CN117717556A - Pharmaceutical preparation containing ibutenib and application - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical preparations, relates to a pharmaceutical preparation containing ibutenib, a preparation method and application thereof, and in particular relates to a pharmaceutical preparation containing ibutenib, a retarder, a surfactant and a lubricant, which has the following advantages: (1) improving patient medication compliance: the content of the active ingredients of the medicine effect is obviously improved, the use of auxiliary materials is reduced, in addition, the bulk density of the content is improved, and the volume of a unit preparation is reduced; (2) reducing production cost: the compressibility of the materials is improved, the particle yield is increased, the process efficiency is further improved, and the production cost is reduced; (3) improving the quality of the medicine: the fluidity of the materials is improved, and the loading difference can be reduced; (4) dissolution is improved: because of the optimization of the composition and the component content of the preparation, compared with the prior art, the capsule has better dissolution in vitro.

Description

Pharmaceutical preparation containing ibutenib and application

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and relates to a pharmaceutical preparation containing ibutenib, a preparation method and medical application thereof. The pharmaceutical preparation can be prepared into pharmaceutical granules by dry granulation and then capsules by filling.

Background

Ibutenib (ibutinib), chemical name (R) -1- [3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidin-1-yl ] prop-2-en-1-one, its structural formula is shown below.

Ibutinib was developed by the american pharmaceutical company for the treatment of mantle cell lymphoma (mantle cell lymphoma, MCL), chronic lymphocytic leukemia (chronic lymphocytic leukemia, CLL)/small lymphocytic lymphoma (smalllymphocytic lymphoma, SLL), waldenstrom macroglobulinemia @macrolobulinaaema, WM), etc., the drug was approved for marketing by the FDA in the united states on 11 and 13 days 2013.

Bruton's tyrosine kinase, BTK, is an important mediator of at least three key B cell survival mechanisms, and its multiple actions can direct B cell malignancies into lymphoid tissues, enabling tumor cells to survive in contact with the necessary microenvironment. The targeting preparation prepared from the ibutenib can selectively inhibit BTK, thereby achieving the anti-tumor effect. The U.S. Food and Drug Administration (FDA) has granted ibutenib "breakthrough therapy" for the treatment of two B cell malignancies.

Packets as shown in Table 1 are disclosed in US2013/0338172A1, WO2013/184572A1 and CN104736178AA capsule containing ibutenib. However, this formulation has the following problems: (1) The ibutinib as a main drug has poor compressibility, so that more auxiliary materials are needed to be added to improve the compressibility, resulting in a large weight of the capsule content; (2) The capsule has low density, large volume of content per unit mass, and poor content flowability, and must use 0 ^# Filling capsule shell, 0 ^# The capsule shell is large in size, the medicine taking mode is inconvenient, and the medication compliance of patients is poor; (3) The disintegrating agent and the lubricant are not distinguished from each other in an internal-external manner, so that the quality problems of non-ideal dissolution rate, large loading difference and the like are easily brought.

TABLE 1

Capsules comprising ibutinib as shown in table 2 are disclosed in WO2016/164404A1 and CN107530293a, wherein ibutinib is micronised and croscarmellose sodium, sodium lauryl sulphate (i.e. sodium lauryl sulphate) and magnesium stearate are added in intra-and extra-granular form respectively. Although the change of the adding mode of the auxiliary materials improves the problems of dissolution rate of the preparation and capsule filling difference, the problems of poor compressibility of the ibutinib still cannot be overcome, more auxiliary materials are needed to be added, and 0 is needed to be adopted ^# The capsule shell is filled, and the medication compliance of patients is poor. In addition, there is a problem of poor flowability. Therefore, the content loading of the ibutenib capsule and the size of the capsule are improved so as to improve the medication compliance of patients, and meanwhile, the fluidity of the content of the preparation is improved, so that the difficult problem to be solved is still urgent for the ibutenib pharmaceutical preparation.

TABLE 2

Disclosure of Invention

Problems to be solved by the invention

Most of the existing ibutenib preparations have the problems of poor main medicine compressibility, more auxiliary material consumption and larger weight of unit preparations, and the medication compliance of patients is poor. Therefore, the inventor of the application surprisingly finds that the pharmaceutical preparation obtained by introducing the insoluble framework material as the auxiliary material has advantages in at least one of the aspects of particle mobility, auxiliary material dosage, unit preparation weight, medicine dissolution, preparation stability, preparation content uniformity and the like through trying different preparation formulas, and particularly has good mobility of the content of the preparation, less content of the content, capability of being filled in smaller capsule shells and good patient compliance.

