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CN-121987638-A - Ibrutinib pharmaceutical composition and preparation as well as preparation method and application thereof

CN121987638ACN 121987638 ACN121987638 ACN 121987638ACN-121987638-A

Abstract

The invention discloses an ibrutinib pharmaceutical composition and preparation as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The invention provides a ibrutinib pharmaceutical composition and a preparation as well as a preparation method and application thereof, aiming at solving the problems of low ibrutinib bioavailability, large administration dosage, high side effect risk and the like; the preparation is capsule or tablet. The preparation of the ibrutinib monolauryl sulfate composition prepared by adopting granulation or direct mixing has the advantages of greatly improved bioavailability, greatly reduced administration dosage under the condition of keeping the blood exposure basically unchanged, capability of keeping relatively stable blood concentration, small toxic and side effects, convenience in administration, high bioavailability and the like.

Inventors

  • YE YONG

Assignees

  • 成都泰立贝医药技术有限公司

Dates

Publication Date
20260508
Application Date
20260204

Claims (10)

  1. 1. The ibrutinib pharmaceutical composition is characterized by comprising an active substance, a filler and a release regulator, or comprising an active substance, a filler, a release regulator and other auxiliary materials, wherein the other auxiliary materials comprise at least one of a disintegrating agent, a lubricant and a glidant; the active substance is ibrutinib monolauryl sulfate; the filler is at least one selected from lactose, sucrose, glucose, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, microcrystalline cellulose, micro cellulose and talcum; The release regulator is at least one selected from sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyoxyethylene, methyl cellulose, ethyl cellulose, povidone, polyethylene glycol, dextrin, sodium alginate and acrylic resin; The disintegrating agent is at least one selected from crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose, sodium carboxymethyl starch, dry starch and low-substituted hydroxypropyl cellulose; The lubricant is at least one of magnesium stearate, sodium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol and magnesium lauryl sulfate; The glidant is at least one selected from talcum powder, colloidal silicon dioxide and starch.
  2. 2. The ibrutinib pharmaceutical composition of claim 1, wherein at least one of the following is satisfied: The other auxiliary materials are a disintegrating agent, a lubricant and a glidant, or a disintegrating agent and a lubricant, or a disintegrating agent, or a lubricant, or a glidant; The filler is microcrystalline cellulose, lactose or a mixture of microcrystalline cellulose and lactose, preferably, the mass ratio of microcrystalline cellulose to lactose in the mixture of microcrystalline cellulose and lactose is 2.5-5; the release regulator is hydroxypropyl methylcellulose, ethyl cellulose or a mixture of hydroxypropyl methylcellulose and ethyl cellulose; The disintegrating agent is selected from crosslinked sodium carboxymethyl cellulose, crosslinked polyvinylpyrrolidone or a mixture of crosslinked sodium carboxymethyl cellulose and crosslinked polyvinylpyrrolidone; the lubricant is selected from magnesium stearate, sodium stearate or a mixture of magnesium stearate and sodium stearate; The glidant is selected from colloidal silicon dioxide.
  3. 3. The ibrutinib pharmaceutical composition of claim 1, wherein at least one of the following is satisfied: the pharmaceutical composition comprises 10-60 wt% of the active ingredient, preferably 20-55 wt% of the active ingredient, and more preferably 30-55 wt% of the active ingredient; The pharmaceutical composition comprises 20-70 wt% of the filler, preferably 25-60 wt% of the filler, more preferably 30-55 wt% of the filler, further preferably 25-45 wt% of microcrystalline cellulose and 5-15 wt% of lactose, which total 30-55 wt%; The pharmaceutical composition comprises 0.5-30 wt% of the release modifier, preferably 1-20 wt% of the release modifier, more preferably 2-10 wt% of the release modifier; When the pharmaceutical composition comprises a disintegrant, the pharmaceutical composition comprises 0.1wt% to 10wt% of the disintegrant, preferably 0.3wt% to 8wt% of the disintegrant, more preferably 0.4wt% to 5wt% of the disintegrant; when the pharmaceutical composition comprises a lubricant, the pharmaceutical composition comprises 0.2wt% to 5wt% of the lubricant, preferably 0.3wt% to 3wt% of the lubricant, more preferably 0.3wt% to 0.8wt% of the lubricant; When the pharmaceutical composition comprises a glidant, the pharmaceutical composition comprises 0.1-5 wt% of the glidant, preferably 0.1-3 wt% of the glidant, more preferably 0.2-1 wt% of the glidant, and even more preferably 0.3-0.8 wt% of the glidant.
  4. 4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition comprises an A component and a B component, the A component comprises an active substance and a filler, or the A component comprises an active substance, a filler and other auxiliary materials, the B component comprises an active substance, a filler and a release regulator, or the B component comprises an active substance, a filler, a release regulator and other auxiliary materials, the content ratio of the A component and the B component is 10wt% to 90wt% in total 100wt%, preferably the content ratio of the A component and the B component is 30wt% to 70wt% to 30wt% in total 100wt%, more preferably the content ratio of the A component and the B component is 40wt% to 60wt% to 40wt%, and the total 100wt%.
