Solid dispersion and method for preparing same

Abstract

Solid dispersion and its preparation method. In a specific embodiment, the solid dispersion contains (R)-4-amino-1-(1-(but-2-yneoyl)pyrrolidin-3-yl))-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or its salt as an active ingredient and a carrier material, and adjusts the pH value; adds an appropriate amount of acid to effectively inhibit the emulsification phenomenon in the anti-solvent operation, thereby obtaining a solid dispersion with a suitable particle size and a uniform content.

Description

[Technical field]

[0001] The present disclosure is in the field of pharmaceutical preparations, and in particular relates to solid dispersions, their preparation methods and their uses. [Background technology]

[0002] The compound (R)-4-amino-1-(1-(but-2-yneoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one represented by formula I is a BTK inhibitor with good target specificity and high kinase selectivity. It can selectively inhibit the proliferation and migration of B-cell tumors by inhibiting the phosphorylation of BTK and downregulating the BCR signaling pathway. Recent clinical trials have shown that this inhibitor has excellent pharmacodynamic activity: [ka]

[0003] The compound of formula I is an active substance with low solubility, and its drug discovery potential needs to be deeply studied and solved by pharmaceutical researchers. WO2019007317 discloses a solid dispersion preparation containing the compound of formula I, which solves the problem of dissolution after applying solid dispersion technology to formulate the compound as a medicine. The preparation methods of solid dispersion include melting method, solvent method, solvent-melting method, solvent spray drying method, or grinding method. The anti-solvent method is the mildest preparation method of solid dispersion that does not expose the active substance to high temperature, and is suitable for various heat-unstable or volatile drugs and is easy to carry out.

[0004] However, during the preparation of solid dispersions, especially when anti-solvent methods are used, emulsification often occurs, which affects the preparation of solid dispersions, resulting in non-uniformity of the active ingredient content between batches, thereby affecting efficacy and safety.

[0005] Common demulsification (emulsion breaking) methods include static methods, high voltage electric field methods, chemical demulsification methods (such as salt fractionation, flocculation, and salt fractionation-flocculation), centrifugation, ultrafiltration, and vacuum separation. Each demulsification method has its own advantages but also disadvantages. Chemical demulsification methods such as salt fractionation require the introduction of inorganic salts as additional chemical reagents into the emulsification system, which increases the subsequent processing costs. At the same time, the selection of the demulsification method should also take into account the characteristics of the product itself. Summary of the Invention

[0006] The present disclosure provides a method for preparing a solid dispersion, the method comprising the steps of: dissolving a carrier material and an active ingredient in a good solvent to obtain a solution, adding the obtained solution to a poor solvent, and adjusting the pH to 1.0-6.0; or, alternatively, dissolving a carrier material and an active ingredient in a good solvent to obtain a solution, and adding the obtained solution to a poor solvent, where the pH of the poor solvent is 1.0-6.0.

[0007] In alternative embodiments, the pH value may be 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0 or any value between any two values, preferably the pH is 2.0 to 4.0.

[0008] By controlling the pH of the anti-solvent or crystallization solution to less than 6.0, the above-mentioned emulsification problem during the anti-solvent method can be effectively avoided. There is no need to carry out additional demulsification methods such as salt fractionation and flocculation, which makes the subsequent filtration or washing process easier and obtains samples with uniform active ingredient content from batch to batch.

[0009] The method of the present disclosure may also further comprise a filtering step, a washing step or a drying step.

[0010] In some embodiments, the good solvent is at least one selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, ethanol, tetrahydrofuran and methanol, preferably N,N-dimethylformamide or N,N-dimethylacetamide; the poor solvent is at least one selected from the group consisting of diethyl ether, n-hexane, petroleum ether and water, for example a mixed solution of water with one or more of ether, n-hexane and petroleum ether.

[0011] In some embodiments, the carrier material and the active ingredient or a pharma- ceutically acceptable salt thereof are dissolved in a good solvent, N,N-dimethylformamide, and the resulting solution is added to a poor solvent, water, where the poor solvent, water, has a pH of 1.0 to 6.0.

[0012] In some embodiments, the carrier material and the active ingredient or a pharma- ceutically acceptable salt thereof are dissolved in a good solvent, N,N-dimethylacetamide, and the resulting solution is added to a poor solvent, water, where the poor solvent, water, has a pH of 1.0 to 6.0.

[0013] In some embodiments, the carrier material and the active ingredient or a pharma- ceutically acceptable salt thereof are dissolved in a good solvent, dimethyl sulfoxide, and the resulting solution is added to a poor solvent, water, where the poor solvent, water, has a pH of 1.0 to 6.0.

[0014] Furthermore, the reagent used to adjust the pH is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid and phosphoric acid, and is preferably sulfuric acid or hydrochloric acid.

[0015] In another embodiment, the rate of dropwise addition (ie, addition of a good solvent to a poor solvent) also influences to some extent the quality of the crystallization, such as the size and uniformity of the precipitated solid particles.

[0016] In some embodiments, the rate of dropwise addition (addition of a good solvent to a poor solvent) can be 1 to 2500 g / min, for example, 1 to 2250 g / min, 1 to 2000 g / min. The rate of dropwise addition can be adjusted according to the needs of the preparation.