Solution for solving the problem

In a first aspect, the present invention provides an oral solid pharmaceutical formulation comprising (R) -1- [3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidin-1-yl ] prop-2-en-1-one (i.e., ibutinib) and pharmaceutically acceptable excipients.

Preferably, the pharmaceutical formulation is a capsule.

Preferably, the pharmaceutical formulation comprises in one dosage unit 70% -90% ibutenib, more preferably 82.84% ibutenib, in weight percent.

In the pharmaceutical formulation, the ibutenib is ibutenib form a, the X-ray powder diffraction (XRPD) spectrum of ibutenib form a having characteristic peaks at 2θ values of 5.2 ° ± 0.2 °, 17.6 ° ± 0.2 °, 22.1 ° ± 0.2 °, 19.3 ° ± 0.2 °, 22.4 ° ± 0.2 °, 20.8 ° ± 0.2 °; more preferably, the XRPD pattern also has characteristic peaks at 2θ values of 16.2 ° ± 0.2 °, 18.1 ° ± 0.2 °, 18.9 ° ± 0.2 °, 23.2 ° ± 0.2 °; most preferably, the XRPD pattern thereof is substantially in accordance with figure 1.

In the pharmaceutical preparation, the pharmaceutically acceptable auxiliary materials are selected from at least one of retarder, surfactant and lubricant.

In the pharmaceutical formulation, the retarder is at least one selected from Ethyl Cellulose (EC) and Cellulose Acetate (CA), preferably cellulose acetate.

Preferably, the pharmaceutical formulation comprises 6% -10% cellulose acetate, more preferably 8.28% cellulose acetate, in weight percent in one dosage unit.

In the pharmaceutical formulation, the surfactant is at least one selected from Sodium Dodecyl Sulfate (SDS) and Poloxamer (Poloxamer), preferably sodium dodecyl sulfate.

Preferably, the pharmaceutical formulation comprises 6% -10% poloxamer, more preferably 8.28% poloxamer, in one dosage unit by weight percent.

In the pharmaceutical preparation, the lubricant is at least one selected from magnesium stearate, stearic acid, talcum powder, micro powder silica gel, glyceryl behenate, hydrogenated vegetable oil and sodium stearyl fumarate, and preferably is glyceryl behenate.

Preferably, the pharmaceutical formulation comprises 0.4% to 0.8% glyceryl behenate, more preferably 0.60% glyceryl behenate, in weight percent of one dosage unit.

More preferably, one dosage unit of the pharmaceutical formulation comprises, in weight percent, 70% -90% ibutenib, 6% -10% cellulose acetate, 6% -10% poloxamer and 0.4% -0.8% glyceryl behenate, preferably 82.84% ibutenib, 8.28% cellulose acetate, 8.28% poloxamer and 0.60% glyceryl behenate.

In a second aspect, the present invention provides a process for the preparation of the above pharmaceutical formulation comprising the steps of:

weighing: respectively weighing ibutinib, a retarder, a surfactant and a lubricant;

primary mixing: mixing the ibutinib, the retarder and the surfactant weighed in the step 1) to obtain a mixed material;

dry pressing: carrying out dry pressing on the mixed material obtained in the step 2) to obtain a sheet, and then crushing the sheet to obtain intermediate particles;

and (3) final mixing: mixing the intermediate particles obtained in the step 3) with the lubricant weighed in the step 1) to obtain a final material;

filling or tabletting: and (3) filling the final material obtained in the step (4) into a capsule shell or tabletting to obtain the pharmaceutical preparation.

Preferably, in the preparation method, the parameters of the dry pressing in step 3) are set as follows: the diameter of the die is 10-25mm, preferably 20mm; the pressure is 5-30kN, preferably 10kN; the tablet weight is 200-2000mg, preferably 500mg.

Preferably, in the preparation method, the pulverizing parameters in step 3) are set as follows: the rotation speed is 100-1000rpm, preferably 800rpm; the mesh size is 0.6-1.5mm, preferably 0.9mm.

