CN115054603A

CN115054603A - Ibrutinib pharmaceutical composition, preparation method and pharmaceutical preparation thereof

Info

Publication number: CN115054603A
Application number: CN202210722376.8A
Authority: CN
Inventors: 沈建人; 李圣男; 万建胜; 盛小茜
Original assignee: Shanghai Xuantai Pharmaceutical Technology Co ltd
Current assignee: Shanghai Xuantai Pharmaceutical Technology Co ltd
Priority date: 2022-06-20
Filing date: 2022-06-20
Publication date: 2022-09-16

Abstract

The invention relates to a pharmaceutical composition, which comprises ibrutinib or pharmaceutically acceptable salt thereof as an active ingredient, a carrier material and a solubilizer. The invention also relates to a preparation method of the pharmaceutical composition and a pharmaceutical preparation containing the pharmaceutical composition.

Description

Ibrutinib pharmaceutical composition, preparation method and pharmaceutical preparation thereof

Technical Field

The invention relates to a pharmaceutical composition, a preparation method thereof and a pharmaceutical preparation. In particular, the present invention relates to a pharmaceutical composition comprising ibrutinib or a pharmaceutically acceptable salt thereof as an active ingredient, a method for preparing the same, and a pharmaceutical formulation comprising the same.

Background

Ibrutinib (Ibrutinib), chemically known as 1- { (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidin-1-yl } prop-2-en-1-one, is a Bruton's Tyrosine Kinase (BTK) inhibitor, is mainly used for clinically treating Mantle Cell Lymphoma (MCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 17 p-deleted chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenstrom's Macroglobulinemia (WM), Marginal Zone Lymphoma (MZL), chronic graft-versus-host disease (VHcGD), and the like, and can also be used for treating autoimmune diseases or disorders, such as Parkinson's disease or disorder, A heteroimmune disease or disorder.

Ibrutinib is soluble in dimethyl sulfoxide and methanol, practically insoluble in water, and slightly soluble in hydrochloric acid solution at pH 1.2. It belongs to the BCS II class of compounds according to the biopharmaceutical classification system. The compound can be prepared into a high-quality pharmaceutical composition or preparation, and has various challenges in water solubility, but the compound can be prepared into a solubilizing preparation to solve the problems of low bioavailability and poor absorption in vivo. Such as a solid dispersion solubilizing formulation. Additionally, Ibrutinib capsules (I) are marketed

) The absolute bioavailability of (a) is about 3%, the food effect is relatively severe. And taking ibrutinib capsule after fasting (

) In contrast, C of ibrutinib taken with a high-fat high-calorie diet (800 calories to 1,000 calories, 50% of diet total calories from fat) _max Increase 2-4 fold, AUC increase about 2 fold.

WO 2013184572 discloses an ibrutinib oral formulation, which comprises ibrutinib, a diluent, a disintegrant, a surfactant and a lubricant, so as to meet the requirements of dissolution rate, stability, bioavailability and the like of ibrutinib during the preparation of the ibrutinib.

CN107427498A discloses a high-load solid tablet formulation comprising ibrutinib, wherein said high-load solid tablet formulation comprises at least 50% w/w of ibrutinib.

CN106573002A discloses a solid dispersion solubilized formulation comprising ibrutinib, prepared using a spray-drying process. The prepared ibrutinib preparation has obvious in-vivo solubilization effect, but the spray drying uses an organic solvent, so that the preparation is not environment-friendly and has the risk of solvent residue.

Disclosure of Invention

In view of the above, it is an object of the present invention to provide pharmaceutical compositions of ibrutinib which overcome the above-mentioned drawbacks of the prior art.

In a first aspect, the present invention provides a pharmaceutical composition comprising ibrutinib or a pharmaceutically acceptable salt thereof, a carrier material and a solubilizer, wherein

The support material is one or more selected from the group consisting of: polyvinylpyrrolidone-vinyl acetate copolymer, ethylene glycol unit-containing polymer, and hydroxypropyl methylcellulose derivative;

the solubilizer is polyethylene glycol 1000 vitamin E succinate

In a second aspect, the present invention provides a process for preparing a pharmaceutical composition of the first aspect, comprising:

preheating a hot melt extruder to about 110 ℃ to about 200 ℃;

feeding the uniformly mixed mixture of the components in the metering ratio into the hot-melt extruder, or directly feeding the components in the metering ratio into the hot-melt extruder;

extruding; and

cooling the resulting extrudate to obtain the pharmaceutical composition.

In a third aspect, the present invention provides a pharmaceutical formulation comprising the pharmaceutical composition of the first aspect.

Drawings

FIG. 1 shows ibrutinib-

XRPD pattern of VA64 pharmaceutical composition.

FIG. 2 shows ibrutinib-

The dissolution curves of VA64 pharmaceutical compositions 1-4 and the raw material medicines in a buffer solution with pH 6.8.

FIG. 3 shows ibrutinib-

VA64 pharmaceutical composition 1-4 and commercially available ibrutinib capsule(s) ((R))

) Mean plasma ibrutinib concentration-time curve after human subjects in fasting condition.

FIG. 4 shows Ebrutinib-

VA64 tablets 1-4 and commercially available ibrutinib capsules (

) Mean plasma ibrutinib concentration-time curve after human subjects under postprandial conditions.

Detailed Description

The present invention will be described in further detail below. Such description is for the purpose of illustration and not for the purpose of limitation. Other advantages and effects of the present invention will be readily apparent to those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways. Various modifications and alterations may be made by those skilled in the art without departing from the spirit of the invention.

General terms and definitions

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety if not otherwise indicated.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the definitions provided herein will control.

When an amount, concentration, or other value or parameter is expressed as a range, preferred range, or upper preferable numerical limit with lower preferable numerical limit, it is understood that any range by combining any pair of a range upper limit or preferred numerical value with any range lower limit or preferred numerical value is specifically disclosed, regardless of whether the range is specifically disclosed. Unless otherwise indicated, numerical ranges set forth herein are intended to include the endpoints of the ranges, and all integers and fractions within the ranges. The scope of the invention is not limited to the specific values recited when defining a range. For example, "1-30" encompasses 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, as well as any subrange consisting of any two values therein, e.g., 2-6, 3-5, 2-10, 3-15, 4-20, 5-19, 4-30, 5-29, etc. The terms "about" and "approximately," when used in conjunction with a numerical variable, generally mean that the value of the variable and all values of the variable are within experimental error (e.g., within 95% confidence interval for the mean) or within ± 10% of the specified value, or more.

