Pharmaceutical Composition Comprising Quinazoline Derivative or Salt Thereof

Abstract

A solid pharmaceutical composition comprising a quinazoline derivative or a medicinal salt thereof, and a preparation method therefor. Specifically, provided is a solid pharmaceutical composition comprising N.sup.6-(1-acryloylpiperidin-4-yl)-N.sup.4-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine or a medicinal salt thereof, and a preparation method therefor and use thereof.

##STR00001##

Claims

1. A solid pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a polymethacrylate ester, ##STR00007##

2. The solid pharmaceutical composition according to claim 1, wherein: the pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of a maleate salt, a hydrochloride salt, a hydrobromide salt, a sulfate salt, a phosphate salt, a nitrate salt, an acetate salt, a lactate salt, a malonate salt, a succinate salt, a fumarate salt, a malate salt, a mandelate salt, a tartrate salt, a citrate salt, an ascorbate salt, a palmitate salt, a benzoate salt, a phenylacetate salt, a cinnamate salt, a salicylate salt, a methanesulfonate salt, a benzenesulfonate salt, and a methylbenzenesulfonate salt; optionally, the pharmaceutically acceptable salt is selected from the group consisting of a maleate salt, a malate salt, a fumarate salt, a tartrate salt, a citrate salt, a lactate salt, a phosphate salt, and an acetate salt; optionally, the pharmaceutically acceptable salt is selected from a maleate salt.

3. The solid pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a compound of formula (II), ##STR00008##

4. The solid pharmaceutical composition according to claim 1, wherein: the polymethacrylate ester is Eudragit®; optionally, the polymethacrylate ester is selected from the group consisting of Eudragit© E100, Eudragit® EPO, Eudragit® S100, Eudragit® L100, Eudragit® E100-55, Eudragit® FS30D, Eudragit® NM30D, Eudragit® NE30D, Eudragit® RL100, Eudragit® RS100, and combinations thereof; optionally, the polymethacrylate ester is selected from Eudragit® E100 E100.

5. The solid pharmaceutical composition according to claim 1, wherein: the solid pharmaceutical composition further comprises an acid; or, the solid pharmaceutical composition further comprises an acid selected from the group consisting of: maleic acid, malic acid, fumaric acid, tartaric acid, citric acid, lactic acid, phosphoric acid, acetic acid, and a combination thereof; optionally, the acid is maleic acid.

6. The solid pharmaceutical composition according to claim 1, wherein: the solid pharmaceutical composition comprises 0.1-50 wt %, or 0.1-20 wt %, or 0.1-10 wt %, or 0.1-5 wt %, or 0.1-4 wt % of the compound of formula (I) or the pharmaceutically acceptable salt thereof based on the total mass of the solid pharmaceutical composition.

7. The solid pharmaceutical composition according to claim 1, wherein: the solid pharmaceutical composition further comprises a surface stabilizer; or the solid pharmaceutical composition further comprises a surface stabilizer selected from the group consisting of hydroxypropylcellulose, lecithin, glycerol monostearate, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)phenol polymers with ethylene oxide and formaldehyde, and poloxamers; optionally, the surface stabilizer is selected from the group consisting of hydroxypropylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and amorphous cellulose; optionally, the surface stabilizer is selected from hydroxypropylcellulose.

8. The solid pharmaceutical composition according to claim 1, wherein: the solid pharmaceutical composition further comprises a dispersant; or the solid pharmaceutical composition further comprises a dispersant selected from the group consisting of: sucrose, lactose, mannitol, or combinations thereof; optionally, the dispersant is selected from sucrose.

9. The solid pharmaceutical composition according to claim 1, wherein: the solid pharmaceutical composition further comprises a carrier; or the solid pharmaceutical composition further comprises a carrier selected from the group consisting of a cellulose sphere, a mannitol pellet core, a tartaric acid pellet core, a lactose/microcrystalline pellet core, a sucrose pellet core, a starch pellet core, and combinations thereof, optionally, the carrier is selected from the group consisting of a cellulose sphere and a sucrose pellet core; optionally, the carrier is selected from a sucrose pellet core.

10. The solid pharmaceutical composition according to claim 1, comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof, the polymethacrylate ester, an acid, a surface stabilizer, a dispersant, and a carrier.

11. The solid pharmaceutical composition according to claim 3, comprising the compound of formula (II), the polymethacrylate ester, an acid, a surface stabilizer, a dispersant, and a carrier.

12. The solid pharmaceutical composition according to claim 11, comprising the compound of formula (II), hydroxypropylcellulose, sucrose, the polymethacrylate ester, maleic acid, and a sucrose pellet core.

