen aperture 1.2mm.

[0084] 2. Preparation of Immediate Release Granules

[0085] A) Material weighing

[0086] Weigh all raw and auxiliary materials according to the prescription and set aside.

[0087] B) Mixed

[0088] Add the weighed raw and auxiliary materials into the three-dimensional mixer, rotate at 10 rpm, and mix for 10 minutes.

[0089] C) Granulation

[0090] The mixed material is granulated by dry granulation process, and the process conditions are: pressing speed 8rpm~25rpm, pressure 15bar~50bar, material gap 1.0mm~2.5mm, granulation speed 100rpm~200rpm, screen aperture 1.2mm.

[0091] 3. Particle mixing

[0092] The sustained-release granules, immediate-release granules and additional magnesium stearate were added into a three-dimensional mixer according to the prescription ratio, the speed was 10 rpm, and the mixing was carried out for 10 minutes.

[0093] 4. Filling capsules

[0094] The granules after total mixing are used to fill capsules using a 0# capsule filling machine, and the theoretical content weight is 500 mg.

[0095] Example 3 Crizotinib Capsules

[0096] The prescription is shown in Table 3. The total designed weight of the capsule contents is 500 mg, the ratio of slow-release granules to quick-release granules is 7:3, and the weight ratio of granules to external excipients is 98:2. Among them, the components of slow-release granules and quick-release granules are calculated by weight respectively.

[0097] Table 3. Crizotinib capsule prescription of Example 3

[0098]

[0099] Preparation process:

[0100] Capsule preparation includes the following steps:

[0101] 1. Preparation of sustained-release particles

[0102] A) Material weighing

[0103] Weigh all raw and auxiliary materials according to the prescription and set aside.

[0104] B) Mixed

[0105] Add the weighed raw and auxiliary materials into the three-dimensional mixer, rotate at 10 rpm, and mix for 10 minutes.

[0106] C) Granulation

[0107] The mixed material is granulated by dry granulation process, and the process conditions are: pressing speed 8rpm~25rpm, pressure 15bar~50bar, material gap 1.0mm~2.5mm, granulation speed 100rpm~200rpm, screen aperture 1.2mm.

[0108] 2. Preparation of Immediate Release Granules

[0109] A) Material weighing

[0110] Weigh all raw and auxiliary materials according to the prescription and set aside.

[0111] B) Mixed

[0112] Add the weighed raw and auxiliary materials into the three-dimensional mixer, rotate at 10 rpm, and mix for 10 minutes.

[0113] C) Granulation

[0114] The mixed material is granulated by dry granulation process, and the process conditions are: pressing speed 8rpm~25rpm, pressure 15bar~50bar, material gap 1.0mm~2.5mm, granulation speed 100rpm~200rpm, screen aperture 1.2mm.

[0115] 3. Particle mixing

[0116] The sustained-release granules, immediate-release granules and additional magnesium stearate were added into a three-dimensional mixer according to the prescription ratio, the speed was 10 rpm, and the mixing was carried out for 10 minutes.

[0117] 4. Filling capsules

[0118] The granules after total mixing are used to fill capsules using a 0# capsule filling machine, and the theoretical content weight is 500 mg.

[0119] Example 4 Crizotinib Capsules

[0120] The prescription is shown in Table 4. The total designed weight of the capsule content is 500 mg, the ratio of slow-release granules to quick-release granules is 4:6, and the weight ratio of granules to added excipients is 98:2. Among them, the composition of slow-release granules and quick-release granules is calculated by weight.

[0121] Table 4. Crizotinib capsule prescription of Example 4

[0122]

[0123]

[0124] Preparation process:

[0125] Capsule preparation includes the following steps:

[0126] 1. Preparation of sustained-release particles

[0127] A) Material weighing

[0128] Weigh all raw and auxiliary materials according to the prescription and set aside.

[0129] B) Mixed

[0130] Add the weighed raw and auxiliary materials into the three-dimensional mixer, rotate at 10 rpm, and mix for 10 minutes.

[0131] C) Granulation

[0132] The mixed material is granulated by dry granulation process, and the process conditions are: pressing speed 8rpm~25rpm, pressure 15bar~50bar, material gap 1.0mm~2.5mm, granulation speed 100rpm~200rpm, screen aperture 1.2mm.

[0133] 2. Preparation of Immediate Release Granules

[0134] A) Material weighing

[0135] Weigh all raw and auxiliary materials according to the prescription and set aside.

[0136] B) Mixed

[0137] Add the weighed raw and auxiliary materials into the three-dimensional mixer, rotate at 10 rpm, and mix for 10 minutes.