Optionally, the preparation method further comprises a step of jet milling the raw material, which is carried out before step 1). Preferably, in the jet milling step, the raw material is jet milled to D ₉₀ The particle size is less than 20. Mu.m, preferably less than 10. Mu.m.

Optionally, the preparation method further comprises a step of sieving the raw materials performed before step 1). Preferably, in the sieving step, the screen used for the ibutenib sieving is a 60-100 mesh screen, preferably an 80 mesh screen; the screen for the surfactant sieving is a 30-50 mesh screen, preferably a 35 mesh screen; the screen used for lubricant sieving is a 30-50 mesh screen, preferably a 35 mesh screen.

Optionally, the preparation method further comprises a lubricant dispensing step performed between step 1) and step 2). Preferably, in the lubricant dispensing step, the lubricant is divided into an internal portion and an external portion, wherein: the internal part is used for mixing with other components in the step 2), so as to prepare a mixed material; the additional fraction is used for mixing with the intermediate particles in step 4) to prepare the final mass. More preferably, in the lubricant dispensing step, the weight ratio of the inner portion to the outer portion is from 1:2 to 2:1, preferably 1:1.

Optionally, the preparation method further comprises content detection, packaging and labeling steps performed after step 5).

In a third aspect, the present invention provides a pharmaceutical composition prepared by the above preparation method.

In a fourth aspect, the present invention provides the use of a pharmaceutical formulation as described above or a pharmaceutical composition as described above for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by bruton's tyrosine kinase.

Preferably, in said use, said diseases mediated at least in part by bruton's tyrosine kinase include mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and waldenstrom's macroglobulinemia.

In a fifth aspect, the present invention provides the use of the above pharmaceutical formulation or the above pharmaceutical composition as a bruton's tyrosine kinase inhibitor.

In a sixth aspect, the present invention provides a method for the prevention and/or treatment of a disease mediated at least in part by bruton's tyrosine kinase, comprising the step of administering a therapeutically effective amount of the above pharmaceutical formulation or the above pharmaceutical composition to a patient in need thereof.

Preferably, in the method, the disease mediated at least in part by bruton's tyrosine kinase includes mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and waldenstrom's macroglobulinemia.

ADVANTAGEOUS EFFECTS OF INVENTION

Compared with the existing ibutenib preparation, the pharmaceutical preparation containing ibutenib has the following advantages:

improving medication compliance of patients: based on the optimization of the formulation composition and the dosage, the API content is obviously improved from 42.4 percent in the prior art preparation to more than 80 percent, the use of auxiliary materials is reduced, the bulk density of the content is improved, the volume of the unit preparation is reduced, and compared with the preparation adopting 0 ^# The raw preparation filled in the capsule shell can be 1 ^# Filling a capsule shell; or the dosage of the unit preparation is reduced, for example, 0 ^# Double filling is carried out on the capsule shells, so that the number of the taken granules is reduced;

the production cost is reduced: compared with the prior art, the granule yield of the pharmaceutical preparation is increased from about 50% to 87%, the granule fluidity is improved, the process efficiency is further improved, and the production cost is reduced;

improving the quality of the medicine: in general, if the flowability of the material is poor, a larger loading difference is introduced after the material is filled into capsules or pressed into tablets, and the flowability of the material of the pharmaceutical preparation is obviously improved, so that the loading difference among unit preparations can be reduced, and the quality of the medicine is greatly improved;

improving the dissolution of the preparation: because of the optimization of the composition and the component content of the preparation, the dissolution condition of the capsule is superior to that of the capsule in the prior art, and the dissolution rate of 41.7 percent in 45 minutes is improved to 74.7 percent and is improved by 1.8 times.

Drawings

Fig. 1 is an XRPD pattern of ibutenib in crystalline form a in the pharmaceutical composition of the present invention.

Detailed Description

First, the present invention provides an oral solid pharmaceutical formulation. The pharmaceutical preparation comprises (R) -1- [3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] piperidin-1-yl ] prop-2-en-1-one (i.e., ibutinib) and pharmaceutically acceptable excipients.