13. The solid pharmaceutical composition according to claim 11, comprising the following components in parts by weight: TABLE-US-00019 the compound of formula (II)  0.1-40 parts the surface stabilizer 0.01-10 parts the dispersant 0.5-350 parts the polymethacrylate ester 0.5-500 parts the acid the carrier   100-500 parts;  or, comprising the following components in parts by weight: TABLE-US-00020 the compound of formula (II) 0.1-40 parts hydroxypropylcellulose 0.01-10 parts sucrose 0.5-350 parts the polymethacrylate ester 0.5-500 parts maleic acid a sucrose pellet core 100-500 parts; or, comprising the following components in parts by weight: TABLE-US-00021 the compound of formula (II) 0.627 parts hydroxypropylcellulose 0.1 parts sucrose 3.13 parts the polymethacrylate ester 5 parts maleic acid a sucrose pellet core 333 parts; or, comprising the following components in parts by weight: TABLE-US-00022 the compound of formula (II) 2.508 parts hydroxypropylcellulose  0.4 parts sucrose 12.54 parts the polymethacrylate ester   20 parts maleic acid a sucrose pellet core    250 parts; or, comprising the following components in parts by weight: TABLE-US-00023 the compound of formula (II) 6.27 parts hydroxypropylcellulose 1 parts sucrose 31.35 parts the polymethacrylate ester 50 parts maleic acid a sucrose pellet core 250 parts; or, comprising the following components in parts by weight: TABLE-US-00024 the compound of formula (II) 12.54 parts hydroxypropylcellulose 2 parts sucrose 62.7 parts the polymethacrylate ester 100 parts maleic acid a sucrose pellet core 250 parts

14. A method for preparing the solid pharmaceutical composition according to claim 1, comprising the following steps: preparing a suspension containing the compound of formula (I) or the pharmaceutically acceptable salt thereof, adding the acid and the polymethacrylate ester to the suspension; and subjecting the suspension to fluidized bed granulation, and more specifically, the fluidized bed granulation comprises loading the resulting suspension on the carrier on a fluidized bed to obtain drug-containing pellets.

15. A method for treating a tumor, comprising administering the solid pharmaceutical composition according to claim 1 to a subject in need thereof, and optionally, the tumor is selected from the group consisting of non-small cell lung cancer and breast cancer.

16. The solid pharmaceutical composition according to claim 2, wherein: a molar ratio of the compound of formula (I) to an acid radical ion in the pharmaceutically acceptable salt of the compound of formula (I) may be 1:1.

17. The solid pharmaceutical composition according to claim 1, wherein: a weight ratio of the polymethacrylate ester to the compound of formula (I) or the pharmaceutically acceptable salt thereof is (50-0.5):1, or (45-1):1, or (40-1.5):1, or (35-2):1, or (30-3):1, or (25-4):1, or (20-5):1, or (18-5.5):1, or (16-5.7):1, or (14-5.9):1, or (12-6.1):1, or (10-6.3):1, or (8.5-6.5):1, or (8.5-7):1, or (8.5-7.5):1; or wherein a weight ratio of the polymethacrylate ester to the compound of formula (II) is 8:1.

18. The solid pharmaceutical composition according to claim 7, wherein: the solid pharmaceutical composition further comprises a surface stabilizer in the following amount: a weight ratio of the surface stabilizer to the compound of formula (I) or the pharmaceutically acceptable salt thereof is (0.06-1):1, or (0.07-0.9):1, or (0.08-0.8):1, or (0.09-0.7):1, or (0.10-0.6):1, or (0.11-0.5):1, or (0.12-0.7):1, or (0.13-0.6):1, or (0.14-0.5):1, or (0.15-0.4):1, or (0.15-0.3):1, or (0.15-0.2):1; or wherein a weight ratio of the surface stabilizer to the compound of formula (II) is 0.16:1.

19. The solid pharmaceutical composition according to claim 8, wherein: the solid pharmaceutical composition further comprises a dispersant in the following amount: a weight ratio of the dispersant to the compound of formula (I) or the pharmaceutically acceptable salt thereof is (0.5-50):1, or (0.8-45):1, or (1.1-40):1, or (1.4-35):1, or (1.7-30):1, or (2-25):1, or (2.3-20):1, or (2.8-15):1, or (3.1-10):1, or (3.4-9):1, or (3.7-8):1, or (4.0-7):1, or (4.3-6):1, or (4.5-5.5):1; or wherein a weight ratio of the dispersant to the compound of formula (II) is 5:1.

20. The solid pharmaceutical composition according to claim 9, wherein: the solid pharmaceutical composition further comprises a carrier in the following amount: a proportion range of the carrier in the pharmaceutical composition is selected from the group consisting of 0.1-99 wt %, 0.5-99 wt %, 1-99 wt %, 5-99 wt %, 10-99 wt %, 15-99 wt %, 20-99 wt %, 25-99 wt %, 30-99 wt %, 35-99 wt %, 40-99 wt %, and 45-99 wt %.