[0017] In another embodiment, the addition of the anti-solvent of the present disclosure is accompanied by a stirring operation, and the stirring speed is selected from 20 to 1000 rpm, and non-limiting examples include 100 rpm, 110 rpm, 120 rpm, 130 rpm, 140 rpm, 150 rpm, 160 rpm, 170 rpm, 180 rpm, 190 rpm, 200 rpm, 210 rpm, 220 rpm, 230 rpm, 240 rpm, 250 rpm, 260 rpm, 270 rpm, 280 rpm, 290 rpm, 300 rpm, 310 rpm, 320 rpm, 330 rpm, 340 rpm, 350 rpm, 360 rpm, 370 rpm, 380 rpm, 39 0rpm, 280rpm, 290rpm, 300rpm, 310rpm, 320rpm, 330rpm, 340rpm, 350rpm, 360rpm, 370rpm, 380rpm, 390rpm, 400r pm, 410rpm, 420rpm, 430rpm, 440rpm, 450rpm, 460rpm, 470rpm, 480rpm, 490rpm, 500rpm, 510rpm, 520rpm, 530rpm, 540rpm, 550rpm, 560rpm, 570rpm, 580rpm, 590rpm, 600rpm, 610rpm, 620rpm, 630rpm, 640rpm, 650rpm, 660rpm, 67 0rpm, 680rpm, 690rpm, 700rpm, 710rpm, 720rpm, 730rpm, 740rpm, 750rpm, 760rpm, 770rpm, 780rpm, 790rpm, 800r pm, 810 rpm, 820 rpm, 830 rpm, 840 rpm, 850 rpm, 860 rpm, 870 rpm, 880 rpm, 890 rpm, 900 rpm, 910 rpm, 920 rpm, 930 rpm, 940 rpm, 950 rpm, 960 rpm, 970 rpm, 980 rpm, 990 rpm, 1000 rpm or any value between any two values, preferably 100 to 600 rpm.

[0018] The preparation method of the solid dispersion of the present disclosure can be applied to any insoluble solid. In an alternative embodiment, the active ingredient is (R)-4-amino-1-(1-(but-ynoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or a pharma-ceutically acceptable salt thereof.

[0019] Further, the carrier material is at least one selected from the group consisting of hydroxypropyl methylcellulose succinate, polyvinylpyrrolidone, hydroxypropyl methylcellulose phthalate and polyvinylpyrrolidone.

[0020] In some embodiments, the carrier material hydroxypropyl methylcellulose acetate succinate and the active ingredient are dissolved in a good solvent N,N-dimethylformamide, and the resulting solution is added to a poor solvent water, where the poor solvent water has a pH of 1.0 to 6.0.

[0021] In some embodiments, the carrier material hydroxypropyl methylcellulose acetate succinate and the active ingredient are dissolved in a good solvent N,N-dimethylacetamide, and the resulting solution is added to a poor solvent water, where the poor solvent water has a pH of 1.0 to 6.0.

[0022] In some embodiments, the carrier material hydroxypropyl methylcellulose acetate succinate and the active ingredient are dissolved in a good solvent dimethyl sulfoxide, and the resulting solution is added to a poor solvent water, where the poor solvent water has a pH of 1.0 to 6.0.

[0023] In some embodiments, the carrier material polyvinylpyrrolidone and the active ingredient are dissolved in a good solvent N,N-dimethylformamide, and the resulting solution is added to a poor solvent water, where the poor solvent water has a pH of 1.0 to 6.0.

[0024] In some embodiments, the carrier material polyvinylpyrrolidone and the active ingredient are dissolved in a good solvent N,N-dimethylacetamide, and the resulting solution is added to a poor solvent water, where the poor solvent water has a pH of 1.0 to 6.0.

[0025] In some embodiments, the carrier material polyvinylpyrrolidone and the active ingredient are dissolved in a good solvent dimethylsulfoxide, and the resulting solution is added to a poor solvent water, where the poor solvent water has a pH of 1.0 to 6.0.

[0026] In some embodiments, the carrier material hydroxypropyl methylcellulose phthalate and the active ingredient are dissolved in a good solvent N,N-dimethylformamide, and the resulting solution is added to a poor solvent water, where the poor solvent water has a pH of 1.0 to 6.0.

[0027] In some embodiments, the carrier material hydroxypropyl methylcellulose phthalate and the active ingredient are dissolved in a good solvent N,N-dimethylacetamide, and the resulting solution is added to a poor solvent water, where the poor solvent water has a pH of 1.0 to 6.0.

[0028] In some embodiments, the carrier material hydroxypropyl methylcellulose phthalate and the active ingredient are dissolved in a good solvent dimethyl sulfoxide, and the resulting solution is added to a poor solvent water, where the poor solvent water has a pH of 1.0 to 6.0.

[0029] In some embodiments, the carrier material hydroxypropyl methylcellulose acetate succinate and the active ingredient are dissolved in a good solvent N,N-dimethylformamide, and the resulting solution is added to a poor solvent water, and the pH is adjusted to 1.0 to 6.0.