The term "pharmaceutical formulation" as it appears in the context of the present invention refers to a finished pharmaceutical product prepared in a certain form, unless otherwise indicated. Pharmaceutical formulations can be classified according to physical form into gaseous formulations (e.g., aerosols, sprays, etc.), liquid formulations (e.g., solutions, suspensions, injections, etc.), solid formulations (e.g., tablets, capsules, granules, etc.), and semisolid formulations (e.g., ointments, creams, gels, etc.).

In some embodiments of the invention, the pharmaceutical formulation described above is a capsule.

In some embodiments of the present invention, the pharmaceutical formulation comprises from 70% to 90% ibutenib in weight percent (or wt%) in one dosage unit. In some preferred embodiments, one dosage unit contains 82.84% ibutenib.

In some embodiments of the present invention, the ibutenib in the pharmaceutical formulation described above is ibutenib form a having an X-ray powder diffraction (XRPD) spectrum of 5.2 ° ± 0.2 °, 17.6 ° ± 0.2 °, 22.1 ° ± 0.2 °, 19.3 ° ± 0.2 ° in 2θ value,

Characteristic peaks at 22.4 ° ± 0.2 °, 20.8 ° ± 0.2 °; more preferably, the XRPD patterns have a2 theta value of 16.2 DEG + -0.2 DEG, 18.1 DEG + -0.2 DEG,

Characteristic peaks at 18.9 ° ± 0.2 °, 23.2 ° ± 0.2 °; most preferably, the XRPD pattern thereof is substantially in accordance with figure 1.

In addition to ibutinib as the main active ingredient, the above pharmaceutical formulation comprises pharmaceutically acceptable excipients. In some embodiments of the invention, the pharmaceutically acceptable adjuvant is selected from at least one of a retarder, a surfactant, a lubricant.

The term "retarder" as used in the context of the present invention, unless otherwise indicated, refers to a pharmaceutical excipient having a relatively strong hydrophobicity for retarding the dissolution and release processes of water-soluble drugs, typically as a matrix material, and sometimes as a slow-release coating material. Common retarders include animal fat, beeswax, carnauba wax, pectin, hydrogenated vegetable oil, higher fatty acids, higher fatty alcohols, higher fatty acid esters, cellulose, and the like.

In some embodiments of the invention, the retarder in the above pharmaceutical formulation is cellulose acetate.

In some embodiments of the present invention, the pharmaceutical formulation comprises from 6% to 10% cellulose acetate in one dosage unit by weight percent. In some preferred embodiments, 8.28% cellulose acetate is included in one dosage unit.

Unless otherwise indicated, the term "surfactant" as it appears in the context of the present invention refers to a pharmaceutical excipient having a strong surface activity for significantly reducing the surface tension of a liquid. Commonly used surfactants include higher fatty acid salts, sulfuric acid ester salts, sulfonic acid salts, quaternary ammonium salts, lecithins and their analogues, betaines and their analogues, polyethers and the like.

In some embodiments of the invention, the surfactant in the above pharmaceutical formulation is a poloxamer.

In some embodiments of the invention, the pharmaceutical formulation comprises 6% to 10% poloxamer in one dosage unit by weight percent. In some preferred embodiments, 8.28% poloxamer is included in one dosage unit.

Unless otherwise indicated, the term "lubricant" as it appears in the context of the present invention is a broad concept, being a generic term for glidants, anti-tackifiers and (narrowly) lubricants, wherein: glidants are pharmaceutical excipients for reducing friction between particles, thereby improving flowability of the powder; the anti-adhesion agent is medicinal auxiliary materials for preventing materials from adhering to the surface of the punch; the (narrow) lubricant refers to a pharmaceutical adjuvant for reducing the friction between the material and the walls of the die hole. Theoretically, the lubricant should have the above three functions of flow aid, anti-adhesion and lubrication, but no ideal lubricant exists at present. Existing lubricants tend to have better performance in one or both aspects, while others perform relatively poorly. Pharmaceutical excipients having any of the above actions are generally referred to as lubricants according to the customary classification method. Common lubricants include stearic acid or its salts, gum acacia, talc, hydrogenated vegetable oils, glyceryl behenate, and the like.

In some embodiments of the invention, the lubricant in the above pharmaceutical formulation is glyceryl behenate.

In some embodiments of the invention, the pharmaceutical formulation comprises from 0.4% to 0.8% glyceryl behenate in one dosage unit by weight percent. In some preferred embodiments, one dosage unit contains 0.60% glyceryl behenate.

