PARP INHIBITOR PELLET PREPARATION AND PREPARATION PROCESS THEREFOR

Abstract

The present invention relates to a PARP inhibitor pellet composition and a preparation process therefor. The pellet composition comprises a pellet and an optional additional excipient, with the pellet comprising (1) a pellet core; (2) a drug-containing layer and (3) an optional protective layer, wherein the drug-containing layer contains (a) an active ingredient and (b) a binder; when the composition comprises the protective layer, the protective layer contains (c) a coating material; and the active ingredient is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one, a pharmaceutically acceptable salt thereof and a hydrate thereof.

Claims

1. A PARP inhibitor pellet composition, comprising a pellet and an optional additional excipient, with the pellet comprising (1) a pellet core; (2) a drug-containing layer and (3) an optional protective layer, wherein the drug-containing layer contains (a) an active ingredient and (b) a binder; when the composition comprises the protective layer, the protective layer contains (c) a coating material; and the active ingredient is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one, a pharmaceutically acceptable salt thereof and a hydrate thereof.

2. A PARP inhibitor pellet composition, comprising (1) an active ingredient that is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one, a pharmaceutically acceptable salt thereof and a hydrate thereof, (2) a pellet core; (3) a binder; (4) an optional coating material; and (5) an optional additional excipient.

3. The pellet composition according to claim 1 or 2, wherein the additional excipient includes one or more of a filler and a lubricant, and more preferably the additional excipient includes a lubricant.

4. The pellet composition according to claim 1 or 2, wherein the pellet core is a blank pellet core selected from one or more of a sucrose pellet core, a microcrystalline cellulose pellet core, and a starch pellet core; and/or the weight percentage of the pellet core based on the total weight of the pellet composition is 50-90%, preferably 60-85% (w/w).

5. The pellet composition according to claim 1 or 2, wherein the active ingredient is crystal forms A-L or a hydrate; preferably, the active ingredient is crystal form C; preferably, the active ingredient is a sesquihydrate with the following structure: ##STR00004##

6. The pellet composition according to claim 5, wherein the active ingredient has a D.sub.90 particle size of less than 100 μm, preferably a D.sub.90 particle size of less than 50 μm, more preferably less than 30 μm; and/or the weight percentage of the active ingredient based on the total weight of the pellet composition is 5-50%, preferably 10-25%, more preferably 10-20% (w/w).

7. The pellet composition according to claim 1 or 2, wherein the active ingredient is crystal form C and/or a sesquihydrate of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one, and has a D.sub.90 particle size of less than 30 μm, and the weight percentage of the active ingredient based on the total weight of the pellet composition is 10-25%.

8. The pellet composition according to claim 1 or 2, wherein the binder is selected from one or more of carbomer, sodium carboxymethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium hydroxypropyl methylcellulose, and povidone; preferably, the binder is selected from hydroxypropyl methylcellulose, sodium hydroxypropyl methylcellulose, and povidone; and/or the weight percentage of the binder based on the total weight of the pellet composition is 1-20%, preferably 1-10%, more preferably 3-8%, most preferably 3-6% (w/w).

9. The pellet composition according to claim 1 or 2, wherein the coating material is selected from one or more of carbomer, sodium carboxymethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium hydroxypropyl methylcellulose, and povidone; preferably, hydroxypropyl methylcellulose and sodium hydroxypropyl methylcellulose; and/or the weight percentage of the coating material based on the total weight of the pellet composition is 1-25%, preferably 1-10%, more preferably 1.5-8%, most preferably 3-6% (w/w).

10. The pellet composition according to claim 3, wherein the lubricant includes, but is not limited to, one or more of calcium stearate, magnesium stearate, zinc stearate, stearic acid, sodium stearyl fumarate, and talc, preferably talc; and/or the weight percentage of the lubricant based on the total weight of the pellet composition is 0.1-5.0%, preferably 0.1-2%, more preferably 0.5-1.5% (w/w).

11. A method for preparing the pellet composition according to any one of claims 1 and 2, comprising the steps of: 1) dispersing an active ingredient in a binder solution to prepare a drug-containing suspension; 2) spraying the drug-containing suspension in step 1) onto the surface of a pellet core to form a drug-containing layer to prepare a drug-loaded pellet; 3) preparing a coating material solution, and spraying the coating material solution onto the surface of the drug-loaded pellet as a protective layer to prepare a protective layer pellet, this step being optionally performed; and 4) mixing the pellet obtained in step 2) or step 3) with an additional excipient to prepare a total mixture of pellet, this step being optionally performed.