[0138] C) Granulation

[0139] The mixed material is granulated by dry granulation process, and the process conditions are: pressing speed 8rpm~25rpm, pressure 15bar~50bar, material gap 1.0mm~2.5mm, granulation speed 100rpm~200rpm, screen aperture 1.2mm.

[0140] 3. Particle mixing

[0141] The sustained-release granules, immediate-release granules, additional magnesium stearate and colloidal silicon dioxide were added into a three-dimensional mixer according to the prescription ratio, the speed was 10 rpm, and the mixing was carried out for 10 minutes.

[0142] 4. Filling capsules

[0143] The granules after total mixing are used to fill capsules using a 0# capsule filling machine, and the theoretical content weight is 500 mg.

[0144] Example 5 Crizotinib Capsules

[0145] The prescription is shown in Table 5. The total designed weight of the capsule content is 500 mg, the ratio of slow-release granules to quick-release granules is 6:4, and the weight ratio of granules to external excipients is 98:2. Among them, the composition of slow-release granules and quick-release granules is calculated by weight.

[0146] Table 5. Crizotinib capsule prescription of Example 5

[0147]

[0148] Preparation process:

[0149] Capsule preparation includes the following steps:

[0150] 1. Preparation of sustained-release particles

[0151] A) Material weighing

[0152] Weigh all raw and auxiliary materials according to the prescription and set aside.

[0153] B) Mixed

[0154] Add the weighed raw and auxiliary materials into the three-dimensional mixer, rotate at 10 rpm, and mix for 10 minutes.

[0155] C) Granulation

[0156] The mixed material is granulated by dry granulation process, and the process conditions are: pressing speed 8rpm~25rpm, pressure 15bar~50bar, material gap 1.0mm~2.5mm, granulation speed 100rpm~200rpm, screen aperture 1.2mm.

[0157] 2. Preparation of Immediate Release Granules

[0158] A) Material weighing

[0159] Weigh all raw and auxiliary materials according to the prescription and set aside.

[0160] B) Mixed

[0161] Add the weighed raw and auxiliary materials into the three-dimensional mixer, rotate at 10 rpm, and mix for 10 minutes.

[0162] C) Granulation

[0163] The mixed material is granulated by dry granulation process, and the process conditions are: pressing speed 8rpm~25rpm, pressure 15bar~50bar, material gap 1.0mm~2.5mm, granulation speed 100rpm~200rpm, screen aperture 1.2mm.

[0164] 3. Particle mixing

[0165] The sustained-release granules, immediate-release granules, additional magnesium stearate and colloidal silicon dioxide were added into a three-dimensional mixer according to the prescription ratio, the speed was 10 rpm, and the mixing was carried out for 10 minutes.

[0166] 4. Filling capsules

[0167] The mixed granules were used to fill capsules with a 0# capsule filling machine, and the theoretical content weight was 500 mg. Comparative Example 1 Crizotinib immediate-release capsules were prepared with reference to Example 1, containing only immediate-release granules and no sustained-release granules, and the designed total content weight was 500 mg.

[0168] Table 6. Crizotinib capsule prescription of comparative example 1

[0169]

[0170] Capsule preparation process:

[0171] The following steps are included:

[0172] 1. Particle Preparation

[0173] A) Material weighing

[0174] Weigh all raw and auxiliary materials according to the prescription and set aside.

[0175] B) Mixed

[0176] Add the weighed raw and auxiliary materials into the three-dimensional mixer, rotate at 10 rpm, and mix for 10 minutes.

[0177] C) Granulation

[0178] The mixed material is granulated by dry granulation process, and the process conditions are: pressing speed 8rpm~25rpm, pressure 15bar~50bar, material gap 1.0mm~2.5mm, granulation speed 100rpm~200rpm, screen aperture 1.2mm.

[0179] 2. Particle mixing

[0180] The prepared particles, as well as the external additives magnesium stearate and colloidal silicon dioxide were added into a three-dimensional mixer according to the prescribed ratio, with a rotation speed of 10 rpm and mixing for 10 minutes.

[0181] 3. Filling capsules

[0182] The granules after total mixing are used to fill capsules using a 0# capsule filling machine, and the theoretical content weight is 500 mg.

[0183] Comparative Example 2 Crizotinib capsules were prepared with reference to Example 1, the ratio of slow-release granules to quick-release granules was 1:1, the slow-release granules did not contain organic acid, and the ratio of granules to external additives was 98:2. The composition of the slow-release granules and quick-release granules were each measured in parts by weight.