[0030] In some embodiments, the carrier material hydroxypropyl methylcellulose acetate succinate and the active ingredient are dissolved in a good solvent N,N-dimethylacetamide, and the resulting solution is added to a poor solvent water, and the pH is adjusted to 1.0 to 6.0.

[0031] In some embodiments, the carrier material hydroxypropyl methylcellulose acetate succinate and the active ingredient are dissolved in a good solvent dimethyl sulfoxide, and the resulting solution is added to a poor solvent water, and the pH is adjusted to 1.0 to 6.0.

[0032] In some embodiments, the carrier material polyvinylpyrrolidone and the active ingredient are dissolved in a good solvent, N,N-dimethylformamide, and the resulting solution is added to a poor solvent, water, and the pH is adjusted to 1.0 to 6.0.

[0033] In some embodiments, the carrier material polyvinylpyrrolidone and the active ingredient are dissolved in a good solvent, N,N-dimethylacetamide, and the resulting solution is added to a poor solvent, water, and the pH is adjusted to 1.0 to 6.0.

[0034] In some embodiments, the carrier material polyvinylpyrrolidone and the active ingredient are dissolved in a good solvent, dimethylsulfoxide, and the resulting solution is added to a poor solvent, water, and the pH is adjusted to 1.0 to 6.0.

[0035] In some embodiments, the carrier material hydroxypropyl methylcellulose phthalate and the active ingredient are dissolved in a good solvent N,N-dimethylformamide, and the resulting solution is added to a poor solvent water, and the pH is adjusted to 1.0 to 6.0.

[0036] In some embodiments, the carrier material hydroxypropyl methylcellulose phthalate and the active ingredient are dissolved in a good solvent N,N-dimethylacetamide, and the resulting solution is added to a poor solvent water, and the pH is adjusted to 1.0 to 6.0.

[0037] In some embodiments, the carrier material hydroxypropyl methylcellulose phthalate and the active ingredient are dissolved in a good solvent dimethyl sulfoxide, and the resulting solution is added to a poor solvent water, and the pH is adjusted to 1.0 to 6.0.

[0038] In some embodiments, the methods of the present disclosure comprise the steps of: a) dissolving a carrier material and an active ingredient, (R)-4-amino-1-(1-(but-2-ynyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or a pharma- ceutically acceptable salt thereof, in a good solvent (wherein the good solvent is at least one selected from the group consisting of dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, ethanol, tetrahydrofuran and methanol); b) adding the solution obtained in step a) to a poor solvent and adjusting the pH to 1.0 to 6.0 (wherein the poor solvent is at least one selected from the group consisting of diethyl ether, n-hexane, petroleum ether and water);

[0039] In another embodiment, the method of the present disclosure comprises the steps of: a) dissolving a carrier material and an active ingredient, (R)-4-amino-1-(1-(but-2-ynyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or a pharma- ceutically acceptable salt thereof, in a good solvent (wherein the good solvent is at least one selected from the group consisting of dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, ethanol, tetrahydrofuran and methanol); b) adding the solution obtained in step a) to an anti-solvent, wherein the anti-solvent is selected from the group consisting of water and a mixed solution of water with one or more of ether, n-hexane and petroleum ether, and the pH of the anti-solvent is 1.0-6.0.

[0040] Additionally, the method may further comprise a filtering step, a washing step or a drying step.

[0041] In other embodiments, the methods of the present disclosure further comprise a spray drying step.

[0042] In another embodiment, the particle size D90 of the solid dispersion is from 50 μm to 2000 μm.