The term "metering ratio" refers to the ratio of various substances according to a certain weight. For example, in the present invention, the active ingredient (ibrutinib or a pharmaceutically acceptable salt thereof), the carrier material, the solubilizer and optionally pharmaceutically acceptable pharmaceutical excipients are proportioned according to a certain weight ratio.

The terms "optional" or "optionally present" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The term "selected from …" means that one or more elements in the later listed groups are independently selected and may include a combination of two or more elements. The term "one or more" or "at least one" as used herein refers to one, two, three, four, five or more. Unless otherwise indicated, the terms "combination thereof" and "mixture thereof" refer to a multi-component mixture of the elements described, such as two, three, four, and up to the maximum possible multi-component mixture.

The expressions "comprising" or similar expressions "including", "containing" and "having" and the like which are synonymous are open-ended and do not exclude additional, unrecited elements, steps or components. The expression "consisting of …" excludes any element, step or ingredient not specified. The expression "consisting essentially of …" means that the scope is limited to the specified elements, steps or components, plus optional elements, steps or components that do not materially affect the basic and novel characteristics of the claimed subject matter. It is understood that the expression "comprising" encompasses the expressions "consisting essentially of …" and "consisting of …".

The term "pharmaceutically acceptable" refers to those materials which are, within the scope of normal medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.

The term "pharmaceutically acceptable excipients" refers to those carrier substances which have no significant irritating effect on the organism and do not impair the biological activity and properties of the active compounds. "pharmaceutically acceptable excipients" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

The term "pharmaceutical composition" refers to a substance comprising one or more active ingredients together with a carrier material and optionally one or more pharmaceutically acceptable pharmaceutical excipients. It may be simply referred to as a composition in the present invention. For example, pharmaceutical composition 1-1 may be referred to simply as composition 1-1.

The term "K value", also known as Fikentscher K value, refers to a measure of the molecular weight of a polymer comprising vinylpyrrolidone units, or a mixture thereof, as is commonly used in the art, and can be determined as a 1% by weight aqueous solution as described in H.Fikentscher, Cellulose-Chemie,13(1932), 58-64/71-74.

The term "blank composition" means a pharmaceutical composition which is free of active ingredient (i.e. ibrutinib or a pharmaceutically acceptable salt thereof) and only comprises carrier material and solubilising agent and optionally other pharmaceutically acceptable pharmaceutical excipients, relative to the pharmaceutical composition.

The terms "pharmaceutical product", "pharmaceutical dosage form", "pharmaceutical preparation" and the like refer to a pharmaceutical composition that is administered to a patient in need of treatment, which may generally be in the form of: powder, granule, pill, capsule, tablet, solution, suspension or patch, etc.

The term "dispersed at the molecular level" means that the drug is dispersed in the carrier material to form a single phase pharmaceutical composition. In the present invention, the term means that ibrutinib or a pharmaceutically acceptable salt thereof is dispersed in the carrier material to form a single-phase pharmaceutical composition (also referred to as a solid solution, dispersion or solid dispersion), and the Tg value of the obtained pharmaceutical composition of ibrutinib or a pharmaceutically acceptable salt thereof is different from the Tg values of the carrier material and the bulk drug of ibrutinib.

The terms "dissolved", "dispersed at the molecular level", "dispersion", "solid solution", "solid dispersion" are used herein as convenient to describe the pharmaceutical compositions of the invention in various stages of preparation and at various temperatures.

The terms "pharmaceutically active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating or preventing a disease or disorder of interest.

The term "apparent solubility" refers to an empirically determined solubility of a solute in a solvent system. The apparent solubility may be higher or lower than the equilibrium solubility due to short supersaturation or incomplete dissolution or insufficient time to reach equilibrium.

The term "bioavailability" refers to the degree to which a drug or other substance is available to a target tissue after administration.

The term "plasma drug concentration time to peak (T) _max ) By "means that the peak plasma drug concentration (C) is reached after administration of the drug _max ) Time of (d).

The term "peak plasma drug concentration (C) _max ) "refers to the maximum plasma drug concentration achieved after administration of the drug.

The term "AUC _0-∞ "refers to the area under the curve of the plasma drug concentration versus time curve from 0 to infinity time after drug administration; and the term "AUC _0-t "refers to the area under the curve of the plasma drug concentration versus time curve from 0 to t at time after drug administration.

All percentages, parts, ratios, etc. herein are by weight unless otherwise indicated.

Pharmaceutical composition, pharmaceutical preparation and preparation thereof

In one aspect, the present invention relates to an ibrutinib pharmaceutical composition comprising ibrutinib or a pharmaceutically acceptable salt thereof, a carrier material and a solubilizing agent.

In one embodiment of the invention, the support material is one or more selected from the group consisting of: polyvinylpyrrolidone-vinyl acetate copolymer, ethylene glycol unit-containing polymer, and hydroxypropyl methylcellulose derivative.

In one embodiment of the invention, ibrutinib or a pharmaceutically acceptable salt thereof is dissolved or dispersed at the molecular level in the carrier material.

In another embodiment, the carrier material used according to the invention is a polyvinylpyrrolidone-vinyl acetate copolymer, obtained, for example, by free-radical polymerization of N-vinylpyrrolidone with vinyl acetate in 2-propanol. The polyvinylpyrrolidone-vinyl acetate copolymer may also be a copolymer of vinylpyrrolidone and vinyl acetate in a weight ratio of 15:85 to 40:60, for example as disclosed in US 5426163A. Vinylpyrrolidone and vinyl acetate in polyvinylpyrrolidone-vinyl acetate copolymers suitable as carrier materials in accordance with the inventionThe weight ratio of alkenyl ester is from about 1:9 to about 9:1, more preferably from about 4:6 to about 6: 4. The copolymers have K values of from about 25 to about 70, preferably from about 25 to about 35. The polyvinylpyrrolidone-vinyl acetate copolymers used in the present invention are also commercially available from BASF, for example

VA64 and/or International Specialty Products

S30 (both being copolymers of vinylpyrrolidone and vinyl acetate in a 6:4 weight ratio), but is not limited thereto.

