An entacapone enteric-coated tablet and a preparation method thereof

Abstract

The application belongs to the technical field of medicine, and specifically provides an entero-soluble ibrexin tablet with high bioavailability and a preparation method thereof. The entero-soluble tablet comprises a tablet core and an enteric coating, wherein the tablet core comprises an ibrexin coating compound, microcrystalline cellulose and magnesium stearate, and the ibrexin coating compound comprises ibrexin or a pharmaceutically acceptable salt thereof, an acid regulator, povidone and cross-linked sodium carboxymethyl cellulose. The ibrexin entero-soluble tablet of the application can make the drug reach the end of the small intestine or the colon for release, thereby avoiding the metabolism of cytochrome P450 (CYP) 3A, and at the same time, the acid regulator can locally provide an acidic environment for the active ingredient, so that the ibrexin is rapidly dissolved and released, and the side effects such as vomiting in the gastrointestinal tract are reduced.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a high-bioavailability ibrutinib enteric-coated tablet and a preparation method thereof. BACKGROUND

[0002] Ibrutinib is a small molecule BTK (Bruton's tyrosine kinase) inhibitor. Ibrutinib forms a covalent bond with the cysteine residue in the active site of BTK, thereby inhibiting the enzymatic activity of BTK. BTK is a signaling molecule of the B cell antigen receptor (BCR) 41 / 45 and cytokine receptor pathway. BTK activates the pathways necessary for B cell migration, chemotaxis and adhesion through B cell surface receptors. Nonclinical research results show that ibrutinib inhibits the in vivo proliferation and survival of malignant B cells and in vitro cell migration and basal adhesion.

[0003] The domestic marketed dosage form of ibrutinib is a capsule, with specifications of 140 mg / grain and 70 mg / grain, and the trade name Imbruvica. The excipients include cross-linked sodium carboxymethyl cellulose, magnesium stearate, microcrystalline cellulose, sodium dodecyl sulfate, and gelatin hollow capsules. The in vivo absorption and metabolism of ibrutinib are as follows: (1) absorption: the absolute bioavailability of ibrutinib taken by healthy subjects on an empty stomach is only 2.9%; (2) metabolism: the main pathway of ibrutinib in vivo elimination is to be metabolized into various metabolites mainly through cytochrome P450 (CYP) 3A, and a small part is metabolized through CYP2D6, and the active metabolite PCI-45227 is a dihydrodiol compound, and the inhibitory activity of BTK is about 1 / 15 of ibrutinib. It can be seen that, as a small molecule inhibitor, the oral bioavailability of ibrutinib is extremely low, the in vivo clearance rate is fast, the blood circulation time is short, the tumor targeting efficiency is extremely low, and the therapeutic effect in solid tumors is seriously affected, and the toxic side effects are increased.

[0004] Patent CN109010844B discloses a ibrutinib phospholipid complex and a preparation method thereof. The specification records that the complex can significantly improve the drug solubility, increase the drug absorption, and improve the drug bioavailability, and especially, the bioavailability of the complex prepared from egg yolk phosphatidylglycerol with a molar ratio of 1:1 is increased by 14 times. However, the prepared phospholipid complex is prone to oxidative degradation, and the preparation process needs to dissolve the raw materials in an organic solvent, which has a carcinogenic safety hazard for patients in the long-term taking process, and the industrialization process is also relatively complex.

[0005] 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. However, piperine is a broad-spectrum anticonvulsant, which may bring safety hazards to patients in the preparation composition.

[0006] Patent CN106619643A discloses a drug composition containing ibrutinib, which contains solvent glycerol formaldehyde and adds a certain amount of surfactant. The preparation is difficult to industrialize, and the use of a large amount of solvent and surfactant also brings certain safety hazards.

[0007] Patent CN111973570B discloses a high-density sialic acid-modified ibrutinib nanocomposite and a preparation method thereof. It can significantly improve the drug solubility, provide an injectable product for reducing the daily dose of the drug, and can be used for clinical critical patients. However, the process is relatively complex, and it is difficult to scale up the production.

[0008] In view of the problems found in the prior art, it is necessary to develop an ibrutinib solid preparation which is easy to commercialize, has high bioavailability and small side effects. SUMMARY

[0009] In view of the deficiencies of the prior art, the present application provides an ibrutinib solid preparation which is high in bioavailability, good in safety and easy to prepare.