12. A PARP inhibitor oral formulation, wherein the PARP inhibitor oral formulation is prepared from the pellet composition according to any one of preceding claims 1-10, and the oral formulation is a tablet, a capsule, or a granule, preferably a capsule.

13. The oral formulation according to claim 12, wherein the capsule comprises a capsule shell; the capsule shell is selected from a gelatin hollow capsule shell, a hydroxypropyl methylcellulose hollow capsule shell, preferably a gelatin hollow capsule shell; and/or different sizes of capsules are filled according to the content of the active ingredient in the pellet and the weight of the pellet, and the size is selected such that each capsule contains 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, or 100 mg of the active ingredient on the basis of the weight of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one.

14. A method for treating a PARP-associated disease, comprising administering to a patient a therapeutically effective amount of the pellet composition according to any one of claims 1-11 or the oral formulation according to any one of claims 12 and 13.

15. The method according to claim 14, wherein the PARP-associated disease is selected from tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, dermatosis, psoriasis and scleroderma, diabetes-induced dermatosis, diabetic retinopathy, retinopathy of prematurity, age-related degenerative macula, cancer, hemangioma, glioma, Kaposi's sarcoma, ovarian cancer, breast cancer; lung cancer, small cell lung cancer, pancreatic cancer, lymphoma, prostatic cancer, colon cancer and dermatoma, and complications thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0083] FIG. 1 is an electron microscope image of the drug substance Pamiparib.

[0084] FIG. 2 is an electron microscope image of the pellet of Example 1.

DETAILED DESCRIPTION OF EMBODIMENTS

[0085] The following examples can help those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention in any way. All raw materials are commercially available.

Example 1

[0086]

TABLE-US-00001 Formula of a 100 g pellet formulation: Microcrystalline cellulose pellet core 80.50 g Drug-containing layer: Pamiparib 12.08 g; and povidone  4.02 g Protective layer: hydroxypropyl methylcellulose  2.90 g Talc  0.50 g

[0087] wherein Pamiparib was based on the total weight of the sesquihydrate of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluorene-4(5H)-one.

[0088] Preparation Process:

[0089] 1) A formula amount (4.02 g) of povidone was weighed to prepare a binder solution with a concentration of 5%, and 12.08 g of Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.

[0090] 2) A formula amount of the microcrystalline cellulose pellet core was taken, and the drug-containing layer coating suspension was sprayed onto the surface of the pellet core to form a drug-containing layer so as to prepare a drug-loaded pellet. A formula amount (2.90 g) of the coating material hydroxypropyl methylcellulose was taken to prepare a coating material solution with a concentration of 5%, and the coating material solution was sprayed onto the surface of the drug-loaded pellet as a protective layer to prepare a drug-loaded pellet comprising the protective layer.

[0091] 3) The drug-loaded pellet (comprising the protective layer) obtained in the above-mentioned step was mixed with a formula amount of talc to prepare a total mixture of pellet.

[0092] 4) The overall hybrid pellet was filled into a capsule.

[0093] Different sizes of capsules could be filled according to the content of the drug substance in the pellet and the weight of the pellet, and the size included, but was not limited to, instances in which each capsule contains 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 100 mg of the active ingredient on the basis of the anhydrous compound.

[0094] FIG. 1 of the description is an electron microscope image of the drug substance Pamiparib, and since the drug substance BGB290 contains crystal water, is very easily agglomerated, and has a poor fluidity, which is not conducive to capsule filling, thereby affecting the industrialized mass production of a formulation. In addition, FIG. 2 of the description is an electron microscope image of the pellets of Example 1. It can be seen from the image that the pellets are round in shape, can be evenly spread under the field of view of an electron microscope, and has a good fluidity. It is sufficient to fulfil the filling of the capsule.

Example 2

[0095]

TABLE-US-00002 Formula of a 100 g pellet formulation: Sucrose pellet core 77.28 g Drug-containing layer: Pamiparib 11.60 g; and hydroxypropyl methylcellulose  7.73 g Protective layer: povidone  2.90 g Talc  0.50 g

[0096] wherein Pamiparib was based on the total weight of the sesquihydrate of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one.

[0097] Preparation Process:

[0098] 1) A formula amount (7.73 g) of hydroxypropyl methylcellulose was weighed to prepare a binder solution with a concentration of 5%, and 11.60 g of Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.

[0099] 2) A formula amount of the sucrose pellet core was taken, and the drug-containing layer coating suspension was sprayed onto the surface of the pellet core to form a drug-containing layer so as to prepare a drug-loaded pellet. A formula amount (2.90 g) of the coating material povidone was taken to prepare a coating material solution with a concentration of 5%, and the coating material solution was sprayed onto the surface of the drug-loaded pellet as a protective layer to prepare a drug-loaded pellet comprising the protective layer.