Also suitable as carrier materials in the present invention include, but are not limited to, polymers containing ethylene glycol units such as polyethylene glycol/vinyl caprolactam/vinyl acetate copolymers which may be polyethylene glycol (PEG)6000, vinyl caprolactam and vinyl acetate in a weight ratio of about 13:57:30, commercially available products such as from BASF corporation

。

Also suitable as carrier materials in the present invention include, but are not limited to, hydroxypropylmethylcellulose derivatives such as Hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose trimellitate (HPMCT), hydroxypropylmethylcellulose phthalate (HPMCP), Hydroxypropylmethylcellulose Succinate (HPMCs), hydroxypropylmethylcellulose trimellitate (HPMCT), hydroxypropylmethylcellulose acetate phthalate (HPMCP) and hydroxypropylmethylcellulose acetate maleate (hpmcm).

In one embodiment of the invention, the solubilizing agent is polyethylene glycol 1000 Vitamin E succinate (D- α -tocopheryl polyethylene glycol 1000succinate, TPGS, Vitamin E TPGS, Tocopherolan). TPGS suitable for use in the present invention is a water-soluble derivative of vitamin E, prepared by esterifying the carboxyl group of Vitamin E Succinate (VES) with polyethylene glycol (PEG)1000The relative molecular weight was about 1513, which was loaded in the United states Pharmacopeia. TPGS acts as a solubilizing agent in the pharmaceutical compositions and pharmaceutical formulations of the present invention and may also contribute to the improvement of oral bioavailability by affecting the efflux of the drug. An example of a TPGS that can be used in the present invention is the commercially available product Kolliphor from BASF corporation ^TM TPGS, but is not limited thereto. In a preferred embodiment of the invention, the TPGS is Kolliphor ^TM TPGS。

In one embodiment of the invention, the carrier material is a polyvinylpyrrolidone-vinyl acetate copolymer, a polyethylene glycol/vinyl caprolactam/vinyl acetate copolymer, a hydroxypropyl methylcellulose derivative, or a combination thereof, preferably a polyvinylpyrrolidone-vinyl acetate copolymer. In another embodiment, the polyvinylpyrrolidone-vinyl acetate copolymer used in the present invention, also referred to as Copovidone, may be a weight ratio of vinylpyrrolidone units to vinyl acetate units of from about 1:9 to about 9:1, preferably from about 4:6 to about 6: 4. The K value of the copolymer is from about 25 to about 70, preferably from about 25 to about 35.

In one embodiment of the invention, the carrier material is a polyvinylpyrrolidone-vinyl acetate copolymer.

In one embodiment of the invention, the carrier material is a polyethylene glycol/vinyl caprolactam/vinyl acetate copolymer. In one embodiment of the invention, the carrier material is a hydroxypropyl methylcellulose derivative.

In a particular embodiment of the invention, the carrier material is a copolymer of vinylpyrrolidone units and vinyl acetate units in a weight ratio of 6:4, for example

VA64 and/or

S30。

In a specific embodiment of the invention, the carrier material is polyethylene glycol (PEG)6000, vinyl hexyl acetateCopolymers of lactam and vinyl acetate in a weight ratio of about 13:57:30, e.g.

. In a particular embodiment of the invention, the carrier material is a hydroxypropyl methylcellulose derivative, such as hypromellose acetate succinate.

In a particular embodiment of the invention, the solubilizing agent is vitamin E polyethylene glycol succinate (TPGS). In one embodiment of the present invention, the support material is

VA64, and the solubilizer is TPGS.

In one embodiment of the present invention, the support material is

And the solubilizer is TPGS.

In a particular embodiment of the invention, the carrier material is HPMCAS and the solubilizing agent is TPGS.

Typically, the solubilizing agent is present in an amount of about 1-30 wt.% relative to the total weight of the active ingredient ibrutinib or a pharmaceutically acceptable salt thereof and the carrier material, e.g., the solubilizing agent is present in about 1 wt.%, 2 wt.%, 3 wt.%, 4 wt.%, 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, 9 wt.%, 10 wt.%, 11 wt.%, 12 wt.%, 13 wt.%, 14 wt.%, 15 wt.%, 16 wt.%, 17 wt.%, 18 wt.%, 19 wt.%, 20 wt.%, 21 wt.%, 22 wt.%, 23 wt.%, 24 wt.%, 25 wt.%, 26 wt.%, 27 wt.%, 28 wt.%, 29 wt.%, 30 wt.% relative to the total weight of the active ingredient ibrutinib or a pharmaceutically acceptable salt thereof, the carrier material, and the solubilizing agent.

In one embodiment of the invention, the weight ratio of the active ingredient ibrutinib or a pharmaceutically acceptable salt thereof to the carrier material is 1:1-1:5, e.g. 1:1, 1:2, 1:3, 1:4, 1: 5; preferably 1:1 to 1:4, such as 1:1, 1:2, 1:3, 1: 4; more preferably 1:2 to 1: 3; most preferably 1: 2.

In one embodiment of the invention, the weight ratio of the active ingredient ibrutinib or a pharmaceutically acceptable salt thereof to the solubilizer is 3:1 to 1:1, such as 3:1.0, 3:1.1, 3:1.2, 3:1.3, 3:1.4, 3:1.5, 3:1.6, 3:1.7, 3:1.8, 3:1.9, 3:2, 3:2.1, 3:2.2, 3:2.3, 3:2.4, 3:2.5, 3:2.6, 3:2.7, 3:2.8, 3:2.9, 1: 1; preferably 3:1 to 3:2, more preferably 3:1.2 to 3:1.9, most preferably 3: 1.8. In one embodiment of the invention, the weight ratio of the active ingredient or a pharmaceutically acceptable salt thereof, the carrier material, the solubilizer is 1:1:0.6 to 1:5:0.6, e.g., 1:1:0.6, 1:2:0.6, 1:3:0.6, 1:4: 0.6; preferably 1:2: 0.6.

The pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable pharmaceutical excipients including, but not limited to, one or more of surfactants, pH adjusters, diluents, disintegrants, binders and lubricants.

In another aspect, the present invention also provides methods of preparing the pharmaceutical compositions of the present invention, including but not limited to hot melt extrusion processes. For example, the hot melt extrusion process comprises the following specific steps:

preheating a hot melt extruder to about 110 ℃ to about 200 ℃;

feeding a uniformly mixed mixture of the components in a metering ratio into the hot-melt extruder, or directly feeding the components in the metering ratio into the hot-melt extruder;

extruding; and

cooling the resulting extrudate to obtain the pharmaceutical composition.

In one embodiment of the invention, each ingredient in the hot-melt extrusion process comprises a mixture of ibrutinib or a pharmaceutically acceptable salt thereof, a carrier material and optionally pharmaceutically acceptable pharmaceutical excipients or a mixture of ibrutinib, a carrier material, polyethylene glycol 1000 vitamin E succinate and optionally pharmaceutically acceptable pharmaceutical excipients.