[0010] The specific technical solutions of the present application are as follows:

[0011] The present application provides an ibrutinib enteric-coated tablet, which comprises a tablet core and an enteric-coated layer.

[0012] Preferably, the tablet core comprises an ibrutinib coating compound, microcrystalline cellulose and magnesium stearate.

[0013] Preferably, the ibrutinib coating compound comprises ibrutinib or a pharmaceutically acceptable salt thereof, an acid regulator, povidone and croscarmellose sodium.

[0014] Preferably, the pharmaceutically acceptable salt of ibrutinib is an acid addition salt.

[0015] Specifically, the pharmaceutically acceptable salt of ibrutinib includes an acid addition salt formed by the reaction of ibrutinib with an organic acid or an inorganic acid; the organic acid includes aliphatic monocarboxylic acid and dicarboxylic acid, phenyl-substituted alkanoic acid, hydroxyalkanoic acid, alkanedioic acid, aromatic acid, aliphatic and aromatic sulfonic acid, amino acid, etc., and includes, 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.

[0016] In some embodiments, ibutinib or a pharmaceutically acceptable salt thereof is prepared in a plurality of forms, including but not limited to amorphous form, crystalline form, solvate form, milled form, and nanoparticle form.

[0017] Preferably, the acid 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.

[0018] Preferably, the weight ratio of ibutinib to acid regulator is 100:0.1-50, preferably 100:10-40.

[0019] Preferably, the enteric coating comprises an enteric material and optionally one or more additives selected from plasticizers, anti-tacking agents, lubricants, opacifiers, and pigments.

[0020] Preferably, the enteric material can be one or more of hydroxypropyl methylcellulose phthalate polymers and acrylic resins.

[0021] Preferably, the hydroxypropyl methylcellulose phthalate polymers include but are not limited to HP55, HP55S.

[0022] Preferably, the acrylic resins include methacrylic acid copolymers and methacrylic acid ester copolymers, in particular, include but are not limited to methacrylic acid amine alkyl ester copolymer type E, methacrylic acid copolymer type C, methacrylic acid-ethyl acrylate copolymer aqueous dispersion, methacrylic acid copolymer type A, methacrylic acid copolymer type B, quaternary amine methacrylic acid ester copolymer type A, quaternary amine methacrylic acid ester copolymer type B, ethyl acrylate-methyl methacrylate copolymer aqueous dispersion.

[0023] Further preferably, the enteric material is methacrylic acid copolymer type A.

[0024] Preferably, the plasticizers include but are not limited to one or more of triethyl citrate, propylene glycol, polyethylene glycol, glycerol.

[0025] Preferably, the anti-tacking agents include but are not limited to one or more of talc, magnesium stearate, microfine silica, preferably talc.

[0026] Preferably, the lubricants include but are not limited to one or more of talc, magnesium stearate, microfine silica, polyethylene glycol, magnesium lauryl sulfate.

[0027] Preferably, the opacifiers include but are not limited to titanium dioxide.

[0028] Preferably, the content of enteric material in the enteric coating is 0.1-15% of the coating weight gain, preferably 5-10%.

[0029] Preferably, the enteric-coated tablet comprises the following components:

[0030]

[0031] Preferably, the enteric-coated tablet comprises the following components:

[0032]

[0033] In one embodiment, the enteric-coated tablet comprises the following components:

[0034]

[0035] The present application also provides a preparation method of the above-mentioned enteric-coated ibritumomab tablet, which comprises the following steps:

[0036] (1) Dissolve the acid regulator in the aqueous solution of povidone, spray in a granulator or a fluidized bed, granulate the mixture of ibritumomab and croscarmellose sodium, and dry to obtain an ibritumomab coating compound;

[0037] (2) Add microcrystalline cellulose and magnesium stearate, mix uniformly, and press into tablets to obtain the enteric-coated tablet core;

[0038] (3) Coat the tablet core with the enteric-coated coating component, and coat to a theoretical weight gain range.