[0184] Table 7. Crizotinib Capsule Prescription of Comparative Example 2

[0185]

[0186]

[0187] Capsule preparation process:

[0188] The following steps are included:

[0189] 1. Particle Preparation

[0190] A) Material weighing

[0191] Weigh all raw and auxiliary materials according to the prescription and set aside.

[0192] B) Mixed

[0193] Add the weighed raw and auxiliary materials into the three-dimensional mixer, rotate at 10 rpm, and mix for 10 minutes.

[0194] C) Granulation

[0195] The mixed material is granulated by dry granulation process, and the process conditions are: pressing speed 8rpm~25rpm, pressure 15bar~50bar, material gap 1.0mm~2.5mm, granulation speed 100rpm~200rpm, screen aperture 1.2mm.

[0196] 2. Particle mixing

[0197] The prepared particles, as well as the external additives magnesium stearate and colloidal silicon dioxide were added into a three-dimensional mixer according to the prescribed ratio, with a rotation speed of 10 rpm and mixing for 10 minutes.

[0198] 3. Filling capsules

[0199] The granules after total mixing are used to fill capsules using a 0# capsule filling machine, and the theoretical content weight is 500 mg.

[0200] Effect experiment example

[0201] The efficacy experiment was conducted using 500mg crizotinib capsules of the same specification.

[0202] Experiment 1: Simulated gastrointestinal tract main drug precipitation test

[0203] Comparative Example 1: Take one capsule sample, take its contents, dissolve it in 200 g of pH 1.0 hydrochloric acid solution, stir to completely dissolve the main drug, filter and discard the insoluble matter. Stir the filtrate, and slowly add a pH 10 solution (prepared with sodium hydroxide, potassium chloride and boric acid according to the United States Pharmacopoeia) until precipitation occurs, and record the amount of pH 10 solution consumed. Add the corresponding amount of pH 10 solution to 200 g of pH 1.0 hydrochloric acid solution, stir and mix, and the pH is 5.24.

[0204] One capsule sample of Example 1 was taken to perform a simulated gastrointestinal main drug precipitation test, with the same operation as before, and the final measured pH was 6.71.

[0205] From the above results, it can be seen that the sample of the present invention, with the addition of organic acid, has a higher pH when the main drug is precipitated. Since the solubility of the product is high at low pH and low at high pH, ​​in the environment where the human gastrointestinal tract gradually increases, the sample of the present invention can dissolve in the intestinal part with higher pH, and the main drug does not precipitate in the body or precipitates less, thereby increasing the bioavailability in the body.

[0206] Experiment 2: Dissolution curve determination

[0207] The dissolution curves of the immediate-release crizotinib capsule samples of the comparative example and the crizotinib capsule samples containing sustained-release particles prepared in Examples 1 to 5 were measured.

[0208] According to the conventional dissolution curve research method, the dissolution of samples in three pH dissolution media, pH 1.0, pH 4.5, and pH 6.8, was measured. The solubility of this product in the pH 6.8 medium is low, and the sink condition is not reached, and the drug cannot be completely dissolved. Therefore, 1.5% Tween 80 was added to pH 6.8 at the same time, and a total of 4 media were compared. The corresponding measurement conditions are shown in Table 8 below, and the experimental results are shown in Tables 9-12 and Figure 1-4 shown.

[0209] Table 8. Dissolution test parameters of crizotinib capsule samples

[0210]

[0211] Table 9. Dissolution test results of crizotinib capsule samples in pH 1.0 medium

[0212]

[0213]

[0214] The results in Table 9 show that the capsule samples of Examples 1-5 exhibited slow drug release characteristics compared with Comparative Example 1.

[0215] Table 10. Dissolution test results of crizotinib capsule samples in pH 4.5 medium (%)

[0216]

[0217] The results in Table 10 show that the capsule samples of Examples 1-5 exhibited slow drug release characteristics compared with Comparative Example 1.

[0218] Table 11. Dissolution test results of crizotinib capsule samples in pH 6.8 medium (%)

[0219]

[0220] The results in Table 11 show that in a pH 6.8 medium, the drug is in a supersaturated state, and the addition of organic acid to the capsule samples of Examples 1-5 can improve drug release compared with Comparative Examples 1 and 2.

[0221] Table 12. Dissolution test results of crizotinib capsule samples in pH 6.8 (containing 1.5% Tween 80) medium (%)

[0222]

[0223] The results in Table 12 show that the capsule samples of Examples 1-5 exhibited slow drug release characteristics compared with Comparative Example 1.