In one embodiment of the present invention, the hot-melt extrusion method further comprises cooling the extrudate of step (iv), pulverizing and sieving, optionally mixing with pharmaceutically acceptable pharmaceutical excipients.

The cooling method described in the production method of the present invention is not particularly limited, and may include air cooling, water cooling, mechanical cooling, and the like.

There is no particular limitation on the type of extruder suitable for use in the present invention, which includes, but is not limited to, single screw or twin screw type hot melt extruders. In one embodiment of the present invention, the extruder used to prepare the pharmaceutical composition of the present invention is a twin screw type extruder. In this case, there is no particular limitation on the type of screw rotation, which includes, but is not limited to, co-rotating twin screws, counter-rotating twin screws, and double-tapered screw rotation modes.

In a preferred embodiment of the present invention, the extruder used for preparing the pharmaceutical composition of the present invention is preferably a co-rotating twin-screw type extruder. The temperature set for the hot melt extruder is about 110 ℃ to about 200 ℃, for example, 110 ℃, 115 ℃, 120 ℃, 125 ℃, 130 ℃, 135 ℃, 140 ℃, 145 ℃, 150 ℃, 155 ℃, 160 ℃, 165 ℃, 170 ℃, 175 ℃, 180 ℃, 185 ℃, 190 ℃, 195 ℃, 200 ℃; preferably from about 120 ℃ to about 190 ℃, more preferably 125 ℃; screw speeds of about 100 to about 400rpm, e.g., 100rpm, 150rpm, 200rpm, 250rpm, 300rpm, 350rpm, 400 rpm; preferably 200 rpm. The ratio of screw length to diameter (L/D) may be selected from about 25 to about 40, for example, the ratio of screw length to diameter (L/D) is 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40. If the temperature of the hot-melting extruder is too low, the L/D is too short, and the rotating speed of the screw is too low, heat energy and mechanical energy are not sufficiently provided in the hot-melting process, so that ibrutinib or pharmaceutically acceptable salts thereof, carrier materials or polyethylene glycol 1000 vitamin E succinate cannot reach a molten state, or ibrutinib or pharmaceutically acceptable salts thereof cannot be dissolved in the molten carrier materials. Therefore, although ibrutinib or a pharmaceutically acceptable salt thereof and a carrier material are well mixed, a single-phase solid dispersion (solid solution) in which ibrutinib or a pharmaceutically acceptable salt thereof is dissolved or dispersed at a molecular level in the carrier material cannot be obtained. If the hot-melt extruder temperature is too high, the L/D is too long, and the screw speed is too fast, thermal and mechanical energy is supplied in excess during the hot-melt process, which can cause unwanted degradation of ibrutinib or its pharmaceutically acceptable salts and/or carrier materials and/or TPGS, even if a single-phase solid dispersion (solid solution) is obtained in which ibrutinib or its pharmaceutically acceptable salts are dissolved or dispersed at the molecular level in the carrier material.

In addition, the invention also provides a pharmaceutical preparation containing the pharmaceutical composition. The pharmaceutical composition of the invention can be further combined with pharmaceutically acceptable pharmaceutical excipients to prepare various dosage forms according to the needs. In one embodiment of the present invention, the pharmaceutical formulation may be in the form of powder, granules, pills, capsules or tablets.

The pharmaceutically acceptable pharmaceutical excipients include, but are not limited to, one or more of surfactants, pH adjusters, diluents, disintegrants, binders, and lubricants.

It should be emphasized that the list of pharmaceutically acceptable pharmaceutical excipients is merely illustrative, representative and not in any way exhaustive. Therefore, the present invention is not limited to the pharmaceutically acceptable excipients listed below.

Advantageous effects

Compared with the prior art, the pharmaceutical composition provided by the invention has the advantages that the in vivo absorption and bioavailability of ibrutinib or pharmaceutically acceptable salts thereof are increased. In addition, the pharmaceutical composition is prepared by a simple and easy-to-operate hot-melt extrusion method, and compared with the prior art, the pharmaceutical composition does not use an organic solvent, reduces energy consumption and improves production capacity. Specifically, a certain proportion of VA64 as a carrier material and ibrutinib or a pharmaceutically acceptable salt thereof can be prepared into a pharmaceutical composition in which ibrutinib or a pharmaceutically acceptable salt thereof is dissolved or dispersed in the carrier material at a molecular level through the hot-melt extrusion process. The inventors of the present invention have more surprisingly found that ibrutinib or a pharmaceutically acceptable salt thereof is dispersed in

The pharmaceutical composition in the VA64 carrier can improve the solubility of the ibrutinib or the pharmaceutically acceptable salt thereof in the gastrointestinal tract, increase the absorption of the ibrutinib or the pharmaceutically acceptable salt thereof in the body and improve the bioavailability in the body.

In addition, the inventors of the present invention have also surprisingly found that the solubility of ibrutinib or a pharmaceutically acceptable salt thereof in the gastrointestinal tract can be further improved after adding TPGS to the pharmaceutical composition, thereby further increasing the absorption and bioavailability of ibrutinib or a pharmaceutically acceptable salt thereof. In addition, when the pharmaceutical composition is prepared by adopting the hot-melt extrusion process, TPGS is added, so that the hot-melt extrusion operating temperature of the pharmaceutical composition is obviously reduced, the torque is obviously reduced, the energy consumption is reduced, the production capacity is improved, and the pharmaceutical composition also has better production process characteristics, such as easy grinding, better compressibility, short disintegration time and the like.

Furthermore, the inventor of the present invention has unexpectedly found that the ibrutinib pharmaceutical composition of the present invention can significantly reduce food effect, and greatly improve the compliance of clinical medication for patients.

Examples

The present invention will be described in further detail with reference to specific examples.

It should be noted that the following examples are only for clearly illustrating the technical solutions of the present invention, and are not intended to limit the present invention. Other variants and modifications will be apparent to those skilled in the art in light of the foregoing description, and it is not necessary or exhaustive to have all embodiments disclosed, and obvious variations and modifications are possible within the scope of the invention. Unless otherwise indicated, both the instrumentation and reagent materials used herein are commercially available.

The measurement methods used for evaluating the physicochemical properties in the respective examples are as follows:

1. glass transition temperature (Tg): accurately weighing more than 3mg of an object to be detected (an ibrutinib raw material drug (hereinafter referred to as a raw material drug), a drug-loaded composition (namely the drug composition of the invention) or a blank composition) to perform modulated differential scanning calorimetry (mDSC, TA Q2000 differential scanning calorimeter), wherein the scanning temperature range is 40-200 ℃.

