An ibrutinib capsule and its preparation method
By preparing ibrutinib solid dispersions combined with fatty acid glycerides, the problems of slow dissolution and low bioavailability of oral ibrutinib formulations have been solved, resulting in ibrutinib capsules with rapid dissolution and high bioavailability, thus improving safety.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- LUNAN PHARMA GROUP CORPORATION
- Filing Date
- 2020-12-31
- Publication Date
- 2026-06-30
AI Technical Summary
Existing oral ibrutinib formulations suffer from slow dissolution and low bioavailability, and the extensive use of surfactants poses safety risks.
By preparing ibrutinib into a solid dispersion with macromolecular polymers and adding fatty acid glycerides and other pharmaceutically acceptable excipients, ibrutinib capsules can be prepared, avoiding the use of organic solvents and surfactants, thus achieving rapid dissolution and high bioavailability.
Ibrutinib capsules dissolve rapidly in water without the need for surfactants, resulting in high bioavailability, good safety profile, and avoiding complex micronization processes.
Smart Images
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical preparation technology, and specifically relates to an ibrutinib capsule and its preparation method. Background Technology
[0002] Ibrutinib is a small molecule inhibitor of BTK. Ibrutinib forms a covalent bond with cysteine residues at the active site of BTK, thereby inhibiting BTK enzyme activity. It is a white to off-white solid with the molecular formula C2. 25 H 24 N6O2, with a molecular weight of 440.50, is readily soluble in dimethyl sulfoxide and methanol, but practically insoluble in water. Ibrutinib is currently marketed as a capsule formulation, 140 mg / capsule. Excipients include sodium carboxymethyl cellulose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. While the addition of a large amount of surfactant improves the solubility of the raw materials to some extent, it also poses a risk of gastrointestinal irritation. Furthermore, ibrutinib has low bioavailability; the absolute bioavailability of oral ibrutinib capsules on an empty stomach is only 2.9%, while the absolute bioavailability after taking it with food is twice that on an empty stomach.
[0003] Patent CN111000806A discloses an ibrutinib tablet composition containing 140g ibrutinib, 26-40g microcrystalline cellulose, 12-22g croscarmellose sodium, 0.8-1.5g sodium dodecyl sulfate, 7-12g polyethylene glycol 6000, 0.8-1.8g soybean lecithin, 7-15g sodium alginate, 0.8-1.8g magnesium stearate, and 4-8g micronized silica gel per 1000 tablets. The ibrutinib tablets prepared are of stable quality, but contain a large amount of surfactants such as sodium dodecyl sulfate and polyethylene glycol 6000, and have low dissolution and low bioavailability.
[0004] Patent CN106619643A discloses a pharmaceutical composition containing ibrutinib, comprising 13-15 parts ibrutinib, 30-35 parts solvent, 20-30 parts solubilizer, 8-12 parts filler, 6-10 parts disintegrant, and 21-26 parts pharmaceutical organic acid. The solvent used is glycerol formaldehyde, and the pharmaceutical organic acid is a mixture of oleic acid and glyceryl oleate in a mass ratio of 1.7-2.1:1. This ibrutinib formulation still has a relatively slow dissolution, and the large amount of solvent and surfactant used also poses certain safety risks.
[0005] Patent CN109010844A discloses an ibrutinib phospholipid complex and its preparation method. The complex can significantly improve drug solubility and increase drug bioavailability. However, the prepared phospholipid complex is prone to oxidative degradation. The preparation process uses organic solvents, and the industrialization process is relatively complex.
[0006] Overall, existing oral ibrutinib formulations suffer from technical issues such as slow dissolution and the extensive use of surfactants, and the bioavailability of oral formulations needs further improvement. Summary of the Invention
[0007] In view of the shortcomings of the prior art, the present invention provides an ibrutinib capsule formulation. Ibrutinib and a macromolecular polymer are prepared into a solid dispersion by hot melt extrusion, then pulverized, and granulated with a certain amount of fatty acid glycerides and other excipients. After adding a lubricant and mixing thoroughly, the mixture is filled into hard capsules. The preparation process of the present invention does not use organic solvents, and the resulting ibrutinib capsules dissolve rapidly in water as the dissolution medium without the need for surfactants, exhibiting high bioavailability.