Description

DETAILED DESCRIPTION

[0121] The following specific examples are intended to allow those skilled in the art to clearly understand and implement the present application. These specific examples should not be considered as limit to the scope of the present application, but merely as exemplary description and representative of the present application.

Example 1

[0122] 1) A formula amount of hydroxypropylcellulose was added to water.sup.1. After complete dissolution, a compound of formula (II) was added with stirring and uniformly dispersed. The resulting mixture was sieved. [0123] 2) The suspension containing the compound of formula (II) above was subjected to high-pressure homogenization, with the particle size of the compound of formula (II) controlled at: D50<2 μm and D90<4 μm. [0124] 3) A 0.5 mol/L solution of maleic acid in water.sup.2 was prepared. A formula amount of Eudragit® E100 was dissolved in half of the prepared maleic acid solution. After complete dissolution, the resulting solution was added to the suspension obtained in step 2), and then the suspension was adjusted to a pH value between 3.0-3.5 with the rest of the maleic acid solution to obtain a suspension. [0125] 4) Sucrose blank pellet cores were coated with the suspension prepared in step 3) in a fluidized bed reactor to obtain drug-containing pellets. [0126] 5) The drug-containing pellets were well mixed in a hopper mixer. [0127] 6) Capsules were filled.

[0128] The specific composition of the pharmaceutical capsule formulation is shown in Table 1 below.

TABLE-US-00008 TABLE 1 Amount Formula component (mg) Compound of formula (II) 0.627 Hydroxypropylcellulose 0.10 (HPC-SL) Sucrose 3.13 Eudragit ® E100 5 Maleic acid Proper amount Sucrose pellet core 333.33 (0.6-0.8 mm)
Note: water.sup.1: 66.67 mg; and water.sup.2: 50 mg.

[0129] Examples 2-4 were prepared by referring to the procedures in Example 1. The specific composition of the pharmaceutical capsule formulations is shown in Table 2 below.

TABLE-US-00009 TABLE 2 Amount (mg) Example Example Example Formula component 2 3 4 Compound of formula 2.508 6.27 12.54 (II) Hydroxypropylcellulose 0.40 1.0 2.0 (HPC—SL) Sucrose 12.54 31.35 62.7 Eudragit ® E100 20 50 100 Maleic acid Proper Proper Proper amount amount amount Sucrose pellet core 250 250 250 (0.6-0.8 mm) Note: Example 2, water.sup.1: 266.68 mg; water.sup.2: 200 mg; Example 3, water.sup.1: 666.7 mg; and water.sup.2: 500 mg; and Example 4, water.sup.1: 1333.4 mg; and water.sup.2: 1000 mg.

Example 5

[0130] The preparation was conducted by referring to steps 1)-6) of Example 1, except that in step 3), the pH value of the suspension was adjusted to 2.0≤pH<3.0; and the amount of water.sup.1 was 25 mg, and the amount of water.sup.2 is 50 mg.

[0131] The specific composition of the pharmaceutical capsule formulation is shown in Table 3 below.

TABLE-US-00010 TABLE 3 Amount Formula component (mg) Compound of formula (II) 2.508 Hydroxypropylcellulose 0.40 (HPC—SL) Sucrose 12.54 Eudragit ® E100 20 Maleic acid Proper amount Sucrose pellet core 250 (0.6-0.8 mm)

Example 6

[0132] 1) Hydroxypropylcellulose was added to water. After complete dissolution, a compound of formula (II) was added with stirring and uniformly dispersed. The resulting mixture was sieved.
2) The drug-containing suspension above was subjected to high-pressure homogenization.
3) A formula amount of sucrose was added to the treated suspension above and dissolved by stirring.
4) Sucrose blank pellet cores were coated with the drug suspension in a fluidized bed reactor to obtain drug-containing pellets.
5) The drug-containing pellets were well mixed in a hopper mixer.
6) Capsules were filled.

[0133] The specific composition of the pharmaceutical capsule formulation is shown in Table 4 below.

TABLE-US-00011 TABLE 4 Formula component Amount (mg) Compound of formula (II) 0.627 Hydroxypropylcellulose 0.10 (HPC—SL) Sucrose 3.13 Sucrose pellet core 333.33 (0.6-0.8 mm)

Example 7

[0134] 1) A compound of formula (II) was mixed with a 9-fold amount of lactose. The mixture was jet-milled until the particle sizes D50<2 μm and D90<4 μm.
2) The milled mixture of the maleate salt of a compound of formula (I) and lactose, the rest of lactose, sodium carboxymethyl starch, talcum powder and silica were mixed in a high-energy mixer at a paddle speed of 400 rpm and a cutter speed of 1000 rpm for 5-10 min.
3) Capsules were filled.