[0043] In some embodiments, the particle size D90 of the solid dispersion provided is 200 μm, 210 μm, 220 μm, 230 μm, 240 μm, 250 μm, 260 μm, 270 μm, 280 μm, 290 μm, 300 μm, 310 μm, 320 μm, 330 μm, 340 μm, 350 μm, 360 μm, 370 μm, 380 μm, 390 μm, 400 μm, 410 μm, 420 μm, 430 μm, 440 μm, 450 μm, 460 μm, 470 μm, 480 μm, 490 μm, 500 μm, 510 μm, 520 μm, 530 μm, 540 μm, 550 μm, 560 μm, 570 μm, 580 μm, 590 μm, 600 μm, 610 μm, 620 μm, 630 μm, 640 μm, 650 μm, 660 μm, 670 μm, 680 μm, 690 μm, 700 μm, 710 μm, 720 μm, 730 μm, 740 μm, 750 μm, 760 μm, 770 μm, 780 μm, 790 μm, 800 μm, 810 μm, 820 μm, 830 μm, 840 μm, 850 μm, 860 μm, 870 μm, 880 μm, 890 μm, 900 μ μm, 570μm, 580μm, 590μm, 600μm, 610μm, 620μm, 630μm, 640μm, 650μm, 660μm , 670μm, 680μm, 690μm, 700μm, 710μm, 720μm, 730μm, 740μm, 750μm, 760μm, 77 0μm, 780μm, 790μm, 800μm, 810μm, 820μm, 830μm, 840μm, 850μm, 860μm, 870μm m, 880μm, 890μm, 900μm, 910μm, 920μm, 930μm, 940μm, 950μm, 960μm, 970μm, 9 80μm, 990μm, 1000μm, 1010μm, 1020μm, 1030μm, 1040μm, 1050μm, 1060μm, 10 70μm, 1080μm, 1090μm, 1100μm, 1110μm, 1120μm, 1130μm, 1140μm, 1150μm, 11 60μm, 1170μm, 1180μm, 1190μm, 1200μm, 1210μm, 1220μm, 1230μm, 1240μm, 1 250μm, 1260μm, 1270μm, 1280μm, 1290μm, 1300μm, 1310μm, 1320μm, 1330μm, 1 340μm, 1350μm, 1360μm, 1370μm, 1380μm, 1390μm, 1400μm, 1410μm, 1420μm, 1430μm, 1440μm, 1450μm, 1460μm, 1470μm, 1480μm, 1490μm, 1500μm, 1510μm, 1520μm, 1530μm, 1540μm, 1550μm, 1560μm, 1570μm, 1580μm, 1590μm, 1600μm, 1610μm, 1620μm, 1630μm, 1640μm, 1650μm, 1660μm, 1670μm, 1680μm, 1690μm,1700μm, 1710μm, 1720μm, 1730μm, 1740μm, 1750μm, 1760μm, 1770μm, 1780μm, 1790μm, 180 0μm, 1810μm, 1820μm, 1830μm, 1840μm, 1850μm, 1860μm, 1870μm, 1880μm, 1890μm, 1900μm, It may be selected from the group consisting of 1910 μm, 1920 μm, 1930 μm, 1940 μm, 1950 μm, 1960 μm, 1970 μm, 1980 μm, 1990 μm, 2000 or any value between any two values, preferably 100 μm to 1500 μm, more preferably 100 μm to 1000 μm.

[0044] Further, in some embodiments, the particle size D50 of the solid dispersion provided is 20 μm to 500 μm. Non-limiting examples include 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm, 160 μm, 170 μm, 180 μm, 190 μm, 200 μm, 210 μm, 220 μm, 230 μm, 240 μm, 250 μm, 260 μm, 270 μm, 280 μm, 290 μm, 300 μm, 310 μm, 320 μm, 330 μm, 340 μm, 350 μm, 360 μm, 370 μm, 380 μm, 390 μm, 400 μm, 410 μm, 420 μm, 430 μm, 440 μm, 450 μm, 460 μm, 470 μm, 480 μm, 490 μm, 500 μm or any value between any two values, preferably 20 μm to 200 μm.

[0045] Further, in some embodiments, the particle size D10 of the solid dispersion provided is 1 μm to 100 μm. Non-limiting examples include 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 95 μm, 100 μm, or any value between any two values, preferably 5 μm to 50 μm.

[0046] Further, in some embodiments, the particle size D[4,3] of the solid dispersion provided is from 100 μm to 800 μm. Non-limiting examples include 100μm, 110μm, 120μm, 130μm, 140μm, 150μm, 160μm, 170μm, 1 80μm, 190μm, 200μm, 210μm, 220μm, 230μm, 240μm, 250μm, 260μm, 270μm, 2 80μm, 290μm, 300μm, 310μm, 320μm, 330μm, 340μm, 350μm, 360μm, 370μm, 3 80μm, 390μm, 400μm, 410μm, 420μm, 430μm, 440μm, 450μm, 460μm, 470μm, 4 80μm, 490μm, 500μm, 510μm, 520μm, 530μm, 540μm, 550μm, 560μm, 570μm, 580μm, 590μm, 600μm, 610μm, 620μm, 630μm, 640μm, 650μm, 660μm, 670μm, 680μm, 690μm, 700μm, 710μm, 720μm, 730μm, 740μm, 750μm, 760μm, 770μm, 780μm, 790μm, 800μm or any value between any two values, preferably 150μm to 600μm.

[0047] The solid dispersion provided in the most preferred embodiment has a particle size D90 of 100 μm to 1000 μm, a particle size D50 of 20 μm to 200 μm, and a particle size D10 of 1 μm to 100 μm.

[0048] The particle size of the solid dispersion of the present disclosure refers to the particle size of the solid dispersion in the suspension obtained after the particles are precipitated from the solvent, or the particle size of the solid dispersion after the solvent is removed and dried. In some embodiments, the particle size refers to the particle size of the solid dispersion in the suspension obtained after the particles are precipitated from the solvent.

[0049] In some embodiments, the active ingredient is in an amorphous form.

[0050] In another aspect, solid dispersion (SD) refers to a solid form of dispersion system formed by highly dispersing a drug in a solid carrier. The carrier material provides a dispersion system for the active ingredient. The higher the content of the carrier material, the easier the active ingredient can change from crystal to amorphous, and the higher the bioavailability of the corresponding solid dispersion. In terms of the balance between drug loading and bioavailability, the weight ratio of the carrier material and the active ingredient of the present disclosure can be 0.5:1 to 4:1. In some embodiments, the weight ratio can be 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, 4:1 or any value between any two values, preferably 0.8:1 to 3:1.