[0008] Specifically, the objective of this invention is achieved through the following technical solution:
[0009] An ibrutinib capsule comprising ibrutinib solid dispersion, fatty acid glycerides, and other pharmaceutically acceptable excipients.
[0010] The ibrutinib solid dispersion comprises the active ingredient ibrutinib and a macromolecular polymer; the macromolecular polymer is selected from hydroxypropyl methylcellulose (AFFINISOL). TM One of polyvinylpyrrolidone K30, copovidone VA64 or S630, preferably hydroxypropyl methylcellulose AFFINISOL TM .
[0011] The ibrutinib solid dispersion has an active ingredient ibrutinib to macromolecular polymer weight ratio of 1:1 to 4; preferably 1:2.
[0012] The fatty acid glycerides are selected from one or more of oleoyl polyoxyethylene glycerides, linoleoyl polyoxyethylene glycerides, caprylic / capric acid glycerides, polyethylene glycol glycerides, polyethylene glycol stearate, and lauroyl polyoxyethylene glycerides.
[0013] The weight ratio of the active ingredient ibrutinib to fatty acid glycerides is 1:0.02 to 0.2.
[0014] Preferably, the weight ratio of the active ingredient ibrutinib to fatty acid glycerides is 1:0.02 to 0.1.
[0015] More preferably, the weight ratio of the active ingredient ibrutinib to fatty acid glycerides is 1:0.05.
[0016] Pharmaceutically acceptable excipients include fillers, disintegrants, and lubricants.
[0017] The filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch, and dextrin.
[0018] Preferably, the weight ratio of the active ingredient ibrutinib to the filler is 1:0.5 to 3, and more preferably 1:1 to 2.
[0019] The disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, croscarmellose and low-substituted hydroxypropyl cellulose.
[0020] Preferably, the weight ratio of the active ingredient ibrutinib to the disintegrant is 1:0.05 to 1.5, and more preferably 1:0.1 to 1.
[0021] The lubricant is selected from one or more of magnesium stearate, talc, sodium stearyl fumarate, silica, and polyethylene glycol.
[0022] Preferably, the weight ratio of the active ingredient ibrutinib to the lubricant is 1:0.1 to 0.2.
[0023] The present invention also provides a method for preparing the above-mentioned ibrutinib capsules, the specific steps of which are: heating and melting ibrutinib and macromolecular polymers at 110-150°C using a hot melt extruder, extruding, and preparing a solid dispersion; pulverizing and sieving the solid dispersion, then mixing it with other pharmaceutically acceptable excipients, granulating it using fatty acid glycerides, adding a lubricant and mixing it evenly before filling it into capsules; preferably, the heating temperature is 115-140°C.
[0024] Compared with the prior art, the present invention has the following advantages:
[0025] (1) Ibrutinib has high bioavailability;
[0026] (2) The drug has high dissolution rate and dissolves rapidly;
[0027] (3) No complex micronization process is required;
[0028] (4) No ionic surfactants are added and no organic solvents are used, making it highly safe. Detailed Implementation
[0029] The following embodiments further illustrate the beneficial effects of the present invention. These embodiments are for illustrative purposes only and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by those skilled in the art according to the present invention are also included within the scope of the present invention.
[0030] Example 1
[0031] prescription:
[0032]
[0033] Preparation process:
[0034] The prescribed amount of hydroxypropyl methylcellulose AFFINSOL TM Mix thoroughly with ibrutinib, heat and melt at 140°C using a hot melt extruder, extrude to prepare a solid dispersion, cool and pulverize through an 80-mesh sieve, add the prescribed amount of microcrystalline cellulose and sodium carboxymethyl starch and mix thoroughly, add oleoyl polyoxyethylene glycerol ester and granulate, pass through a 20-mesh sieve, add the prescribed amount of silica and mix thoroughly before filling into capsules.