In some embodiments of the invention, the above pharmaceutical formulation comprises ibutenib and cellulose acetate, poloxamer and glyceryl behenate.

In some embodiments of the invention, the above pharmaceutical formulation comprises crystalline form a of ibutenib together with cellulose acetate, poloxamer and glyceryl behenate.

In some preferred embodiments, the pharmaceutical formulation comprises, in weight percent, 70% -90% ibutenib, 6% -10% cellulose acetate, 6% -10% poloxamer and 0.4% -0.8% glyceryl behenate in one dosage unit.

In some more preferred embodiments, one dosage unit of the above pharmaceutical formulation comprises 82.84% ibutenib, 8.28% cellulose acetate, 8.28% poloxamer and 0.60% glyceryl behenate in weight percent.

In some preferred embodiments, the pharmaceutical formulation comprises, in weight percent, from 70% to 90% of crystalline form a of ibutenib, from 6% to 10% of cellulose acetate, from 6% to 10% of poloxamer and from 0.4% to 0.8% of glyceryl behenate in one dosage unit.

In some more preferred embodiments, one dosage unit of the above pharmaceutical formulation comprises 82.84% crystalline form a of ibutenib, 8.28% cellulose acetate, 8.28% poloxamer and 0.60% glyceryl behenate in weight percent.

Second, the invention provides a preparation method of the pharmaceutical preparation. The preparation method comprises the following steps:

1) Weighing: respectively weighing ibutinib, a retarder, a surfactant and a lubricant;

2) Primary mixing: mixing the ibutinib, the retarder and the surfactant weighed in the step 1) to obtain a mixed material;

3) Dry pressing: carrying out dry pressing on the mixed material obtained in the step 2) to obtain a sheet, and then crushing the sheet to obtain intermediate particles;

4) And (3) final mixing: mixing the intermediate particles obtained in the step 3) with the lubricant weighed in the step 1) to obtain a final material;

5) Filling or tabletting: and (3) filling the final material obtained in the step (4) into a capsule shell or tabletting to obtain the pharmaceutical preparation.

The term "dry compaction" as used in the context of the present invention refers to the process of forming the dry powder material obtained by the sieving process into intermediate granules, unless otherwise indicated.

In some embodiments of the invention, the dry compression in step 3) of the above-described preparation method is carried out using a tablet press.

In some preferred embodiments, the parameters of the above dry pressing are set as follows: the diameter of the die is 10-25mm, the pressure is 5-30kN, and the weight of the tablet is 200-2000mg. In some more preferred embodiments, the parameters of the above dry pressing are set as follows: the die diameter was 20mm, the pressure was 10kN and the tablet weight was 500mg.

In some embodiments of the invention, the comminution in step 3) of the above-described preparation process is effected using a granulator.

In some preferred embodiments, the above-mentioned parameters of comminution are set as follows: the rotating speed is 100-1000rpm, and the aperture of the screen is 0.6-1.5mm. In some more preferred embodiments, the parameters for the comminution described above are set as follows: the rotation speed was 800rpm and the mesh diameter was 0.9mm.

The term "capsule shell" as it appears in the context of the present invention refers to a hollow shell made of gelatin and excipients for filling solid powders or granules, unless otherwise indicated. The capsule shell is generally composed of a capsule cap and a capsule body, after solid powder or particles are filled into the capsule body, the capsule cap is buckled on the capsule body for locking, and finally the capsule is prepared. At present, the commonly used capsule shells comprise 6 types of capsules which are sequentially arranged from large to small in volume and are sequentially 00 ^# 、0 ^# 、1 ^# 、2 ^# 、3 ^# And 4 ^# The specific parameters are shown in Table 3.

TABLE 3 model and parameter correspondence of commonly used capsule shells

In some embodiments of the invention, the above-described preparation process further comprises a step of jet milling the feedstock prior to step 1).

Unless otherwise indicated, the term "jet milling" as used in the context of the present invention refers to a process in which high velocity air or other gas is used (typically in the form of a swirling or circulating stream) to bombard particles of material to substantially deagglomerate the particulate agglomerates produced during or after the formation of the particles.

In some preferred embodiments, in the above jet milling step, the raw material is jet milled to D ₉₀ The particle size is less than 20. Mu.m, preferably less than 10. Mu.m.