[0224] According to Tables 9 to 12 and Figures 1 to 4The experimental results show that: in the four dissolution media, the crizotinib capsule sample of comparative example 1 shows the characteristics of a rapid-release preparation, and the drug release is basically completed once within 1.5 hours, and the drug release rate is relatively fast; the crizotinib capsule samples of Examples 1 to 5 have the characteristics of a sustained-release preparation, and the drug release is not completed once, and the drug release rate is relatively slow. In vivo, the dissolution of the crizotinib capsule samples of Examples 1-5 also has a sustained-release characteristic, the drug is dissolved in stages, and the drug does not precipitate or the amount of precipitation is less, thereby increasing bioavailability. In a pH 6.8 medium without a surfactant, the drug is in a supersaturated state. Compared with Comparative Examples 1 and 2, the addition of organic acids in the capsule samples of Examples 1-5 can increase drug release. Correspondingly, in the high pH intestinal part of the body, organic acids can also increase drug release, thereby improving bioavailability.

[0225] Experiment 3: Determination of blood drug concentration

[0226] Six adult healthy dogs weighing 8kg to 12kg were fasted for 12 hours before medication, fasted for 4 hours after medication, and deprived of water for 2 hours. They were divided into two groups and given capsules of comparative example 1 and embodiment 1, respectively, using a crossover two-period design. Blood was collected at 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, and 48h after administration. The blood samples were processed and the blood drug concentration was determined by HPLC-MS. The relationship curve between the average blood drug concentration and time of the crizotinib capsules of the present invention and the comparative example is shown in Figure 2. Figure 5 .Depend on Figure 5 It can be seen that the average blood drug concentration of the crizotinib capsules of the present invention in the body is significantly higher than that of the crizotinib capsules of the comparative example, showing higher bioavailability.

Claims

1. A crizotinib capsule comprising immediate-release granules and sustained-release granules, and optional granular additional excipients, wherein: The weight ratio of the sustained-release granules to the immediate-release granules is 3:7 to 7:3, and the preferred ratio is 4:6 to 7:

3.

2. The crizotinib capsule according to claim 1, wherein the weight proportion of crizotinib in each of the sustained-release granules and the immediate-release granules is 50 parts.

3. The crizotinib capsule according to claim 1 or 2, wherein the sustained-release granules comprise: 50 parts of crizotinib, 15 parts to 35 parts of hydrophilic gel-type skeleton material, 12 parts to 32 parts of organic acid, 0 parts to 7 parts of filler, and 1 part to 1.5 parts of lubricant, all in parts by weight.

4. The crizotinib capsule according to claim 1 or 2, wherein the immediate-release granules comprise: 50 parts of crizotinib, 40 parts to 44 parts of filler, 3 parts to 6 parts of disintegrant, and 1 part to 1.5 parts of lubricant, all in parts by weight.

5. The crizotinib capsule according to claim 3, wherein the hydrophilic gel-type skeleton material is selected from one or two of hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium alginate, and xanthan gum, preferably hydroxypropyl methylcellulose.

6. The crizotinib capsule according to claim 3, wherein the organic acid is selected from one or two of fumaric acid, adipic acid, citric acid and succinic acid, preferably fumaric acid.

7. The crizotinib capsule according to claim 3 or 4, wherein the filler is selected from one or two of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, calcium sulfate and calcium carbonate; and the lubricant is magnesium stearate.

8. The crizotinib capsule according to claim 4, wherein the disintegrant is selected from one or more of sodium starch glycolate, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethylcellulose. 9 . The crizotinib capsule according to claim 2 , wherein the particle size of crizotinib d(0.9) is ≤230 μm.

10. A method for preparing the crizotinib capsule according to any one of claims 1 to 9, the method comprising: (1) Preparation of sustained-release granules The prescribed amount of crizotinib, a hydrophilic gel-type matrix material, an organic acid and other optional pharmaceutically acceptable adjuvants are mixed and then dry granulated to prepare granules; (2) Preparation of immediate-release granules Mixing the prescribed amount of crizotinib, a filler, a disintegrant and any other pharmaceutically acceptable adjuvants and preparing granules by dry granulation; (3) Total mixing of particles The sustained-release granules obtained in step (1), the immediate-release granules obtained in step (2), and the additional excipients are mixed uniformly in a mixer; (4) filling capsules, placing the total mixed granules from step (3) into capsules, in, The added auxiliary material is selected from one or both of magnesium stearate and colloidal silicon dioxide.

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