[0035] Example 2
[0036] prescription:
[0037]
[0038]
[0039] Preparation process:
[0040] The prescribed amount of hydroxypropyl methylcellulose AFFINSOL TM Mix thoroughly with ibrutinib, heat and melt at 135°C using a hot melt extruder, extrude to prepare a solid dispersion, cool and pulverize through an 80-mesh sieve, add the prescribed amounts of lactose, microcrystalline cellulose, and croscarmellose sodium, mix thoroughly, add caprylic / capric acid glyceride polyethylene glycol glycerol ester to granulate, pass through a 20-mesh sieve, add the prescribed amount of silica, mix thoroughly, and then fill into capsules.
[0041] Example 3
[0042] prescription:
[0043]
[0044] Preparation process:
[0045] The prescribed amount of copovidone S630 and ibrutinib were mixed evenly, and then heated and melted at 125°C using a hot melt extruder. The mixture was then extruded to prepare a solid dispersion. After cooling, the dispersion was pulverized and passed through an 80-mesh sieve. The prescribed amount of microcrystalline cellulose and sodium carboxymethyl starch were added and mixed evenly. The mixture was then heated and melted at 60°C with polyethylene glycol stearate. While still hot, the mixture was added to the powder mixture and granulated. The granules were then passed through a 20-mesh sieve. The prescribed amount of magnesium stearate was added and mixed evenly before being filled into capsules.
[0046] Example 4
[0047] prescription:
[0048]
[0049] Preparation process:
[0050] The prescribed amount of copovidone VA64 and ibrutinib were mixed evenly, and a solid dispersion was prepared using a hot melt extruder at 115°C. After cooling, the mixture was pulverized and passed through an 80-mesh sieve. The prescribed amount of starch, lactose, and low-substituted hydroxypropyl cellulose were added and mixed evenly. Linoleyl polyoxyethylene glycerol ester was added and granulated. The mixture was then passed through a 20-mesh sieve. The prescribed amount of sodium stearate fumarate was added, mixed evenly, and then filled into capsules.
[0051] Example 5
[0052] prescription:
[0053]
[0054] Preparation process:
[0055] The prescribed amount of hydroxypropyl methylcellulose AFFINSOL TM Mix thoroughly with ibrutinib, prepare a solid dispersion using a hot melt extruder at 140°C, cool and pulverize through an 80-mesh sieve, add the prescribed amount of dextrin, lactose, and crospovidone and mix thoroughly, then add linoleyl polyoxyethylene glycerol ester and caprylic / capric acid glycerol ester to granulate, then pass through a 20-mesh sieve, add the prescribed amount of polyethylene glycol and mix well before filling into capsules.
[0056] Example 6
[0057] prescription:
[0058]
[0059] Preparation process:
[0060] The prescribed amount of hydroxypropyl methylcellulose AFFINSOL TM Mix thoroughly with ibrutinib, heat and melt at 140°C using a hot melt extruder, extrude to prepare a solid dispersion, cool and pulverize through an 80-mesh sieve, add the prescribed amount of microcrystalline cellulose and croscarmellose sodium, mix thoroughly, add linoleyl polyoxyethylene glycerol ester to granulate, then pass through a 20-mesh sieve, add the prescribed amount of magnesium stearate, mix thoroughly, and then fill into capsules.
[0061] Example 7
[0062] prescription:
[0063]
[0064] Preparation process:
[0065] Mix polyvinylpyrrolidone K30, sorbitol and ibrutinib in the prescribed amounts evenly, heat and melt them at 130°C using a hot melt extruder, extrude to prepare a solid dispersion, cool and pulverize through an 80-mesh sieve, add mannitol, microcrystalline cellulose and sodium carboxymethyl starch in the prescribed amounts and mix evenly, heat and melt lauroyl polyoxyethylene glycerol at 50°C, add to the mixed powder and granulate, then pass through a 20-mesh sieve, add talc in the prescribed amount and mix evenly before filling into capsules.