In some embodiments of the invention, the above-described preparation method further comprises a step of sieving the raw material performed before step 1).

In some preferred embodiments, in the above screening step, the screen used for the ibutenib screening is a 60-100 mesh screen, preferably an 80 mesh screen; the screen for the surfactant sieving is a 30-50 mesh screen, preferably a 35 mesh screen; the screen used for lubricant sieving is a 30-50 mesh screen, preferably a 35 mesh screen.

In some embodiments of the invention, the above-described preparation method further comprises a lubricant dispensing step performed between step 1) and step 2).

In some preferred embodiments, in the above lubricant dispensing step, the lubricant is divided into an inner portion and an outer portion, wherein: the internal part is used for mixing with other components in the step 2), so as to prepare a mixed material; the additional fraction is used for mixing with the intermediate particles in step 4) to prepare the final mass. In a more preferred embodiment, in the above lubricant dispensing step, the weight ratio of the inner portion to the outer portion is from 1:2 to 2:1, preferably 1:1.

In some embodiments of the invention, the above-described preparation method further comprises content detection, packaging and labeling steps performed after step 5). While these steps do not directly affect the availability of the above-described ibutenib-containing pharmaceutical formulation, they facilitate its use as a mature commodity for subsequent market distribution and use.

Third, the present invention provides a pharmaceutical composition prepared by the above preparation method.

Fourth, the present invention provides the use of the above pharmaceutical formulation or the above pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of a disease mediated at least in part by bruton's tyrosine kinase.

The term "disease mediated at least in part by bruton's tyrosine kinase" in the context of the present invention refers to a disease in which the pathogenesis includes at least a portion of the factors associated with bruton's tyrosine kinase, including, but not limited to, mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and waldenstrom's macroglobulinemia, unless otherwise indicated.

In some embodiments of the invention, diseases in which at least a portion of the above uses are mediated by bruton's tyrosine kinase include mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and waldenstrom's macroglobulinemia.

Fifth, the present invention provides the use of the above pharmaceutical formulation or the above pharmaceutical composition as a bruton's tyrosine kinase inhibitor.

The term "bruton's tyrosine kinase inhibitor" as it appears in the context of the present invention, unless otherwise indicated, refers to an agent capable of exerting an inhibitory effect on the activity of bruton's tyrosine kinase, thereby affecting the subsequent physiological or pharmacological function of the pathway.

In some embodiments of the invention, the above pharmaceutical formulation or the above pharmaceutical composition may be used as a bruton's tyrosine kinase inhibitor for the prevention and/or treatment of diseases mediated at least in part by bruton's tyrosine kinase, such as mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and waldenstrom's macroglobulinemia.

In a sixth aspect, the present invention provides a method for preventing and/or treating a disease mediated at least in part by bruton's tyrosine kinase, comprising the step of administering a therapeutically effective amount of the above pharmaceutical formulation or the above pharmaceutical composition to a patient in need thereof.

The term "therapeutically effective amount" as used in the context of the present invention, unless otherwise indicated, refers to a dose of a pharmaceutically active ingredient capable of eliciting a biological or medical response in a cell, tissue, organ or organism (e.g. a patient).

Unless otherwise indicated, the term "administering" or a process of contacting a cell, tissue, organ, biological fluid, etc., thereof, occurs in the context of the present invention. Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like.

The term "in need thereof" as it appears in the context of the present invention, unless otherwise indicated, refers to a judgment of a doctor or other caregiver that the patient needs or is about to benefit from the prevention and/or treatment process, the judgment being based on various factors of the doctor or other caregiver in their expertise.

The term "patient" (or subject) as used in the context of the present invention refers to a human or non-human animal (e.g., mammal) unless otherwise indicated.

In some embodiments of the invention, the diseases mediated at least in part by bruton's tyrosine kinase in the above methods include mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and waldenstrom's macroglobulinemia.

The technical scheme of the invention will be further described in the following with reference to specific examples. It should be understood that the following examples are illustrative and not intended to limit the scope of the present invention. In addition, unless otherwise indicated, the instruments, materials, reagents, and the like used in the following examples are all available by conventional commercial means.