[0100] 3) The drug-loaded pellet (comprising the protective layer) obtained in the above-mentioned step was mixed with a formula amount of talc to prepare a total mixture of pellet.

[0101] 4) The overall hybrid pellet was filled into a capsule.

[0102] Different sizes of capsules could be filled according to the content of the drug substance in the pellet and the weight of the pellet, and the size included, but was not limited to, instances in which each capsule contains 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 100 mg of the active ingredient on the basis of the anhydrous compound.

Example 3

[0103]

TABLE-US-00003 Formula of a 100 g pellet formulation: Microcrystalline cellulose pellet core 80.50 g Drug-containing layer: Pamiparib 12.08 g; and hydroxypropyl methylcellulose  4.02 g Protective layer: hydroxypropyl methylcellulose  2.90 g Talc  0.50 g

[0104] wherein Pamiparib was based on the total weight of the sesquihydrate of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one.

[0105] Preparation Process:

[0106] 1) A formula amount (4.02 g) of hydroxypropyl methylcellulose was weighed to prepare a binder solution with a concentration of 5%, and 12.08 g of Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.

[0107] 2) A formula amount of the microcrystalline cellulose pellet core was taken, and the drug-containing layer coating suspension was sprayed onto the surface of the pellet core to form a drug-containing layer so as to prepare a drug-loaded pellet. A formula amount (2.90 g) of the coating material hydroxypropyl methylcellulose was taken to prepare a coating material solution with a concentration of 5%, and the coating material solution was sprayed onto the surface of the drug-loaded pellet as a protective layer to prepare a drug-loaded pellet comprising the protective layer.

[0108] 3) The drug-loaded pellet (comprising the protective layer) obtained in the above-mentioned step was mixed with a formula amount of talc to prepare a total mixture of pellet.

[0109] 4) The overall hybrid pellet was filled into a capsule.

[0110] Different sizes of capsules could be filled according to the content of the drug substance in the pellet and the weight of the pellet, and the size included, but was not limited to, instances in which each capsule contains 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 100 mg of the active ingredient on the basis of the anhydrous compound.

Example 4

[0111]

TABLE-US-00004 Formula of a 100 g pellet formulation: Microcrystalline cellulose pellet core 79.91 g Drug-containing layer: Pamiparib 12.13 g; sodium carboxymethylcellulose  4.04 g Protective layer: sodium carboxymethylcellulose  2.42 g Talc  1.50 g

[0112] wherein Pamiparib was based on the total weight of the sesquihydrate of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one.

[0113] Preparation Process:

[0114] 1) A formula amount (4.04 g) of sodium carboxymethylcellulose was weighed to prepare a binder solution with a concentration of 5%, and 12.13 g of Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.

[0115] 2) A formula amount of the microcrystalline cellulose pellet core was taken, and the drug-containing layer coating suspension was sprayed onto the surface of the pellet core to form a drug-containing layer so as to prepare a drug-loaded pellet. A formula amount (2.42 g) of the coating material sodium carboxymethylcellulose was taken to prepare a coating material solution with a concentration of 5%, and the coating material solution was sprayed onto the surface of the drug-loaded pellet as a protective layer to prepare a drug-loaded pellet comprising the protective layer.

[0116] 3) The drug-loaded pellet (comprising the protective layer) obtained in the above-mentioned step was mixed with a formula amount of talc to prepare a total mixture of pellet.

[0117] 4) The overall hybrid pellet was filled into a capsule.

[0118] Different sizes of capsules could be filled according to the content of the drug substance in the pellet and the weight of the pellet, and the size included, but was not limited to, instances in which each capsule contains 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 100 mg of the active ingredient on the basis of the anhydrous compound.

Example 5

[0119]

TABLE-US-00005 Formula of a 100 g pellet formulation: Sucrose pellet core 80.50 g Drug-containing layer: Pamiparib 12.08 g; sodium carboxymethylcellulose  4.02 g Protective layer: carbomer  2.90 g Talc  0.50 g

[0120] wherein Pamiparib was based on the total weight of the sesquihydrate of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one.

[0121] Preparation Process:

[0122] 1) A formula amount (4.02 g) of sodium carboxymethylcellulose was weighed to prepare a binder solution with a concentration of 5%, and 12.08 g of Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.

[0123] 2) A formula amount of the sucrose pellet core was taken, and the drug-containing layer coating suspension was sprayed onto the surface of the pellet core to form a drug-containing layer so as to prepare a drug-loaded pellet. A formula amount (2.90 g) of the coating material carbomer was taken to prepare a coating material solution with a concentration of 5%, and the coating material solution was sprayed onto the surface of the drug-loaded pellet as a protective layer to prepare a drug-loaded pellet comprising the protective layer.