2. Powder X-ray diffraction (XRPD): taking a proper amount of a substance to be detected (a raw material drug, a drug-loaded composition or a blank composition), and recording a powder X-ray diffraction pattern (a D8ADVANCE X-ray diffractometer manufactured by BRUKER) under the conditions of a Cu target, a voltage of 45kv and a current of 45 mA.

3. Apparent solubility: weighing excess ibrutinib pharmaceutical composition into a container, adding phosphate buffer with pH 6.8 corresponding to about 2/3, and shaking the container in a shaker at 37 deg.C for 2 h. The contents of the vessel were filtered through a 0.45 μm filter, the filtrate was collected, diluted with an appropriate amount of acetonitrile, vortex mixed and assayed for ibrutinib concentration by HPLC analysis as follows:

4. dissolution rate

Dissolution sample analysis method: the same HPLC analysis method as described above for the apparent solubility determination.

EXAMPLE 1 Ibrutinib-polyvinylpyrrolidone-vinyl acetate copolymer pharmaceutical composition 1.1 preparation

Ibrutinib-

The composition and the dosage of each component of the VA64 pharmaceutical composition are shown in the table 1-1.

The preparation method comprises the following steps: ibrutinib and carrier material were mixed in the amounts shown in Table 1-1

VA64 and/or solubilizer

TPGS was fed into the hopper of a co-rotating twin screw extruder (Omicron 12, Steer, india) directly or after being mixed homogeneously in a mixer, and extrusion was carried out while controlling the temperature of the co-rotating twin screw extruder between about 120 ℃ and about 190 ℃, with the screw rotation speed being about 100 to about 400 rpm. Cooling, crushing and sieving the obtained extrudate to obtain the ibrutinib-

VA64 pharmaceutical composition 1-1 to composition 1-9.

TABLE 1-1 Ibrutinib-

VA64 pharmaceutical composition (parts by weight)

1.2. Evaluation of physicochemical Properties

1.2.1. The results of the appearance and glass transition temperature (Tg) tests are detailed in tables 1-2.

TABLE 1-2 Ebrutinib-

Appearance and glass transition temperature (Tg) of VA64 composition

As can be seen from Table 1-2, compositions 1-1 to 1-6 all formed transparent extrudates. And the pharmaceutical compositions 1-1 to 1-6 all have only one Tg value, and compared with the Tg values of the corresponding blank compositions 1-2 and 1-4, the Tg values of the compositions 1-2 and 1-4 are obviously shifted, and the difference of the Tg values with the melting peak of an ibrutinib bulk drug is obvious. The above results clearly show that in the pharmaceutical compositions 1-1 to 1-6 of the present invention, ibrutinib is dissolved or dispersed at the molecular level in the carrier material, forming a solid dispersion in the form of a molecular dispersion, i.e. a glass solution.

In addition, compositions 1-7 and 1-8 did not form clear extrudates, indicating that ibrutinib was not dissolved or molecularly dispersed in the support material and that no molecularly dispersed solid dispersion, i.e., glass solution, was formed. The extrudates of compositions 1-9 were still in powder form, indicating that the solubilizer poloxamer P407 is not compatible with the carrier and drug.

1.2.2. Apparent solubility determination

The test results are detailed in tables 1-3.

Tables 1-3 Ebrutinib-

Apparent solubility of VA64 composition in pH 6.8 buffer

Note:

is a commercially available ibrutinib capsule.

As can be seen from tables 1-3, compositions 1-1, 1-2, 1-5 and 1-6 of the present invention, which were prepared using a hot melt extrusion process, all had significant solubilization of ibrutinib, indicating that

VA64 has better solubilizing effect on ibrutinib.

(ii) a carrier material within the composition: (

VA64) and bulk drug were adjusted from 1:1 (composition 1-1) to 5:1 (composition 1-6) increasing the apparent solubility from 0.15mg/ml to 0.44mg/ml, indicating that the weight ratio of carrier material to bulk drug had an effect on ibrutinib solubilityLarger, but when the carrier material is increased to some extent (compositions 1-5 and compositions 1-6), the solubility does not change much. However, the addition of a small amount of TPGS (compositions 1-3) on the basis of compositions 1-2 increased the apparent solubility from 0.21mg/ml to 0.43mg/ml, indicating that compositions comprising TPGS could greatly increase the solubility of ibrutinib with a reduced amount of carrier material.

1.2.3pH 6.8 dissolution determination

Most of the drugs are mainly absorbed in the human body at the small intestine, which has a pH of about 6.8, and all the compositions of the present invention were tested for dissolution in phosphate buffer at pH 6.8, and the results are shown in tables 1 to 4.

Tables 1-4 Ebrutinib-

Dissolution rate of VA64 composition in pH 6.8 buffer

As can be seen from the data in the table, the dissolution rate of the raw material drug within 2h is only 10.2%. Compared with the bulk drugs, the dissolution rates of the compositions 1-3, 1-4, 1-5 and 1-6 in the phosphate buffer solution with the pH value of 6.8 for 120min are all higher than 85%, and are remarkably higher than the dissolution rates of the bulk drugs, which shows that the compositions can remarkably improve the absorption of the ibrutinib in the body. In particular, the dissolution rate of the compositions 1 to 4 at the time point of 30min is already above 60%, indicating that the composition can better improve the absorption of the ibrutinib in the body.

Example 2 Ibrutinib-polyethylene glycol/vinyl caprolactam/vinyl acetate copolymer, Ibrutinib-hydroxypropyl methylcellulose derivative composition

2.1. Preparation of

Ibrutinib-

The combination of ibrutinib-HPMCAS composition and the amounts of each component are shown in table 2-1.

TABLE 2-1 Ebrutinib-

Composition of Ibrutinib-HPMCAS composition (parts by weight)

The preparation method comprises the following steps: ibrutinib and carrier material were mixed in the amounts shown in Table 2-1

Or HPMCAS, either directly or after mixing homogeneously in a mixer, was fed into the hopper of a co-rotating twin screw extruder (Omicron 12, Steer, india) at a screw speed of about 100 to about 400rpm, with the co-rotating twin screw extruder temperature controlled between about 120 ℃ and about 190 ℃. Cooling, crushing and sieving the obtained extrudate to obtain the ibrutinib-

And an ibrutinib-HPMCAS composition.