  5. 5. The ibrutinib pharmaceutical composition according to claim 4, wherein: In the component A, at least one of the following is satisfied in terms of 100 wt%: the component A comprises 10-60 wt% of the active ingredient, preferably 20-55 wt% of the active ingredient, and more preferably 30-55 wt% of the active ingredient; The component A comprises 20-70 wt% of the filler, preferably 25-60 wt% of the filler, more preferably 30-60 wt% of the filler, further preferably 25-50 wt% of microcrystalline cellulose and 5-15 wt% of lactose, and the total of the two components is 30-60 wt%; When the A component contains the disintegrating agent, the A component contains 0.1-10wt% of the disintegrating agent, preferably 0.3-8wt% of the disintegrating agent, and more preferably 0.4-5wt% of the disintegrating agent; When the A-component contains a lubricant, the A-component contains 0.2wt% to 5wt% of the lubricant, preferably 0.3wt% to 3wt% of the lubricant, more preferably 0.3wt% to 0.8wt% of the lubricant; When the component A contains the glidant, the component A contains 0.1-5 wt% of the glidant, preferably 0.1-3 wt% of the glidant, more preferably 0.2-1 wt% of the glidant, and further preferably 0.3-0.8 wt% of the glidant; in the component B, at least one of the following is satisfied in terms of 100 wt%: the component B comprises 10-60 wt% of the active ingredient, preferably 20-55 wt% of the active ingredient, and more preferably 30-55 wt% of the active ingredient; The component B comprises 20-70 wt% of the filler, preferably 25-60 wt% of the filler, more preferably 30-55 wt% of the filler, further preferably 25-45 wt% of microcrystalline cellulose and 5-15 wt% of lactose, and the total of the two components is 30-55 wt%; The component B comprises 0.5-30 wt% of the release regulator, preferably 1-20 wt% of the release regulator, and more preferably 2-10 wt% of the release regulator; when the B component contains a lubricant, the B component contains 0.2wt% to 5wt% of the lubricant, preferably 0.3wt% to 3wt% of the lubricant, more preferably 0.3wt% to 0.8wt% of the lubricant; When the component B contains the glidant, the component B contains 0.1-5 wt% of the glidant, preferably 0.1-3 wt% of the glidant, more preferably 0.2-1 wt% of the glidant, and further preferably 0.3-0.8 wt% of the glidant.
  6. 6. The ibrutinib pharmaceutical composition according to claim 4, wherein in the component A, the other auxiliary materials are a disintegrating agent, a lubricant and a glidant, and in the component B, the other auxiliary materials are a lubricant and a glidant.
  7. 7. The preparation of the ibrutinib pharmaceutical composition of any one of claims 1-6, wherein the preparation is a capsule or a tablet.
  8. 8. The preparation according to claim 7, wherein the preparation method of the preparation comprises the following steps: the first process comprises the following steps: (1) Sieving the materials respectively; (2) Uniformly mixing the component A according to the proportion of active substances, filling agents and disintegrating agents to obtain a first physical mixture; (3) Uniformly mixing the component B according to the proportion of the active substances, the filler and the release regulator to obtain a second physical mixture; (4) Granulating the first physical mixture, and sieving after granulating to obtain first dry granules; granulating the second physical mixture, and sieving after granulating to obtain second dry granules; (5) Uniformly mixing the lubricant, the glidant, the first dry particles and the second dry particles, or mixing the lubricant, the glidant, the first physical mixture and the second dry particles, or mixing the lubricant, the glidant, the first dry particles and the second physical mixture, or mixing the lubricant, the glidant, the first physical mixture and the second physical mixture according to a proportion to obtain a total mixed material; (6) Filling the total mixed material into capsules to obtain capsules, or tabletting the total mixed material to obtain tablets; And a second process: (1) Sieving the materials respectively; (2) Uniformly mixing the active substances, the filling agent, the release regulator and the disintegrating agent in proportion to obtain a mixture; (3) Granulating the mixture, and sieving after granulating to obtain dry granules; (4) Uniformly mixing the lubricant, the glidant and the dry particles, or uniformly mixing the lubricant, the glidant and the mixture to obtain a total mixed material; (5) And filling the total mixed material into capsules to obtain capsules, or tabletting the total mixed material to obtain tablets.
  9. 9. Use of a pharmaceutical composition according to any one of claims 1 to 6 or a formulation according to any one of claims 7 to 8 for the preparation of a bruton's tyrosine kinase inhibitor.
  10. 10. Use of a pharmaceutical composition according to any one of claims 1 to 6 or a formulation according to any one of claims 7 to 8 for the manufacture of a medicament for the prevention and/or treatment of neoplastic diseases, autoimmune diseases, xenogenic immune diseases or disorders thereof, and inflammatory diseases.

