CN117064862A - Ibutenib enteric-coated tablet and preparation method thereof - Google Patents

Ibutenib enteric-coated tablet and preparation method thereof Download PDF

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Publication number
CN117064862A
CN117064862A CN202310374488.3A CN202310374488A CN117064862A CN 117064862 A CN117064862 A CN 117064862A CN 202310374488 A CN202310374488 A CN 202310374488A CN 117064862 A CN117064862 A CN 117064862A
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enteric
acid
ibutenib
coated tablet
tablet
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Chinese (zh)
Inventor
刘忠
郑华
卢红华
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Shandong New Time Pharmaceutical Co Ltd
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Shandong New Time Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention belongs to the technical field of medicines, and particularly provides an ibutenib enteric-coated tablet with high bioavailability and a preparation method thereof. The enteric coated tablet comprises a tablet core and an enteric coating, wherein the tablet core comprises an ibutinib coating compound, microcrystalline cellulose and magnesium stearate, and the ibutinib coating compound comprises ibutinib or pharmaceutically acceptable salt thereof, an acidity regulator, povidone and croscarmellose sodium. The ibutinib enteric-coated tablet can enable the medicine to reach the tail end of small intestine or release colon, so that metabolism of cytochrome P450 (CYP) 3A is avoided, meanwhile, the acidic regulator can provide an acidic environment for active ingredients locally, the ibutinib is rapidly dissolved and released, and meanwhile, side effects such as vomiting in gastrointestinal tracts are reduced.