[0051] In some embodiments, the solid dispersion provided herein is at least one selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone, hydroxypropyl methylcellulose phthalate, and polyvinylpyrrolidone.

[0052] In some preferred embodiments, a solid dispersion is provided that comprises polyvinylpyrrolidone and the active ingredient, (R)-4-amino-1-(1-(but-2-yneoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or a pharma-ceutically acceptable salt thereof.

[0053] Further, the solid dispersion of the present disclosure consists of the active ingredient (R)-4-amino-1-(1-(but-2-yneoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or a pharma- ceutically acceptable salt thereof and a carrier material.

[0054] The present disclosure also provides a solid dispersion prepared by the above method.

[0055] The present disclosure also provides a solid dispersion comprising an active ingredient, (R)-4-amino-1-(1-(but-2-yneoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or a pharma- ceutically acceptable salt thereof, and a carrier material, wherein the solid dispersion has a particle size D90 of 50 μm to 2000 μm.

[0056] In some embodiments, the particle size D90 of the solid dispersion provided is 200 μm, 210 μm, 220 μm, 230 μm, 240 μm, 250 μm, 260 μm, 270 μm, 280 μm, 290 μm, 300 μm, 310 μm, 320 μm, 330 μm, 340 μm, 350 μm, 360 μm, 370 μm, 380 μm, 390 μm, 400 μm, 410 μm, 420 μm, 430 μm, 440 μm, 450 μm, 460 μm, 470 μm, 480 μm, 490 μm, 500 μm, 510 μm, 520 μm, 530 μm, 540 μm, 550 μm, 560 μm, 570 μm, 580 μm, 590 μm, 600 μm, 610 μm, 620 μm, 630 μm, 640 μm, 650 μm, 660 μm, 670 μm, 680 μm, 690 μm, 700 μm, 710 μm, 720 μm, 730 μm, 740 μm, 750 μm, 760 μm, 770 μm, 780 μm, 790 μm, 800 μm, 810 μm, 820 μm, 830 μm, 840 μm, 850 μm, 860 μm, 870 μm, 880 μm, 890 μm, 900 μ μm, 570μm, 580μm, 590μm, 600μm, 610μm, 620μm, 630μm, 640μm, 650μm, 660μm , 670μm, 680μm, 690μm, 700μm, 710μm, 720μm, 730μm, 740μm, 750μm, 760μm, 77 0μm, 780μm, 790μm, 800μm, 810μm, 820μm, 830μm, 840μm, 850μm, 860μm, 870μm m, 880μm, 890μm, 900μm, 910μm, 920μm, 930μm, 940μm, 950μm, 960μm, 970μm, 9 80μm, 990μm, 1000μm, 1010μm, 1020μm, 1030μm, 1040μm, 1050μm, 1060μm, 10 70μm, 1080μm, 1090μm, 1100μm, 1110μm, 1120μm, 1130μm, 1140μm, 1150μm, 11 60μm, 1170μm, 1180μm, 1190μm, 1200μm, 1210μm, 1220μm, 1230μm, 1240μm, 1 250μm, 1260μm, 1270μm, 1280μm, 1290μm, 1300μm, 1310μm, 1320μm, 1330μm, 1 340μm, 1350μm, 1360μm, 1370μm, 1380μm, 1390μm, 1400μm, 1410μm, 1420μm, 1430μm, 1440μm, 1450μm, 1460μm, 1470μm, 1480μm, 1490μm, 1500μm, 1510μm, 1520μm, 1530μm, 1540μm, 1550μm, 1560μm, 1570μm, 1580μm, 1590μm, 1600μm, 1610μm, 1620μm, 1630μm, 1640μm, 1650μm, 1660μm, 1670μm, 1680μm, 1690μm,1700μm, 1710μm, 1720μm, 1730μm, 1740μm, 1750μm, 1760μm, 1770μm, 1780μm, 1790μm, 180 0μm, 1810μm, 1820μm, 1830μm, 1840μm, 1850μm, 1860μm, 1870μm, 1880μm, 1890μm, 1900μm, It may be selected from the group consisting of 1910 μm, 1920 μm, 1930 μm, 1940 μm, 1950 μm, 1960 μm, 1970 μm, 1980 μm, 1990 μm, 2000, and any value between any two values, preferably 100 μm to 1500 μm, more preferably 100 μm to 1000 μm.

[0057] Further, in some embodiments, the particle size D50 of the solid dispersion provided is 20 μm to 500 μm. Non-limiting examples include 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm, 160 μm, 170 μm, 180 μm, 190 μm, 200 μm, 210 μm, 220 μm, 230 μm, 240 μm, 250 μm, 260 μm, 270 μm, 280 μm, 290 μm, 300 μm, 310 μm, 320 μm, 330 μm, 340 μm, 350 μm, 360 μm, 370 μm, 380 μm, 390 μm, 400 μm, 410 μm, 420 μm, 430 μm, 440 μm, 450 μm, 460 μm, 470 μm, 480 μm, 490 μm, 500 μm or any value between any two values, preferably 20 μm to 200 μm.

[0058] Further, in some embodiments, the particle size D10 of the solid dispersion provided is 1 μm to 100 μm. Non-limiting examples include 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 95 μm, 100 μm, or any value between any two values, preferably 5 μm to 50 μm.