[0135] The specific composition of the pharmaceutical capsule formulation is shown in Table 5 below.

TABLE-US-00012 TABLE 5 Formula component Amount (mg) Compound of formula 0.625 (II) Lactose 250.8 Sodium carboxymethyl 8.475 starch Silicon dioxide 1.1275 Talcum powder 5.65

Experimental Example 1: Stability

1.1. Preparation of Samples

[0136] The samples prepared in the above examples (a paper box was adopted for outer packaging; a composite hard sheet formed from polyamide/aluminum/polyvinyl chloride by cold stamping and aluminum foil for pharmaceutical packaging were adopted for inner packaging) were let stand in sample boxes under different conditions for stability testing (40° C.±2° C. and 75%±5% RH; 30° C.±2° C. and 65%±5% RH; 25° C.±2° C. and 60%±5% RH; and 20° C.±2° C. and 60%±5% RH) for 1 month, 2 months, 3 months or 6 months and taken for analysis to determine the change in the compound A (impurity) content.

1.2. Instrument

[0137] Instrument: SHIMADAZU LC-20AD HPLC with a Waters Xbridge Shield RP18 (150×4.6 mm, 3.5 μm) chromatography column or a column with equivalent performance.

[0138] 0.01 mol/L ammonium formate buffer (0.63 g of ammonium formate was dissolved in 1000 mL of water, 1 mL of formic acid was added, and the pH value was adjusted to 7.4 with triethylamine) was used as mobile phase A, and acetonitrile as mobile phase B.

[0139] Linear gradient elution is performed according to the table below.

TABLE-US-00013 Mobile phase Mobile phase B Time (min) A %) (%) 0 77 23 50 20 80 51 77 23 60 77 23

1.3. Preparation of Sample Solution

[0140] A proper amount of the capsule's contents of each of the samples above was added to a 20 mL measuring flask, and a solvent [acetonitrile-water (40:60)] was precisely added. The sample was ultrasonically dissolved, and the resulting mixture was well mixed by shaking, and then centrifuged. The supernatant was taken as a test solution. A proper amount of the test solution was precisely measured out and 100-fold diluted with the solvent to prepare a control solution.

[0141] Compound A had a retention time of 28-30 min, a relative retention time RRT of 1.3 (standard sample: the compound of formula (I)), and a peak at m/z 456.1600 ([M+2H]++) in a mass spectrum.

[0142] The results are shown in Tables 6-9 below.

TABLE-US-00014 TABLE 6 (40° C. ± 2° C. and 75% ± 5% RH) 0 month 1 month 2 months 3 months 6 months Example Test item (%) (%) (%) (%) (%) Exam- Com- 0.07 0.12 0.14 0.15 0.16 ple 1 pound A Exam- Com- 0.06 0.09 0.11 0.11 0.13 ple 2 pound A Exam- Com- 0.06 0.47 0.62 0.78 1.24 ple 6 pound A Exam- Com- Unde- 8.66 / / / ple 7 pound A tectable

TABLE-US-00015 TABLE 7 (30° C. ± 2° C. and 65% ± 5% RH) 0 month 3 months 6 months Example Test item (%) (%) (%) Example 1 Compound A 0.07 0.11 0.13 Example 2 Compound A 0.06 0.09 0.10 Example 6 Compound A 0.06 0.29 0.45

TABLE-US-00016 TABLE 8 (25° C. ± 2° C. and 60% ± 5% RH) Example Test item 0 month (%) 3 months (%) 6 months (%) Example 1 Compound A 0.07 0.09 0.10 Example 2 Compound A 0.06 0.07 0.08 Example 6 Compound A 0.06 0.18 0.29 Example 7 Compound A Undetectable 1.63 /

TABLE-US-00017 TABLE 9 (20° C. ± 2° C. and 60% ± 5% RH) Example Test item 0 month (%) 3 months (%) 6 months (%) Example 1 Compound A 0.07 0.08 / Example 2 Compound A 0.06 / 0.07 Example 6 Compound A 0.06 0.13 0.19 Example 7 Compound A Undetectable 0.48 /

[0143] The “/” above indicates no detection.

Experimental Example 2: Dissolution Rate

[0144] The dissolution rates were measured by referring to the Method 2 (paddle, 0.1 mol/L hydrochloric acid medium, 900 mL, 75 rpm) of General Chapter 0931, Chinese Pharmacopoeia, Volume IV, 2015 Edition. The results are shown in Table 10.

TABLE-US-00018 TABLE 10 Example Dissolution rate Example 1  100% Example 2  103% Example 6 93.7% Example 7 90.7%