Description

Ibrutinib pharmaceutical composition and preparation as well as preparation method and application thereof Technical Field The invention relates to the technical field of pharmaceutical preparations, in particular to a pharmaceutical composition and a preparation containing ibrutinib, and a preparation method and application thereof. Background Ibrutinib (Ibrutinib), also known as ibrutinib, is commonly developed by us PHARMACYCLICS and us predniso (Johnson & Johnson), is approved by the us FDA first to be marketed in 2013, is approved by the chinese CFDA in 2017, and is incorporated into the medical insurance class b under the trade name IMBRUVICA (velcade). The chemical name is 1- ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-1-yl) piperidin-1-yl) prop-2-en-1-one, the molecular formula is C 25H24N6O2, the structural formula is shown in the specification。 And Ibrutinib is the first small molecule BTK (bruton's tyrosine kinase) inhibitor. BTK is a potential therapeutic target for B-cell related malignancies including Chronic Lymphocytic Leukemia (CLL), non-hodgkin lymphoma (NHL), mantle Cell Lymphoma (MCL), etc., and at the same time, BTK inhibitors are also expected to be the first disease modifying therapeutic drugs targeting the origin of brain injury in Multiple Sclerosis (MS) patients with brain permeability and selectivity, and drugs for Systemic Lupus Erythematosus (SLE) treatment, etc., with broad indication potential. The clinical ibrutinib has better curative effect on various malignant tumors, but ibrutinib is a drug with low solubility and high permeability, belongs to the class of BCS, and is almost insoluble in water. In order to ensure bioavailability, ibrutinib capsule developed by original research company adopts surfactant sodium dodecyl sulfate to increase solubility of medicine after ibrutinib is micronized, but the bioavailability of the preparation produced by the method is still not high, the absolute bioavailability of oral absorption of patients in fasting state is 2.9%, and absorption in fed state is doubled. And the single dose of ibrutinib clinical is larger, for example, 560mg is used for the single daily dose of the obtained batch for treating mantle cell lymphoma and marginal zone lymphoma, and 420mg is used for the single daily dose of the chronic lymphocytic leukemia, small lymphocytic lymphoma, fahrenheit macroglobulinemia and chronic graft-versus-host disease. Higher doses lead to greater incidence of gastrointestinal adverse effects (constipation, abdominal pain, diarrhea, nausea, vomiting, etc.). Wherein diarrhea is the adverse reaction with the highest incidence of ibrutinib. The results of the RESONATE phase III study showed a total diarrhea incidence of 47.7% and a grade 3 diarrhea incidence of 4.1% at 9 months follow-up. In addition, ibrutinib has common side effects such as hypertension, atrial fibrillation, transaminase elevation, fatigue, rash, etc. How to reduce the side effects of ibrutinib in clinical application, besides reducing the dosage of ibrutinib in proper amount according to the pharmaceutical use guidelines, scientific researchers develop various methods aiming at improving the bioavailability of ibrutinib, and try to reduce the clinical side effects caused by the method. Meanwhile, according to retrospective study of real-world clinical data, it is found that the highest blood concentration C max in a patient of ibrutinib has a correlation with certain specific adverse reactions, for example, higher blood concentration may increase the risk of bleeding, including epistaxis, gingival bleeding, skin ecchymosis, and the like. Studies have shown that when Css (steady state plasma concentration) is greater than 500 ng/mL, the risk of developing ≡3 grade bleeding increases 2.1 fold (ratio versus or= 2.1,95% confidence interval of 1.3-3.4). Therefore, a preparation scheme which can not only effectively improve the bioavailability, but also enable the medicine to be released relatively stably is developed, the risk of aggravating side effects in the process of taking the medicine by patients is reduced, and the preparation method has important clinical significance. Scientists have studied on the aspects of raw materials, preparation improvement, administration route change and the like, so as to improve the defects of the original preparation in clinic. WO2016/207172A1 reports the preparation of amorphous forms of ibrutinib by adding base to an organic solution of ibrutinib hydrochloride. The preparation of ibrutinib amorphous form by rotary evaporation and anti-solvent methods is reported in WO2016/088074A1 filed by Dr. Reddy's Laboratories, inc. and in WO2017/085628A1 filed by Olon S.P.A. Inc., but neither solubility nor stability data are reported. WO2016/160604A1 filed by PHARMACYCLICS discloses a eutectic form formed by ibrutinib and various carboxylic acids and amides, wherein the preparation method comprises a solvent method