2.2. Evaluation of physicochemical Properties

2.2.1. Apparent solubility determination

TABLE 2-2 Ebrutinib-

Apparent solubility of Ibrutinib-HPMCAS composition in pH 6.8 buffer

As can be seen from Table 2-2, ibrutinib-

And the ibrutinib-HPMCAS composition can obviously improve the apparent solubility of ibrutinib, wherein the improvement of the compositions 2 to 5 is most obvious, which indicates that the improvement is realized by adoptingBy using

The Ibrutinib serving as a carrier material can obviously improve the apparent solubility of the Ibrutinib and can further improve the absorption of the Ibrutinib in a body.

On the other hand, when the weight ratio of the bulk drug to the carrier material is kept to be 1:2, after a proper amount of TPGS is added on the basis of the composition 2-2 (corresponding to the composition 2-3), the apparent solubility is increased from 0.15mg/ml to 0.38mg/ml, which shows that the TPGS can further improve the dissolution rate of the ibrutinib and can further improve the absorption of the ibrutinib in vivo.

2.2.2 pH 6.8 dissolution determination

Tables 2-3 Ebrutinib-

Dissolution of the composition at pH 6.8

As can be seen from tables 2-3, compared with the bulk drugs:

1) the dissolution rate of the composition of the invention in pH 6.8 within 2h is remarkably improved, wherein the improvement of the composition 2-5 is most obvious, the dissolution rate in 30min is more than 50 percent, which indicates that the composition adopts

The carrier material can obviously improve the dissolution rate of the ibrutinib and further improve the absorption of the ibrutinib in vivo.

2) The dissolution rate of the composition 2-3 containing TPGS is obviously higher than that of the composition 2-2 without TPGS, which shows that the TPGS can further improve the dissolution rate of ibrutinib and can further improve the absorption of ibrutinib in vivo.

Example 3 Ibrutinib-polyvinylpyrrolidone-vinyl acetate copolymer, Ibrutinib-

Evaluation of preparation method of composition

3.1 Hot melt extrusion Process

TABLE 3-1 Hot melt extrusion Process parameters

The specific procedure is described in the preparation of each of the compositions of examples 1-2. As shown in Table 3-1, the compositions 1-3, 1-4 and 2-3 prepared by adding proper amount of TPGS have lower energy consumption per kilogram and lower generated torque percentage under the same carrier material condition, which shows that the composition prepared by using TPGS can obviously reduce the energy consumption and the instrument torque of the hot-melt extrusion process and greatly improve the operability.

3.2 crushing Process

TABLE 3-2 extrudate crush Process parameters

The extrudate from each composition was cut into strips of about 2cm with scissors and comminuted with a Fitzmill pulverizer (model: RP-L1A) at 4500RPM for 60 seconds. And (4) sieving the crushed particles with a 60-mesh sieve, weighing the weight of the powder obtained after drying in the sun, and calculating the crushing yield.

As shown in Table 3-2, the compositions prepared by the formulation with TPGS added had higher sieving efficiency (more than 85%) compared to the sieving efficiency of compositions 1-2 and 2-2 prepared without TPGS (less than 75%), indicating greater operability of the comminution process.

3.3 tabletting Process

Tables 3-3 tablet composition (% by weight) and tableting process parameters

Composition/parameter	Compositions	1 to 2	Composition 2-2	Compositions 1 to 3	Compositions 1 to 4	Compositions 2 to 3
							Solid dispersion powder	46.8	46.8	53.8	56.2	56.2
Mannitol	34.4	34.4	28.7	25.6	25.6
						Croscarmellose sodium	15.8	15.8	14.5	15.2	15.2
Colloidal silica	1.5	1.5	1.4	1.5	1.5
						Magnesium stearate	1.5	1.5	1.6	1.5	1.5
Principal pressure of tablet press (KN)	15.5	15.5	15.5	15.5	15.5
						Tabletting speed (rpm)	28	28	28	28	28
Target fill volume (mg)	900	900	900	900	900
						Hardness of the tablet core (N)	150	160	200	220	235
Disintegration time (min)	18	20	12	10	13

Note: refers to a solid powder prior to mixing with pharmaceutical excipients in the preparation of the composition.

The solid powder sieved with a 60-mesh sieve and other auxiliary materials were uniformly mixed in the amounts shown in tables 3 to 3, and compressed by a rotary tablet press (type traditional Chinese medicine longli ZP-14) under the same main pressure and material filling amount to prepare tablets 1 to 2, tablets 2 to 2, tablets 1 to 3, tablets 1 to 4 and tablets 2 to 3, respectively.

When the compressibility (hardness tester: type YD-35 from TIANDAITIANTIANJIESHI Co., Ltd.) and the disintegration property (disintegrator: type ZB-1 from TIANDAITIANJIESHI Co., Ltd.) of different formulations were examined, it can be seen from Table 3-3 that compositions 1-3, 1-4 and 2-3 prepared by adding a proper amount of TPGS had better compressibility, i.e., the hardness of the tablets under the same main compression condition was higher and the disintegration time was shorter, as compared with tablets 1-2 prepared by compressing composition 1-2 and 2-2 prepared by compressing composition 2-2 without TPGS, which was advantageous for rapid dissolution in vitro and rapid absorption in vivo.

Example 4 in vivo pharmacokinetic Studies of Ibrutinib-polyvinylpyrrolidone-vinyl acetate copolymer compositions

Studies were performed in humans using open, randomized, three-cycle, three-cross self-control pharmacokinetic contrast tests in fasting and postprandial conditions, respectively.

Subject screening: all of which satisfy the following criteria:

1) age 18 < age 40 (subject to the time of signing an informed consent), male or female;

2) weight: male is greater than or equal to 50kg, female is greater than or equal to 45kg, and Body Mass Index (BMI) is 19-26kg/m ² Between (include)Boundary values);

3) no history of diseases such as heart, liver, kidney, digestive tract, nervous system, mental abnormality, metabolic abnormality and the like, no history of preparation allergy, no history of serious infection, serious injury and the like;

4) physical examination, vital sign measurements, 12-lead electrocardiographic examination, laboratory examinations (blood routine, urine routine, blood biochemistry) are all normal or within a range deemed acceptable by the investigator;

5) agreeing to no childbearing plan, no sperm/egg donation plan and reliable contraceptive measures during the trial period and within 3 months after the last dose;

6) the purpose and the requirement of the test are fully known, the clinical test is voluntarily carried out, written informed consent is signed, and the whole test process can be completed according to the test requirement.