[0059] Further, in some embodiments, the particle size D[4,3] of the solid dispersion provided is from 100 μm to 800 μm. Non-limiting examples include 100μm, 110μm, 120μm, 130μm, 140μm, 150μm, 160μm, 170μm, 1 80μm, 190μm, 200μm, 210μm, 220μm, 230μm, 240μm, 250μm, 260μm, 270μm, 2 80μm, 290μm, 300μm, 310μm, 320μm, 330μm, 340μm, 350μm, 360μm, 370μm, 3 80μm, 390μm, 400μm, 410μm, 420μm, 430μm, 440μm, 450μm, 460μm, 470μm, 4 80μm, 490μm, 500μm, 510μm, 520μm, 530μm, 540μm, 550μm, 560μm, 570μm, 580μm, 590μm, 600μm, 610μm, 620μm, 630μm, 640μm, 650μm, 660μm, 670μm, 680μm, 690μm, 700μm, 710μm, 720μm, 730μm, 740μm, 750μm, 760μm, 770μm, 780μm, 790μm, 800μm or any value between any two values, preferably 150μm to 600μm.

[0060] In the most preferred embodiment, the solid dispersion provided has a particle size D90 of 100 μm to 1000 μm, a particle size D50 of 20 μm to 200 μm, and a particle size D10 of 1 μm to 100 μm.

[0061] In some embodiments, the active ingredient is in an amorphous form.

[0062] From the viewpoint of the balance between drug loading and bioavailability, the weight ratio of the carrier material and the active ingredient of the present disclosure can be 0.5:1 to 4:1. In some embodiments, the weight ratio can be 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, 4:1 or any value between any two values, preferably 0.8:1 to 3:1.

[0063] In some embodiments, the solid dispersion provided herein is at least one selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone, hydroxypropyl methylcellulose phthalate, and polyvinylpyrrolidone.

[0064] In some preferred embodiments, a solid dispersion is provided comprising polyvinylpyrrolidone and the active ingredient (R)-4-amino-1-(1-(but-2-yneoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or a pharma-ceutically acceptable salt thereof.

[0065] Further, the solid dispersion of the present disclosure consists of the active ingredient (R)-4-amino-1-(1-(but-2-yneoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or a pharma- ceutically acceptable salt thereof and a carrier material.

[0066] In another aspect, the present disclosure provides a solid formulation comprising the above solid dispersion or the solid dispersion prepared by the above method and optionally a pharma- ceutically acceptable excipient, wherein the excipient is at least one selected from the group consisting of a disintegrant, a filler, a binder and a lubricant. The solid formulation may be a tablet, a pill, a granule, a capsule, etc.

[0067] In some embodiments, the active ingredient content is 8% to 40% by weight based on the weight of the pharmaceutical composition. The active ingredient content may be 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40% by weight or any value between any two values ​​based on the weight of the pharmaceutical composition, preferably 15% to 25% by weight.

[0068] In another embodiment, the amount (weight or mass) of the active ingredient is 10 mg to 500 mg. The amount (weight or mass) of the active ingredient may be 200 mg, 190 mg, 180 mg, 170 mg, 160 mg, 150 mg, 140 mg, 130 mg, 120 mg, 110 mg, 100 mg, 95 mg, 75 mg, 50 mg, 25 mg, 15 mg, 10 mg or any value between any two values, preferably 200 mg, 100 mg or 25 mg.

[0069] Disintegrants of the present disclosure are known to or identifiable by those of skill in the art and include, but are not limited to, at least one selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch, starch, pregelatinized starch, and alginic acid. Preferably, the disintegrant is present in an amount of 1% to 20% by weight based on the weight of the pharmaceutical composition. Non-limiting examples include 1.0% by weight, 1.5% by weight, 2% by weight, 2.5% by weight, 3% by weight, 3.5% by weight, 4% by weight, 4.5% by weight, 5% by weight, 5.5% by weight, 6% by weight, 6.5% by weight, 7% by weight, 7.5% by weight, 8% by weight, 8.5% by weight, 9% by weight, 9.5% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, 15% by weight, 16% by weight, 17% by weight, 18% by weight, 19% by weight, 20% by weight or any value between any two values, preferably 5% by weight to 15% by weight.

[0070] Binders of the present disclosure are known to or identifiable by those of skill in the art and include, but are not limited to, at least one of polyvinylpyrrolidone, starch, methylcellulose, carboxycellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and alginate, preferably at least one of polyvinylpyrrolidone (trade name K30) and hydroxypropylcellulose. More preferably, the binder is present in an amount of 0.5% to 10% by weight based on the weight of the pharmaceutical composition. Non-limiting examples include 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% by weight of the pharmaceutical composition or any value between any two of these values.

[0071] Lubricants of the present disclosure are known or identifiable by those of skill in the art and include, but are not limited to, at least one of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, and sodium stearyl fumarate. Preferably, the lubricant is present in an amount of 0.1% to 5% by weight based on the weight of the pharmaceutical composition. Non-limiting examples include 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% by weight or any value between any two values, preferably 0.1% to 2% by weight based on the weight of the pharmaceutical composition.