Description

Ibutenib enteric-coated tablet and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an ibutenib enteric-coated tablet with high bioavailability and a preparation method thereof.
Background
Ibutenib is a small molecule BTK (Bruton's tyrosine kinase) inhibitor. Ibutenib forms a covalent bond with a cysteine residue of the BTK active site, thereby inhibiting the enzymatic activity of BTK. BTK is a signaling molecule for B cell antigen receptor (BCR) 41/45 and cytokine receptor pathway. BTK activates pathways necessary for B cell migration, chemotaxis and adhesion through B cell surface receptor signaling. Non-clinical findings indicate that ibutenib inhibits proliferation and survival of malignant B cells in vivo, and cell migration and basal adhesion in vitro.
The domestic market formulation of the ibutenib is capsules with the specification of 140 mg/granule and 70 mg/granule, the trade name of Imbruvica, and the auxiliary materials comprise croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium dodecyl sulfate and gelatin hollow capsules. Its in vivo absorption, metabolism: (1) absorption: the absolute bioavailability of ibutinib taken on an empty stomach in healthy subjects is only 2.9%; (2) metabolism: is the main way of eliminating ibutinib in vivo, is mainly metabolized into various metabolites through cytochrome P450 (CYP) 3A, and a small part of the metabolites are metabolized through CYP2D6, and the active metabolite PCI-45227 is a dihydrodiol compound, and the inhibition activity of the active metabolite on BTK is about 1/15 of that of the active metabolite on ibutinib. As a small molecule inhibitor, the oral bioavailability of ibutenib is extremely low, the in vivo clearance rate is high, the blood circulation time is short, the tumor targeting efficiency is extremely low, the curative effect of ibutenib in solid tumors is seriously influenced, and the toxic and side effects of ibutenib are increased.
Patent CN109010844B discloses a ibrutinib-phospholipid complex and a preparation method thereof. The specification records that the compound can obviously improve the drug dissolution performance, increase the drug absorption and improve the drug bioavailability, and in particular, the compound prepared by yolk phosphatidylglycerol with the molar ratio of 1:1 improves the bioavailability by 14 times. However, the prepared phospholipid complex is easy to oxidize and degrade, the raw materials are required to be dissolved in an organic solvent in the preparation process, the patient has potential safety hazard of cancer in the long-term taking process, and the industrialization process is also complex.
Patent CN111565721a discloses a pharmaceutical composition for treating B cell proliferative diseases. The composition comprises a therapeutically effective amount of ibrutinib and a therapeutically effective amount of at least one alkaloid or derivative thereof. Piperine is a broad spectrum anticonvulsant and may present a safety hazard to patients in such formulation compositions.
Patent CN106619643a discloses a pharmaceutical composition containing ibrutinib, which contains the solvent glycerol formal and is added with a certain amount of surfactant. The preparation is difficult to industrialize, and the use of a large amount of solvents and surfactants also brings certain potential safety hazards.
Patent CN111973570B discloses a high-density sialic acid modified ibrutinib nanocomposite and a preparation method thereof. Can obviously improve the dissolution performance of the medicine, provides an injectable product for reducing the daily dosage of the medicine, and can be used for clinical critical patients. However, the process is complex and difficult for industrial scale-up production.
Aiming at the problems found in the prior art, it is necessary to develop an ibutenib solid preparation which is easy to be commercially produced, has high bioavailability and small side effect.
Disclosure of Invention
In view of the defects of the prior art, the invention provides an ibutinib solid preparation which has high bioavailability, good safety and easy preparation.
The specific technical scheme of the invention is as follows:
the invention provides an ibutenib enteric-coated tablet, which comprises a tablet core and an enteric coating.
Preferably, the tablet core comprises an ibutenib coated composite, microcrystalline cellulose and magnesium stearate.
Preferably, the ibutenib coated complex comprises ibutenib or a pharmaceutically acceptable salt thereof, an acidity regulator, povidone, croscarmellose sodium.
Preferably, the pharmaceutically acceptable salt of ibutenib is an acid addition salt.
Specifically, the pharmaceutically acceptable salts of ibutenib include acid addition salts formed by reacting ibutenib with organic or inorganic acids; the organic acids include aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc., and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.; the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.
In some embodiments, ibutenib, or a pharmaceutically acceptable salt thereof, is prepared in a variety of forms including, but not limited to, amorphous, crystalline, solvate, milled, and nanoparticle forms.
Preferably, the acidity regulator is selected from one or more of fumaric acid, tartaric acid, malic acid, citric acid, benzoic acid, salicylic acid, acetic acid, succinic acid, more preferably succinic acid.
Preferably, the weight ratio of the ibutenib to the acidity regulator is 100:0.1-50, preferably 100:10-40.
Preferably, the enteric coating comprises an enteric material and optionally one or more additives selected from plasticizers, anti-adhesion agents, lubricants, opacifiers and pigments.
Preferably, the enteric material may be one or more of a hydroxypropyl methylcellulose phthalate polymer and an acrylic resin.
Preferably, the hydroxypropyl methylcellulose phthalate polymer includes, but is not limited to, HP55S.
Preferably, the acrylic resin includes methacrylic acid copolymers and methacrylate ester copolymers, specifically including but not limited to aminoalkyl methacrylate copolymer type E, methacrylic acid copolymer type C, aqueous methacrylic acid-ethyl acrylate copolymer dispersion, methacrylic acid copolymer type a, methacrylic acid copolymer type B, quaternary amino methacrylate ester copolymer type a, quaternary amino methacrylate ester copolymer type B, ethyl acrylate-methyl methacrylate copolymer aqueous dispersion.
Further preferably, the enteric material is methacrylic acid copolymer type a.
Preferably, the plasticizer includes, but is not limited to, one or more of triethyl citrate, propylene glycol, polyethylene glycol, glycerin.
Preferably, the anti-sticking agent includes, but is not limited to, one or more of talc, magnesium stearate, and silica fume, preferably talc.
Preferably, the lubricant includes, but is not limited to, one or more of talc, magnesium stearate, micro silica gel, polyethylene glycol, magnesium lauryl sulfate.
Preferably, the opacifying agent includes, but is not limited to, titanium dioxide.
Preferably, the enteric material content of the enteric coating is 0.1-15%, preferably 5-10% of the coating weight gain.
Preferably, the enteric-coated tablet comprises the following components:
preferably, the enteric-coated tablet comprises the following components:
in one embodiment, the enteric-coated tablet comprises the following components:
the invention also provides a preparation method of the ibutenib enteric-coated tablet, which comprises the following steps:
(1) Dissolving an acid regulator in a povidone aqueous solution, spraying in a granulator or a fluidized bed, granulating a mixture of ibutinib and croscarmellose sodium, and drying to obtain an ibutinib coating compound;
(2) Adding microcrystalline cellulose and magnesium stearate, mixing, and tabletting to obtain enteric coated tablet core;
(3) The tablet cores are coated with an enteric coating composition, and the coating weight gain reaches a theoretical range.
The invention has the beneficial effects that:
the oral solid enteric-coated tablet disclosed by the invention enables the medicine to reach the tail end of small intestine or colon for release, can avoid metabolism of cytochrome P450 (CYP) 3A, and meanwhile, the acidic regulator can provide an acidic environment for active ingredients locally, so that ibutinib is rapidly dissolved and released, and meanwhile, side effects such as vomiting in gastrointestinal tracts are reduced. Compared with the prior art, the enteric solid preparation has the advantages of good medicine taking compliance, good safety, high bioavailability, good curative effect, simple preparation process, convenient amplification and suitability for industrial production.
Detailed Description
The advantageous effects of the present invention are further described below by way of examples, it being understood that the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention, and that obvious changes and modifications made by those skilled in the art in light of the present invention are also included in the scope of the present invention.
Example 1
Prescription:
the preparation process comprises the following steps:
(1) Dissolving succinic acid with a prescription amount in povidone water solution, spraying into a granulator, granulating a mixture of ibutinib and croscarmellose sodium, drying by a fluidized bed, and granulating.
(2) Adding microcrystalline cellulose and magnesium stearate, mixing, and tabletting.
(3) Enteric coating solution containing methacrylic acid copolymer type a was used to coat to 10% weight gain.
Example 2
Prescription:
the preparation process comprises the following steps: reference is made to example 1.
Example 3
Prescription:
the preparation process comprises the following steps: reference is made to example 1.
Example 4
Prescription:
the preparation process comprises the following steps: reference is made in particular to example 1.
Example 5
Prescription:
the preparation process comprises the following steps: reference is made to example 1.
Example 6
Prescription:
the preparation process comprises the following steps: reference is made to example 1.
Example 7
Prescription:
the preparation process comprises the following steps: reference is made to example 1.
Comparative example 1
Prescription:
the preparation process comprises the following steps:
(1) Spraying povidone aqueous solution into a granulator, granulating a mixture of ibutinib and croscarmellose sodium, drying by a fluidized bed, and finishing granules.
(2) Adding microcrystalline cellulose and magnesium stearate, mixing, and tabletting.
Comparative example 2
Prescription:
the preparation process comprises the following steps:
(1) Dissolving succinic acid with a prescription amount in povidone water solution, spraying into a granulator, granulating a mixture of ibutinib and croscarmellose sodium, drying by a fluidized bed, and granulating.
(2) Adding microcrystalline cellulose and magnesium stearate, mixing, and tabletting.
Comparative example 3
Prescription:
the preparation process comprises the following steps:
(1) Spraying povidone aqueous solution into a granulator, granulating a mixture of ibutinib and croscarmellose sodium, drying by a fluidized bed, and finishing granules.
(2) Adding microcrystalline cellulose and magnesium stearate, mixing, and tabletting.
(3) Enteric coating solution containing methacrylic acid copolymer type a was used to coat to 10% weight gain.
Comparative example 4
Prescription:
the preparation process comprises the following steps: capsules were prepared according to the procedure described in the examples section of patent US11433072B1, page 9.
Comparative example 5
Prescription:
the preparation process comprises the following steps:
(1) Ibutenib and croscarmellose sodium were sieved and mixed.
(2) The povidone is dissolved in purified water to prepare a binder solution.
(3) Granulating and drying the mixture in the step (1) by using the binder solution in the step (2).
(4) Sieving the dried granules of step (3) and lubricating with sodium stearyl fumarate.
(5) And (3) pressing the lubricated granules obtained in the step (4) into tablets.
Verification embodiment
1. Dissolution measurement
According to the second method of the fourth edition rule 0931 of the year 2020 edition of Chinese pharmacopoeia, dissolution rate measurement was performed on 140mg of the sample of Imbruvica capsule, which is a raw development agent, of examples 1 to 7 and comparative example: the dissolution in 0.1N HCl, pH6.8 phosphate solution was measured. The dissolution medium was used in 900ml, the rotation speed was 50rpm, the sampling time in 0.1N HCl was 120 minutes, and the sampling time in phosphate solution at pH6.8 was 60 minutes. Taking 10ml of solution, filtering, discarding 5ml, and taking the subsequent filtrate as a sample solution; taking a proper amount of the ibutenib reference substance, precisely weighing, dissolving in methanol, and preparing a solution containing 160 mug/ml of ibutenib as the reference substance solution. The method is measured according to high performance liquid chromatography (China pharmacopoeia 2020 edition four general rules 0512). The elution results are shown in Table 1.
TABLE 1 dissolution test results
Sample of 0.1N HCl(％) phosphate solution at pH6.8 (%)
Example 1 Less than 3% 99.8
Example 2 Less than 3% 98.6
Example 3 Less than 3% 98.4
Example 4 Less than 3% 99.0
Example 5 Less than 3% 97.3
Example 6 Less than 5% 96.5
Example 7 Less than 3% 98.4
Comparative example 1 72.9 15.2
Comparative example 2 80.3 95.0
Comparative example 3 Less than 5% 14.8
Comparative example 4 82.7 95.3
Comparative example 5 99.9 90.5
Takecab (original grinding) 77.0 21.2
2. Stability test
According to the guidelines of four 9001 raw material medicaments and preparation stability tests of the Chinese pharmacopoeia 2020 edition, the stability of 140mg of the sample of the Imbruvica capsule of the original preparation in examples 1, 5-7 and comparative example is measured under the conditions of 40 ℃ +/-2 ℃ and 75+/-5% of relative humidity for 6 months. The specific results are shown in Table 2.
Table 2 stability test measurement results
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3. Pharmacokinetic test
The test method comprises the following steps: every 6 healthy Beagle dogs with weight of 12.5-15Kg are used as a group, each preparation is orally taken once for 12 hours before taking medicine, 25ml warm water is simultaneously taken, 15min, 30min, 45min, 60min, 90min, 2h, 3h, 4h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 10h, 11h, 12h, 16h, 20h and 24h are taken for about 3ml by subcutaneous vein in forelimbs, blood concentration is measured in heparinization test tubes, and C is calculated max AUC, and compared to commercially available ibrutinib capsules. The results are shown in Table 3.
TABLE 3 pharmacokinetic assay results
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Claims (10)