[0039] The present application has the following beneficial effects:

[0040] The oral solid enteric-coated tablet of the present application allows the drug to be released at the end of the small intestine or the colon, thereby avoiding the metabolism of cytochrome P450 (CYP) 3A, and the acid regulator can locally provide an acidic environment for the active ingredient, allowing ibritumomab to be quickly dissolved and released, while reducing the side effects such as vomiting in the gastrointestinal tract. Compared with the prior art, the enteric-coated solid preparation of the present application has good drug compliance, good safety, high bioavailability, good efficacy, simple preparation process, easy to scale up, and is suitable for industrial production. DETAILED DESCRIPTION

[0041] The beneficial effects of the present application will be further described by the following examples, which should be understood as being for illustrative purposes only, and the scope of protection of the present application is not limited by the following examples, and the changes and modifications made by those skilled in the art according to the present application are also within the scope of protection of the present application.

[0042] Example 1

[0043] Prescription:

[0044]

[0045]

[0046] Preparation process:

[0047] (1) Dissolve the prescribed amount of succinic acid in the aqueous solution of povidone, spray into the granulator, granulate the mixture of ibrexinib and croscarmellose sodium, fluidized bed dry, and size.

[0048] (2) Add microcrystalline cellulose and magnesium stearate and mix well, and press into tablets.

[0049] (3) Coated with enteric coating solution containing methacrylic acid copolymer type A to increase the weight by 10%.

[0050] Example 2

[0051] Prescription:

[0052]

[0053] Preparation process: Refer to Example 1.

[0054] Example 3

[0055] Prescription:

[0056]

[0057]

[0058] Preparation process: Refer to Example 1.

[0059] Example 4

[0060] Prescription:

[0061]

[0062] Preparation process: Refer to Example 1.

[0063] Example 5

[0064] Prescription:

[0065]

[0066]

[0067] Preparation process: Refer to Example 1.

[0068] Example 6

[0069] Prescription:

[0070]

[0071] Preparation process: Refer to Example 1.

[0072] Example 7

[0073] Formulation:

[0074]

[0075] Preparation process: Refer to Example 1.

[0076] Comparative Example 1

[0077] Formulation:

[0078]

[0079] Preparation process:

[0080] (1) Dissolve the prescribed amount of succinic acid in the aqueous solution of povidone, spray into the granulator, granulate the mixture of ibrexinib and croscarmellose sodium, fluidized bed dry, and size.

[0081] (2) Add microcrystalline cellulose, magnesium stearate, mix evenly, and press into tablets.

[0082] Comparative Example 2

[0083] Formulation:

[0084]

[0085] Preparation process:

[0086] (1) Dissolve the prescribed amount of succinic acid in the aqueous solution of povidone, spray into the granulator, granulate the mixture of ibrexinib and croscarmellose sodium, fluidized bed dry, and size.

[0087] (2) Add microcrystalline cellulose, magnesium stearate, mix evenly, and press into tablets.

[0088] Comparative Example 3

[0089] Formulation:

[0090]

[0091]

[0092] Preparation process:

[0093] (1) Dissolve the prescribed amount of succinic acid in the aqueous solution of povidone, spray into the granulator, granulate the mixture of ibrexinib and croscarmellose sodium, fluidized bed dry, and size.

[0094] (2) Add microcrystalline cellulose, magnesium stearate, mix evenly, and press into tablets.

[0095] (3) Coated with enteric coating solution containing methacrylic acid copolymer type A to increase weight by 10%.

[0096] Comparative Example 4

[0097] Formulation:

[0098]

[0099] Preparation process: The capsules were prepared according to the process described in the specification of patent US11433072B1, page 9, example section.

[0100] Comparative Example 5

[0101] Formulation:

[0102]

[0103] Preparation process:

[0104] (1) Ibuprofen and croscarmellose sodium were sieved and mixed.

[0105] (2) Povidone was dissolved in purified water to prepare a binder solution.

[0106] (3) The mixture in step (1) was granulated using the binder solution of step (2) and dried.

[0107] (4) The dried granules of step (3) were sieved and lubricated with sodium stearyl fumarate.

[0108] (5) The lubricated granules of step (4) were compressed into tablets.