[ Instrument ]

Dry granulator: miniDC, shenzhen market Xinyite technology Co., ltd;

tablet press: type a258RC5P14X001, U.S. enpark (belonging to the utility power group);

vibration screening instrument: AS200, leachi Germany (Retsch);

compaction instrument: ZS-2E type, tianjin, tiantianfa technology Co., ltd.

[ Material and reagent ]

Ibutenib (form a): self-made, prepared by adopting a preparation method of the crystal form A recorded in CN 104327085B;

ibutenib (amorphous, micronized): self-making;

ethyl cellulose:standard 7FP premium, carlekang (Colorcon) U.S.;

sodium dodecyl sulfate: BASF, germany;

magnesium stearate: #5712, U.S. Mo Lingke (Mallinckrodt).

Example 1: preparation of capsules comprising an amorphous form of ibutenib.

The capsules were prepared according to the recipe in Table 4 to give 0 ^# (or 1) ^# ) Capsules (content weight 169 mg/granule). In addition, when 0 is used ^# In the case of capsule shells, a double-filled filling mode can be adopted to obtain capsules (the weight of the content is 338 mg/granule).

TABLE 4 formulation composition and dosage of capsules in this example

The specific preparation process is as follows:

1) Jet milling: jet milling the amorphous form of ibutinib to D ₉₀ Particle size is less than 10 μm;

2) Weighing: respectively weighing ibutinib, a retarder, a surfactant and a lubricant according to the formulation dosage in table 4;

3) And (3) distribution: dividing the weighed lubricant into an internal part and an external part according to the formula dosage in table 4 to obtain the lubricant of the internal part and the lubricant of the external part;

4) Primary mixing: firstly, mixing a retarder and a surfactant for 2min; secondly, the above mixture is mixed with ibutinib for 2min (ibutinib may also be mixed with the above mixture in batches, for example in two batches); finally, mixing the mixture and the lubricant added with the mixture for 1min to obtain a mixed material;

5) Dry pressing: dry pressing the mixed material, and crushing the obtained slices to obtain intermediate particles; wherein: parameters for dry pressing were set as follows: the diameter of the die is 20mm, the pressure is 10kN, and the weight of the tablet is 500mg; the parameters for comminution were set as follows: the rotation speed is 800rpm, and the aperture of the screen is 0.9mm;

6) And (3) final mixing: mixing the intermediate particles with the lubricant of the added part for 1min to obtain a final material;

7) Filling capsules: filling the final material into 1000 grains 0 ^# (or 1) ^# ) In the capsule shell, a capsule (content weight of 169 mg/granule) was obtained;

8) Detecting the content of the capsule, packaging and labeling.

The capsule in this embodiment may be 1 ^# The capsule shell is filled, so that the size of the capsule is reduced; in addition, double-filling can be adopted to reduce the number of particles for taking medicine.

The capsule of the present invention can be prepared by a process of differentiating between internal and external addition (i.e., dividing the lubricant into an internal addition portion and an external addition portion), and also by a process of differentiating between internal and external addition (i.e., adding no lubricant in the granulating step and leaving it to be separately added in the final mixing step). In addition, in the capsule of the present invention, ibutenib can exist not only in the form of an amorphous substance but also in other crystalline forms, and even in the form of a mixture of two or more solid forms. The above formulation cases are all included in the scope of the present invention.

Example 2: preparation of capsules comprising crystalline form a of ibutenib.

The capsules were prepared according to the recipe in Table 5, with the specific procedure being similar to example 1, except that the retarder was replaced with cellulose acetate, the surfactant was replaced with poloxamer, and the lubricant was replaced with glyceryl behenate, giving 0 ^# (or 1) ^# ) Capsules (content weight 169 mg/granule). In addition, when 0 is used ^# In the case of capsule shells, a double-filled filling mode can be adopted to obtain capsules (the weight of the content is 338 mg/granule).

TABLE 5 formulation composition and dosage of capsules in this example

The capsule in this embodiment may be 1 ^# The capsule shell is filled, so that the size of the capsule is reduced; in addition, 0 can also be used ^# The capsule shell is filled in double filling amount, so that the particle number of medicine taking is reduced.

Comparative example 1: preparation of capsules comprising an amorphous form of ibutenib.

Capsules were prepared according to the formulation described in table 2, wherein ibutenib was a micronized amorphous form, and the preparation process was consistent with the method of example 1, and was designated as control capsule 1.