4.1 fasting test

4.1.1 test formulations

Test formulations: tablets 1 to 4 (specification of 140 mg/tablet, hereinafter referred to as "T1") and tablets 1 to 2 (dosage of 140 mg/tablet, hereinafter referred to as "T2") were prepared according to the tablet composition and tabletting process parameters shown in tables 3 to 3 of example 3.

Reference formulation: commercially available ibrutinib capsules (

The specification was 140 mg/pellet, hereinafter referred to as "R").

4.1.2 Subjects grouping:

the 9 healthy subjects enrolled were randomized into 3 groups, group I, group II and group iii, each group consisting of 3 people. In the first cycle, group I oral reference formulation R, group II oral test formulation T1, group iii oral test formulation T2. The administration dose is 560 mg/time, i.e. 4 tablets of test preparation T1 or T2, or 4 reference preparations R. Crossover tests were performed after a 1-cycle interval. The detailed grouping and dosing is shown in the table below.

TABLE 4-1 test groupings

Group of	Group I	Group II	Group III
				Subject number	1,5,8	2,6,7	3,4,9
First period	R	T1	T2
				Second period	T2	R	T1
The third period	T1	T2	R

4.1.3 dosing and blood sample collection:

subjects in each group entered the clinical trial ward at 18:00 on the first day and began fasting at 20: 00; blood samples were collected on the following day 07:00 (blank blood samples before administration), and 08:00 was taken 4 tablets (commercial formulation) with 240mL of warm water on an empty stomach under the direction of the physician

Tablets or tablets containing compositions 1 to 4 prepared in example 4 or tablets containing compositions 1 to 2 prepared in example 4), the dose relative to 560mg of ibrutinib, and confirmed by oral examination. The subjects should avoid strenuous exercise after taking the drug. Smoking, drinking, intake of chocolate, caffeine (coffee, dark tea, cola, etc.) enriched food or beverage, intake of grapefruit, dragon fruit, mango, lime, carambola or food or beverage prepared therefrom, were prohibited during the test period.

The blood sampling time points are pre-administration (0h) and post-administration 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.33, 2.67, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 48h (22 blood sampling points in total), 4mL of elbow venous blood is collected, placed in a heparin anticoagulation tube, centrifuged at 4000rpm for 5min at 4 ℃, plasma is separated, the plasma is divided into two parts, 1mL of plasma is taken and added to the test sample tube, and the remaining plasma is added to a backup tube. The separated plasma is stored in a refrigerator at the temperature of 20 ℃ below zero for testing. The administration was performed on day 8 and day 15, respectively, in the same manner as the second day, and then the same blood collection procedure was performed. Subjects were observed for vital signs and adverse events throughout the experiment to ensure their safety.

4.1.4 blood concentration determination:

determining the concentration of ibrutinib in each plasma sample by adopting an LC-MS/MS method, and completing the biological statistical analysis by calculating with pharmacokinetic statistical software WinNonlin v6.4 to obtain the commercially available preparation

Pharmacokinetic parameters for compositions 1-4 and 1-2, geometric mean ratios for each parameter were calculated. C of each test preparation _max 、AUC _0-48h 、AUC _0-∞ After logarithmic transformation, analysis of variance is carried out, and bidirectional one-sided t-test is carried out.

4.1.5 results of the experiment

Table 4-2 pharmacokinetic parameters of ibrutinib under fasting conditions (n ═ 6)

As can be seen from Table 4-2, under fasting condition, with commercially available ibrutinib capsules (

) Compared with, use

The Ibrutinib of T1 (tablets 1-4) and T2 (tablets 1-2) prepared from VA64 carrier material has faster absorption speed in vivo, higher blood concentration and higher corresponding bioavailability. C _max The geometric mean ratios (T1/R, T2/R) of 5.16 and 2.54, respectively; AUC _0-∞ The geometric mean ratios (T1/R, T2/R) of (2.52) and (1.13) respectively. Therefore, under the condition of empty stomach, the method adopts

VA64 Ibrutinib tablets 1-4 and 1-2 prepared from carrier material are compared with commercially available Ibrutinib capsules (

) Under the condition of obviously improving in vitro solubility and dissolution rate, the in vivo bioavailability is also obviously improved on the whole.

Compared with T2 (tablets 1-2) without TPGS, T1 (tablets 1-4) with TPGS has better absorption rate and blood concentration, and C _max And AUC _0-∞ The geometric mean ratios (T1/T2) of 2.03 and 2.23, respectively. Further indicates that TPGS not only can obviously improve the solubility and dissolution rate of ibrutinib in vitro, but also can obviously improve the bioavailability of ibrutinib in vivo.

4.2 postprandial testing

4.2.1 test formulations

Test formulation (T1): tablets 1-4 (specification of 140 mg/tablet) were prepared according to the tablet composition and tabletting process parameters in tables 3-3 of example 3.

Reference formulation (R): commercially available ibrutinib capsules (

The specification is 140 mg/grain). 4.2.2 subject groups:

the 6 healthy subjects enrolled were randomly divided into 2 groups, I, II, each with 3 people. In the first cycle, group I orally took test formulation T1 and group II orally took reference formulation R. The dose is 560 mg/time, i.e. 4 tablets of test preparation T1 or 4 reference preparations R are taken. Crossover tests were performed after a 1-cycle interval.

4.2.3 dosing and blood sample collection:

subjects in each group entered the clinical trial ward at 18:00 on the first day and began fasting at 20: 00; on the following day 07:00 blood samples (blank blood samples before administration) were collected and 08:00 subjects were instructed by the doctor to eat a high fat high calorie meal (containing approximately 800kcal of calories) within 30 min. Subjects took 4 tablets (containing compositions 1-4 prepared in example 4 or a commercial formulation) with 240mL of warm water 30min after the start of a meal (+ -2 min)

Tablets), dose relative to 560mg ibrutinib, and confirmed by oral examination. The subjects should avoid strenuous exercise after taking the drug. Smoking, drinking, intake of chocolate, caffeine (coffee, dark tea, cola, etc.) enriched food or beverage, intake of grapefruit, dragon fruit, mango, lime, carambola or food or beverage prepared therefrom, were prohibited during the test period. Lunch and dinner are taken 4h and 10h after administration.