[0072] In some embodiments, the solid formulation of the present disclosure comprises: 1) 10mg to 500mg of active ingredient; 2) 5% to 15% by weight of a disintegrant; 3) 30% to 90% by weight of a filler; 4) 0.5% to 10% by weight of a binder; 5) 0.1% to 5% by weight of a lubricant.

[0073] Furthermore, the dissolution rate is measured by the second method (paddle method) of the dissolution rate test described in the general rule of volume IV of Chinese Pharmacopoeia 2015 Edition, using a 0.15% aqueous solution of SDS as the dissolution medium at 37±0.5° C. and a paddle speed of 50 rpm. The dissolution rate (%) of the active ingredient in the solid formulation of the present disclosure in 45 minutes is 85% or more, and may be 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% or more, and is preferably 90% or more. Furthermore, the dissolution rate (%) of the active ingredient in the solid formulation in 15 minutes is 70% or more, and may be 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% or more. The solid formulation dissolves quickly and completely and has good bioavailability. The preparation process of the solid formulation is simple and suitable for mass production.

[0074] Furthermore, the present disclosure also provides a method for preparing the above solid formulation, which includes the steps of grinding the solid dispersion, mixing thoroughly with fillers and / or disintegrants required for forming the pharmaceutical composition, adding binders, subjecting to wet or dry granulation, drying the obtained granules, screening through sieves, milling, mixing thoroughly with lubricants, and preparing into pills or granules or compressing into tablets or filling into capsules; or the solid dispersion may be directly added to capsules or compressed into tablets together with suitable auxiliary agents. The obtained granules or raw tablets or capsules may be further coated as necessary.

[0075] The present disclosure also provides the use of the solid dispersion or solid formulation of the present disclosure in the preparation of a medicament for treating a condition or disease mediated by protein tyrosine kinase.In some embodiments, the condition or disease is cancer or an autoimmune disease.In some embodiments, the cancer is a B-cell malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, multiple myeloma (MM), follicular lymphoma (FL), marginal zone lymphoma and Waldenstrom's macroglobulinemia (WM).In some embodiments, the autoimmune disease is rheumatoid arthritis or systemic lupus erythematosus.

[0076] The active ingredient of the present disclosure, (R)-4-amino-1-(1-(but-2-yneoyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one, can form pharma- ceutically acceptable salts with acids known to or identifiable by those of skill in the art, including, but not limited to, hydrochloric acid, methanesulfonic acid, fumaric acid, trifluoroacetic acid, and phosphoric acid.

[0077] The expression "by weight of the pharmaceutical composition" in this disclosure means that the calculation of the range of amounts of active ingredients or other types of pharmaceutical auxiliaries is based on the weight of the tablet cores, without coating agents.

[0078] In the present disclosure, "good solvents" and "poor solvents (weak solvents)" are classified according to the solubility of the active ingredient. Generally, poor solvents and good solvents are classified according to the solubility of 20 mg / ml. A solvent in which the solubility of the active ingredient is less than about 20 mg / ml is a poor solvent. On the other hand, a solvent in which the solubility of the active ingredient is more than about 20 mg / ml is a good solvent.

[0079] The term "D10" in this disclosure refers to the corresponding particle size when the cumulative particle size distribution percentage of the sample reaches 10%. The term "D50" refers to the corresponding particle size when the cumulative particle size distribution percentage of the sample reaches 50%. The term "D90" refers to the corresponding particle size when the cumulative particle size distribution percentage of the sample reaches 90%. D[4,3] refers to the "fourth instantaneous / volume" mean diameter, also called the volume (or weight) mean diameter. Those skilled in the art will understand that there is a certain degree of error in measuring particle size. Generally, about plus or minus 10% is a reasonable error range. D10, D50, D90, and D[4,3] have a certain degree of error variation depending on the situation of use, and the error variation is within a range not exceeding plus or minus 10%.

[0080] HPLC detection conditions of the present disclosure: Octadecylsilane-bonded silica was used as the packing material (Waters Symmetry C18 column), 0.01 mol / L potassium dihydrogen phosphate buffer and acetonitrile were used as the mobile phase and eluent, and the detection wavelength was 210 nm.

[0081] Pharmaceutical auxiliaries and reagents, such as hydroxypropyl methylcellulose acetate succinate, are commercially available.(R)-4-amino-1-(1-(but-2-ynyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (Compound A) or its pharma-ceutically acceptable salt can be prepared by the method described in the examples of WO2016007185. [Brief description of the drawings]

[0082] The above and other objects and features of the present disclosure will become apparent from reference to the following drawings, each of which illustrates:

[0083] [Figure 1] SECM image of the sample in Example 3

[0084] [Diagram 2] SECM image of sample from Example 4

[0085] (Detailed Description) The present disclosure will now be described in further detail with reference to the following examples and experimental examples, which are for illustrative purposes only and should not be construed as limiting the scope of the present disclosure. EXAMPLES

[0086] Example 1: 1 g of (R)-4-amino-1-(1-(but-2-ynyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (abbreviated as compound A) and 1 g of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were added to 15 ml of dimethylacetamide and dissolved by stirring. The resulting solution was added dropwise to 100 ml of water at a rate of 4 g / min or 2 g / min and stirred for about 1 hour. The resulting suspension was filtered. Initially, aggregation was observed, filtration (or suction filtration) was difficult, and the suction filtrate showed a milky white color.