[0066] Example 8
[0067] prescription:
[0068]
[0069] Preparation process:
[0070] The prescribed amount of copovidone VA64 and ibrutinib were mixed evenly, heated and melted at 110°C using a hot melt extruder, and extruded to prepare a solid dispersion. After cooling, the dispersion was pulverized and passed through an 80-mesh sieve. The prescribed amounts of starch, lactose, and cross-linked polyvinylpyrrolidone were added and mixed evenly. Linoleyl polyoxyethylene glycerol ester was added and granulated. The granules were then passed through a 20-mesh sieve. The prescribed amount of sodium stearate fumarate was added, mixed evenly, and then filled into capsules.
[0071] Example 9
[0072] prescription:
[0073]
[0074] Preparation process:
[0075] Mix the prescribed amount of Soluplus with ibrutinib evenly, heat and melt it at 135°C using a hot melt extruder, extrude it to prepare a solid dispersion, cool it and pulverize it through an 80-mesh sieve, add the prescribed amount of lactose, microcrystalline cellulose and croscarmellose sodium and mix evenly, add monooleic glyceryl ester to granulate, pass through a 20-mesh sieve, add the prescribed amount of magnesium stearate and mix evenly, and then fill into capsules.
[0076] Example 10
[0077] prescription:
[0078]
[0079] Preparation process:
[0080] Mix polyvinylpyrrolidone K30, sorbitol and ibrutinib in the prescribed amounts evenly, heat and melt them at 130°C using a hot melt extruder, extrude them to prepare a solid dispersion, cool them and pulverize them through an 80-mesh sieve, add microcrystalline cellulose and sodium carboxymethyl cellulose in the prescribed amounts and mix evenly, heat and melt lauroyl polyoxyethylene glycerol ester at 50°C, add it to the mixed powder and granulate, then pass it through a 20-mesh sieve, add magnesium stearate in the prescribed amounts and mix well before filling capsules.
[0081] Example 11
[0082] prescription:
[0083]
[0084]
[0085] Preparation process:
[0086] The prescribed amount of hydroxypropyl methylcellulose AFFINSOL TM Mix thoroughly with ibrutinib, heat and melt at 150°C using a hot melt extruder, extrude to prepare a solid dispersion, cool and pulverize through an 80-mesh sieve, add the prescribed amount of lactose, microcrystalline cellulose, and sodium carboxymethyl starch and mix thoroughly, add caprylic / capric acid glyceride polyethylene glycol glycerol ester to granulate, pass through a 20-mesh sieve, add the prescribed amount of sodium stearate fumarate and mix thoroughly before filling into capsules.
[0087] Comparative Example 1
[0088] prescription:
[0089]
[0090] Preparation process:
[0091] Ibrutinib is micronized, then polyvinylpyrrolidone K30, microcrystalline cellulose, lactose and low-substituted hydroxypropyl cellulose are added and mixed evenly. The mixture is then granulated with water, passed through a 20-mesh sieve, dried, and then magnesium stearate is added and mixed evenly before being compressed into tablets.
[0092] Comparative Example 2
[0093] prescription:
[0094]
[0095]
[0096] Preparation process:
[0097] Ibrutinib is micronized, then hydroxypropyl methylcellulose 2910, microcrystalline cellulose, and sodium carboxymethyl starch are added and mixed evenly. Granulation is performed using polyethylene glycol glycerol ester with caprylic / capric acid and passed through a 20-mesh sieve. Magnesium stearate is then added and mixed evenly before tableting.