Comparative example 2: preparation of a capsule comprising crystalline form B of ibutenib (form B is form a described in patent CN104736178A, which is distinguished from form a described herein and designated as form B).

Capsules were prepared according to the formulation described in table 2, the specific preparation method being similar to example 1, except that ibutenib was present as form B (prepared according to the preparation method of form a described in CN 104736178A), and was recorded as control capsule 2.

Also, the powder density of the prescription is small, so that the prescription cannot be filled into 1 ^# The capsule shell cannot be filled to 0 in double filling quantity ^# In the capsule shell.

Experimental example 1: powder testing of capsules.

The capsules prepared in example 1 were recorded as sample capsules 1 and were subjected to a powder test along with the control capsules 1 prepared in comparative example 1, the test items including particle yield, bulk density (including bulk density and tap density), flowability and tensile strength.

1. The testing method comprises the following steps:

(1) Particle yield:

respectively taking intermediate particles corresponding to the capsule to be detected, vibrating for 20min with 100% amplitude by adopting a vibrating screen, sieving with a 80-mesh sieve, collecting a residual sample on the sieve and a sieved sample, weighing, and calculating the particle yield;

(2) Bulk density:

respectively taking the final materials corresponding to the capsules to be tested, vibrating 1250 times by adopting a compaction meter, and respectively calculating the bulk density and the compaction density;

(3) Fluidity:

from the bulk density test results, the compressibility factor was calculated according to the following formula, and fluidity was evaluated, wherein the definition criteria of compressibility factor to powder fluidity are shown in Table 6.

TABLE 6 definition criteria of compressibility factor versus powder flowability

2. Test results:

TABLE 7 results of the powder testing of sample capsules and control capsules

Name of the name

Source

Yield of particles

Bulk density (g/cm) 3 )

Tap density (g/cm) 3 )

Coefficient of compressibility

Fluidity of the product

Control 1

Comparative example 1

52％

0.43

0.62

31％

Difference of difference

Control 2

Comparative example 2

44％

0.37

0.54

31％

Difference of difference

Sample 1

Example 1

77％

0.42

0.47

11％

Good (good)

As can be seen from table 7, both control capsules 1 and 2 exhibited lower particle yields and poorer flowability, whether ibutenib was in amorphous or crystalline form B. Sample capsule 1 employing the prescription system of the present invention exhibited higher particle yields and better flowability.

Experimental example 2: and (5) testing the dissolution rate of the capsules.

The dissolution test was performed on sample capsule 1 along with control capsule 1.

1. The testing method comprises the following steps:

dissolution test 900mL of phosphate buffer at ph6.8 containing 3% tween 20 was used according to USP <711>, paddle at 75rpm and cumulative dissolution of the drug was measured using HPLC detector and samples were taken at 5, 10, 20, 30 and 45min, respectively.

2. Test results:

table 8 dissolution test results for sample capsules and control capsules

As shown in table 8, it was found that the comparative capsule 1 was only capable of achieving a dissolution of 41.7% in a test period of 45 minutes, and the sample capsule 1 was capable of achieving a dissolution of 74.7% in a test period of 45 minutes, which was about 1.8 times higher than the comparative capsule 1, and the dissolution effect was better.

The above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.

Claims (10)

1. An oral solid pharmaceutical formulation comprising ibutenib, a retarder, a surfactant and a lubricant.

2. The pharmaceutical formulation according to claim 1, wherein one dosage unit contains 70% -90% ibutenib in weight percent.

3. The pharmaceutical formulation of claim 1, wherein the retarder is cellulose acetate.

4. A pharmaceutical formulation according to claim 3, wherein the cellulose acetate is present in a dosage unit in an amount of 6% to 10% by weight.

5. The pharmaceutical formulation according to claim 1, wherein the surfactant is selected from poloxamers.

6. The pharmaceutical formulation according to claim 5, wherein one dosage unit comprises 6% -10% poloxamer by weight.

7. A pharmaceutical formulation according to claim 1, wherein the lubricant is glyceryl behenate.

8. The pharmaceutical formulation according to claim 7, wherein one dosage unit comprises 0.4% to 0.8% glyceryl behenate by weight percent.

9. The pharmaceutical formulation of claim 1, wherein the ibutenib is form a as shown in figure 1.

10. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is a capsule.