1. An ibutenib enteric coated tablet comprising a tablet core and an enteric coating, wherein the tablet core comprises an ibutenib coated complex, microcrystalline cellulose and magnesium stearate.
2. The enteric coated tablet of claim 1, wherein the ibutenib coated complex comprises ibutenib or a pharmaceutically acceptable salt thereof, an acidity regulator, povidone, croscarmellose sodium.
3. The enteric coated tablet of claim 2, wherein the pharmaceutically acceptable salt of ibutenib is an acid addition salt.
4. The enteric coated tablet of claim 2, wherein the acidity regulator is selected from one or more of fumaric acid, tartaric acid, malic acid, citric acid, benzoic acid, salicylic acid, acetic acid, succinic acid.
5. Enteric tablet according to any one of claims 1 to 4, wherein the enteric coating comprises an enteric material and optionally one or more additives selected from plasticizers, anti-sticking agents, lubricants, opacifiers and pigments.
6. The enteric sheet of claim 5, wherein the enteric material is one or more of a hydroxypropyl methylcellulose phthalate polymer and an acrylic resin.
7. The enteric tablet of claim 6, wherein the hydroxypropyl methylcellulose phthalate polymer comprises HP55, HP55S.
8. The enteric sheet of claim 6, wherein the acrylic resin comprises methacrylic acid copolymer and methacrylate ester copolymer.
9. The enteric coated tablet according to any one of claims 1 to 4, wherein the enteric coated tablet comprises the following components:
10. a process for the preparation of the ibutenib enteric-coated tablet according to any one of claims 1 to 4, characterized in that it comprises the following steps:
(1) Dissolving an acid regulator in a povidone aqueous solution, spraying in a granulator or a fluidized bed, granulating a mixture of ibutinib and croscarmellose sodium, and drying to obtain an ibutinib coating compound;
(2) Adding microcrystalline cellulose and magnesium stearate, mixing, and tabletting to obtain enteric coated tablet core;
(3) The tablet cores are coated with an enteric coating composition, and the coating weight gain reaches a theoretical range.
CN202310374488.3A 2023-04-10 2023-04-10 Ibutenib enteric-coated tablet and preparation method thereof Pending CN117064862A (en)

Priority Applications (1)

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CN202310374488.3A CN117064862A (en) 2023-04-10 2023-04-10 Ibutenib enteric-coated tablet and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202310374488.3A CN117064862A (en) 2023-04-10 2023-04-10 Ibutenib enteric-coated tablet and preparation method thereof

Publications (1)

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Country Status (1)

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