[0087] Example 2: 1 g of compound A and 1 g of hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were added to 15 ml of dimethylacetamide and dissolved by stirring. The resulting solution was added dropwise to 100 ml of water with different pH values ​​(shown in Table 1) at a rate of 4 g / min and stirred for about 1 hour. The resulting suspension was filtered to obtain a solid. The observed phenomena are as follows: [Table 1]

[0088] Conclusion: The solid dispersions prepared using phosphoric acid or sulfuric acid have a low amount of residual ions. For example, when phosphoric acid is used, the phosphorus content in the resulting solid dispersion is about 20 μg / g; when sulfuric acid is used, the sulfur content in the resulting solid dispersion is 10 μg / g.

[0089] The samples obtained in Experimental Examples 1, 4 and 5 were placed under conditions of 93%, 60°C, 40°C / 75%RH and 25°C / 60%RH, respectively, and their physical and chemical stability was examined. The data are shown below: [Table 2]

[0090] Example 3: 1 g of compound A and 1 g of HPMC-AS were dissolved in 15 ml of N,N-dimethylacetamide. The resulting solution was added dropwise at a rate of 4 g / min to 100 ml of an aqueous solution (adjusted to pH=2 with 36.5% hydrochloric acid) and stirred for 30 minutes. The resulting suspension was filtered and the filter cake was washed with water. The resulting solid was dried at 40° C. overnight and subjected to SEM measurement.

[0091] SEM results show that the obtained samples are microsphere-like and uniformly distributed, see Figure 1.

[0092] Example 4: 1 g of Compound A and 1 g of HPMC-AS were dissolved in 15 ml of N,N-dimethylacetamide. The resulting solution was added dropwise to 100 ml of water at a rate of 4 g / min and stirred. Water was used as the dispersion medium to obtain a sample, which was used for particle size measurement. The resulting suspension was filtered, the suction filtrate showed milky white color, and the filter cake was washed with water. The resulting solid was dried at 40° C. overnight and SEM measurements were performed.

[0093] Particle sizes of the sample obtained using water as the dispersion medium: D10 = 7.6 μm, D50 = 27.2 μm, D90 = 86 μm, D[4,3] = 39.4 μm.

[0094] SEM results show that the obtained samples are granular and have non-uniform grain size, see Figure 2.

[0095] Example 5: A certain amount of compound A and HPMC-AS-LF were weighed and dissolved in 15 ml of N,N-dimethylacetamide (DMAC). The resulting solution was added dropwise to 100 ml of water at a rate of 4 g / min (adjusted to pH=2 with 36.5% hydrochloric acid) and stirred. The specific parameters are as shown in the table below: [Table 3]

[0096] The particle size of each sample obtained using water as a dispersion medium was measured. The specific data are as follows: [Table 4]

[0097] Example 6: A solid dispersion containing Compound A and hydroxypropyl methylcellulose acetate succinate was prepared by the method of Test Example 9. The formulation amounts of solid dispersion, lactose, microcrystalline cellulose and croscarmellose sodium were weighed according to the formulation specified as follows. The mixture was poured into a granulation tank, mixed well, and polyvinylpyrrolidone was added as a binder to prepare granules. The moistened and softened material was wet milled and dried, and the dried granules (moisture content less than 3%) were then dry milled. Granular external additives were added and mixed well with the granules. The resulting total mixed granules were compressed into tablets. The specific formulation ratios are shown in Table 2. [Table 5]

[0098] Dissolution Test The dissolution rates of the tablets of Experimental Examples 11 and 12 were measured according to the second method (paddle method) of the dissolution rate test described in the General Provisions of Volume 4 of the Chinese Pharmacopoeia, 2015. The dissolution test was carried out at 37±0.5°C and a paddle speed of 50 rpm using 1000 ml of a 0.15% aqueous solution of SDS as the dissolution medium. [Table 6]

Claims

1. A method for preparing a solid dispersion, comprising the steps of dissolving a carrier material, hydroxypropyl methylcellulose acetate succinate, and an active ingredient, (R)-4-amino-1-(1-(but-2-ynyl)pyrrolidin-3-yl)-3-(4-(2,6-difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one or a pharma- ceutically acceptable salt thereof, in a good solvent to obtain a solution, and adding the obtained solution to a poor solvent, wherein the pH of the poor solvent is 2.0-3.0, the good solvent is N,N-dimethylacetamide, and the poor solvent is water.

2. 2. The process according to claim 1, wherein the temperature for precipitation of the solid is selected from 0 to 40°C.

3. 2. The method according to claim 1, wherein the particle size D90 of the solid dispersion is from 50 μm to 2000 μm; and / or the particle size D50 of the solid dispersion is from 20 μm to 500 μm; and / or the particle size D10 of the solid dispersion is from 1 μm to 100 μm.

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