[0098] Comparative Example 3
[0099] prescription:
[0100]
[0101] Preparation process:
[0102] The prescribed amounts of ibrutinib, oleic acid, oleic acid glycerides, and polyoxyethylene fatty alcohol ethers are added to glyceryl formaldehyde, mixed evenly, and then the mixture is sprayed evenly onto N-methylcarbamoyl chloride using a fluidized bed. Granulation and drying are then performed. Carboxymethyl cellulose calcium and microcrystalline cellulose are added, mixed evenly, and then tableted.
[0103] Comparative Example 4
[0104] prescription:
[0105]
[0106] Preparation process:
[0107] The prescribed amount of ibrutinib and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer were dissolved in acetone and spray-dried at a rate of 15 mL / min using a 1.5 mm nozzle size and a nozzle pressure of 20 psi. The inlet temperature was set to 70–80 °C, and the outlet temperature was set to 10–45 °C. The drying gas flow rate was maintained at 35 m. 3 / h, then perform secondary drying in an oven at 40℃ for about 16h, then mix with lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silica and 0.05g magnesium stearate in a V-type mixer for 10 minutes, sieve through 20 mesh, add another 0.05g magnesium stearate to the sieved blend and mix for another 3 minutes, use a rolling mill or a single press station to roll the final blend to obtain belts or bars, grind and compact the belts or bars in a grinding granulator, sieve through 20 mesh, and compress into tablets.
[0108] Comparative Example 5
[0109] prescription:
[0110]
[0111] Preparation process:
[0112] The prescribed amount of ibrutinib and povidone are added to an appropriate amount of purified water to form a mixed solution. Microcrystalline cellulose is placed in a high-shear mixer and stirred, so that the microcrystalline cellulose is kept in motion while the mixed solution is sprayed onto the microcrystalline cellulose particles. After drying, it is mixed with lactose, low-substituted hydroxypropyl cellulose, magnesium stearate, and silicon dioxide, and then filled into capsules.
[0113] Comparative Example 6
[0114] prescription:
[0115]
[0116]
[0117] Preparation process:
[0118] Prepare 100 tablets according to the preparation method described below:
[0119] (1) Ibrutinib passed through a 120-mesh sieve, and other excipients passed through an 80-mesh sieve;
[0120] (2) Mix the prescribed amount of ibrutinib with the prescribed amount of sodium dodecyl sulfate, micronized silica gel and soybean lecithin evenly; moisten with 55% ethanol aqueous solution to soften; dry at 60℃, granulate and pass through a 60-mesh sieve;
[0121] (3) The product obtained in step (2) is moistened with the prescribed amount of microcrystalline cellulose, croscarmellose sodium, polyethylene glycol 6000, and 55% ethanol aqueous solution to make a soft granule; dried at 60°C, granulated, and passed through a 40-mesh sieve.
[0122] (4) The amount of magnesium stearate obtained in step (3) is added to the prescription amount, mixed well, and compressed into tablets.
[0123] Comparative Example 7
[0124] prescription:
[0125]
[0126] Preparation process:
[0127] The prescribed amount of hydroxypropyl methylcellulose AFFINSOL TM Mix thoroughly with ibrutinib, heat and melt at 135°C using a hot melt extruder, extrude to prepare a solid dispersion, cool and pulverize through an 80-mesh sieve, add the prescribed amounts of lactose, microcrystalline cellulose, and croscarmellose sodium, mix thoroughly, add polyoxyethylene hydrogenated castor oil to granulate, pass through a 20-mesh sieve, add the prescribed amount of magnesium stearate, mix thoroughly, and then fill into capsules.
[0128] Verification of Examples
[0129] 1. Dissolution test
[0130] The dissolution rate of the ibrutinib preparations obtained in Examples 1-11 and Comparative Examples 1-7 was determined using the following method. Take the product and, following the dissolution test method, use 900 mL of pure water as the dissolution medium and a rotation speed of 75 rpm. At 5 minutes, 10 minutes, and 30 minutes, take 10 mL of the solution, filter, and collect the filtrate as the test solution. Separately, take an appropriate amount of ibrutinib reference standard, place it in a 10 mL volumetric flask, dissolve it in methanol and dilute to the mark. Accurately measure 1 mL of this solution and place it in a 10 mL volumetric flask, dilute to the mark with the dissolution medium, and mix well to obtain the reference solution. Inject 10 μL each of the test solution and the reference solution into the liquid chromatograph, record the chromatogram, and calculate the dissolution rate per tablet using the external standard method based on the peak area. The limit is 80% of the labeled amount and should comply with regulations.