The blood sampling time points are 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.33, 2.67, 3, 3.67, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 24 and 48h (total 25 blood sampling points) before administration (0h) and after administration, 4mL of elbow venous blood is collected respectively, the elbow venous blood is placed in a heparin anticoagulation tube, the blood is centrifuged at 4000rpm for 5min at 4 ℃, the blood plasma is separated, the blood plasma is divided into two parts, 1mL of the blood plasma is taken and added into a test sample tube, and the rest of the blood plasma is added into a backup tube. The separated plasma is stored in a refrigerator at the temperature of 20 ℃ below zero for testing. The dosing was staggered on day 8, administered in the same manner as the next day, and followed by the same blood sample collection procedure. Subjects were observed for vital signs and adverse events throughout the experiment to ensure their safety.

4.2.4 test results

Table 4-3 pharmacokinetic parameters of ibrutinib under postprandial conditions (n ═ 6)

As can be seen from Table 4-3, under postprandial conditions, the commercially available ibrutinib capsules (II) were mixed with

) Compared with, use

The Ibrutinib of the preparation T1 (tablets 1-4) prepared from VA64 carrier material has basically consistent absorption speed and bioavailability in vivo, and C _max Has a geometric mean ratio (T1/R) of 1.04; AUC _0-48h And AUC _0-∞ The geometric mean ratios (T1/R) of 0.96 and 0.95, respectively. Therefore, under postprandial conditions, use is made of

VA64 Ibrutinib tablet 1-4 prepared from carrier material and commercially available Ibrutinib capsule(s) ((R))

) Essentially uniform in vivo performance.

4.3 food Effect

Tablets 1 to 4 and commercially available ibrutinib capsules (c) prepared according to the tablet compositions and the tabletting process parameters in tables 3 to 3 of example 3, respectively

) In vivo pharmacokinetic parameters were compared under fasting and postprandial conditions to assess food effects of both formulations.

TABLE 4-4 pharmacokinetic parameters of tablets 1-4 under fasting and postprandial conditions

TABLE 4-5 commercially available Ibrutinib capsules (

) Pharmacokinetic parameters under fasting and postprandial conditions

As can be seen from tables 4-4 and tables 4-5, the absorption rate and bioavailability of tablets 1-4 in vivo were substantially similar under postprandial and fasting conditions, varying within 30%, taking into account the number of samples (n)<10) Less, within the normal fluctuation range. And commercially available ibrutinib capsules (

) The difference between absorption rate and bioavailability is obvious under the postprandial and fasting conditions, and the absorption rate C is compared with that under the fasting condition _max The improvement is more than about 5 times, the bioavailability AUC is improved more than about 3 times, and the food effect is obvious.

In conclusion, the method adopts

The Ibrutinib tablets 1-4 prepared by using VA64 as a carrier material and TPGS as a solubilizer have obviously improved in-vitro solubility and dissolution rate, the in-vivo bioavailability is obviously improved on the whole, no obvious food effect exists, more selectivity is provided for clinical medication, and the compliance of patients is greatly improved.

Claims

1. A pharmaceutical composition comprising ibrutinib or a pharmaceutically acceptable salt thereof as active ingredient, a carrier material and a solubilising agent, wherein

The support material is one or more selected from the group consisting of: polyvinylpyrrolidone-vinyl acetate copolymer, polymer containing ethylene glycol unit, and hydroxypropyl methylcellulose derivative;

the solubilizer is polyethylene glycol 1000 vitamin E succinate;

wherein the active ingredient is dissolved or dispersed at the molecular level in the carrier material.

2. The pharmaceutical composition of claim 1, wherein

The polymer containing ethylene glycol units is a polyethylene glycol/vinyl caprolactam/vinyl acetate copolymer.

3. The pharmaceutical composition of any one of claims 1-2, wherein

The carrier material is polyvinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol/vinyl caprolactam/vinyl acetate copolymer, hydroxypropyl methyl cellulose derivative or the combination thereof, preferably polyvinylpyrrolidone-vinyl acetate copolymer.

4. The pharmaceutical composition of any one of claims 1-3, wherein

The polyvinylpyrrolidone-vinyl acetate copolymer is a copolymer having a weight ratio of vinylpyrrolidone units to vinyl acetate units of about 1:9 to about 9:1, preferably a copolymer having a weight ratio of vinylpyrrolidone units to vinyl acetate units of about 6: 4;

the polyethylene glycol/vinyl caprolactam/vinyl acetate copolymer is polyethylene glycol (PEG)6000, and the weight ratio of vinyl caprolactam to vinyl acetate is about 13:57: 30;

the hydroxypropyl methylcellulose derivative is hydroxypropyl methylcellulose acetate succinate.

5. The pharmaceutical composition of any one of claims 1-4, wherein

The solubilizer is present in an amount of 1-30% by weight relative to the total weight of the active ingredient ibrutinib or a pharmaceutically acceptable salt thereof and the carrier material.

6. The pharmaceutical composition of any one of claims 1-5, wherein the ratio of the active ingredient ibrutinib or a pharmaceutically acceptable salt thereof to other ingredients in the composition is at least one of:

the weight ratio of the active ingredient to the carrier material is 1:1-1:5, preferably 1:1-1:4, more preferably 1:2-1: 3; most preferably 1: 2;

the weight ratio of the active ingredient to the solubilizer is 3:1-1:1, preferably 3:1-3:2, more preferably 3:1.2-3: 1.9; most preferably 3: 1.8;

the weight ratio of the active ingredient, the carrier material and the solubilizer is 1:1:0.6-1:5:0.6, preferably 1:2: 0.6.

7. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 6, characterized in that it is a hot-melt extrusion process and comprises the following steps:

preheating a hot-melt extruder to 110-200 ℃;

feeding a mixture of the components in a uniformly mixed metering ratio into the hot-melt extruder, or directly feeding the components in a metering ratio into the hot-melt extruder;

extruding; and

cooling the resulting extrudate to obtain the pharmaceutical composition.

8. The process for preparing a pharmaceutical composition according to claim 7, wherein the process employs at least one of the following parameters:

the temperature set by the hot-melt extruder is 120-190 ℃, the preferred temperature is 125 ℃, the screw rotating speed is 100-400rpm, and the preferred screw rotating speed is 200 rpm;

the ratio (L/D) of the length and the diameter of the screw of the hot-melt extruder is 25-40.

9. A pharmaceutical formulation comprising the pharmaceutical composition of any one of claims 1-6.

10. Use of a pharmaceutical composition according to any one of claims 1-6 or a pharmaceutical formulation according to claim 9 in the manufacture of a medicament for the treatment of autoimmune diseases, heteroimmune diseases or disorders, cancer including lymphoma, and inflammatory diseases.