[0124] 3) The drug-loaded pellet (comprising the protective layer) obtained in the above-mentioned step was mixed with a formula amount of talc to prepare a total mixture of pellet.

[0125] 4) The overall hybrid pellet was filled into a capsule.

[0126] Different sizes of capsules could be filled according to the content of the drug substance in the pellet and the weight of the pellet, and the size included, but was not limited to, instances in which each capsule contains 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 100 mg of the active ingredient on the basis of the anhydrous compound.

Example 6

[0127]

TABLE-US-00006 Formula of a 100 g pellet formulation: Microcrystalline cellulose pellet core 68.43 g Drug-containing layer: Pamiparib 20.53 g; and povidone  6.84 g Protective layer: sodium carboxymethylcellulose  3.70 g Talc  0.50 g

[0128] wherein Pamiparib was based on the total weight of the sesquihydrate of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one.

[0129] Preparation Process:

[0130] 1) A formula amount (6.84 g) of povidone was weighed to prepare a binder solution with a concentration of 5%, and 20.53 g of Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.

[0131] 2) A formula amount of the microcrystalline cellulose pellet core was taken, and the drug-containing layer coating suspension was sprayed onto the surface of the pellet core to form a drug-containing layer so as to prepare a drug-loaded pellet. A formula amount (3.70 g) of the coating material sodium carboxymethylcellulose was taken to prepare a coating material solution with a concentration of 5%, and the coating material solution was sprayed onto the surface of the drug-loaded pellet as a protective layer to prepare a drug-loaded pellet comprising the protective layer.

[0132] 3) The drug-loaded pellet (comprising the protective layer) obtained in the above-mentioned step was mixed with a formula amount of talc to prepare a total mixture of pellet.

[0133] 4) The overall hybrid pellet was filled into a capsule.

[0134] Different sizes of capsules could be filled according to the content of the drug substance in the pellet and the weight of the pellet, and the size included, but was not limited to, instances in which each capsule contains 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 100 mg of the active ingredient on the basis of the anhydrous compound.

Example 7

[0135]

TABLE-US-00007 Formula of a 100 g pellet formulation: Microcrystalline cellulose pellet core 89.40 g Drug-containing layer: Pamiparib  5.16 g; hydroxypropylcellulose  1.72 g Protective layer: hydroxypropyl methylcellulose  3.22 g Talc  0.50 g

[0136] wherein Pamiparib was based on the total weight of the sesquihydrate of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one.

[0137] Preparation Process:

[0138] 1) A formula amount (1.72 g) of hydroxypropylcellulose was weighed to prepare a binder solution with a concentration of 5%, and 5.16 g of Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.

[0139] 2) A formula amount of the microcrystalline cellulose pellet core was taken, and the drug-containing layer coating suspension was sprayed onto the surface of the pellet core to form a drug-containing layer so as to prepare a drug-loaded pellet. A formula amount (3.22 g) of the coating material hydroxypropyl methylcellulose was taken to prepare a coating material solution with a concentration of 5%, and the coating material solution was sprayed onto the surface of the drug-loaded pellet as a protective layer to prepare a drug-loaded pellet comprising the protective layer.

[0140] 3) The drug-loaded pellet (comprising the protective layer) obtained in the above-mentioned step was mixed with a formula amount of talc to prepare a total mixture of pellet.

[0141] 4) The overall hybrid pellet was filled into a capsule.

[0142] Different sizes of capsules could be filled according to the content of the drug substance in the pellet and the weight of the pellet, and the size included, but was not limited to, instances in which each capsule contains 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 100 mg of the active ingredient on the basis of the anhydrous compound.

Example 8

[0143]

TABLE-US-00008 Formula of a 100 g pellet formulation: Sucrose pellet core 81.30 g Drug-containing layer: Pamiparib 12.19 g; and hydroxypropyl methylcellulose  4.06 g Protective layer: sodium carboxymethylcellulose  1.95 g Talc  0.50 g

[0144] wherein Pamiparib was based on the total weight of the sesquihydrate of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one.

[0145] Preparation Process:

[0146] 1) A formula amount (4.06 g) of hydroxypropyl methylcellulose was weighed to prepare a binder solution with a concentration of 5%, and 12.19 g of Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.