[0131] Chromatographic conditions: Octadecylsilane-bonded silica gel column; mobile phase: 0.1% TFA deionized water and 0.1% TFA in acetonitrile solution; gradient elution; flow rate: 1.5 mL / min; column temperature: 40℃; detection wavelength: 260 nm. Three parallel experiments were performed, and the average value was taken.
[0132] The test results are shown in Table 1.
[0133] Table 1 Dissolution test results
[0134]
[0135]
[0136] 2. Pharmacokinetic studies
[0137] Pharmacokinetic experiments were conducted on Examples 1-11 and Comparative Examples 1-7. Six healthy Beagle dogs, weighing 12.5–15 kg, were used in each group. Twelve hours before administration, the dogs were fed once and given 140 mg of ibrutinib orally, along with 25 mL of warm water. Approximately 3 ml of blood was collected from the subcutaneous vein of the forelimb at 15, 30, 45, 60, 90, 120, 240, 480, and 720 minutes after administration. The blood concentration was measured in heparinized tubes, and Cmax and AUC were calculated. The results were compared with those of commercially available ibrutinib tablets (trade name: [omitted]). In comparison, further calculations were performed for... The ratio of Cmax to AUC.
[0138] The test results are shown in Table 2.
[0139] Table 2 Results of Pharmacokinetic Measurements
[0140]
[0141]
Claims
1. An ibrutinib capsule comprising an ibrutinib solid dispersion, esters, and other pharmaceutically acceptable excipients, said solid dispersion being prepared by hot melt extrusion of ibrutinib and a macromolecular polymer; said ibrutinib solid dispersion comprising ibrutinib and a macromolecular polymer selected from hydroxypropyl methylcellulose (AFFINISOL). TM The active ingredient ibrutinib is selected from one or more of polyvinylpyrrolidone VA64 or S630, wherein the weight ratio of ibrutinib to the macromolecular polymer is 1:1 to 4; the ester is selected from one or more of oleoyl polyoxyethylene glycerol ester, linoleoyl polyoxyethylene glycerol ester, caprylic / capric glycerol ester, polyethylene glycol stearate, and lauroyl polyoxyethylene glycerol ester, wherein the weight ratio of ibrutinib to the ester is 1:0.02 to 0.2; the pharmaceutically acceptable excipients include fillers, disintegrants, and lubricants, wherein the fillers are selected from one or more of microcrystalline cellulose, lactose, mannitol, starch, and dextrin, wherein the disintegrants are selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, croscarmelloidone, and low-substituted hydroxypropyl cellulose, and the lubricants are selected from one or more of magnesium stearate, talc, sodium stearyl fumarate, silica, and polyethylene glycol.
2. The ibrutinib capsules as described in claim 1, characterized in that, The weight ratio of the active ingredient ibrutinib to the filler is 1:0.5 to 3.
3. The ibrutinib capsules as described in claim 1, characterized in that, The weight ratio of the active ingredient ibrutinib to the disintegrant is 1:0.05 to 1.
5.
4. The ibrutinib capsules as described in claim 1, characterized in that, The weight ratio of the active ingredient ibrutinib to the lubricant is 1:0.1 to 0.
2.
5. A method for preparing ibrutinib capsules according to any one of claims 1 to 4, comprising the following steps: Ibrutinib and macromolecular polymers are heated and melted at 110–150°C using a hot melt extruder, and then extruded to prepare a solid dispersion. The solid dispersion is pulverized and sieved, then mixed with other pharmaceutically acceptable excipients, granulated using esters, and filled into capsules with lubricant.