[0109] Validation Example

[0110] 1. Dissolution test

[0111] The samples of Examples 1-7 and Comparative Examples, and the original research formulation Imbruvica capsules 140 mg were subjected to dissolution test according to the second method of Chinese Pharmacopoeia 2020 edition four chapters 0931: the dissolution in 0.1N HCl and pH6.8 phosphate solution was determined respectively. The amount of dissolution medium was 900 ml, the rotation speed was 50 rpm, the sampling time in 0.1N HCl was 120 minutes, and the sampling time in pH6.8 phosphate solution was 60 minutes. 10 ml of solution was filtered, 5 ml was discarded, and the subsequent filtrate was used as the test solution; an appropriate amount of ibuprofen reference substance was accurately weighed, dissolved in methanol to prepare a solution containing about 160 μg / ml of ibuprofen, which was used as the reference solution. The determination was carried out according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 edition four chapters 0512). The dissolution results are shown in Table 1.

[0112] Table 1 Dissolution test results

[0113] Sample 0.1 N HC1 (%) pH 6.8 phosphate solution (%) 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) 77.0 21.2

[0114] 2. Stability test

[0115] According to the Stability Test Guiding Principles of Raw Materials and Preparations in Chinese Pharmacopoeia 2020 Edition Part IV 9001, the stability of the samples of Example 1, Example 5-7, Comparative Example, and the original research preparation Imbruvica Capsule 140 mg was determined under the condition of 40℃±2℃, relative humidity 75%±5% for 6 months. The specific results are shown in Table 2.

[0116] Table 2 Stability test results

[0117]

[0118]

[0119] 3. Pharmacokinetic test

[0120] Test method: 6 healthy Beagle dogs weighing 12.5-15 kg per group, fed once 12 h before administration, orally administered each preparation with 25 ml of warm water, and 3 ml of blood was taken from the subcutaneous vein of the forelimb at 15 min, 30 min, 45 min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h, 7.5 h, 8 h, 8.5 h, 9 h, 10 h, 11 h, 12 h, 16 h, 20 h, and 24 h after administration, and placed in a heparinized test tube. The blood drug concentration was determined, and C max , AUC were calculated and compared with the commercially available Ibrutinib Capsule. The results are shown in Table 3.

[0121] Table 3 Pharmacokinetic test results

[0122]

[0123]

Claims

1. An enteric-coated ibrutinib tablet, wherein the enteric-coated tablet comprises a tablet core and an enteric coating, wherein, The tablet core comprises an ibrutinib coating complex, microcrystalline cellulose, and magnesium stearate. The ibrutinib coating complex comprises ibrutinib or a pharmaceutically acceptable salt thereof, an acid modifier, povidone, and croscarmellose sodium. The acid modifier is selected from one or more of fumaric acid, tartaric acid, malic acid, citric acid, benzoic acid, salicylic acid, acetic acid, and succinic acid. The enteric coating comprises an enteric material and optionally one or more additives selected from plasticizers, anti-adhesives, lubricants, opacifiers, and pigments. The enteric material is one or more of a hydroxypropyl methylcellulose phthalate polymer and an acrylic resin. The hydroxypropyl methylcellulose phthalate polymer is HP55 or HP55S. The acrylic resin includes a methacrylic acid copolymer and a methacrylic acid copolymer. The enteric tablet comprises the following components: Component weight parts 100 doses of ibrutinib Acidity regulator 0.1-50 parts 5-25 parts of croscarmellose sodium cellulose 1-10 parts of povidone 1-100 parts of microcrystalline cellulose Magnesium stearate 0.1-5 parts The weight gain of enteric-coated materials is 0.1-15%.

2. The enteric-coated tablet according to claim 1, characterized in that, The pharmaceutically acceptable salt of ibrutinib is an acid addition salt.

3. A method for preparing ibrutinib enteric-coated tablets according to any one of claims 1 to 2, characterized in that, Includes the following steps: (1) Dissolve the acid regulator in an aqueous solution of povidone and spray it into a granulator or fluidized bed to granulate the mixture of ibrutinib and cross-linked carboxymethyl cellulose sodium. After drying, ibrutinib coating complex is obtained. (2) Add microcrystalline cellulose and magnesium stearate, mix well and compress into tablets to obtain enteric-coated tablet cores; (3) The tablet core was coated with enteric coating components, and the weight gain of the coating reached the theoretical range.

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