[0147] 2) A formula amount of the sucrose pellet core was taken, and the drug-containing layer coating suspension was sprayed onto the surface of the pellet core to form a drug-containing layer so as to prepare a drug-loaded pellet. A formula amount (1.95 g) of the coating material sodium carboxymethylcellulose was taken to prepare a coating material solution with a concentration of 5%, and the coating material solution was sprayed onto the surface of the drug-loaded pellet as a protective layer to prepare a drug-loaded pellet comprising the protective layer.

[0148] 3) The drug-loaded pellet (comprising the protective layer) obtained in the above-mentioned step was mixed with a formula amount of talc to prepare a total mixture of pellet.

[0149] 4) The overall hybrid pellet was filled into a capsule.

[0150] Different sizes of capsules could be filled according to the content of the drug substance in the pellet and the weight of the pellet, and the size included, but was not limited to, instances in which each capsule contains 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 100 mg of the active ingredient on the basis of the anhydrous compound.

Example 9

[0151]

TABLE-US-00009 Formula of a 100 g pellet formulation: Microcrystalline cellulose pellet core 78.97 g Drug-containing layer: Pamiparib 11.85 g; and povidone  3.95 g Protective layer: hydroxypropyl methylcellulose  4.74 g Talc  0.50 g

[0152] wherein Pamiparib was based on the total weight of the sesquihydrate of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one.

[0153] Preparation Process:

[0154] 1) A formula amount (3.95 g) of povidone was weighed to prepare a binder solution with a concentration of 5%, and 11.85 g of Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.

[0155] 2) A formula amount of the microcrystalline cellulose pellet core was taken, and the drug-containing layer coating suspension was sprayed onto the surface of the pellet core to form a drug-containing layer so as to prepare a drug-loaded pellet. A formula amount (4.74 g) of the coating material hydroxypropyl methylcellulose was taken to prepare a coating material solution with a concentration of 5%, and the coating material solution was sprayed onto the surface of the drug-loaded pellet as a protective layer to prepare a drug-loaded pellet comprising the protective layer.

[0156] 3) The drug-loaded pellet (comprising the protective layer) obtained in the above-mentioned step was mixed with a formula amount of talc to prepare a total mixture of pellet.

[0157] 4) The overall hybrid pellet was filled into a capsule.

[0158] Different sizes of capsules could be filled according to the content of the drug substance in the pellet and the weight of the pellet, and the size included, but was not limited to, instances in which each capsule contains 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 100 mg of the active ingredient on the basis of the anhydrous compound.

Example 10—Effect of the Particle Size of the Drug Substance on the Content of the Active Ingredient in the Pamiparib Pellet Capsule

[0159] The inventors surprisingly discovered during the formulation development process that the D.sub.90 value of the drug substance Pamiparib had a certain impact on the content of the active ingredient in the final product of the pellet capsule formulation. The same prescription as in Example 3 was used:

TABLE-US-00010 Formula of a 100 g pellet formulation: Microcrystalline cellulose pellet core 80.50 g Drug-containing layer: Pamiparib 12.08 g; and povidone  4.02 g Protective layer: hydroxypropyl methylcellulose  2.90 g Talc  0.50 g

[0160] wherein Pamiparib was based on the total weight of the sesquihydrate of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one.

[0161] Experimental group 1: Pamiparib D.sub.90=7.87 μm

[0162] Experimental group 2: Pamiparib D.sub.90=21.9 μm

[0163] Experimental group 3: Pamiparib D.sub.90=35.6 μm

[0164] Experimental group 4: Pamiparib D.sub.90=45.5 μm

[0165] According to the method of Example 3, capsules with a content of 20 mg were prepared. The D90 was determined by using Malvern Laser Particle Sizer 3000 and using a laser diffraction method.

[0166] Determination of content: 225 mg of the capsule content pellets was weighed (allowable weighing range: 158-292 mg), the content pellets was diluted 250 times with a diluent and uniformly mixed, 3 ml was discarded using a 0.45 μm PTFE syringe filter, and the filtrate was collected and detected at a wavelength of 297 nm using a UV method or determined using HPLC. The analysis content results were as follows.

TABLE-US-00011 TABLE 1 Content results of products prepared from the drug substance with different particle sizes Experimental group Content % Experimental group 1 (D.sub.90 = 7.87 μm) 99.2% Experimental group 2 (D.sub.90 = 21.9 μm) 99.9% Experimental group 3 (D.sub.90 = 35.6 μm) 91.5% Experimental group 4 (D.sub.90 = 45.5 μm) 90.6%

[0167] It could be seen from the experimental results that when the D.sub.90 was less than 30 μm, the final product had a higher content result.

[0168] The present invention has been described in detail above with the general descriptions, detailed description of embodiments and examples. Modifications or improvements based on not departing from the spirit of the present invention all fall within the scope of protection of the present invention.